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
  • A61K31/535—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
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid

Definitions

• This invention provides a method of treating or inhibiting neutropenia in a mammal in need thereof, using tetraazaacenaphthylen-3-one derivatives.
• a method of treating or inhibiting neutropenia in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound having the formula:
• R ⁇ and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl,
• R j and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring; wherein when R ⁇ or R2 is benzoyl, the phenyl ring of the benzoyl moiety may be optionally mono- or di-substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, acyloxy of 2-7 carbon atoms, halogen, nitro, and trifluoromethyl; R is hydroxy, 4-morpholinyl, lH-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms ⁇ , ⁇ -hydroxybenzyl, or phenyl; wherein the phenyl ring may be optionally substituted with a substituent selected from the group consisting of halogen and alkyl of 1-6 carbon atoms; R3 is hydrogen or alkyl of 1-6 carbon atoms; R4 is hydrogen, halogen
• a method of accelerating neutrophil recovery in a mammal in need thereof which comprises administering an effective amount of the compound of the formula described above.
• alkyl includes both straight chain as well as branched moieties.
• Particular alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec -butyl, tert-butyl and pentyl.
• Particular alkoxy groups are methoxy, ethoxy, propoxy and butoxy.
• halogen includes fluorine, chlorine, bromine, and iodine.
• the pharmaceutically acceptable salts are those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
• treating covers treatment of an existing condition, ameliorating the condition, or providing palliation of the condition and inhibiting includes inhibiting or preventing the progress or development of the condition.
• the ability of the compounds of this invention to treat or inhibit neutropenia was evaluated in the 5-fluorouracil (5-FU) induced neutropenia standard pharmacological test procedure which measures a compound's ability to enhance neutrophil recovery post chemotherapy. Based on the results obtained in this test procedure, the compounds of this invention demonstrated a substantial acceleration of neutrophil recovery following administration of 5-FU.
• the test procedure used and results obtained with a representative compound of this invention are provided below.
• mice C3HHeb/Fej male mice, 8-10 weeks of age, were used to evaluate the ability of a compound to accelerate neutrophil recovery post chemotherapy.
• the mice were routinely housed for ten days prior to testing in order to stabilize their immune responses.
• the mice were housed 5-per-cage and received food and water ad libitum throughout the experiment.
• Fluorouracil injection 500 mg/10 ml, was diluted in phosphate-buffered saline for intraperitoneal injection at 150 mg/kg, 0.5 cc.
• mice Twenty- four hours following 5-FU, the mice were treated with either vehicle or a representative compound of this invention, which was mixed in 0.2% Klucel and sonicated, resulting in a milky white suspension, and 0.2 cc was administered for subcutaneous or oral dosing and 0.5 cc when the compound is dosed intraperitoneally.
• Compound was either given as a single injection 24 hours following 5-FU, or as multiple daily doses for 10 days beginning 24 hours following 5-FU.
• a neutrophil recovery curve following 5-FU administration was generated by measuring circulating neutrophils. Mice were retro-orbitally bled and a 20 ⁇ l sample was taken for measurement of total white blood cells using a Coulter Counter. In addition, a blood smear was also prepared.
• the compounds of this invention are useful as agents for the treatment or inhibition of neutropenia, particularly following chemotherapy, when administered in amounts ranging from about 5 mg to about 200 mg/kg of body weight per day.
• a preferred dosage regimen for optimum results would be from about 10 mg to about 50 mg/kg of body weight per day and such dosage units are employed that a total of from about 700 mg to about 3.5 g of the active compound for a subject of about 70 kg of body weight are administered in a 24 hour period.
• the dosage regimen for treating neutropenia in mammals may be adjusted to provide the optimum therapeutic response. For example, several divided doses may be administered daily or the dose may be proportionally reduced as indicated by the exigencies of the therapeutic situation.
• a decidedly practical advantage is that these active compounds may be administered in any convenient manner such as by the oral, intravenous, intramuscular or subcutaneous routes.
• the active compounds may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard or soft shell gelatin capsules, or they may be compressed into tablets or they may be incorporated directly with the food of the diet.
• these active compounds may be incorporated with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like.
• Such compositions and preparations should contain at least 0.1% of active compound.
• the percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 2% to about 60% of the weight of the unit.
• the amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.
• -Preferred compositions or preparations according to the present invention are prepared so that an oral dosage unit form contains between about 5 and 200 mg of active compound.
• the tablets, troches, pills, capsules and the like may also contain the following: a binder such as gum tragacanth, acacia, com starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
• a binder such as gum tragacanth, acacia, com starch or gelatin
• excipients such as dicalcium phosphate
• a disintegrating agent such as corn starch, potato starch, alginic acid and the like
• a lubricant such as magnesium stearate
• a sweetening agent such as sucrose, lactose, or saccharin may be added or a flavoring agent such
• tablets, pills or capsules may be coated with shellac, sugar or both.
• a syrup or elixir may contain the active compound, sucrose, as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
• any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used.
• these active compounds may be incorporated into sustained-release preparations and formulations.
• active compounds may also be administered parenterally or intraperitoneally.
• Solutions or suspensions of these active compounds as a free base or pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose.
• Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
• the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.
• the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid poly-ethylene glycol), suitable mixtures thereof, and vegetable oils.

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• Health & Medical Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Engineering & Computer Science (AREA)
• General Chemical & Material Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Organic Chemistry (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

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Citations (3)

• 1997
  • 1997-12-17 CA CA002273288A patent/CA2273288A1/en not_active Abandoned
  • 1997-12-17 AU AU56113/98A patent/AU5611398A/en not_active Abandoned
  • 1997-12-17 ZA ZA9711342A patent/ZA9711342B/xx unknown
  • 1997-12-17 WO PCT/US1997/023419 patent/WO1998026781A1/en not_active Application Discontinuation
  • 1997-12-17 EP EP97952527A patent/EP0957918A1/en not_active Withdrawn
  • 1997-12-17 JP JP52798098A patent/JP2001506998A/ja active Pending
  • 1997-12-18 AR ARP970105989A patent/AR010808A1/es unknown

Patent Citations (3)

Non-Patent Citations (2)

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