WO1998026781A1 - Method of treating or inhibiting neutropenia - Google Patents

Method of treating or inhibiting neutropenia Download PDF

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Publication number
WO1998026781A1
WO1998026781A1 PCT/US1997/023419 US9723419W WO9826781A1 WO 1998026781 A1 WO1998026781 A1 WO 1998026781A1 US 9723419 W US9723419 W US 9723419W WO 9826781 A1 WO9826781 A1 WO 9826781A1
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Prior art keywords
carbon atoms
alkyl
phenyl
trifluoromethyl
hydrogen
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PCT/US1997/023419
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French (fr)
Inventor
Joseph William Epstein
Jeremy Ian Levin
James Joseph Gibbons
Judy Lucas
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American Cyanamid Company
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Publication date
Application filed by American Cyanamid Company filed Critical American Cyanamid Company
Priority to AU56113/98A priority Critical patent/AU5611398A/en
Priority to EP97952527A priority patent/EP0957918A1/en
Priority to CA002273288A priority patent/CA2273288A1/en
Priority to JP52798098A priority patent/JP2001506998A/en
Publication of WO1998026781A1 publication Critical patent/WO1998026781A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535Heterocyclic 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
    • A61K31/53751,4-Oxazines, e.g. morpholine
    • A61K31/53771,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic 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
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00Drugs 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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  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention is a method of treating or inhibiting neutropenia, or accelerating neutrophil recovery in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound, or a medicament containing said compound having formula (I) wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, optionally substituted benzoyl, (a), (b), (c), (d), (e), (f), and -(CH2)n-R; or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring; R is hydroxy, 4-morpholinyl, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, α-hydroxybenzyl, or optionally substituted phenyl; R3 is hydrogen or alkyl; R4 is hydrogen, halogen, alkyl, alkoxy, or trifluoromethyl; R5 is hydrogen or alkyl; and n = 1-3, or a pharmaceutically acceptable salt thereof.

Description

METHOD OF TREATING OR INHIBIΗNG NEUTROPENIA
BRIEF SUMMARY OF THE INVENTION
This invention provides a method of treating or inhibiting neutropenia in a mammal in need thereof, using tetraazaacenaphthylen-3-one derivatives.
According to the present invention there is provided 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:
Figure imgf000003_0001
wherein Rγ and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl,
O O O
II II
- C-CF3 - C-CCH2C1 - C-OCH2CH3
Figure imgf000003_0002
Figure imgf000003_0003
or Rj 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^, α-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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl; R5 is hydrogen or alkyl of 1-6 carbon atoms; and n - 1-3, or a pharmaceutically acceptable salt thereof.
According to a second aspect of this invention there is provided 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. In additional aspects of the invention there is provided use of the compound of the formula described above for the manufacture of a medicament for the treatment or inhibition of neutropenia and/or for accelerating neutrophil recovery, in a mammal in need thereof.
As used in describing this invention, the term 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. The term 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. As used in accordance with this invention, 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. DETAILED DESCRIPTION OF THE INVENΗQN
The preparation of the compounds of this invention is described in U.S. Patent 4,916,137, which is hereby incorporated herein by reference.
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.
Briefly, 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. 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 μl sample was taken for measurement of total white blood cells using a Coulter Counter. In addition, a blood smear was also prepared. The slides were stained using Diff-Quick and the percent neutrophils was determined by scoring 100, stained, white-blood-cells. The total number of neutrophils per cubic mm was calculated and plotted against time (days post 5-FU). A dose-related acceleration of neutrophil recovery following 5-FU in mice results from subcutaneous treatment with compound of Example 14 as shown in Table I. The compound of Example 14, when dosed either subcutaneously or intraperitoneally, is effective in accelerating neutrophil recovery after 5-fluorouracil treatment in mice as shown in Table EL Table E
A dose-related acceleration of neutrophil recoverv following 5-fluorouracil (5-FU) in mice results from subcutaneous treatment with compound of Example 14
Figure imgf000006_0001
Table EE
Compound of Example 14. when dosed either subcutaneously or intraperitoneally. is effective in accelerating neutrophil recovery after 5-fluorouracil treatment in mice
Figure imgf000006_0002
Based on the results of these standard pharmacological test procedures, 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. For oral therapeutic administration, 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. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, 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. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts used. In addition, these active compounds may be incorporated into sustained-release preparations and formulations.
These 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. It must be stable under the conditions of manufacture and storage and must be prepared against the contaminating action of microorganisms such as bacteria and fungi. 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.
The following are representative examples of compounds of this invention which are useful in treating or inhibiting neutropenia. The preparation of these compounds are described in U.S. Patent 4,916,137, which is hereby incorporated by reference. Examples 1-10, 11, 65-67 and 69-71 are intermediates in the preparation of the exemplified compounds.
EXAMPLE 1
7-[3-(Trifluoromethyl)phenyl]pyrazolo[ 1 ,5-a]-pyrimidine-3-carboxamide
EXAMPLE 2 7-Phenylpyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide
EXAMPLE 3
4,5-Dihydro-7-phenylpyrazolo[l,5-a]pyrimidine-3-carboxamide
EXAMPLE 4
4,5-Dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidine-3-carboxamide
EXAMPLE 5
7-(3-Fluorophenyl)pyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide EXAMPLE 6
7-(3-Huorophenyl)-4,5-dihydropyrazolo[l,5-a]pyrimidine-3-carboxamide
EXAMPLE 7
4,5-Dihydro-8-phenyl-5-thioxo-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 8
4,5-Dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 9
5-(Methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H- 1 ,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 10
8-(3-Fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3- one
EXAMPLE 11
N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5-yl]- benzamide
EXAMPLE 12
[[3-(Aminocarbonyl)-7-[3-(trifluoromethyl)phenyl]pyrazolo[l,5-a]pyrimidin-4(5H)- yl]-thioxomethyl] carbamic acid, ethyl ester
EXAMPLE 13
[3-Oxo-8[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5-yl]- carbamic acid, ethyl ester
EXAMPLE 14
5-(2-Memylpropylamine)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaace- naphthylen-3-one
EXAMPLE 15
5-(l-Pyrrolidinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaace- naphthylen-3-one
EXAMPLE 16
5-[(l-Methylethyl)amino]-8- [3-(trifluoromethyl)phenyl]-3H,6H- 1 ,4,5a,8a-tetraazaace- naphthylen-3-one EXAMPLE 17
5-[(2,2-Dimethoxyethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetra- azaacenaphthylen-3-one
EXAMPLE 18
5-[(l-Methylpropyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraaza- acenaphthylen-3-one
EXAMPLE 19
5-(l-Piperidinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a,tetraazaacenaphthy- len-3-one
EXAMPLE 20
5-[[2-(4-Mo holinyl)ethyl]amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 21
5-[(2-Hydroxy-2-phenylethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 22
5-(Butylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen- 3 -one
EXAMPLE 23
5-[(2-Hydroxyethyl)amino]8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraaza- acenaphthylen-3-one
EXAMPLE 24
5-(Methylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-3-one
EXAMPLE 25
5-[[(2-Methylphenyl)methyl]amino]-8-[3-(trifluoromethyl) phenyl]-3H,6H-l,4,5a-8a- tetraazaacenaphthylen-3-one
EXAMPLE 26
5-(4-Morpholinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthy- len-3-one EXAMPLE 27
5-Ethylamino-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3- one
EXAMPLE 28
5-[(Phenylmethyl)amino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaace- naphthylen-3-one
EXAMPLE 29
5-Amino-8-[3-(trifluoromethyl)phenyl]-3H,6H- 1 ,4,5a,8a-tetraazaacenaphthylen-3- one
EXAMPLE 30
2,2,2-Trifluoro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaace- naphthylen-5-yl] acetamide
EXAMPLE 31
2-Chloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl] acetamide
EXAMPLE 32
[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5-yl) carbamic acid, 2,2,2-trichloroethyl ester
EXAMPLE 33
4-Methoxy-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl]benzamide
EXAMPLE 34
N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5- yl] -3-(trifluoromethyl)benzamide
EXAMPLE 35
4-Methyl-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl]benzamide
EXAMPLE 36
2-(Acetyloxy)~N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaace- naphthylen-5-yl] benzamide
EXAMPLE 37
N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5-yl]- 2-phenoxyacetamide EXAMPLE 38
5-Methoxy-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl]benzamide
EXAMPLE 39
3-Nitro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl]benzamide
EXAMPLE 40
4-Bromo-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl] benzamide
EXAMPLE 41
3,4-Dichloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaace- naphthylen-5-yl]benzamide
EXAMPLE 42
4-Fluoro-N-[3 -oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-5-yl] benzamide
EXAMPLE 43
5-[[(4-Chlorophenyl)methyl]amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 44
5-[(2-Methylpropyl)amino]-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 45
5-[(2,2-Dimethoxyethyl)amino]-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3- one
EXAMPLE 46
5-(Butylamino)-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 47
5-Amino-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 48 5-(Ethylamino)-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one EXAMPLE 49
5-[(Methylethyl)amino]-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 50
5-[(2-Hydroxyethyl)amino]-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 51 5-(Methylamino)-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 52
8-(3-Fluorophenyl)-5-[(2-methylpropyl)amino]-3H,6H- 1 ,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 53
5-(Butylamino)-8-(3-fluorophenyl)-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 54
8-(3-Fluorophenyl)-5-[(methylpropyl)amino]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen- 3-one
EXAMPLE 55
5-(Ethylamino)-8-(3-fluorophenyl)-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 56
5-[(2,2-Dimethoxyethyl)amino]-8-(3-fluorophenyl)-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-3-one
EXAMPLE 57
8-(3-Fluorophenyl)-5-[(l-methylethyl)amino]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen- 3-one
EXAMPLE 58
8-(3-Fluorophenyl)-5-[[3-( IH-imidazol- 1 -yl)propyl]amino]-3H,6H- 1 ,4,5a,8a-tetraaza- acenaphthylen-3-one
EXAMPLE 59
5-[[3-(lH-Imidazol-l-yl)propyl]amino]-8-phenyl-3H,6H-l,4,5a,8a-tetraazaace- naphthylen-3-one
EXAMPLE 60
5-Amino-8-(3-fluorophenyl)-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one EXAMPLE 61
N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-5- yl] -4- (phenylmethyl)- 1 -piperazineacetamide
EXAMPLE 62
7-Methyl-5-[(l-methylethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a- tetraazaacenaphthylen-3-one
EXAMPLE 63
8-(4-Chlorophenyl)-7-methyl-5-[(2-methylpropyl)amino)-3H,6H- 1 ,4,5a,8a- tetraaza- acenaphthylen-3-one
EXAMPLE 64
5-(Butylamino)-2,7-dimethyl-8-phenyl-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3-one
EXAMPLE 65
7-(3-methylphenyl)pyrazolo[ 1 ,5-a]pyrimidine-3-carboxamide
EXAMPLE 66 4,5-Dihydro-7-(3-methylphenyl)pyrazolo [1 ,5-a]pyrimidine-3-carboxamide
EXAMPLE 67
4,5-Dihydro-5-thioxo-8-)3-methylphenyl)-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3- one
EXAMPLE 68
8-(3-Methylphenyl)-5-[(2-methylpropyl)amino]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-3-one
EXAMPLE 69
7-(3-Methoxyphenyl)pyrazolo[l,5-a]pyrimidine-3-carboxamide
EXAMPLE 70
4,5-Dihydro-7-(3-methoxyphenyl)pyrazolo[l,5-a]pyrimidine
EXAMPLE 71
4,5-Dihydro-8-(3-methoxyphenyl)-5-thioxo-3H,6H-l,4,5a,8a-tetraazaacenaphthylen-3 -one
EXAMPLE 72
8-(3-Methoxyphenyl)-5-[2-methylpropyl)amino]-3H,6H-l,4,5a,8a-tetraazaacenaph- thylen-3-one

Claims

1. 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:
Figure imgf000015_0001
wherein R and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl,
O O O
II II II
C-CF3 , - C-CCH2C1 ) - C-OCH2CH
Figure imgf000015_0002
Figure imgf000015_0003
or Ri 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, IH-imidazol- 1-yl, -CH(alkoxy of 1-6 carbon atoms)2, α-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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl; R5 is hydrogen or alkyl of 1-6 carbon atoms; and n = l-3; or a pharmaceutically acceptable salt thereof.
2. The method of Claim 1 wherein said compound is 5-(2-methylpropylamino)- 8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4-5a,8a-tetraazaacenaphthylen-3-one or 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4,5a,8a-tetraazaace-naphthylen-3-one.
3. A method of accelerating neutrophil recovery in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound having the formula:
Figure imgf000016_0001
wherein Rj and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, O O O
II II II
- C-CF3 , - C-CCH2C1 ) - C-OCH2CH3
Figure imgf000017_0001
Figure imgf000017_0002
or Rj and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring; wherein when Rj 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, IH-imidazol- 1-yl, -CH(alkoxy of 1-6 carbon atoms)2, α-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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl;
R5 is hydrogen or alkyl of 1-6 carbon atoms; and n = 1-3; or a pharmaceutically acceptable salt thereof. Use of a compound of formula :
Figure imgf000018_0001
wherein
Rj and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl,
O O O
II II
- C-CF3 - C-CCH2C1 - C-OCH CH,
O O II
- C-OCH CCl, - C— CH.
Figure imgf000018_0002
or R\ 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, IH-imidazol- 1-yl, -CH(alkoxy of 1-6 carbon atoms)2, α-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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl; R5 is hydrogen or alkyl of 1-6 carbon atoms; and n = 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating or inhibiting neutropenia in a mammal in need thereof.
Use of a compound of formula :
Figure imgf000019_0001
wherein
Rj and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl,
O O O
II II
- C-CF3 - C-CCH2C1 - C- OCH CH0
Figure imgf000019_0002
Figure imgf000019_0003
or Rγ and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring; wherein when Rj 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, IH-imidazol- 1-yl, -CH(alkoxy of 1-6 carbon atoms^, α-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, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, or trifluoromethyl; R5 is hydrogen or alkyl of 1-6 carbon atoms; and n = 1-3, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for accelerating neutrophil recovery in a mammal in need thereof.
6. The use according to Claim 4 or 5 wherein said compound is 5-(2-methyl- propylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-l,4-5a,8a-tetraazaacenaphthylen-3- one or 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H- l,4,5a,8a-tetraazaacenaphthylen- 3-one.
PCT/US1997/023419 1996-12-19 1997-12-17 Method of treating or inhibiting neutropenia WO1998026781A1 (en)

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CA002273288A CA2273288A1 (en) 1996-12-19 1997-12-17 Method of treating or inhibiting neutropenia
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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0329940A1 (en) * 1988-02-22 1989-08-30 American Cyanamid Company 5-(substituted)amino)-8- (phenyl or substituted phenyl)-3H,6H-1,2,5,a,8 a-tetraazaacenaphthylen-3-ones
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
EP0362236A1 (en) * 1987-05-15 1990-04-11 Thomson-Csf Method for testing a radar in operation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0362236A1 (en) * 1987-05-15 1990-04-11 Thomson-Csf Method for testing a radar in operation
EP0329940A1 (en) * 1988-02-22 1989-08-30 American Cyanamid Company 5-(substituted)amino)-8- (phenyl or substituted phenyl)-3H,6H-1,2,5,a,8 a-tetraazaacenaphthylen-3-ones
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 (2)

* Cited by examiner, † Cited by third party
Title
J.I.LEVIN ET AL.: "SYNTHESIS OF SUBSTITUTED 5-AMINO-8-PHENYL-3H,6H-1,4,5a,8a-TETRAAZAACEMAPHTHALEN-3-ONES, A NEW CLASS OF AGENTS FOR THE IMPROVEMENT OF COGNITION", BIOORG.MED.CHEM.LETT., vol. 1, no. 9, 1991, pages 435 - 440, XP002061788 *
S.CACCIA ET AL.: "Brain-to-blood Distribution of the Potential Cognitive-enhancing Agent CL 287,663 and its Main Metabolites in the Rat", PHARM. SCI., vol. 2, no. 8, 1996, pages 389 - 392, XP002061789 *

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