Loading patent…
AssigneeBristol-Myers Squibb Pharma Company
InventorsDonald J.P. Pinto, Mimi L. Quan, Michael J. Orwat, Yun-Long Li, Wei Han, Jennifer X. Qiao, Patrick Y.S. Lam, Stephanie L. Koch
Estimating the term…
The present application describes lactam-containing compounds and derivatives thereof of Formula I: 1 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.
A compound of Formula I:
Dependencies are inferred from the claim text.
Drawings are temporarily unavailable. Open the PDF at USPTO
From the US filing history. Foreign family members aren’t listed.
Backward citations are indexed for grants only.
Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms:…
Ortho- or peri-condensed with heterocyclic ring systems: the heterocyclic ring system having sulfur as a ring hetero atom, e.g. ticlopidine
Having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid: by carboxylic acids, e.g. acetylsalicylic acid
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
Term end not estimated
This invention relates generally to lactam-containing compounds and derivatives thereof which are inhibitors of trypsin-like serine protease enzymes, especially factor Xa, pharmaceutical compositions containing the same, and methods of using the same as anticoagulant agents for treatment of thromboembolic disorders.
WO94/20460 describes angiotensin II compounds of the following formula: 2
wherein X can be a number of substituents and Het can be a nitrogen-containing heterobicycle. However, WO94/20460 does not suggest Factor Xa inhibition or exemplify compounds like those of the present invention.
Part A. To a solution of 1.91 g of DMAP in 10 mL of methylene chloride was added 1.45 mL of trichloroacetyl chloride at 0° C. After stirring at rt for 30 min, 1.0 g of 1-(4-iodophenyl)-3-(4-morpholinyl)-5,6-dihydro-2(1H)-pyridinone was added. The reaction mixture was refluxed overnight, then quenched with water, extracted with ether. The organic layers were dried over Na2SO4 and concentrated to dryness to provide the crude product that was used in the next step without further purification.
Part B. The crude material from above in a mixture of 20 mL of ether, 1 mL of water and 1 mL of conc. HCl was heated to reflux (oil bath 65° C.) for 3 h. The mixture was then allowed to cool to rt and filtered to collect the product as a solid (0.97 g, 81% in 2 steps). 1H NMR (DMSO-d6, 300 MHz) δ7.79 (2H, d, J=8.7 Hz), 7.25 (2H, d, J=8.7 Hz), 3.89 (2H, t, J=6.2 Hz), 2.92 (2H, t, J=6.2 Hz) ppm.
Part C. A mixture of the “trione” made above (0.5 g, 1.09 mmol), p-methoxyphenylhyrazine HCl salt (0.152 g, 1.09 mmol) in 20 mL of THF was treated with 0.30 mL of triethylamine at rt overnight. To the reaction mixture was added 20 mL of 1N HCl. The resulting mixture was refluxed for 2 h. After cooling to rt, the compound was collected by filtration (0.42 g, 84%). 1H NMR (DMSO-d6, 300 MHz) δ8.78 (1H, s), 8.26 (2H, m), 7.92 (2H, m), 7.72 (2H, m), 7.46 (2H, m), 4.59 (2H, m) 4.09 (3H, s), 3.42 (2H, m) ppm. LRMS (AP+) 462 (M++1).