Heterocycle-substituted piperazino-dihydrothienopyrimidines

摘要

Dihydrothienopyrimidinesulphoxides of formula 1;
wherein X is SO or SO2, R1 is H or C1-6-alkyl, R2 is H or an organic group as disclosed herein, and R3 is an optionally substituted, mono- or bicyclic, unsaturated, partially saturated or saturated heterocycle or an optionally substituted, mono- or bicyclic heteroaryl, and the pharmacologically acceptable salts thereof, as well as pharmaceutical compositions which contain these compounds. These dihydrothienopyrimidinesulphoxides are suitable for the treatment of respiratory or gastrointestinal complaints or diseases, inflammatory diseases of the joints, skin or eyes, diseases of the peripheral or central nervous system, or cancers.

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 1: wherein: X is SO, R1 is H, R2 is H or C1-10-alkyl 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, COOR2.11, CH2—NR2.2R2.3, and NR2.2R2.3, R2 is a mono- or polycyclic C3-10 cycloalkyl optionally bridged one or more times by 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 be 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, CF3, CHF2, CH2F, oxo, halogen, CF3, CHF2, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or R2 is a group selected from het and 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, C1-5-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, CHF, CH2F, C1-6-alkyl, C6-10-aryl, and NR2.2R2.3, or NR1R2 together are 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-OR1, oxo, halogen, C1-6-alkyl, C6-10-aryl, COOR2.1, CH2—NR2.2COO—R2.1, CH2—NR2.2—CO—R2.1, CH2—NR2.2CO—CH2—NR2.2—SO2—NR2.2R2.3, CH2—NR2.2—CO—NR2.2—CO—NR2.2R2.3, CO—NR2.2R2.3, CH2—NR2.2R2.3 and NR2.2R2.3, and R3 is a bicyclic 9- or 11-membered saturated, unsaturated, or partially saturated heterocycle optionally substituted by one or mom groups selected from F, Cl, Br, CF3 CHF2, CH2F, CN, OH, oxo, methyl, ethyl, propyl, iso-propyl, O-methyl, O-ethyl, —COOmethyl, —COOethyl, SO2—(CH3), SO—(CH3), SO2—(CH2CH3), SO—(CH2CH3), phenyl, -methylene-phenyl, -ethylene-phenyl, —NH2, —NH(CH3), N(CH3)2, -methylene-NH2, -methylene-NH(CH3), -methylene-N(CH3)2, a —C3-6-cycloalkyl, a -methylene-C3-6-cycloalkyl, a saturated, partially unsaturated or unsaturated 5- to 6-membered heterocycle, a 5- to 6-membered heteroaryl, -methylene-hetaryl, methylene-het, each optionally substituted by one or more groups selected from OH, F, Cl, Br, CF3, CHF2, CH2F, methyl, ethyl, propyl, isopropyl, phenyl, —COO(CH3), O-methyl, and O-ethyl, wherein: R2.1 is H or a group selected from C1-6-alkyl, C1-6-alkanol, C1-3-haloalkyl, mono- or bicyclic C3-10-cycloalkyl, C6-10-aryl-C1-6-alkylene, mono- or bicyclic 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, het, hetaryl, CO—NH2, CO—NHCH3, CO—N(CH3)2, SO2—(C1-C2alkyl), 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 anellated or optionally bridged heterocycle, which contains 1, 2, 3, or 4 heteroatoms independently selected from N, S, or O, hetaryl is a five- to eleven-membered, mono- or bicyclic, optionally anellated 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.