Piperazino-dihydrothienopyrimidine derivatives

摘要

A method for treating diseases associated with the inhibition of phosphodiesterase 4 (PDE4) enzyme in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a dihydrothienopyrimidinesulphoxide of formula 1, as well as pharmacologically acceptable salts, diastereomers, enantiomers, racemates, hydrates or solvates thereof;

主权项

1. A method for the inhibition of phosphodiesterase 4 (PDE4) enzyme in a patient comprising administering to the patient in need thereof a therapeutically effective amount of a compound of formula 1wherein:
X is SO or SO2, R1 is H or C1-6-alkyl, R2 is H or a group selected from C1-10-alkyl and C2-6-alkenyl, each optionally substituted by one or more groups selected from halogen and C1-3-fluoroalkyl or optionally substituted by one or more groups selected from OR2.1, COOR2.1, CONR2.2R2.3, SR2.1, SO—R2.1, SO2—R2.1, C6-10-aryl, a het, a hetaryl, a mono- or bicyclic C3-10-cycloalkyl, CH2—NR2.2R2.3, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, halogen, OR2.1, oxo, CF3, CHF2, CH2F, C1-6-alkyl, C1-6-alkanol, C6-10-aryl, COOR2.1, CH2—NR2.2R2.3, and NR2.2R2.3, R2 is a mono- or polycyclic C3-10 cycloalkyl optionally mono- or poly-bridged via C1-3-alkyl groups and optionally substituted by a group selected from branched or unbranched C1-6-alkanol, C1-3-fluoroalkyl, C1-3-alkylene-OR2.1, OR2.1, COOR2.1, SO2—NR2.2R2.3, het, C6-10-aryl, C1-6-alkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C3-10 cycloalkyl, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, R2 is a mono- or polycyclic C6-10-aryl optionally substituted by OH, SH, or halogen or by one or more groups selected from OR2.1, COOR2.1, NR2.2R2.3, CH2—NR2.2R2.3,C3-10-cycloalkyl, het, C1-6-alkyl, C1-3-fluoroalkyl, C6-10-aryl-C1-6-alkylene, het-C1-6-alkylene, hetaryl-C1-6-alkylene, C6-10-aryl, SO2—CH3, SO2—CH2CH3, and SO2—NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, R2 is a group selected from a het and a hetaryl, each optionally substituted by one or more groups selected from halogen, OH, oxo, CF3, CHF2, and CH2F or by one or more groups selected from OR2.1, C1-3-alkylene-OR2.1, SR2.1, SO—R2.1, SO2—R2.1, COOR2.1, COR2.1, C1-6-alkanol, C3-10-cycloalkyl, C6-10-aryl, C1-6-alkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, het, hetaryl, C1-3-alkylene-OR2.1, and NR2.2R2.3, each optionally substituted by one or more groups selected from OH, OR2.1, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or NR1R2 together is a heterocyclic four- to seven-membered ring optionally bridged, which contains 1, 2, or 3 heteroatoms selected from N, O, and S and optionally substituted by one or more groups selected from OH, OR2.1, C1-3-alkylene-OR2.1, oxo, halogen, C1-6-alkyl, C6-10-aryl, COOR2.1, CH2—NR2.2—COO—R2.1, CH2—NR2.2—CO—R2.1, CH2—NR2.2—CO—CH2—NR2.2R2.3, CH2—NR2.2—SO2—C1-3-alkyl, CH2—NR2.2—SO2—NR2.2R2.3, CH2—NR2.2—CO—NR2.2R2.3, CO—NR2.2R2.3, CH2—NR2.2R2.3, and NR2.2R2.3, R3 is a group selected from a mono- or bicyclic C6-10-aryl, a het, and a hetaryl, each optionally substituted by one or more groups selected from halogen, —C1-3-alkyl, cyclopropyl, —C1-3-fluoroalkyl, —C1-3-alkylene-OR2.1, —OH, and —O—C1-3-alkyl, R4 is H, C1-6-alkyl, F, C1-3-fluoroalkyl, (C1-6-alkylene)-OH, (C1-6-alkylene)-OCH3, (C1-6-alkylene)-NH2, (C1-6-alkylene)-NH(C1-3-alkyl), or (C1-6-alkylene)-N(C1-3-alkyl)2, R4′ is H or F, and R5 is H, F, C1-6-alkyl, C1-3-fluoroalkyl, C1-6-alkylene-OH, C1-6-alkylene-OCH3, C1-6-alkylene-NH2, C1-6-alkylene-NH(C1-3-alkyl), or C1-6-alkylene-N(C1-3-alkyl)2, and R6 and R7 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from —CH3, —OH, —F, —CF3, —CHF2, —CH2F, —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, and O—(C1-3-alkyl), or R7 is H, F, C1-6-alkyl, C1-3-fluoroalkyl, C1-6-alkylene-OH, C1-6-alkylene-OCH3, C1-6-alkylene-NH2, C1-6-alkylene-NH(C1-3-alkyl), or C1-6-alkylene-N(C1-3-alkyl)2, and R5 and R6 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from CH3, —OH, —F, —CF3, —CHF2, —CH2F, —NH2, —NH(C1-3-alkyl), —N(C1-3-alkyl)2, and OCH3, wherein: R2.1 is H or a group selected from C1-6-alkyl, C1-6-alkanol, C1-3-fluoroalkyl, mono- or bicyclic C3-10 cycloalkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, het-C1-6-alkylene, C3-10-cycloalkyl-C1-6-alkylene, a mono- or bicyclic C6-10-aryl, a hetaryl, and a het, each optionally substituted by one or more groups selected from OH, O—(C1-3-alkyl), halogen, C1-6-alkyl, and C6-10-aryl, R2.2 and R2.3 are each independently H or a group selected from C1-6-alkyl, mono- or bicyclic C3-10-cycloalkyl, C6-10-aryl-C1-6-alkylene, hetaryl-C1-6-alkylene, mono- or bicyclic C6-10-aryl, a het, a hetaryl, CO—NH2, CO—NH(CH3), CO—N(CH3)2, SO2—(C1-2-alkyl), CO—R2.1, and COOR2.1, each optionally substituted by one or more groups selected from OH, halogen, C1-6-alkyl, C6-10-aryl, and COOR2.1, het is a three- to eleven-membered, mono- or bicyclic, saturated or partially saturated, optionally annelated or optionally bridged heterocyclic group, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, hetaryl is a five- to ten-membered, mono- or bicyclic, optionally annelated heteroaryl, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, and cycloalkyl is saturated or partially saturated,and the pharmacologically acceptable salts thereof.