Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Silicon containing doai
Utility Patent
1998-02-11
2001-01-02
Huang, Evelyn Mei (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Silicon containing doai
C514S283000, C546S014000, C546S048000
Utility Patent
active
06169080
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to novel derivatives of camptothecin, and will have special application to derivatives having substitutions at the C-7 position, and also at one of the C-9, C-10, C-11 or C-12 positions.
BACKGROUND OF THE INVENTION
Camptothecin (CPT) and certain of its derivatives are potent anti-cancer agents and have been the subject of intensive research since the discovery and isolation of camptothecin more than 30 years ago.
CPT was isolated in 1966 by Wall and Wani from
Camptotheca accuminata
, a Chinese yew. CPT was subsequently observed to have potent anti-cancer activity and was introduced into human clinical trials in the late 1970's. CPT lactone was noted to be very poorly water soluble (about 1 &mgr;g/mL), and in order for CPT to be administered in human clinical trials it was originally formulated with sodium hydroxide which increased the solubility of the drug. Sodium hydroxide formulation of camptothecin resulted in hydrolysis of the lactone E-ring of the camptothecin molecule, and formed the water soluble CPT carboxylate species. The sodium hydroxide formulation of CPT created a water soluble CPT species that permitted clinicians to administer larger doses of the drug to cancer patients undergoing Phase I and Phase II clinical trials.
Years later that it was learned that the carboxylate species of parenterally administered CPT had approximately one-tenth or less of the antitumor potency of the lactone form. Clinical trials with sodium hydroxide formulated CPT were disappointing due to significant systemic toxicity and the lack of substantive anti-tumor activity, and clinical studies of CPT were temporarily abandoned in the early 1980's.
Further clinical development of camptothecin derivatives was not pursued until the mid-1980's. At that time it was reported that CPT had a unique mechanism of action which involved the inhibition of DNA synthesis and DNA replication by interactions with the ubiquitous cellular enzyme Topoisomerase I (Topo I). This new information about the mechanism of action of camptothecin derivatives rekindled the interest in developing new Topo I inhibitors as anti-cancer drugs. Subsequently, several research groups began attempting to develop new camptothecin derivatives for cancer therapy. In general, it was observed that camptothecin and many of its derivatives exhibited very poor water solubility. This poor water solubility limited the clinical utility of the drug because prohibitively large volumes (e.g., 5 or more liters) of water had to be delivered to the patient in order to administer an effective dose of the drug. Because of the poor water solubility, a great deal of research effort was directed at generating water soluble CPT derivatives.
Some of the more well-known water soluble camptothecin derivatives include: 9-dimethylaminomethyl-10-hydroxy camptothecin (Topotecan), 7-[(4-methylpiperazino)methyl]-10,11-ethylenedioxy camptothecin, 7-[(4-methylpiperazino) methyl]-10,11-methylenedioxy camptothecin, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy camptothecin (CPT-11).
Other substituted camptothecin derivatives with different solubility and pharmacologic properties have been synthesized as well; examples of these camptothecin derivatives include 9-amino camptothecin and 9-nitro camptothecin which are both are poorly soluble in aqueous and nonaqueous media and have been tested in humans.
Of this diverse group of substituted camptothecin derivatives undergoing human clinical development, CPT-11 is one of the most extensively studied in clinical trials in human patients with cancer. CPT-11 (Irinotecan/Camptosar®) was approved for human use by the FDA in June, 1996. It is noteworthy that CPT-11 is biologically inactive and requires activation by a putative carboxylesterase enzyme. The active species of CPT-11 is the depiperidenylated 10-hydroxy 7-ethyl camptothecin (claimed in Miyasaka et al. U.S. Pat. No. 4,473,692 (1984)), also known as SN38. SN38 is a toxic lipophilic metabolite which results from in vivo bioactivation of CPT-11 by a carboxylesterase enzyme. SN38 is very poorly soluble in water and has not been directly administered to human patients with cancer. Recently it has been reported in human patients that SN38 undergoes further metabolism to form an inactive glucuronide species. The glucuronide species also appears to be involved in producing human toxicity (diarrhea and leukopenia are the major dose-limiting toxicities) and substantial interpatient variability in drug levels of the free metabolite and its glucuronide. CPT-11 has been studied in human clinical trials in the United States, Europe and Japan and several patient deaths due to drug toxicity have been reported in association with the use of CPT-11.
In view of the very limited number of potentially active camptothecin derivatives in the poorly water soluble/highly lipid soluble category, there clearly remains a large unmet need to develop potent, poorly water soluble, highly lipophilic camptothecins which do not require metabolism to an active species and are less susceptible to metabolic inactivation and clinically important types of drug resistance in tumors.
SUMMARY OF THE INVENTION
The new compositions of matter disclosed and claimed in the present invention address these unmet needs and can, in addition to topical and parenteral routes of administration, be administered orally which is more convenient for many patients undergoing treatment for cancer.
The present invention overcomes the prior art limitations and has significant utility in patient safety, because these new compositions do not undergo A-ring or B-ring glucuronidation (and implicitly deglucuronidation) and they are not prodrugs which require metabolic activation. Also, because the compounds are lipophilic and can be directly administered in their active lactone form, it is submitted that they will have superior bioavailability relative to CPT-11, Topotecan, 9-amino camptothecin, 9-nitro camptothecin, 7-[(4-methylpiperazino)methyl]-10,11-ethylenedioxy camptothecin, 7-[(4-methylpiperazino)methyl]-10,11-methylenedioxy camptothecin, and other forms of the drug.
The instant invention is also aimed at overcoming other important limitations in bioavailability/pharmacokinetics and common tumor mediated drug resistance mechanisms (e.g., MDR, MRP, LRP) observed with the use of water soluble camptothecins or 9-amino or 9-nitro substituted camptothecins as anticancer agents.
The novel camptothecin derivatives claimed in the present invention represent a new class of antitumor compounds that do not require metabolic activation and exhibit potent antitumor activity against common types of human cancer including but not limited to cancers of the lung, breast, prostate, pancreas, head and neck, ovary and colon. The compounds described by the instant invention have also been shown effective against malignant melanoma neoplasms.
The compounds of this invention all possess Topoisomerase I inhibitory activity similar to that of other camptothecin derivatives but have significant structural modifications rationally designed for superior active site binding capability and tissue penetration. The compounds are designed to avoid untoward metabolism and drug resistance mechanisms which are common in mammalian tumors. Until now, lipophilic camptothecin derivatives with poor water solubility have not been pursued because of limitations in pharmaceutical formulations and methods of use. These novel camptothecin derivatives can be readily formulated in a pharmaceutically acceptable manner by dissolving the drug composition in an organic solvent, or in a mixture of organic solvents which have a high degree of physiologic safety. This allows for the direct administration of these new and non-obvious compounds to cancer patients.
The inventors have discovered several new derivatives of CPT, essentially an entirely new class of molecules which include substitutions at one or more of the a) C-7; and/or b) one of the C-9,
Haridas Kochat
Hausheer Frederick H.
Murali Dhanabalan
Petluru Pavankumar N.V.
Reddy Dasharatha G.
BioNumerik Pharmaceuticals, Inc.
Dodd Thomas J.
Huang Evelyn Mei
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