CA2273288A1 - Method of treating or inhibiting neutropenia - Google Patents
Method of treating or inhibiting neutropenia Download PDFInfo
- Publication number
- CA2273288A1 CA2273288A1 CA002273288A CA2273288A CA2273288A1 CA 2273288 A1 CA2273288 A1 CA 2273288A1 CA 002273288 A CA002273288 A CA 002273288A CA 2273288 A CA2273288 A CA 2273288A CA 2273288 A1 CA2273288 A1 CA 2273288A1
- Authority
- CA
- Canada
- 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.)
- Abandoned
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
Landscapes
- Health & Medical Sciences (AREA)
- 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 16 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, .alpha.-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 = 13, or a pharmaceutically acceptable salt thereof.
Description
WO 98/26781 ~ PCT/US97/23419 METHOD OF TREATING OR INHIBITING NE ROPENIA
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:
N
N
Ra N~ N
~R
N~
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, O O O
- C- CF3 , - C- CCH2C1 , - C- OCH2CH3 , (O
- C- OCH2CCI3 , - C- CH2 O
- C- CH2 ~ - CH2 \ / , and -(CH2~,-R ;
WO 98/6781 ' PCT/US97/23419 or R 1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, a-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, malefic, 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.
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:
N
N
Ra N~ N
~R
N~
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, O O O
- C- CF3 , - C- CCH2C1 , - C- OCH2CH3 , (O
- C- OCH2CCI3 , - C- CH2 O
- C- CH2 ~ - CH2 \ / , and -(CH2~,-R ;
WO 98/6781 ' PCT/US97/23419 or R 1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, a-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, malefic, 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 INVENTION
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 p.l 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 subcutaneouslv or intraperitoneally, is effective in accelerating neutrophil recovery after 5-fluorouracil treatment in mice as shown in Table II.
Table I
A dose-related acceleration of neutrophil recovery followin~~ 5-fluorouracil (5-FLJ) in mice results from subcutaneous treatment with compound of Example 14 Days Post 7 8 9 TREATMENT Neutrophils/mm3 0.2% Klucel 3214 36386 881277 200 m /k 21349 73891 1951388 100 m /k 160139 961148 1833253 50 mg/kg 16638 753134 966143 25 mg/kg 7619 540104 II93232 Table II
~ompQran~ of Example 14 when dosed either subcutaneouslv or intraneritoneall~
i~ effective in acceleratin neutrophil recovery after 5-fluorouracil treatment in mice Days Post 5-FU7 8 9 TREATMENT Neutrophils/mm3 none /3052 923419 1884812 50 m /k ,sc 798160 2979400 4178625 50 mg/kg,ip 733133 2600395 3423343 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, corn 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.
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 p.l 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 subcutaneouslv or intraperitoneally, is effective in accelerating neutrophil recovery after 5-fluorouracil treatment in mice as shown in Table II.
Table I
A dose-related acceleration of neutrophil recovery followin~~ 5-fluorouracil (5-FLJ) in mice results from subcutaneous treatment with compound of Example 14 Days Post 7 8 9 TREATMENT Neutrophils/mm3 0.2% Klucel 3214 36386 881277 200 m /k 21349 73891 1951388 100 m /k 160139 961148 1833253 50 mg/kg 16638 753134 966143 25 mg/kg 7619 540104 II93232 Table II
~ompQran~ of Example 14 when dosed either subcutaneouslv or intraneritoneall~
i~ effective in acceleratin neutrophil recovery after 5-fluorouracil treatment in mice Days Post 5-FU7 8 9 TREATMENT Neutrophils/mm3 none /3052 923419 1884812 50 m /k ,sc 798160 2979400 4178625 50 mg/kg,ip 733133 2600395 3423343 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, corn 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.
7-[3-(Trifluoromethyl)phenyl]pyrazolo[1,5-a]-pyrimidine-3-carboxamide 7-Phenylpyrazolo[1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-7-phenylpyrazolo[ 1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[ 1,5-a]pyrimidine-3-carboxamide 7-(3-Fluorophenyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide 7-(3-Fluorophenyl)-4,5-dihydropyrazolo[ 1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-8-phenyl-5-thioxo-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 4,5-Dihydro-5-thioxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one 5-(Methylthio)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 8-(3-Fluorophenyl)-4,5-dihydro-5-thioxo-3H,6H-1,4,5a, 8a-tetraazaacenaphthylen-one N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-5-yl]-benzamide [[3-(Aminocarbonyl)-7-[3-(trifluoromethyl)phenyl)pyrazolo[ 1,5-a]pyrimidin-4(5H)-yl]-thioxomethyl] carbamic acid, ethyl ester [3-Oxo-B[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-5-yl]-carbamic acid, ethyl ester 5-(2-Methylpropylamine)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-3-one 5-( 1-Pyrrolidinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-3-one 5-[(1-Methylethyl)amino]-8- [3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaace-naphthylen-3-one -g_ 5-[(2,2-Dimethoxyethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetra-azaacenaphthylen-3-one 5-[( 1-Methylpropyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraaza-acenaphthylen-3-one 5-( 1-Piperidinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a,tetraazaacenaphthy-len-3-one 5-[[2-(4-Morpholinyl)ethyl]amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-[(2-Hydroxy-2-phenylethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-(Butylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one S-[(2-Hydroxyethyl)amino] 8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraaza-acenaphthylen-3-one 5-(Methylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-3-one 5-[[(2-Methylphenyl)methyl]amino]-8-[3-(trifluoromethyl) phenyl]-3H,6H-1,4,Sa-8a-tetraazaacenaphthylen-3-one 5-(4-Morpholinyl)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthy-len-3-one WO 98/26781 ' PCT/US97/23419 _g_ 5-Ethylamino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-[(Phenylmethyl)amino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-3-one 5-Amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 2,2,2-Trifluoro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-5-yl]acetamide 2-Chloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-5-yl]acetamide [3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-5-yl) carbamic acid, 2,2,2-trichloroethyl ester 4-Methoxy-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-5-yl]benzamide N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-5-yl]-3-(trifluoromethyl)benzamide 4-Methyl-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-5-yl]benzamide EXAMPLE 3b 2-(Acetyloxy)--N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-5-yl]benzamide N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-5-yl]-2-phenoxyacetamide 5-Methoxy-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaph-thylen-5-yI] benzamide 3-Nitro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaph-thylen-5-yl]benzamide 4-Bromo-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaph-thylen-5-yl]benzamide 3,4-Dichloro-N-[3-oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-5-yl]benzamide 4-Fluoro-N-[3 -oxo-8-[3-(trifluoromethyl)phenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-5-yl]benzamide 5-[[(4-Chlorophenyl)methyl]amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one 5-[(2-Methylpropyl)amino]-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one 5-[(2,2-Dimethoxyethyl)amino]-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-(Butylamino)-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one 5-Amino-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one 5-(Ethylamino)-8-phenyl-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one WO 98/26781 ' PCT/US97/23419 5-[(Methylethyl)amino]-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-[(2-Hydroxyethyl)amino]-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-(Methylamino)-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 8-(3-Fluorophenyl)-5-[(2-methylpropyl)amino]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-(Butylamino)-8-(3-fluorophenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 8-(3-Fluorophenyl}-5-[(methylpropyl)amino]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-(Ethylamino)-8-(3-fluorophenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 5-[(2,2-Dimethoxyethyl)amino]-8-(3-fluorophenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-3-one 8-(3-Fiuorophenyl)-5-[(1-methylethyl)amino]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 8-(3-Fluorophenyl)-5-[[3-( 1H-imidazol-1-yl)propyl]amino]-3H,6H-1,4,Sa,8a-tetraaza-acenaphthylen-3-one 5-([3-( 1H-Imidazol-1-yl)propyl] amino]-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaace-naphthylen-3-one 5-Amino-8-(3-fluorophenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one N-[3-Oxo-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-S-yl]-4-(phenylmethyl)-1-piperazineacetamide 7-Methyl-5-[(1-methylethyl)amino]-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 8-(4-Chlorophenyl)-7-methyl-S-[(2-methylpropyl)amino)-3H,6H-1,4,Sa,8a-tetraaza-acenaphthylen-3-one 5-(Butylamino)-2,7-dimethyl-8-phenyl-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-3-one 7-(3-methylphenyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-7-(3-methylphenyl)pyrazolo [ 1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-5-thioxo-8-)3-methylphenyl)-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen-one 8-(3-Methylphenyl)-5-[(2-methylpropyl)amino]-3H,6H-1,4,Sa, Sa-tetraazaacenaph-thylen-3-one 7-(3-Methoxyphenyl)pyrazolo[ 1,5-a]pyrimidine-3-carboxamide 4,5-Dihydro-7-(3-methoxyphenyl)pyrazolo[1,5-a]pyrimidine 4,5-Dihydro-8-(3-methoxyphenyl)-5-thioxo-3H,6H-1,4,Sa,8a-tetraazaacenaphthylen--one 8-(3-Methoxyphenyl)-5-[2-methylpropyl)amino]-3H,6H-1,4,Sa,8a-tetraazaacenaph-thylen-3-one
Claims (6)
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:
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
2. The method of Claim 1 wherein said compound is 5-(2-methylpropylamino)-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4-5a,8a-tetraazaacenaphthylen-3-one or 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,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:
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
4. Use of a compound of formula:
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, , , , , , , and -(CH2)n-R;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
5. Use of a compound of formula:
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, ,~,~, , ~, , and -(CH2)n-R ;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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.
wherein R1 and R2 are each, independently selected from the group consisting of hydrogen, alkyl of 1-6 carbon atoms, benzoyl, ,~,~, , ~, , and -(CH2)n-R ;
or R1 and R2 are methylene groups which are taken together to form a 4-7 membered saturated heterocyclic ring;
wherein when R1 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, 1H-imidazol-1-yl, -CH(alkoxy of 1-6 carbon atoms)2, .alpha.-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-1,4-5a,8a-tetraazaacenaphthylen-3-one or 5-amino-8-[3-(trifluoromethyl)phenyl]-3H,6H-1,4,5a,8a-tetraazaacenaphthylen-3-one.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US77074396A | 1996-12-19 | 1996-12-19 | |
| US08/770,743 | 1996-12-19 | ||
| PCT/US1997/023419 WO1998026781A1 (en) | 1996-12-19 | 1997-12-17 | Method of treating or inhibiting neutropenia |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2273288A1 true CA2273288A1 (en) | 1998-06-25 |
Family
ID=25089545
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002273288A Abandoned CA2273288A1 (en) | 1996-12-19 | 1997-12-17 | Method of treating or inhibiting neutropenia |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0957918A1 (en) |
| JP (1) | JP2001506998A (en) |
| AR (1) | AR010808A1 (en) |
| AU (1) | AU5611398A (en) |
| CA (1) | CA2273288A1 (en) |
| WO (1) | WO1998026781A1 (en) |
| ZA (1) | ZA9711342B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11116738B2 (en) | 2012-06-07 | 2021-09-14 | Children's Hospital Los Angeles | Methods for treating neutropenia using retinoid agonists |
| US10286039B2 (en) | 2014-02-18 | 2019-05-14 | Children's Hospital Los Angeles | Compositions and methods for treating neutropenia |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2615291B1 (en) * | 1987-05-15 | 1989-07-13 | Thomson Csf | METHOD FOR TESTING OPERATION OF A RADAR INFORMATION DISPLAY DEVICE AND IMPLEMENTATION OF THIS METHOD |
| 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 |
| ATE99686T1 (en) * | 1988-02-22 | 1994-01-15 | American Cyanamid Co | 5-(SUBSTITUTED AMINO)-8-(PHENYL OR SUBSTITUTED PHENYL)-3H,6H-1,4,5A,8ATETRAAZAACENAPHTHYLENE-3-ONE. |
-
1997
- 1997-12-17 EP EP97952527A patent/EP0957918A1/en not_active Withdrawn
- 1997-12-17 CA CA002273288A patent/CA2273288A1/en not_active Abandoned
- 1997-12-17 ZA ZA9711342A patent/ZA9711342B/en unknown
- 1997-12-17 WO PCT/US1997/023419 patent/WO1998026781A1/en not_active Application Discontinuation
- 1997-12-17 JP JP52798098A patent/JP2001506998A/en active Pending
- 1997-12-17 AU AU56113/98A patent/AU5611398A/en not_active Abandoned
- 1997-12-18 AR ARP970105989A patent/AR010808A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AU5611398A (en) | 1998-07-15 |
| WO1998026781A1 (en) | 1998-06-25 |
| AR010808A1 (en) | 2000-07-12 |
| JP2001506998A (en) | 2001-05-29 |
| EP0957918A1 (en) | 1999-11-24 |
| ZA9711342B (en) | 1999-06-17 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US11464781B2 (en) | PDE1 inhibitors for ophthalmic disorders | |
| US6294565B1 (en) | Methods of combatting infectious diseases using dicationic bis-benzimidazoles | |
| JP5810157B2 (en) | Protein kinase inhibitors and methods of treatment | |
| RU2423980C2 (en) | Combinations containing epothilones and protein kinase inhibitors and pharmaceutical application thereof | |
| US20100323997A1 (en) | Novel uses | |
| US20100087450A1 (en) | Organic compounds | |
| US20110243891A1 (en) | Dihydropyrazolopyrimidinone derivative | |
| EP0729758A2 (en) | Pyrazolopyrimidines and pyrrolopyrimidines for treatment of neuronal and other disorders | |
| CA2287122A1 (en) | Treatment of bph with cgmp elevators | |
| HU217132B (en) | Use of riluzole for preparing pharmaceutical compositions treating aids-related neural disorders | |
| CA2273288A1 (en) | Method of treating or inhibiting neutropenia | |
| US6051578A (en) | Pyrazolopyrimidines for treatment of CNS disorders | |
| US5932585A (en) | Method of treating or inhibiting neutropenia | |
| AU2006224623A1 (en) | Method for preventing cardiovascular diseases | |
| US20020169154A1 (en) | Novel methods and compositions involving trk tyrosine kinase inhibitors and antineoplastic agents | |
| JP2020528052A (en) | Use of eribulin and cyclin-dependent kinase inhibitors in cancer treatment | |
| US4916137A (en) | 5-(Substituted-amino)-8-(phenyl or substituted-phenyl)-3H,6H-1,4,5A,8A-tetraazaacenaphthylen-3-ones and treatment of neural behavior disorders | |
| NZ297424A (en) | Use of an aminopurine derivative to treat latent infection of the herpes virus | |
| WO2014174478A1 (en) | Pharmaceutical combinations of a pkc inhibitor and a c-met receptor tyrosine kinase inhibitor | |
| JP2641556B2 (en) | 5- (substituted amino) -8- (phenyl or substituted phenyl) -3H, 6H-1,4,5a, 8a-tetraazaacenaphthylene-3-one | |
| US7018999B2 (en) | Methods for the treatment and prevention of pain | |
| WO1986007537A2 (en) | Pharmaceutical compositions containing azanaphthalenes | |
| CA3155068A1 (en) | Drug combination containing tlr7 agonist | |
| US20020198379A1 (en) | Active compound from a sponge | |
| RU97116717A (en) | 6-SUBSTITUTED DERIVATIVES OF PYRAZOLO [3,4-D] Pyrimidin-4-SHE, COMPOSITIONS ON THEIR BASIS AND METHODS OF THEIR APPLICATION |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Dead |