NOVEL CHROMANE DERIVATIVES, THEIR APPLICATION IN PRODUCTION OF PHARMACEUTIC AGENTS AND PHARMACEUTIC AGENT AS SUCH

摘要

New chroman derivatives (I) are useful for treating e.g. atrial fibrillation, digestive tract ulcers, reflux oesophagitis, diarrhea and arrhythmia, and as diagnostics. They selectively block potassium channels that are opened by cyclic adenosine monophosphate (cAMP), and also the IKs channel in the heart musculature. Chroman compounds of formula (I) and their salts are new. R1, R2 = independently H, CF3, C2F5, C3F7, 1-6C alkyl or phenyl, which is optionally substituted by 1 or 2 F, Cl, Br, I, CF3, NO2, CN, NH2, OH, CH3, C2H5, OCH3, N(CH3)2, sulfamoyl, methylsulfonyl or methylsulfonylamino groups, or R1 and R2 together form a 2-10C alkylene group; R3 = R10-CnH2n-NR11 or R10-CnH2n, where one CH2 group in CnH2n may be replaced by O, CO, S, SO, SO2 or NR12a; R12a = H, CH3 or C2H5; R10 = H, CH3, 3-8C cycloalkyl, CF3, C2F5 or C3F7; n = 0-10; R11 = H or 1-6C alkyl, or R10 and R11 together form a bond, provided that n is not less than 3; Or R3 and R4 together form 4-8C alkylene, one of whose CH2 groups may be replaced by O, CO, S, SO, SO2 or NR12a; R4 = R13-CrH2r; one CH2 group in CrH2r may be replaced by O, CH=CH, C(C, CO, COO, OCO, S, SO, SO2, NR14 or CO-NR14, r = 0-20; R14 = H, 1-3C alkyl, CyH2y-OR12b or CyH2y-NR12b2; R12b = H, CH3 or C2H5; y = 2 or 3; R13 = H, CF3, C2F5, C3F7, 3-8C cycloalkyl, NR15R16, CONR15R16, OR17, COOR17, phenyl or 1-9C N-containing heterocycle, where the last two groups are optionally substituted by 1 or 2 F, Cl, Br, I, CF3, NO2, CN, NH2, OH, CH3, C2H5, OCH3, N(CH3)2, sulfamoyl, methylsulfonyl or methylsulfonylamino groups; R15, R16 = independently H or 1-4C alkyl, or together form (CH2)4 or (CH2)5, in which one CH2 group may be replaced by O, S, NH, N(CH3) or N(benzyl); R17 = H, 1-3C alkyl or CxH2xOR12c; R12c = H, CH3 or C2H5; x = 2 or 3; at least one of R5, R6, R7 and R8 = Y-CsH2s-R18, thienyl, furyl, or a 1-9C N-containing heterocycle, where the furyl, thienyl or N-containing heterocycle are optionally substituted by 1 or 2 F, Cl, Br, I, CF3, NO2, CN, NH2, OH, CH3, C2H5, OCH3, NH(CH3), N(CH3)2, ethylamino, diethylamino, sulfamoyl, methylsulfonyl or methylsulfonylamino groups; Y = O, CO, OCO, S, SO, SO2, SO2O, SO2-NR12d, NR12d or CO-NR12d in which the coupling to the benzene ring is via the left hand atom; R12d = H, CH3 or C2H5; s = 1-6; R18 = phenyl substituted by 1 or 2 NO2, CN, NH2, OH, C2H5, COOH, COOCH3, COOCH2CH3, CONH2 or CON(CH3)2 groups, or R18 = a 1-9C N-containing heterocycle (containing 1 or 2 F, Cl, Br, I, CF3, NO2, CN, NH2, OH, CH3, C2H5, OCH3, N(CH3)2, sulfamoyl, methylsulfonyl or methylsulfonylamino substituents), OR19, SO2R19, NR19R20 or CONR19R20; R19, R20 = independently CtH2t-R21; t = 0-6; R21 = H, 3-8C cycloalkyl, CF3, C2F5, C3F7, NR22R23, OR24, phenyl, thienyl or a 1-9C N-containing heterocycle, where the last three groups are optionally substituted by 1 or 2 F, Cl, Br, I, CF3, NO2, CN, NH2, OH, CH3, C2H5, OCH3, N(CH3)2, sulfamoyl , methylsulfonyl or methanesulfonyl groups; R22, R23 = independently H or 1-3C alkyl, or together form (CH2)4 or (CH2)5, in which one CH2 group may be replaced by O, S, NH, N(CH3) or N(benzyl); R24 = H or 1-3C alkyl; The other R5, R6, R7 and R8 groups are independently H, F, Cl, Br, I, 1-5C alkyl, 3-8C cycloalkyl, CN, CF3, NO2, OR12e or NR12eR12f; R12e, R12f = independently H or 1-4C alkyl; R9 = H, OR12g or OCOR12g; R12g = H or 1-3C alkyl; B = H or R9 and B together form a bond.