WO1997018818A1 - Antineoplastic methods and compositions employing (+)-fotemustine - Google Patents
Antineoplastic methods and compositions employing (+)-fotemustine Download PDFInfo
- Publication number
- WO1997018818A1 WO1997018818A1 PCT/US1996/018488 US9618488W WO9718818A1 WO 1997018818 A1 WO1997018818 A1 WO 1997018818A1 US 9618488 W US9618488 W US 9618488W WO 9718818 A1 WO9718818 A1 WO 9718818A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- fotemustine
- cells
- malignancy
- racemic
- stereoisomer
- Prior art date
Links
- JHVOFMMGGQTAEV-OVCLIPMQSA-N CC/[N+](/[I-]C)=C\C(C)NC(N(CCCl)N=O)=C Chemical compound CC/[N+](/[I-]C)=C\C(C)NC(N(CCCl)N=O)=C JHVOFMMGGQTAEV-OVCLIPMQSA-N 0.000 description 1
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
- A61K31/66—Phosphorus compounds
- A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
- A61P35/04—Antineoplastic agents specific for metastasis
Definitions
- This invention relates to pharmaceutical compositions containing (+) -fotemustine.
- this invention relates to treatment of malignancies, including lymphomas, melanomas, gliomas and other brain tumors, lung cancer, liver metastases and hematological and gastrointestinal malignancies.
- fotemustine is [1- [ [ [ (2-chloroethyl) - nitosoamino] carbonyl] amino] ethylphosphonic acid diethyl ester.
- Fotemustine is also known as l-[N-(2- chloroethyl) -N-nitrosoureido] ethylphosphonic acid diethyl ester and as diethyl-1- [3- (2-chloroethyl) -3- nitrosoureido] ethylphosphonate .
- Early references refer to fotemustine as S10036. The preparation of racemic fotemustine is described in U.S. Patent 4,567,169. The patent mentions that "the invention also relates to the optical isomers of the compounds --, but no such isomers are disclosed.
- Racemic fotemustine has been used clinically tc treat malignant melanoma, primary and metastatic brain tumors, colorectal cancer, soft tissue and bor.e sarcomas and hematological malignancies.
- Mahya- et al . J_ Nat ' 1. Cancer Inst . 80 , 1407-1408 (1988) Khayat et al . Cancer Res . 47 , 6782-6785 (1987) ; Jacquillat et al . Proc . Am. Assoc . Cancer Res . 30 , A1088 (1989) ; Rougier et al. Eur. J. Cancer 29A(2) .
- racemic fotemustine is clinically useful in treating these cancers, but its use is accompanied by delayed, cumulative toxicity in bone marrow.
- the dose-limiting toxicity is usually myelosuppression leading to neutropenia, leucopenia and thrombocytopenia. Renal, pulmonary and hepatic toxicity are observed with a lesser frequency.
- Racemic fotemustine is also believed to be mutagenic [See Ashby et al. Mutation Res. 286, 101-109 (1993)] . Nausea is a problem in some cases.
- optically pure (+) isomer of fotemustine is an effective agent for treating malignancies.
- the optically pure (+) isomer of fotemustine provides this effective treatment while substantially reducing one or more adverse effects associated with administration of racemic fotemustine including, but not limited to, neutropenia, leucopenia and thrombocytopenia; renal, pulmonary and hepatic toxicity; mutagenicity; and nausea.
- the invention relates to a method of treating a malignancy which comprises ad inistering to a mammal suffering from the malignancy, a therapeutically effective amount of (+) -fotemustine, substantially free of its (-) stereoisomer.
- the invention in another aspect, relates to a pharmaceutical composition which comprises (+) - fotemustine, substantially free of its (-) stereoisomer, and a pharmaceutically acceptable carrier.
- the active compound used in the compositions and methods of the invention is the dextrorotatary or (+) optical isomer of fotemustine.
- the absolute stereochemistry of the (+) isomer is presently unknown.
- Formula I indicates a single enantiomer of undetermined absolute stereochemistry, here presented arbitrarily as R * :
- the graphic representation of enantiomerically pure fotemustine is taken from Maehr J. Chem. Ed. 62, 114 120 (1985) .
- representations involving wedge outlines and dotted or broken lines denote enantiomerically pure compounds of indeterminate absolute configuration.
- the present invention encompasses a method of treating a malignancy which comprises administering a therapeutically effective amount of (+) -fotemustine, substantially free of its ⁇ -) stereoisomer.
- compositions contain at least 90% by weight of (+) - fotemustine and.10% ' by weight or less of (-) fotemustine.
- the term “substantially free of the (-) isomer” means that the composition contains at least 99% by weight of (+) - fotemustine, and 1% or less of (-) fotemustine.
- the term “substantially free of its (-) stereoisomer” as used herein means that the composition contains greater than 99% by weight of (+) -fotemustine. These percentages are based upon the total amount of fotemustine in the composition.
- substantially optically pure (+) isomer of fotemustine or “substantially optically pure (+)- fotemustine” and “optically pure (+) isomer of fotemustine” and “optically pure (+) -fotemustine” are also encompassed by the above-described amounts.
- treating a malignancy means treating, alleviating or palliating such condition, suppressing the growth of cancerous tissue and thus providing increased survival time.
- terapéuticaally effective amount refers to that amount of (+) -fotemustine which is sufficient to treat a malignancy.
- Malignancies against which (+) fotemustine is active include lymphomas, melanomas, gliomas and other brain tumors, lung cancer, liver metastases and hematological and gastrointestinal malignancies.
- the method of the invention reduces the concomitant liability of adverse effects associated with the administration of racemic fotemustine.
- adverse effects includes, but is not limited to, neutropenia, leucopenia and thrombocytopenia; renal, pulmonary and hepatic toxicity; mutagenicity; and nausea.
- a therapeutically effective amount may be administered in a single dose, or a fraction of a therapeutically effective amount may be administered in each of several doses.
- a pharmaceutical composition of the invention may contain a therapeutically effective amount of (+) -fotemustine or it may be necessary to administer several individual compositions in order to achieve therapeutic effectiveness.
- the amount of (+) -fotemustine that constitutes a therapeutically effective amount varies with the severity and nature of the condition to be treated and the route of administration. Dose size and dose frequency may also vary according to the age, body weight and response of the individual patient. In general, the dose range for a single administration of (+) -fotemustine for the conditions described herein is from about 20 mg/kg to about 150 mg/kg by intravenous or intraarterial infusion. Preferably a single dose range should be about 20 mg/m 2 to about 80 mg/m 2 . Generally, dosing is carried out periodically (e.g., weekly) for a period of several weeks (e.g., about two to about to about eight weeks) .
- therapy should be initiated at a lower dose, perhaps at about 20 mg/m 2 to about 40 mg/m 2 , and increased up to about 40 mg/m 2 or higher depending on the patient's global response. It is further recommended that patients over 65 years of age and those with impaired renal or hepatic function initially receive low doses and that they be titrated based on individual response(s) and blood level(s) . It may be necessary to use dosages outside these ranges in some cases, as will be apparent to those skilled in the art. Further, the clinician or treating physician will know how and when to interrupt, adjust, or terminate therapy in conjunction with individual patient response. The term "an amount sufficient to suppress cancer but insufficient to cause said adverse effects" is encompassed by the above-described dosage amounts and dose frequency schedule.
- Any suitable route of administration may be employed for providing the patient with an effective dosage of (+) -fotemustine, but parenteral (particularly intravenous and intraarterial) forms of administration are preferred.
- Dosage forms include dispersions, suspensions, solutions, and the like.
- compositions of the present invention comprise (+) -fotemustine as the active ingredient, and may also contain a pharmaceutically acceptable carrier, and optionally, other adjuvants, excipients, or therapeutic ingredients.
- Compositions suitable for parenteral administration may be presented as an aqueous solution, optionally containing conventional adjuvants, and excipients. Such compositions may be prepared by methods well known to those skilled in the art of pharmacy. All methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients.
- the chemical synthesis of the racemic mixture of fotemustine can be performed by the method described in U.S. Patent 4,567,1-69 cited above.
- the (+) isomer of fotemustine may then be resolved by chromatography on a chiral medium.
- (+) -fotemustine may be obtained by resolution of the enantiomers of the amine precursor to fotemustine using fractional crystallization or chromatography of diastereomeric esters of chiral acids.
- Other standard methods of resolution known to those skilled in the art can also be used. (See for example, E.L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill
- Relative activity, potency and specificity of optically pure fotemustine and racemic fotemustine as an antineoplastic agent can be determined by pharmacological studies in vi tro and in vivo.
- mice bearing tumorous cells inoculated by intraperitoneal or intramuscular route in accordance with the protocols established by the National Cancer Institute (U.S.A.) and published by R.I. Geran et al. in Cancer Chemotherapy Reports, part III, Vol. 2(2), 1-87 (1972).
- Hematopoietic toxicity is assessed, in animals treated with one or several administrations of the compound according to the invention, by the count of the peripheral blood cells and of the bone marrow, and the stem cells contained in the bone marrow [Till and McCulloch, Radiation Res. 14. 213 (1961)] .
- the lowest cellular concentrations are noted 3 days after the start of treatment.
- the extent of this decrease is measured after treatment with one dose of N-N' - bis(2-chloroethyl) -N-nitrosourea ("BCNU”) used as a reference [Tang and Eisenbrand, Arch. Pharm. 314, 910 (1981)] and is compared to the cell count after racemic fotemustine and (+) fotemustine.
- BCNU N-N' - bis(2-chloroethyl) -N-nitrosourea
- Hepatic toxicity is assessed according to Wroblewski's method by measuring the pyruvic glutamic transaminase activity in serum from Long Evans rats treated with an intraperitoneal injection of doses of racemic, (+) and (-) fotemustine.
- Murine leukemia cell line P388 is obtained from NCI. Cells are grown and maintained in RPMI 1640 medium supplemented with 10% fetal bovine serum, 10 *5 M 2-mercaptoethanol and standard antibiotics. All cultures are grown at 38° in a humidified atmosphere of 5% C0 2 . Cell growth inhibition studies are carried out on exponential cultures in the continuous presence of drug. Resultant cell numbers are estimated on a Coulter Counter model ZBI, Coulter Electronics, Hialeah, Fl.
- Racemic, (+) and (-) fotemustine are individually dissolved in ethanol immediately before use. Convenient standard stock solutions are 35 mM.
- For radioisotope labelling and X-irradiation 2.5X 10 s P388 cell/mL are grown in medium containing either 0.05 ⁇ Ci/mL of ( 14 C) -thymidine or 0.5 ⁇ Ci/mL of ( 3 H) - thymidine. After labelling for 20 hours, medium is removed and cells washed with cold PBS. Standard chase treatments using lO ⁇ M non-radioactive thymidine for 4 hours are employed. Tritiated cells are exposed, on ice, to 300 rads of X-irradiation as an internal standard.
- Emesis in Ferrets Experiments are performed on adult male ferrets. The animals are first adapted to wearing a nylon jacket connected to a stainless-steel cable, which in turn is attached to a brass swivel at the cage top. After habituation to the tether- harness, each animal receives a surgically implanted catheter in its right jugular vein. The catheter is flushed daily with heparinized sodium chloride. The drug studies are conducted 1 week after the surgical procedure. Tethered animals are individually housed.
- Eight to eleven animals are used to evaluate each dose of each test compound. Individual animals are weighed weekly and randomly given, at greater than 48 hour intervals, a single i.v. or p.o. dose of racemic fotemustine, (+) -fotemustine or (-)- fotemustine. At least three dose levels of each test compound are evaluated.
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU77378/96A AU7737896A (en) | 1995-11-20 | 1996-11-19 | Antineoplastic methods and compositions employing (+)-fotemustine |
JP9519829A JP2000500495A (en) | 1995-11-20 | 1996-11-19 | Methods and compositions for treating neoplasms using (+)-fotemustine |
EP96940517A EP0868189A4 (en) | 1995-11-20 | 1996-11-19 | Antineoplastic methods and compositions employing (+)-fotemustine |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US735895P | 1995-11-20 | 1995-11-20 | |
US60/007,358 | 1995-11-20 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1997018818A1 true WO1997018818A1 (en) | 1997-05-29 |
Family
ID=21725712
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1996/018488 WO1997018818A1 (en) | 1995-11-20 | 1996-11-19 | Antineoplastic methods and compositions employing (+)-fotemustine |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0868189A4 (en) |
JP (1) | JP2000500495A (en) |
AU (1) | AU7737896A (en) |
CA (1) | CA2237909A1 (en) |
WO (1) | WO1997018818A1 (en) |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4567169A (en) * | 1982-11-17 | 1986-01-28 | Adir, S.A.R.L. | Nitrosourea substituted phosphonates and pharmaceutical use |
-
1996
- 1996-11-19 JP JP9519829A patent/JP2000500495A/en active Pending
- 1996-11-19 CA CA002237909A patent/CA2237909A1/en not_active Abandoned
- 1996-11-19 EP EP96940517A patent/EP0868189A4/en not_active Withdrawn
- 1996-11-19 WO PCT/US1996/018488 patent/WO1997018818A1/en not_active Application Discontinuation
- 1996-11-19 AU AU77378/96A patent/AU7737896A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4567169A (en) * | 1982-11-17 | 1986-01-28 | Adir, S.A.R.L. | Nitrosourea substituted phosphonates and pharmaceutical use |
Non-Patent Citations (1)
Title |
---|
See also references of EP0868189A4 * |
Also Published As
Publication number | Publication date |
---|---|
CA2237909A1 (en) | 1997-05-29 |
AU7737896A (en) | 1997-06-11 |
JP2000500495A (en) | 2000-01-18 |
EP0868189A1 (en) | 1998-10-07 |
EP0868189A4 (en) | 1998-12-23 |
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