EP0957918A1 - Traitement ou inhibition de la neutropenie - Google Patents

Traitement ou inhibition de la neutropenie

Info

Publication number
EP0957918A1
EP0957918A1 EP97952527A EP97952527A EP0957918A1 EP 0957918 A1 EP0957918 A1 EP 0957918A1 EP 97952527 A EP97952527 A EP 97952527A EP 97952527 A EP97952527 A EP 97952527A EP 0957918 A1 EP0957918 A1 EP 0957918A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
phenyl
trifluoromethyl
hydrogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP97952527A
Other languages
German (de)
English (en)
Inventor
Joseph William Epstein
Jeremy Ian Levin
James Joseph Gibbons
Judy Lucas
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth Holdings LLC
Original Assignee
American Cyanamid Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by American Cyanamid Co filed Critical American Cyanamid Co
Publication of EP0957918A1 publication Critical patent/EP0957918A1/fr
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • 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)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Méthode pour traiter ou inhiber la neutropénie, ou pour accélérer la récupération de neutrophiles chez le mammifère présentant une insuffisance de ces derniers. Cette méthode consiste à administrer à ce mammifère une quantité efficace d'un composé ou d'un médicament contenant le composé de la formule (I) dans laquelle R1 et R2 sont chacun sélectionnés indépendamment dans un groupe constitué de l'hydrogène, d'un alkyl comprenant entre 1 et 6 atomes de carbone, de benzoyle éventuellement substitué, (a), (b), (c), (d), (e), (f) et -(CH2)n-R ou R1 et R2 sont des groupes méthylène réunis pour former un noyau hétérocyclique saturé comprenant 4 à 7 chaînons; R est hydroxy, 4-morpholinyle, 1H-imidazol-1-yl, -CH(alkoxy à 1-6 atomes de carbone)2, α-hydroxybenzyle ou phényle éventuellement substitué; R3 est l'hydrogène ou l'alkyle; R4 est l'hydrogène, halogène, alkyle, alkoxy ou trifluorométhyle; R5 est l'hydrogène ou l'alkyle; et n=1-3, ou un sel pharmaceutiquement acceptable de ce composé.
EP97952527A 1996-12-19 1997-12-17 Traitement ou inhibition de la neutropenie Withdrawn EP0957918A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US77074396A 1996-12-19 1996-12-19
US770743 1996-12-19
PCT/US1997/023419 WO1998026781A1 (fr) 1996-12-19 1997-12-17 Traitement ou inhibition de la neutropenie

Publications (1)

Publication Number Publication Date
EP0957918A1 true EP0957918A1 (fr) 1999-11-24

Family

ID=25089545

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97952527A Withdrawn EP0957918A1 (fr) 1996-12-19 1997-12-17 Traitement ou inhibition de la neutropenie

Country Status (7)

Country Link
EP (1) EP0957918A1 (fr)
JP (1) JP2001506998A (fr)
AR (1) AR010808A1 (fr)
AU (1) AU5611398A (fr)
CA (1) CA2273288A1 (fr)
WO (1) WO1998026781A1 (fr)
ZA (1) ZA9711342B (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2691493T3 (es) 2012-06-07 2018-11-27 Childrens Hospital Los Angeles Métodos para tratar la neutropenia usando agonistas retinoides
AU2015219038B2 (en) 2014-02-18 2018-10-18 Children's Hospital Los Angeles Compositions and methods for treating neutropenia

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2615291B1 (fr) * 1987-05-15 1989-07-13 Thomson Csf Procede de test en fonctionnement d'un dispositif de visualisation d'informations radar et mise en oeuvre de ce procede
DE68911951T2 (de) * 1988-02-22 1994-06-01 American Cyanamid Co 5-(Substituierte Amino)-8-(phenyl oder substituierte phenyl)-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
US4916137A (en) * 1988-02-22 1990-04-10 American Cyanamid Company 5-(Substituted-amino)-8-(phenyl or substituted-phenyl)-3H,6H-1,4,5A,8A-tetraazaacenaphthylen-3-ones and treatment of neural behavior disorders

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9826781A1 *

Also Published As

Publication number Publication date
AU5611398A (en) 1998-07-15
JP2001506998A (ja) 2001-05-29
ZA9711342B (en) 1999-06-17
WO1998026781A1 (fr) 1998-06-25
AR010808A1 (es) 2000-07-12
CA2273288A1 (fr) 1998-06-25

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