Preparation of biphenyl isoxazole sulfonamides and intermediates

摘要

Compound and salts of formula II and IIa wherein the phenyl ring may be further substituted and where 'prot' denotes a nitrogen-protecting group and wherein one of X and Y is N and the other is O, R3 and R4 are each directly bonded to a ring carbon and are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy, any of which may be substituted with Z1, Z2 and Z3, halo, hydroxyl, cyano, nitro, C(O)H or C(O)R5, CO2H or CO2R5, Z4NR6R7, Z4N(R10)Z5NR8R9 or R3 and R4 together may also be alkylene or alkenylene, optionally substituted with Z1, Z2 and Z3, completing a 4 to 8 membered saturated, unsaturated or aromatic ring together with the carbon atoms to which they are attached, R5 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl or aralkyl, any of which may be substituted with Z1, Z2 and Z3, R6, R7 R8, R9 and R10 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, optionally substituted with Z1, Z2 and Z3 or R6 and R7 together may be alkylene or alkenylene optionally substituted with Z1, Z2 and Z3, completing a 3 to 8 membered saturated or unsaturated ring together with the nitrogen atom to which they are attached or any two of R8, R9 and R10 together are alkylene or alkenylene, optionally substituted with Z1, Z2 and Z3, completing a 3 to 8 membered saturated or unsaturated ring together with the atoms to which they are attached, Z1, Z2 and Z3 are each independently hydrogen, halo, hydroxy, alkyl, alkenyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, heterocycle, substituted heterocycle or heterocyclooxy, SH, S(O)nZ6, S(O)mOH, S(O)mOZ6, OS(O)mZ6, OS(O)mOH or OS(O)mOZ6, oxo, nitro, cyano, C(O)H or C(O)Z6, CO2H or CO2Z6, Z4NZ7Z8, Z4N(Z11)Z5H, Z4N(Z11)Z5Z6, or 4N(Z11)Z5NZ7Z8, Z4 and Z5 are each independently a single bond, Z9S(O)nZ10, Z9C(O)Z10, Z9C(S)Z10, Z9OZ10, Z9SZ10, Z9OC(O)Z10, or Z9C(O)OZ10, Z6 is alkyl, alkyl substituted with one to three groups selected from halogen, aryl, aryloxy and alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkyl substituted with one to three groups selected from alkyl, aryl, alkenyl and alkoxyaryl, cycloalkyl to which is fused a benzene ring, aryloxy substituted with one or two halogens, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryl substituted with methylenedioxy or one to four groups selected from alkyl, dialkylamino, cyano, halogen, trihaloalkyl, alkoxy and trihaloalkoxy; or heterocycle or substituted heterocycle, Z7 and Z8 are each independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl, or Z7 and Z8 together are alkylene or alkenylene, completing a 3 to 8 membered saturated or unsaturated ring together with the nitrogen atom to which they are attached, Z9 and Z10 are each independently a single bond, alkylene, alkenylene or alkynylene, Z11 is hydrogen; alkyl, alkyl substituted with one, two or three halogens, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, aryl or aralkyl; or any two of Z7 Z8 and Z11 together are alkylene or alkenylene, completing a 3 to 8 membered saturated or unsaturated ring together with the atoms to which they are attached, R13 and R14 are each independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, aryloxy, aralkyl or aralkoxy any of which may be substituted with Z1, Z2 and Z3, heterocycle, substituted heterocycle or heterocyclooxy, halo, hydroxyl, cyano, nitro, C(O)H or C(O)R5, CO2H or CO2R5, SH, S(O)nR5, S(O)mOH, S(O)mOR5, OS(O)mOR5, OS(O)mOH or OS(O)mOR5, Z4NR6R7 or Z4N(R10)Z5NR8R9, m is independently 1 or 2 and each n is independently 0, 1 or 2. Methods for the preparation of these compounds and their intermediates are also described. These compounds are useful, inter alia, for the treatment of hypertension.