- Pyrazolo [3, 4 - c] pyridine - 7 - ketone compound and use thereof
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Belonging to the technical field of medicine, the invention relates to a 4, 5-dihydro-1H-pyrazolo[3, 4-c]pyridine-7-one containing derivative shown as general formula I, and pharmaceutically acceptable salt, hydrate or prodrug thereof, wherein the substituents A, R1 and R2 have meanings given in the specification. The preparation also relates to a preparation method of the general formula I compound and its pharmaceutically acceptable salt or prodrug, medicinal compositions containing the compound and application of the compound as an Xa factor inhibitor, especially application in preparation of drugs for treatment and/or prevention of thromboembolic diseases. (formula I).
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Paragraph 0201; 0293; 0294
(2017/09/01)
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- Transition-Metal-Free Amine Oxidation: A Chemoselective Strategy for the Late-Stage Formation of Lactams
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A metal-free strategy for the formation of lactams via selective oxidation of cyclic secondary and tertiary amines is described. Molecular iodine facilitates both chemoselective and regioselective oxidation of C-H bonds directly adjacent to a cyclic amine. The mild conditions, functional group tolerance, and substrate scope are demonstrated using a suite of diverse small molecule cyclic amines, including clinically approved drug scaffolds.
- Griffiths, Robert J.,Burley, Glenn A.,Talbot, Eric P. A.
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supporting information
p. 870 - 873
(2017/02/26)
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- PROCESS FOR THE PREPARATION OF APIXABAN
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The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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- AN IMPROVED PROCESS FOR THE PREPARATION OF APIXABAN
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The present invention relates to an improved process for the preparation of Apixaban and its intermediates.
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- LACTAM-CONTAINING COMPOUNDS AND DERIVATIVES THEREOF AS FACTOR XA INHIBITORS
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The present application describes lactam-containing compounds and derivatives thereof of Formula I: P4—P-M-M4??I or pharmaceutically acceptable salt forms thereof, wherein ring P, if present is a 5-7 membered carbocycle or heterocycle and ring M is a 5-7 membered carbocycle or heterocycle. Compounds of the present invention are useful as inhibitors of trypsin-like serine proteases, specifically factor Xa.
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Paragraph 0699
(2017/04/28)
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- Novel intermediate and polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetra hydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide and process thereof
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The present invention provides a novel intermediate as well as novel polymorphs of 1-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide compound represented by the following structural formula-1 and processes for their preparation.
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- NOVEL PROCESS FOR THE PREPARATION OF A LACTAM-CONTAINING COMPOUND
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Provided herein is a novel, commercially viable and industrially advantageous process for the preparation of 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxo-1-piperidinyl)phenyl]-4,5,6,7-tetrahydro-1H-pyrazole-[3,4-c]pyridine-3-carboxamide, in high yield and with high purity, using a novel intermediate 3-chloro-1-(4-iodophenyl)-5,6-dihydropyridin-2(1H)-one.
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- PYRAZOLE CARBOXAMIDE INHIBITORS OF FACTOR XA
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The present invention relates to new pyrazole carboxamide inhibitors of factor Xa, pharmaceutical compositions thereof, and methods of use thereof.
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Page/Page column 28
(2010/04/06)
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- Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (Apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa
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Efforts to identify a suitable follow-on compound to razaxaban (compound 4) focused on modification of the carboxamido linker to eliminate potential in vivo hydrolysis to a primary aniline. Cyclization of the carboxamido linker to the novel bicyclic tetrahydropyrazolopyridinone scaffold retained the potent fXa binding activity. Exceptional potency of the series prompted an investigation of the neutral P1 moieties that resulted in the identification of the p-methoxyphenyl P1, which retained factor Xa binding affinity and good oral bioavailability. Further optimization of the C-3 pyrazole position and replacement of the terminal P4 ring with a neutral heterocycle culminated in the discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4, 5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, compound 40). Compound 40 exhibits a high degree of fXa potency, selectivity, and efficacy and has an improved pharmacokinetic profile relative to 4.
- Pinto, Donald J. P.,Orwat, Michael J.,Koch, Stephanie,Rossi, Karen A.,Alexander, Richard S.,Smallwood, Angela,Wong, Paneras C.,Rendina, Alan R.,Luettgen, Joseph M.,Knabb, Robert M.,He, Kan,Xin, Baomin,Wexler, Ruth R.,Lam, Patrick Y. S.
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p. 5339 - 5356
(2008/03/13)
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- PYRIDIL-LACTAMS AND THEIR USE 5 -HTl RECEPTORS LIGAN
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The present invention relates to novel pyridyl-lactams, compounds of the formula (I), wherein R1 is a group of the formula G1, G2, G3 or G4 depicted below, and R3, Y, R6, R7, R8, R13, a, n and m are as defined herein, their pharmaceutically acceptable salts, pharmaceutical compositions, their preparation and intermediates therefrom, and their use in treating or preventing depression, anxiety, obsessive compulsive disorder (OCD) and other disorders for which a 5-HT1B antagonist is indicated.
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Page/Page column 42
(2010/11/24)
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- 1-[3-Aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one (BMS-740808) a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa
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Attempts to further optimize the pyrazole factor Xa inhibitors centered on masking the aryl aniline P4 moiety. Scaffold optimization resulted in the identification of a novel bicyclic pyrazolo-pyridinone scaffold which retained fXa potency. The novel bicyclic scaffold preserved all binding interactions observed with the monocyclic counterpart and importantly the carboxamido moiety was integrated within the scaffold making it less susceptible to hydrolysis. These efforts led to the identification of 1-[3-aminobenzisoxazol-5′-yl]-3-trifluoromethyl-6-[2′-(3-(R)-hydroxy-N-pyrrolidinyl)methyl-[1,1′]-biphen-4-yl]-1,4,5,6-tetrahydropyrazolo-[3,4-c]-pyridin-7-one 6f (BMS-740808), a highly potent (fXa Ki = 30 pM) with a rapid onset of inhibition (2.7 × 107 M-1 s-1) in vitro, selective (>1000-fold over other proteases), efficacious in the AVShunt thrombosis model, and orally bioavailable inhibitor of blood coagulation factor Xa.
- Pinto, Donald J.P.,Orwat, Michael J.,Quan, Mimi L.,Han, Qi,Galemmo Jr., Robert A.,Amparo, Eugene,Wells, Brian,Ellis, Christopher,He, Ming Y.,Alexander, Richard S.,Rossi, Karen A.,Smallwood, Angela,Wong, Pancras C.,Luettgen, Joseph M.,Rendina, Alan R.,Knabb, Robert M.,Mersinger, Lawrence,Kettner, Charles,Bai, Steven,He, Kan,Wexler, Ruth R.,Lam, Patrick Y.S.
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p. 4141 - 4147
(2007/10/03)
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- Discovery of potent, efficacious, and orally bioavailable inhibitors of blood coagulation factor Xa with neutral P1 moieties
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The bicyclic dihydropyrazolopyridinone scaffold allowed for incorporation of multiple P1 moieties with subnanomolar binding affinities for blood coagulation factor Xa. The compound 3-[6-(2′-dimethylaminomethyl-biphenyl-4-yl)-7-oxo-3-trifluoro-methyl-4,5,6,7-tetrahydro-pyrazolo[3,4-c]pyridine-l-yl]-benzamide 6d shows good fXa potency, selectivity, in vivo efficacy and oral bioavailability. Compound 6d was selected for further pre-clinical evaluations.
- Pinto, Donald J.P.,Galemmo Jr., Robert A.,Quan, Mimi L.,Orwat, Michael J.,Clark, Charles,Li, Renhua,Wells, Brian,Woerner, Francis,Alexander, Richard S.,Rossi, Karen A.,Smallwood, Angela,Wong, Pancras C.,Luettgen, Joseph M.,Rendina, Alan R.,Knabb, Robert M.,He, Kan,Wexler, Ruth R.,Lam, Patrick Y.S.
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p. 5584 - 5589
(2007/10/03)
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- Glycinamides as factor Xa inhibitors
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The present application describes glycinamidic compounds and derivatives thereof, or pharmaceutically acceptable salt forms thereof, which are useful as inhibitors of factor Xa.
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