- 1,5-diarylpyrazole derivative, and synthetic method and application thereof
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The invention relates to a 1,5-diaryl pyrazole derivative and antibacterial application thereof. On the basis of a celecoxib structure, structural modification is conducted on 1,5-diaryl to obtain the 1,5-diaryl pyrazole derivative; and after structural c
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Paragraph 0039; 0041; 0044-0046
(2021/07/01)
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- A CONTINUOUS FLOW MICRO-TOTAL PROCESS SYSTEM FOR PREPARATION OF CELECOXIB AND ANALOGS THEREOF
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The present invention relates to preparation of pyrazoles. This invention further relates to a continuous flow micro-total process system for preparation of celecoxib, a COX-2 selective non-steroidal anti-inflammatory drug, and analogs thereof.
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Page/Page column 16-18
(2020/08/22)
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- An Integrated Continuous Flow Micro-Total Ultrafast Process System (μ-TUFPS) for the Synthesis of Celecoxib and Other Cyclooxygenase Inhibitors
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Integrated continuous manufacturing has emerged as a promising device for the rapid manufacturing of active pharmaceutical ingredients (APIs). We herein report a newly designed continuous flow micro-total process system platform for the rapid manufacturing of celecoxib, a selective nonsteroidal anti-inflammatory drug. This approach has been proven generally for the synthesis of several alkyl and aryl substituted pyrazoles. In order to minimize the tedious work-up process of potential reaction intermediates/products, we have developed a continuous flow extraction and separation platform to carry out the entire reaction sequence resulting in a short residence time with good yield. The present process was further extended to gram-scale synthesis of the COX-2-related API, viz. celecoxib, in the continuous flow process.
- Sthalam, Vinay Kumar,Singh, Ajay K.,Pabbaraja, Srihari
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p. 1892 - 1899
(2019/10/11)
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- Late-Stage Aromatic C-H Oxygenation
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Synthetic methods for oxidative aromatic C-O bond formation are sparse, despite their demand in metabolite synthesis for drug discovery and development. We report a novel methodology for late-stage C-O bond formation of arenes. The reaction proceeds with excellent functional group tolerance even for highly functionalized substrates. The resulting aryl mesylates provide access to potential human metabolites of pharmaceuticals, and may be used directly to install a C-F bond to block metabolic hotspots. A charge-transfer interaction between the reagent bis(methanesulfonyl) peroxide and the substrate arenes may be relevant for the chemoselective functionalization of arenes over other functional groups.
- B?rgel, Jonas,Tanwar, Lalita,Berger, Florian,Ritter, Tobias
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supporting information
p. 16026 - 16031
(2018/12/13)
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- Selective, Metal-Free Approach to 3- or 5-CF3-Pyrazoles: Solvent Switchable Reaction of CF3-Ynones with Hydrazines
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A detailed study of the reaction of trifluoroacetylated acetylenes and aryl (alkyl) hydrazines was performed, aimed to the regioselective synthesis of 3- or 5-trifluoromethylated pyrazoles. It was found that the regioselectivity of reaction depends dramatically on the solvent nature. Highly polar protic solvents (hexafluoroisopropanol) favor the formation of 3-trifluoromethylpyrazoles. In contrast, when the reaction was performed in polar aprotic solvents (DMSO), the formation of their 5-CF3-substituted isomers was preferentially observed. Alternatively, the regioselective assembly of 3-CF3-substituted pyrazoles can be performed via two-step one-pot procedure. The reaction of trifluoromethylated ynones with aryl (alkyl) hydrazines in the presence of acidic catalysts leads to formation of the corresponding hydrazones. The latter can be smoothly transformed into 3-CF3-pyrazoles by treatment with a base. This solvent-switchable procedure was used for the preparation of such important drugs as Celebrex and SC-560 as well as their isomers in gram scale. The possible reaction mechanism is discussed.
- Muzalevskiy, Vasiliy M.,Rulev, Alexander Yu.,Romanov, Alexey R.,Kondrashov, Evgeniy V.,Ushakov, Igor A.,Chertkov, Vyacheslav A.,Nenajdenko, Valentine G.
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p. 7200 - 7214
(2017/07/26)
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- Radiochemistry on electrodes: Synthesis of an 18F-labelled and in vivo stable COX-2 inhibitor
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New radiochemistry techniques can yield novel PET tracers for COX-2 and address the shortcomings in in vivo stability and specificity, which have held back clinical translation of tracers to image COX-2 expression. Current techniques limit radiosynthesis to analogs of the COX-2 inhibitors with fluorine-18 added via a carbon chain, or on an aromatic position which renders the radiolabeled analog less specific towards COX-2, resulting in tracers with low in vivo stability or specificity. To solve this problem, we have developed a new high affinity, 18F-labelled COX-2 inhibitor that is radiolabeled directly on a heteroaromatic ring. This molecule exhibits favorable biodistribution and increased metabolic stability. Synthesis of this molecule cannot be achieved by traditional means; consequently, we have developed an automated electrochemical radiosynthesis platform to synthesize up to 5 mCi of radiochemically pure 18F-COX-2ib in 4 hours (2% decay-corrected radiochemical yield). In vitro studies demonstrated clear correlation between COX-2 expression and uptake of the tracer. PET imaging of healthy animals confirmed that the molecule is excreted from blood within an hour, mainly through the hepatobiliary excretion pathway. In vivo metabolism data demonstrated that > 95% of the injected radioactivity remains in the form of the parent molecule 1 hour after injection.
- Lebedev, Artem,Jiao, Jing,Lee, Jason,Yang, Fan,Allison, Nathanael,Herschman, Harvey,Sadeghi, Saman
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- Solvent- and transition metal catalyst-dependent regioselectivity in the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines: Switchable access to 3- and 5-trifluoromethylpyrazoles
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The regioselectivity of the [3+2]cyclocondensation of trifluoromethyl-α,β-ynones with hydrazines can be readily tuned to preferentially afford either 3- or 5-trifluoromethylpyrazoles through variation of the reaction conditions. Under catalysis with copper(II) acetate (2.0 mol%), cyclocondensation proceeded smoothly to yield 3-trifluoromethylpyrazoles with high regioselectivity. In contrast, when the reaction was conducted in dimethyl sulfoxide under catalyst-free conditions, the formation of 5-trifluoromethylpyrazoles was predominantly observed.
- Hsieh, Min-Tsang,Kuo, Sheng-Chu,Lin, Hui-Chang
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p. 683 - 689
(2015/03/18)
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- Structure-activity relationship of celecoxib and rofecoxib for the membrane permeabilizing activity
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Non-steroidal anti-inflammatory drugs (NSAIDs) achieve their anti-inflammatory effect by inhibiting cyclooxygenase activity. We previously suggested that in addition to cyclooxygenase-inhibition at the gastric mucosa, NSAID-induced gastric mucosal cell death is required for the formation of NSAID-induced gastric lesions in vivo. We showed that celecoxib exhibited the most potent membrane permeabilizing activity among the NSAIDs tested. In contrast, we have found that the NSAID rofecoxib has very weak membrane permeabilizing activity. To understand the membrane permeabilizing activity of coxibs in terms of their structure-activity relationship, we separated the structures of celecoxib and rofecoxib into three parts, synthesized hybrid compounds by substitution of each of the parts, and examined the membrane permeabilizing activities of these hybrids. The results suggest that the sulfonamidophenyl subgroup of celecoxib or the methanesulfonylphenyl subgroup of rofecoxib is important for their potent or weak membrane permeabilizing activity, respectively. These findings provide important information for design and synthesis of new coxibs with lower membrane permeabilizing activity.
- Yamakawa, Naoki,Suzuki, Koichiro,Yamashita, Yasunobu,Katsu, Takashi,Hanaya, Kengo,Shoji, Mitsuru,Sugai, Takeshi,Mizushima, Tohru
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p. 2529 - 2534
(2014/05/06)
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- HETEROCYCLES USEFUL AS INHIBITORS OF CARBONIC ANHYDRASE
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Sulfonamides and pharmaceutical compositions containing the compounds useful in controlling intraocular pressure are disclosed. Methods for controlling intraocular pressure through administration of the compositions are also disclosed.
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Page/Page column 192
(2008/06/13)
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- Highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles
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A highly regioselective synthesis of 1-aryl-3,4,5-substituted pyrazoles based on the condensation of 1,3-diketones with arylhydrazines is described. The reaction proceeds at room temperature in N,N-dimethylacetamide and furnishes pyrazoles in 59-98% yield
- Gosselin, Francis,O'Shea, Paul D.,Webster, Robert A.,Reamer, Robert A.,Tillyer, Richard D.,Grabowski, Edward J. J.
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p. 3267 - 3270
(2008/09/17)
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- METHOD OF USING CYCLOOXYGENASE-2 INHIBITORS IN THE TREATMENT AND PREVENTION OF NEOPLASIA
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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.
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- Method of using cyclooxygenase-2 inhibitors in maintaining the fetal ductus ateriosus during treatment and prevention of preterm labor
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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.
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- Compounds and methods for inducing apoptosis in proliferating cells
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Compounds useful for inducing apoptosis in proliferative cells, particularly cancer cells, including but not limited to prostate cancer, leukemia, non-smalll cell lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, renal cancer, bladder cancer, lymphoma, and breast cancer. These compounds are particularly useful in the treatment of androgen-independent cancers, including hormone-refractory prostate cancer. Further provided are methods of treating cancer in a subject in need of such treatment using the compounds of the present invention. Further provided are methods for using the compounds of the present invention to treat, inhibit, or delay the onset of cancer in a subject. Further provided are methods of inducing apoptosis in rapidly proliferating cells, particularly, though not necessarily cancer cells, using the compounds of the present invention.
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- Combination therapy in the prevention of cardiovascular disorders
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This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing cardiovascular disorders.
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- Method of using cyclooxegenase-2 inhibitors in the treatment and prevention of dementia
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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.
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- Method of using cyclooxygenase-2 inhibitors as anti-angiogenic agents
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This invention relates to the use of cyclooxygenase-2 inhibitors or derivatives thereof in preventing and treating angiogenic disorders.
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- Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor
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Combinations of a cyclooxygenase-2 inhibitor and a 5-lipoxygenase inhibitor are described for treatment of inflammation and inflammation-related disorders.
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- Method of using cyclooxygenase-2 inhibitors in the treatment and prevention of neoplasia
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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.
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- Treatment of inflammation and inflammation-related disorders with a combination of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor
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Combinations of a cyclooxygenase-2 inhibitor and a leukotriene A4 hydrolase inhibitor are described for treatment of inflammation and inflammation-related disorders.
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- Substituted pyrazolyl benzenesulfonamides for use in veterinary therapies
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A method of using pyrazolyl benzenesulfonamide compounds in treating inflammation and inflammation-related disorders in companion animals is disclosed.
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- Substituted pyrazolyl benzenesulfonamides for the treatment of inflammation
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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.
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- 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)
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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.
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p. 1347 - 1365
(2007/10/03)
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