Potentiating compounds

Details Potentiating compounds Potentiating compounds

2002-03-15

2003-11-04

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Radical -xh acid, or anhydride, acid halide or salt thereof...

C514S563000, C514S710000, C549S510000, C562S058000, C562S126000

Reexamination Certificate

active

06642271

ABSTRACT:

RELATED APPLICATIONS
This application claims priority to Swedish Application No. SE 0101702-9 filed May 15, 2001 and United States Provisional Application No. 60/302,790 filed Jul. 3, 2001, each of which are hereby incorporated by reference.
FIELD OF THE INVENTION
This invention relates to novel compounds having therapeutic properties in themselves, and being capable of potentiating the efficacy of other therapeutically active compounds, for example cytotoxic compounds used in the treatment of cancer. The novel compounds have been shown to possess a cell growth inhibiting property, and in addition to this, also to increase the pharmacological activity of a conventional paclitaxel formulation and to make it possible to manufacture a new formulation of paclitaxel, exhibiting improved solubility and therapeutic efficacy.
BACKGROUND OF THE INVENTION
While the term “chemotherapy” originally had a very broad meaning, encompassing the treatment of various diseases with chemical agents, it has today a more specific meaning. In modern language, the term “chemotherapy” usually refers to the use of chemical agents to destroy cancer cells. Among the chemical agents currently used as anticancer drugs, most function by impairing the ability of the cancer cells to replicate by interfering with DNA and RNA activities associated with cell division.
Paclitaxel is a diterpenoid compound {(2R,3S)-3-Benzamido-3-fenyl-2-hydroxy propionic acid-[(2aR, 4S, 4aS, 6R, 9S, 11S, 12S, 12aR, 12bS)-6,12b-diacetoxy-12-benzoyloxy-2a, 3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahydro-4,11-dihydroxy-4a, 8, 13, 13-tetramethyl-7,11-methano-5-oxo-1H-cyclodeca[3,4]benz[1,2-b]oxet-9-yl]ester, the active ingredient in Taxol®, Bristol-Myers Squibb} originally isolated from the western yew, a cone-bearing evergreen tree of the genus Taxus. Paclitaxel is one example of an important chemotherapeutic agent or anticancer drug currently in use. It has a wide spectrum of activity against solid tumours: primarily breast cancer, ovarian, colon and non-small cell lung carcinomas. It binds to the &bgr;-subunit of tubulin, resulting in the formation of stable non-functional microtubule bundles and thus interfering with mitosis. The drug can also induce apoptosis and has anti-angiogenic properties.
Paclitaxel is highly protein-bound, has large volumes of distribution, but poor penetration into the central nervous system. This compound is primarily eliminated from the body via hepatic metabolism, and its use is therefore generally precluded in severe hepatic dysfunction.
In recent years, considerable emphasis has been given to the development of new formulations of paclitaxel that are suitable for intravenous administration, in order to address the solubility and toxicity issues associated with this particular drug. Examples include dispersed systems such as emulsions, liposomes, mixed micelles prepared by co-precipitation using bile salts and phospholipids (Alkan-Onyuksel H, et al. Pharm. Res. vol 2. pp. 206-212, 1994), cyclodextrins, and microspheres. Water-soluble prodrugs such as polyethylene glycol- and polyglutamate-paclitaxel with promising antitumor activity have also been developed.
The commercially available product, Taxol® (a paclitaxel concentrate for preparation of solutions for infusion, marketed by Bristol-Myers Squibb Co., New York, N.Y., USA), is currently formulated in a vehicle containing a mixture of polyoxyethylated castor oil (Cremophor® EL) and ethanol, in the approximate proportions 1:1 (v/v). Cremophor® EL, which is a commonly used surfactant for lipophilic compounds, has however been associated with adverse side-effects, such as bronchospasms, hypotension, and other manifestations of hypersensitivity particularly following rapid administration. Therefor, long infusion times, high dilution of the ethanol:Cremophor® EL solution, and pre-medication (e.g. using corticosteroids, antihistamine, and H2-blockers) are actions resorted to in order to reduce these adverse effects.
Furthermore, the commercially available formulation is associated with a number of difficult technical issues such as stability, including the possibility of drug precipitation upon dilution, filtering requirements and restrictions regarding the use of PVC-containing vessels and administration sets. It is thus apparent that there is a need for a new formulation of paclitaxel that is efficacious and less toxic than the commercial product and which formulation can alleviate the side-effects and set aside the problems currently associated with preparation and administration of this drug.
Further, the small difference between the therapeutic and the toxic concentration severely limits the clinical usefulness of paclitaxel. The therapeutic efficacy could be improved by delivering the drug with an appropriate microcarrier system, which is able to change temporal and spatial biodistribution of the drug. This approach has been suggested for the highly toxic and poorly soluble amphotericin B, which has been successfully incorporated into disk-like micelles of cholersteryl sulphate (Lasic D. D. Nature. Vol. 355, 16 Jan., pp. 279-280, 1992).
In later years, great deal of effort has been given to the development of polymeric micellar paclitaxel formulations using amphiphilic diblock copolymers (K. Kataoka et al., JMS-Pure Appl. Chem. A31 (11), pp. 1759-1769, 1994).
In one study, using a human cancer cell line model, a new formulation containing biodegradable amphiphilic diblock copolymer, monomethoxy poly(ethylene glycol)-block-poly (D,L-lactide) (m PEG-PDLLA) and paclitaxel (Genexol®-PM) and Taxol® showed comparable in vitro cytotoxicity at the same concentrations. The polymeric micellar formulation of paclitaxel produced an increase in a maximum tolerated dose (MTD) as compared with that of Taxol® when administered i.p. in vivo. This formulation was said to have advantages over the commercially available injectable preparation of Taxol® in terms of low toxicity levels and increased paclitaxel dose (2 to 3-fold higher levels) (Kim S. C. et al., J. Controlled Release, v.72, pp. 191-202, 2001).
The advantages mentioned by the above authors are related to the slow release of paclitaxel from the micelles, due to a strong hydrophobic association between paclitaxel and the high molecular weight m PEG-PDLLA. At the same time, according to the authors, additional studies of a polymeric micellar formulation, comprising paclitaxel in unusually high doses will be required to fully characterize the nature of toxicities and especially the more distant consequences this kind of treatment.
The present inventors have taken a principally different approach. They have made available novel compounds, comprising the residues of naturally occurring substances only. These compounds, numbered I through VI, in themselves have low toxicity. A single dose i.p. toxicity study in rats was carried out in accordance with the OECD principles of Good Laboratory Practice. It was found that the compounds I-VI, at a dose level of 100 mg/kg body weight did not produce mortality. The minimal lethal dose is thus above 100 mg/kg body weight for these compounds (I-VI).
Considering “chemotherapy” in it widest meaning, i.e. the administration of chemical agents for the prevention, treatment or alleviation of a medical condition, a manifold of similar problems arise. It is important to optimise efficacy, e.g. the uptake and target-specificity of the compound, its distribution in the body and its clearance, simultaneously as minimising the possible side-effects, risks to medical staff etc. Also the cost of production, ease of preparation, modes of administration, stability during storage etc must be taken into consideration. In particular, it is desirable to be able to increase the solubility and bio-availability of poorly soluble pharmaceutical agents, increasing their efficacy and reducing their side-effects.
Considering “chemotherapy” in its more specific meaning, i.e. the use of chemical agents to destroy cancer cells, it remains an urgent task to ma

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