- Copper-Catalyzed Reductive Ring-Cleavage of Isoxazoles: Synthesis of Fluoroalkylated Enaminones and Application for the Preparation of Celecoxib, Deracoxib, and Mavacoxib
-
We have identified a new reactivity of copper/diamine catalysis for the reductive ring-cleavage of isoxazoles to yield fluoroalkylated enaminones. This protocol has the advantage of using commercially available reagents, ease of setting up, broad tolerance of functionality, and is regiospecific and free of defluorination and reduction of reducible functional groups. The utility was demonstrated by a one-step, regioselective synthesis of fluoroalkylated pyrazole-based drugs such as celecoxib, deracoxib, and mavacoxib.
- Wan, Chao,Pang, Jian-Yu,Jiang, Wei,Zhang, Xiao-Wei,Hu, Xiang-Guo
-
p. 4557 - 4566
(2021/03/01)
-
- Preparation method of Deracoxib
-
The invention discloses a preparation method of Deracoxib, and belongs to the field of Deracoxib preparation. The preparation method of Deracoxib disclosed by the invention comprises the following steps: (1) taking methane chloride as a reaction solvent, and reacting 2-fluoroanisole with acetylchloride under the effect of acid so as to obtain 3-fluoro-4-methoxyacetophenone; (2) taking methane chloride as a reaction solvent, and reacting 3-fluoro-4-methoxyacetophenone with ethyl difluoroacetate under the effect of alkaline so as to obtain 4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-1,3-butanedione; and (3) under the existence of an ethyl alcohol solvent, reacting 4,4-difluoro-1-(3-fluoro-4-methoxyphenyl)-1,3-butanedione with para-sulfamine phenylhydrazine or salt thereof so as to obtain Deracoxib. According to the preparation method of Deracoxib disclosed by the invention, dichloromethane is used as a solvent, the toxicity of the solvent is low, the cost of the solvent is lower than thatof methyl tertiary butyl ether, and the production cost is obviously reduced on the premise of guaranteeing the yield.
- -
-
-
- COMBINATION OF A SELECTIVE NMDA NR2B ANTAGONIST AND A COX-2 INHIBITOR
-
The present invention provides a combination of a selective NMDA NR2B antagonist and a COX-2 inhibitor for the treatment or prevention of pain or nociception.
- -
-
-
- METHOD OF USING CYCLOOXYGENASE-2 INHIBITORS IN THE TREATMENT AND PREVENTION OF NEOPLASIA
-
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating neoplasia. In particular, the invention describes the method of preventing and treating epithelial cell neoplasia in a subject, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula (I) wherein A, R and R are as described in the specification.
- -
-
-
- Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
-
This invention relates to the use of a tocolytic agent or agents in combination with selective cyclooxygenase-2 inhibitors of Formula (II) or a pharmaceutically-acceptable salt or derivative thereof for preparing a medicament for maintaining circulation through fetal ductus arteriosus during treatment or prevention of preterm labor in a subject in need of such treatment or prevention.
- -
-
-
- Use of a COX-2 inhibitor and a NK-1 receptor antagonist for treating inflammation
-
The present invention provides the use of a COX-2 inhibitior and an NK-1 receptor antagonist for the treatment or prevention of inflammatory disorders.
- -
-
-
- THERAPEUTIC COMBINATIONS FOR CARDIOVASCULAR AND INFLAMMATORY INDICATIONS
-
The present invention provides therapeutic combinations and methods for treating or preventing a hypercholesterolemia-related or an inflammation-related condition in a subject in need of such treatment or prevention. One therapeutic combination comprises
- -
-
-
- Method for the treatment and prevention of cachexia
-
Cachexia, including anorexia and other forms of weight loss, is a frequent complication of acute and chronic infections, and result from induction of cytokines, prostaglandins, and other inflammatory mediators that are critical for pathogen elimination. The present invention includes methods for the treatment or prevention of cachexic conditions while maintaining the production of factors essential for infection control through the administration of an effective amount of a cyclooxygenase-2 selective inhibiting compound.
- -
-
-
- Combination therapy using COX-2 selective inhibitor and thromboxane inhibitor and compositions therefor
-
The present invention provides a method for the treatment or prophylaxis of COX-2-mediated conditions in patients who are at risk of developing thromboembolic events which comprises administering to said patient a therapeutically or prophylactically effective amount of a COX-2 selective inhibitor and a cardiovascular protective amount of a thromboxane inhibitor, as well as compositions therefor.
- -
-
-
- Combination therapy in the prevention of cardiovascular disorders
-
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing cardiovascular disorders.
- -
-
-
- Method of using cyclooxegenase-2 inhibitors in the treatment and prevention of dementia
-
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating dementia. In particular, the invention describes the method of preventing and treating dementia in a subject, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I wherein R2, R3, and R4 are as described in the specification.
- -
-
-
- Antiangiogenic combination therapy for the treatment of cancer
-
The present invention provides combinations of a DNA topoisomerase I inhibiting agent and a selective COX-2 inhibiting agent for preventing, treating, and/or reducing the risk of developing a neoplasia disorder in a mammal.
- -
-
-
- Combination of a GABAA alpha 5 inverse agonist and COX-2 inhibitor, NSAID, estrogen or vitamin E
-
Combinations of a GABAAalpha 5 inverse agonist and a COX-2 inhibitor, NSAID, estrogen or vitamin E are disclosed for treating neurodegenerative conditions such as Alzheimer's Disease.
- -
-
-
- Combination therapy for treating neurodegenerative disease
-
The instant invention provides a novel drug combination comprised of an HMG-CoA reductase inhibitor and a selective COX-2 inhibitor, which is useful for treating, preventing, delaying the onset of and/or reducing the risk of developing Alzheimer's disease. One object of the instant invention is to administer the above-described combination therapy to people who do not yet show clinical signs of Alzheimer's disease, but who are at risk of developing Alzheimer's disease. These individuals may already show signs of mild cognitive impairment. Toward this end, the instant invention provides methods for preventing or reducing the risk of developing Alzheimer's by administering the above-described combination therapy to said at risk persons. Such treatment may halt or reduce the rate of further cognitive decline or, in fact, reverse cognitive decline. The present invention also provides for a method of preventing cognitive impairment or dementia, reducing the risk of cognitive decline or impairment or reducing cognitive decline or impairment resulting from stroke, stroke, cerebral ischemia or de-myelinating disorders.
- -
-
-
- Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitors and a leukotriene B4 receptor antagonist
-
Combinations of a cyclooxygenase-2 inhibitor and a leukotriene B4receptor antagonist are described for treatment of inflammation and inflammation-related disorders.
- -
-
Page column 28 - 29
(2010/01/30)
-
- Method for treating inflammatory diseases by administering a thrombin inhibitor
-
The invention is a method for treating an inflammatory disease in a patient which comprises treating the patient with a composition comprising a thrombin inhibitor. Such diseases include but are not limited to nephritis, systemic lupus erythematosus, rheumatoid arthritis, glomerulonephritis, and sacoidosis. In one class of the method, the thrombin inhibitor is selected from the group consisting of 3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyrazinone, N′-[[1-(aminoiminomethyl)-4-piperidinyl]methyl]-N-(3,3-diphenylpropionyl)-L-proline amide, and 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone or a pharmaceutically acceptable salt thereof. The invention is also a method for treating an inflammatory disease in a patient which comprises treating the patient with a composition comprising a thrombin inhibitor and an NSAID, e.g., a COX-2 inhibitor. Such diseases include but are not limited to nephritis, systemic lupus, erythematosus, rheumatoid arthritis, glomerulonephritis, and sacoidosis. In one class of the method, the thrombin inhibitor is selected from the group consisting of 3-(2-phenylethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylene-carboxamidomethylpyridinyl)-2-pyrazinone, N′-[[1-(aminoiminomethyl)-4-piperidinyl]methyl]-N-(3,3-diphenylpropionyl)-L-proline amide, and 3-(2-phenethylamino)-6-methyl-1-(2-amino-6-methyl-5-methylenecarboxamidomethylpyridinyl)-2-pyridinone or a pharmaceutically acceptable salt thereof and the COX-2 inhibitor is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone or a pharmaceutically acceptable salt thereof.
- -
-
-
- Combination therapy for reducing the risks associated with cardio-and-cerebrovascular disease
-
The instant invention provides a drug combination comprised of an HMG-CoA reductase inhibitor in combination with a COX-2 inhibitor, which is useful for treating, preventing, and/or reducing the risk of developing atherosclerosis and atherosclerotic disease events.
- -
-
-
- Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
-
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating angiogenic disorders.
- -
-
-
- Combination therapy for treating, preventing, or reducing the risks associated with acute coronary ischemic syndrome and related conditions
-
The invention provides a method for treating, preventing, or reducing the risk of developing a condition selected from the group consisting of acute coronary ischemic syndrome, thrombosis, thromboembolism, thrombotic occlusion and reocclusion, restenosis, transient ischemic attack, and first or subsequent thrombotic stroke, in a patient, comprising administering to the patient a therapeutically effective amount of an antiplatelet agent in combination with a therapeutically effective amount of a COX-2 inhibitor. The invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a COX-2 inhibitor, or a pharmaceutically acceptable salt thereof, and an antiplatelet agent, or a pharmaceutically acceptable salt thereof.
- -
-
-
- Process for preparing 3-haloalkyl-1H-pyrazoles
-
An efficient synthesis of 3-haloalkyl-1H-pyrazoles, suitable for adoption in a safe, large-scale process, has been developed.
- -
-
-
- Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
-
This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating neoplasia. In particular, the invention describes the method of preventing and treating epithelial cell neoplasia in a subject, said method comprising treating the subject with a therapeutically-effective amount of a compound of Formula I. STR1 wherein A, R2 and R3 are as described in the specification.
- -
-
-
- Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies
-
A method of using pyrazolyl benzenesulfonamide compounds in treating inflammation and inflammation-related disorders in companion animals is disclosed.
- -
-
-
- Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
-
A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula II: STR1 or a pharmaceutically-acceptable salt thereof.
- -
-
-
- Synthesis and biological evaluation of the 1,5-diarylpyrazole class of cyclooxygenase-2 inhibitors: Identification of 4-[5-(4-methylphenyl)- 3(trifluoromethyl)-1h-pyrazol-1-yl]benzenesulfonamide (sc-58635, celecoxib)
-
A series of sulfonamide-containing 1,5-diarylpyrazole derivatives were prepared and evaluated for their ability to block cyclooxygenase-2 (COX-2) in vitro and in vivo. Extensive structure-activity relationship (SAR) work was carried out within this series, and a number of potent and selective inhibitors of COX-2 were identified. Since an early structural lead (1f, SC- 236) exhibited an unacceptably long plasma half-life, a number of pyrazole analogs containing potential metabolic sites were evaluated further in vivo in an effort to identify compounds with acceptable pharmacokinetic profiles. This work led to the identification of 1i (4-[5-(4-methylphenyl)-3- (trifluoromethyl)-1H-pyrazol-1-y1]benzenesulfonamide, SC-58635, celecoxib), which is currently in phase III clinical trials for the treatment of rheumatoid arthritis and osteoarthritis.
- Penning, Thomas D.,Talley, John J.,Bertenshaw, Stephen R.,Carter, Jeffery S.,Collins, Paul W.,Docter, Stephen,Graneto, Matthew J.,Lee, Len F.,Malecha, James W.,Miyashiro, Julie M.,Rogers, Roland S.,Rogier,Yu, Stella S.,Anderson, Gary D.,Burton, Earl G.,Cogburn, J. Nita,Gregory, Susan A.,Koboldt, Carol M.,Perkins, William E.,Seibert, Karen,Veenhuizen, Amy W.,Zhang, Yan Y.,Isakson, Peter C.
-
p. 1347 - 1365
(2007/10/03)
-
- Substituted pyrazolyl benzenesulfonamide for the treatment of inflammation
-
A class of pyrazolyl benzenesulfonamide compounds is described for use in treating inflammation and inflammation-related disorders. Compounds of particular interest are defined by Formula I: STR1
- -
-
-
