Patent ID: 6677369
Filing Date: 2004-01-13
Classification: A61K,A61P,C07C,C07D

Abstract:
A method of inhibiting factor Xa in a mammal comprising administering to a mammal in need of treatment, a factor Xa inhibiting amount of a compound of formula I whereinA3, A4, A5 and A6, together with the two carbons to which they are attached, complete a substituted heteroaromatic ring in which two adjacent residues of A3, A4, A5 and A6 together form S, and each of the others is CR3, CR4, CR5 or CR6, respectively; wherein each of R3, R4, R5 and R6 is hydrogen, or one or two of R3, R4, R5 and R6 is independently chloro, bromo or methyl and the others are hydrogen; L1 is â€”NHâ€”COâ€”, â€”COâ€”NHâ€” or â€”Oâ€”CH2â€” such that â€”L1â€”Q1 is â€”NHâ€”COâ€”Q1, â€”COâ€”NHâ€”Q1 or â€”Oâ€”CH2â€”Q1 (provided that when â€”L1â€”Q1 is â€”COâ€”NHâ€”Q1, then R2 is not â€”COâ€”NHâ€”Q1 or â€”COâ€”NHâ€”Q2B); Q1 is Q1A, Q1B or Q1C wherein Q1A is in which Ra is hydrogen, Rb is hydrogen and Rc is hydrogen or hydroxy; or Ra is hydroxy, Rb is hydrogen and Rc is hydrogen; or Ra and Rb together form a methylene or oxo group and Rc is hydrogen;Q1B is in which Rd is hydrogen or hydroxy and Re is hydrogen or fluoro; andQ1C is â€ƒR2 is a residue defined for â€”NHâ€”COâ€”Q1 or â€”COâ€”NHâ€”Q1; or R2 is â€”L2Aâ€”Q2A, â€”L2Bâ€”Q2B, â€”L2Câ€”Q2C or â€”L2Dâ€”Q2D wherein L2A is a direct bond; and Q2A is in which D is carbonyl or â€”CHRkâ€” in which Rk is hydrogen, hydroxy, (1-6C)alkoxy or â€”CH2â€”Rj in which Rj is carboxy, [(1-4C)alkoxy]carbonyl or carbamoyl which may bear one or two (1-2C)alkyl substituents on the nitrogen; and one of Rm and Rn is hydrogen and the other is amino, bromo, (1-4C)alkyl or (1-4C)alkoxy, or Rm and Rn together form a benz ring;L2B is â€”NHâ€”COâ€”, â€”COâ€”NHâ€”, â€”Oâ€”COâ€”, â€”CH2â€”Oâ€” or â€”Oâ€”CH2â€” such that â€”L2Bâ€”Q2B is â€”NHâ€”COâ€”Q2B, â€”COâ€”NHâ€”Q2B, â€”Oâ€”COâ€”Q2B, â€”CH2â€”Oâ€”Q2B or â€”Oâ€”CH2â€”Q2B; and Q2B is in which Ro is hydrogen, halo, (1-6C)alkyl, (1-4C)alkoxy, benzyloxy or (1-4C)alkylthio; and Rp is 1-hydroxyethyl, 1-hydroxy-1-methylethyl, 1-methoxy-1-methylethyl, 4-piperidinyl, 4-pyridinyl, dimethylaminosulfonyl or â€”Jâ€”Rq in which J is a single bond, methylene, carbonyl, oxo, â€”S(O)qâ€” (wherein q is 0, 1 or 2), or â€”NRrâ€” (wherein Rr is hydrogen or methyl); and Rq is (1-6C)alkyl, phenyl, 3-pyridyl or 4-pyridyl;L2C is â€”NRvâ€”COâ€”Xâ€”, â€”NRvâ€”CSâ€”Yâ€”, â€”CH2â€”COâ€”NRwâ€”CH2â€”, â€”Oâ€”COâ€”, â€”Oâ€”CH2â€”, â€”Sâ€”CH2â€” or â€”CH2â€”NRxâ€”CH2â€” such that â€”L2Câ€”Q2C is â€”NRvâ€”COâ€”Xâ€”Q2C, â€”NRvâ€”CSâ€”Yâ€”Q2C, â€”CH2â€”COâ€”NRwâ€”CH2â€”Q2C, â€”Oâ€”COâ€”Q2C, â€”Oâ€”CH2â€”Q2C, â€”Sâ€”CH2â€”Q2C or â€”CH2â€”NRxâ€”CH2â€”Q2C in which X is â€”(CH2)xâ€” (wherein x is 0, 1 or 2), â€”NRwâ€”CH2â€”, â€”Oâ€”CH2â€” or â€”Sâ€”CH2â€”; Y is â€”NRwâ€”CH2â€” or â€”Oâ€”CH2â€”; each of Rv and Rw is independently hydrogen, benzyl or (1-6C)alkyl which is not branched at the &agr;-position; and Rx is hydrogen, benzyloxycarbonyl or [(1-4C)alkoxy]carbonyl; and Q2C is 1-(4-pyridyl)piperidin-4-yl in which the pyridyl may bear a substituent at its 2-position selected from cyano, aminomethyl, carboxy, hydroxymethyl and (1-2C)alkyl; L2D is â€”NHâ€”COâ€” such that â€”L2Dâ€”Q2D is â€”NHâ€”COâ€”Q2D; and Q2D is selected from 4-(4-pyridinyl)benzyloxy, 9-oxo-9H-fluoren-3-yl, benzo[b]thiophen-2-yl (which may bear a chloro, methyl or methoxy substituent), benzofuran-2-yl (which may bear a chloro, methyl or methoxy substituent), 4-(4-morpholinyl)-4-oxobutyl, and 4-piperidinyl bearing a substituent at the 1-position selected from methylsulfonyl, phenylsulfonyl and â€”CH2â€”Rz in which Rz is isopropyl, cyclopropyl, phenyl, furyl, thienyl, 2-thiazolyl, or pyridyl in which the phenyl may bear one or two substituents independently selected from halo, cyano, hydroxy, methoxy, acetoxy, benzyloxy, amino, acetylamino, nitro and 3,4-methylenedioxy, and the thienyl or furyl may bear a methyl or nitro substiutent; or a prodrug of the compound of formula I; or a pharmaceutically acceptable salt of the compound of formula I or prodrug thereof.