LEUKOTRIENE ANTAGONISTS

摘要

This invention provides novel benzene derivatives which are leukotriene antagonists, formulations of those derivatives, intermediates for preparing the derivatives, and a method of using those derivatives for the treatment of conditions characterized by an excessive release of leukotxienes. More specifically the invention as disclosed provides compounds of the Formula I and pharmaceutically acceptable salts thereof, wherein: R1 is hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl-substituted-(C1-13 alkyl), phenyl, or phenyl substituted with halo, C1-C4 alkyl, or C1-C4 alkoxy; R2 is C1-C10 alkyl, C2-C6 alkenyl, benzyl, or 2-phenylethyl; R3 is hydrogen, bromo, or chloro; Z is -O , -NR-, or , or when taken together, m is 0-4; A is a bond, -o-, -NR, -?-'', or -CHOH-; n is 0-4, Q is a bond, -O-, , or -NR " -; and R4 is -CN, hydroxy, -SC(=NH)NH2, -NR14-R15, or ; where each of R, R', and R'' is independently hydrogen or C1-C3 alkyl; each of R5 and R6 is independently hydrogen, C1-C3 alkyl, phenyl, or benzyl; R9 is hydroxy, Cl-C4 alkoxy, -NHOH, or -NR14R15; R10 is hydrogen, hydroxy, C1-C4 alkoxy, halo, C1-C4 alkyl, amino, mono- or di-(C1-C3 alkyl)amino, or (C1-C3 alkyl)CONH-; R11 is - (CR16R17) r-COR9, -O-(CR16R17)s-COR9, -(CR16R17)r-T-CN, -O-(CR16R17)s-T-CN, or ; R12 is hydrogen or C1-C3 alkyl; R13 is hydrogen or methyl; each of R14 and R15 is independently hydrogen, C1-C3 alkyl, or when taken together with the nitrogen atom form a morpholine or N-methyl piperazine ring; each of R16 and R17 is independently hydrogen or C1-C3 alkyl; r is 0-4; s is 1-4; T is a bond or -S-, W is a bond, -o-, -NR'''-, or ; R''' is hydrogen or C1-C3 alkyl; and p is 0, 1, or 2; provided that: (a) when R4 is -CN, -COR9, hydroxy, -NR11R12, or -SC(=NH3~2, Q may only be a bond and n may not be 0; (b) when A is -O-, , -NR'-, or -CHOH-, and Z is -o-,, or -NR-, m may not be 0; (c) when A is -o-,, -NR'-, or -CHOH-, and Q is -O-,, or -NR " -, n may not be 0; (d) when Z is -O-, , or -NR-, Q is -O-, , or NR " -, and A is a bond, m and n may not both be 0; and (e) if A is (1) when Z is m may not be 0, (2) when Q is , n may not be 0, and (3) when Z is -C- or -NR- and Q is -O- or -NR " -, m and n may not both be 0. Also provided are certain intermediates useful in preparing the compounds of Formula I. These compounds have the general formula XVI wherein R1, R2, R3, R5, and R6 are the same as previously defined and G is halo, hydroxy, thiol, -NR18R19, or -P(C6H5)3X', where each of R18 and R19 is independently hydrogen or C1-C3 alkyl, and X' is halo.