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
  • A61K31/495—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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • 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
  • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
• • 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
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
  • A61K31/525—Isoalloxazines, e.g. riboflavins, vitamin B2
• • 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
  • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
  • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
  • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
  • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
  • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
  • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents

Definitions

• DHFR dihydrofolate reductase
• lymphomas refers to a variety of disease states, including Non-Hodgkins Lymphoma (NHL); diffuse large B-cell lymphoma (DLBCL); follicular lymphoma (FL); Hodgkin's Disease; Burkitt's Lymphoma; cutaneous T cell lymphoma; primary central nervous system lymphoma, and lymphomatous metastases. In most cases, lymphoma is characterized by the presence of cancerous B cells. However, in T cell lymphomas, the disease state is characterized by cancerous T lymphocytes.
• T cell non-Hodgkin's lymphoma is treated using PDX.
• a method for the treatment of T cell non-Hodgkin's lymphoma comprising administering to a patient suffering from lymphoma a therapeutically effective amount of PDX.
• PDX a therapeutically effective amount of PDX.
• Fig. 1 shows the structure of PDX and methotrexate
• Fig. 2 shows an HPLC of an impure 10-propargyl-lOdAM preparation prepared in accordance with the prior art
• Fig. 3 shows an HPLC of a highly purified PDX preparation in accordance with the invention
• Fig. 4 shows a synthetic scheme useful in preparing the compound in accordance with the invention.
• T-cell lymphomas are lymphomas in which the T cells of the patient are determined to be cancerous. T cell lymphomas encompass a variety of conditions including without limitation:
• T cell prolymphocytic leukemia T- cell granular lymphocytic leukemia, aggressive NK-cell leukemia, cutaneous T cell lymphoma (Mycosis fungoides/Sezary syndrome), anaplastic large cell lymphoma, T cell type, enteropathy- type T cell lymphoma, Adult T-cell leukemia/lymphoma including those associated with HTLV-1, and angioimmunoblastic T cell lymphoma, and subcutaneous panniculitic T cell lymphoma; and
• Fig. 2 shows an HPLC of a highly purified preparation consisting essentially of 10- propargyl-lOdAM in accordance with the invention prepared using the method described in Example 1.
• the amount of PDX (as determined by HPLC peak area) approaches 98%, and the peak corresponding to 10-deazaaminopterin is not detected by the processing software although there is a minor baseline ripple in this area.
• PDX has been used in a Phase I/ ⁇ study in which patients with aggressive lymphoma were enrolled, including three patients with drug-resistant T cell lymphoma. The following case summaries have been obtained. Each of these patients was also treated with folic acid (lmg/m 2 daily starting 1 week prior to treatment with PDX) and B 12 (1 mg/m 2 monthly) supplementation.
• Pre-Treatment Staging Extensive disease cutaneous disease Treatment on Study: PDX 135 mg m 2 x 1 dose Toxicities: Grade 3 stomatitis; neutropenia grade 3; sepsis Response: Essentially complete remission by PET scan Comment: This patient ultimately died after developing a bacteremia and sepsis from open skin lesions with Gram positive bacteria.
• Diagnosis Lymphoblastic Lymphoma, Precursor T-cell, Stage rv
• Toxicities None Response: Complete remission by PET and CT scans Comment: Patient with essentially methotrexate resistant disease with extensive sinus based disease which began resolving after one dose of PDX.
• Patient 4 Diagnosis: Panniculitic T-cell Lymphoma Demographics: 25 Year old male Prior Treatment: Ontak (refractory), 9/02-11/02; Targretin and TEN ⁇ 1/03-10/03 (durable partial remission); CHOP 4/04 - 6/04; ICE 6/04, CyPen 7/04-8/04, Targretin/MTX 9/04 to 2/05
• PDX is advantageously formulated as part of a pharmaceutical preparation.
• the specific dosage form will depend on the method of administration, but may include tablets, capsules, oral liquids, and injectable solutions for intravenous, intramuscular or intraperitoneal administration.
• One suitable dosing schedule involves the administration of 150 mg/m 2 every two weeks.
• Lower levels may of course be indicated depending on the tolerance of an individual patient, or if more frequent administration were adopted. For example, levels on the order of 40 to 120 mg/m 2 of body surface area/day are appropriate. Dosages of 30 mg/m 2 weekly for 3 weeks followed by a one week rest, 30 mg/m 2 weekly x 6 weeks followed by a one week rest, or gradually increasing doses of PDX on the weekly x 6 week schedule are also suitable. Higher levels could be utilized if less frequent administration were used. Thus, in a general sense, dosages of 30 to 275 mg/m 2 are suitably used with various dosing schedules, for example 135 to 275 mg/m 2 for biweekly dosages, and 30 to 150 mg/m 2 for weekly dosages.
• PDX may be used in combinations with other cytotoxic and antitumor compounds, including vinca alkaloids such as vinblastine, navelbine and vindesine; probenicid, nucleotide analogs such as gemcitabine, 5-fluorouracil, and cytarabine; alkylating agents such as cyclophosphamide or ifosfamide; cisplatin or carboplatin; leucovorin; taxanes such a paclitaxel or docetaxel; anti-CD20 monoclonal antibodies, with or without radioisotopes, and antibiotics such as doxorubicin and mitomycin.
• vinca alkaloids such as vinblastine, navelbine and vindesine
• probenicid nucleotide analogs such as gemcitabine, 5-fluorouracil, and cytarabine
• alkylating agents such as cyclophosphamide or ifosfamide
• cisplatin or carboplatin le
• PDX and other agents may be concurrently administered or utilized in combination as part of a common treatment regimen, in which the PDX and the other agent(s) are administered at different times.
• the other agent may be administered before, immediately afterward or after a period of time (for example 24 hours) relative to the PDX administration.
• administering refers generally to concurrent administration or to sequential administration of the drugs and in either order in a parallel treatment regimen with or without a separation in time between the drugs unless otherwise specified.
• PDX is suitably used in combination with folic acid and vitamin B12 supplementation to reduce the side effects of the treatment.
• patients may be treated with folic acid (lmg/m 2 daily starting 1 week prior to treatment with PDX) and B 12 (1 mg/m 2 monthly).
• a mixture was formed by combining 0.36 g of a 60% NaH (9 mmol) in oil dispersion with 10 mL of dry DMF and cooled to 0-5 °C.
• the cold mixture was treated drop-wise with a solution of the product of the first reaction (compound 2) (2.94 g, 12 mmol) in 10 mL dry DMF and then stirred at 0°C for 30 minutes.
• a solution of 2,4,diamino-6-(bromomethyl)-pteridine hydrobromide-0.2 2-propanol (1.00 g, 2.9 mmol) in 10 mL dry DMF was added drop-wise while the temperature was maintained near -25 °C.
• the temperature of the stirred mixture was allowed to rise to -10°C over a period of 2 hours. After an additional 2 hours at -10°C, the temperature was allowed to rise to 20 °C; stirring at room temperature was continued for 2 hours longer.
• the reaction was then adjusted to pH 7 by addition of solid CO 2 , After concentration in vacuo to remove solvent, the residue was stirred with diethyl ether and the ether insoluble material was collected, washed with water, and dried in vacuo to give 1.49 g of a crude product. This crude product was dissolved in CHCl 3 -MeOH (10:1) for application to a silica gel column.

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• Medicinal Chemistry (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
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• Chemical & Material Sciences (AREA)
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• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (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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