Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class, such as topotecan.
• the structure of the DNA helix within eukaryotic cells imposes certain topological problems that the cellular apparatus must solve in order to use its genetic material as a template.
• the separation of the DNA strands is fundamental to cellular processes such as DNA replication and transcription. Since eukaryotic DNA is organized into chromatin by chromosomal proteins, the ends are constrained and the strands cannot unwind without the aid of enzymes that alter topology. It has long been recognized that the advancement of the transcription or replication complex along the DNA helix would be facilitated by a swivel point which would relieve the torsional strain generated during these processes.
• Topoisomerases are enzymes that are capable of altering DNA topology in eukaryotic cells. They are critical for important cellular functions and cell proliferation. There are two classes of topoisomerases in eukaryotic cells, type I and type II.
• Topoisomerase I is a monomeric enzyme of approximately 100,000 molecular weight. The enzyme binds to DNA and introduces a transient single-strand break, unwinds the double helix (or allows it to unwind) , and subsequently reseals the break before dissociating from the DNA strand. Camptothecin, a water-insoluble alkaloid produced by trees indigenous to China and India, and a few other congeners thereof, are the only class of compounds known to inhibit topoisomerase I.
• Camptothecin and other topoisomerase I inhibiting congeners have not proven to be attractive for clinical drug development as cytolytic agents because of lack of clinical efficacy, unacceptable dose- limiting toxicity, unpredictable toxicity, poor aqueous solubility, and/or unacceptable shelf life stability.
• topoisomerase I inhibiting agents which avoid the aforementioned undesirable features of camptothecin and related topoisomerase I inhibiting congeners.
• Topotecan or any compound of the water soluble camptothecin analog class, is a specific -inhibitor of DNA topoisomerase I which fulfills such need.
• This invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of a compound of the water soluble camptothecin analog class.
• This invention also relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
• a compound of the water soluble camptothecin analog class is meant any compound claimed in U.S. Patent Number 5,004,758, the entire disclosure of which is hereby incorporated by reference.
• the preparation of any compound of the water soluble camptothecin analog class (including pharmaceutically acceptable salts, hydrates and solvates thereof) as well as the preparation of oral and parenteral pharmaceutical compositions comprising a compound of the water soluble camptothecin analog class and an inert, pharmaceutically acceptable carrier or diluent, is extensively described in U.S. Patent Number 5,004,758. The same extensive description is found in European Patent Application Number 88311366.4, published on June 21, 1989 as
• Preferred compounds of the water soluble camptothecin analog class include those compounds of the formula:
• X is hydroxy and R is trimethylammoniummethyl; b) X is hydroxy and R is N- methylpiperazinylmethyl/ c) X is hydroxy and R is N-methylanilinomethyl; d) X is hydroxy and R is cyclohexylaminomethyl; e) X is hydroxy and R is N,N- dimethylaminoethyloxymethy1/ f) X is hydroxy and R is cyclopropylaminomethy1; g) X is hydroxy and R is morpholinomethyl; h) X is hydroxy and R is aminomethyl; and i) X is hydroxy and R is cyanomethyl; and j) X is hydroxy and R is dimethylaminomethyl or any pharmaceutically acceptable salts, hydrates and solvates thereof.
• Topotecan is the most preferred compound of the water soluble camptothecin analog class.
• Topotecan is water-soluble by virtue of the presence of the basic side-chain at position 9 which forms salts with acids.
• Preferred salt forms of topotecan include the hydrochloride salt, acetate salt and ethanesulfonic acid salt.
• a alkali metal salt form of the carboxylate formed on alkaline hydrolysis of the E-ring lactone of topotecan would also yield a soluble salt, such as the sodium salt.
• topotecan including pharmaceutically acceptable salts, hydrates and solvates thereof
• oral and parenteral pharmaceutical compositions comprising topotecan and an inert, pharmaceutically acceptable carrier or diluent
• European Patent Application Number 88311366.4 published on June 21, 1989 as Publication Number EP 0 321 122.
• This invention relates to a method of treating esophageal cancer in a human afflicted therewith which
• One preferred aspect of this invention relates to a method of treating esophageal cancer in a human afflicted therewith which comprises administering to such human an effective amount of topotecan.
• esophageal cancer cancer of the esophagus .
• treating esophageal cancer is meant the inhibition of the growth of esophageal cancer cells.
• treatment also leads to the regression of tumor growth, i.e., the decrease in size of a measurable tumor.
• such treatment leads to the complete regression of the tumor.
• parenteral is meant intravenous, subcutaneous and intramuscular administration.
• effective amount of a compound of the water soluble camptothecin analog class and “effective amount of topotecan” as used herein is meant a course of therapy which will result in treating esophageal cancer. It will be appreciated that the actual preferred course of therapy will vary according to, inter alia, the mode of administration, the particular formulation of a compound of the water soluble camptothecin analog class (such as topotecan) being utilized, the mode of administration and the particular host being treated.
• the course of therapy generally employed is from about 0.5 to about 2 5 25.0 mg/m of body surface area per day for about one to about five consecutive days. More preferably, the course of therapy employed is from about 1.0 to about
• 2 10 therapy employed is from about 1.5 to about 2 mg/m of body surface area per day for about five consecutive days.
• the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy)
• the parenteral administration will be any suitable parenteral administration.
• the parenteral administration will be any suitable parenteral administration.
• the topotecan will be administered by a 30 minute intravenous infusion.
• 25 preferred course of parenteral therapy to be employed with topotecan for a previously non-treated or lightly pretreated patient is an initial course of therapy of
• course of therapy of 1.5 mg of topotecan/m of body surface area per day is administered by short intravenous infusion for five consecutive days, such course of therapy to be repeated based on tumor response.
• the course of therapy generally employed is from about 1.0 to about 2 50.0 mg/m of body surface area per day for about one to five consecutive days. More preferably, the course of
• 2 therapy employed is from about 1.5 to about 5.0 mg/m of body surface area per day for about five consecutive days.
• the course of therapy is repeated at least once at about a seven day to about a twenty-eight day interval (from the date of initiation of therapy) depending upon the initial dosing schedule and the patient's recovery of normal tissues. Most preferably, the course of therapy continues to be repeated based on tumor response.
• Topotecan is currently undergoing Phase I clinical investigation.
• the following pharmaceutical information is being supplied to the clinicians:
• Topotecan diluted in saline (10 ug/ml or 500 ug/ml) or dextrose (6.7 ug/ml or 330 ug/ml) is stable in a hang-bag for 24 hours with at least 95% recovery.
• Treatment dose The treatment dose is to be diluted in a final volume of 150 ml of Sodium Chloride Injection, USP (without preservatives) and administered over a 30 minute period.
• the treatment dose is to be kept under refrigeration and protected from light and it is to be used within 24 hours.
• One human patient with metastatic esophageal cancer who was refractory to at least one previous chemotherapeutic regimen with a compound or compounds other than a water soluble camptothecin analog, received a course of therapy comprising intravenous

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• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Material From Animals Or Micro-Organisms (AREA)

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• 1992
  • 1992-02-07 JP JP4507807A patent/JPH06505487A/ja active Pending
  • 1992-02-07 WO PCT/US1992/001029 patent/WO1992014470A1/en not_active Application Discontinuation
  • 1992-02-07 KR KR1019930702492A patent/KR930702985A/ko not_active Application Discontinuation
  • 1992-02-07 AU AU15406/92A patent/AU664172B2/en not_active Ceased
  • 1992-02-07 CA CA002104449A patent/CA2104449A1/en not_active Abandoned
  • 1992-02-07 EP EP19920908199 patent/EP0572563A4/en not_active Withdrawn
  • 1992-02-21 PT PT100154A patent/PT100154A/pt not_active Application Discontinuation
  • 1992-02-21 MX MX9200725A patent/MX9200725A/es unknown

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