Piperazino-dihydrothienopyrimidine derivatives
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
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 or SO 2 ,
R 1 is H or C 1-6 -alkyl,
R 2 is H or a group selected from C 1-10 -alkyl and C 2-6 -alkenyl, each optionally substituted by one or more groups selected from halogen and C 1-3 -fluoroalkyl or optionally substituted by one or more groups selected from OR 2.1 , COOR 2.1 , CONR 2.2 R 2.3 , SR 2.1 , SO—R 2.1 , SO 2 —R 2.1 , C 6-10 -aryl, a het, a hetaryl, a mono- or bicyclic C 3-10 -cycloalkyl, CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, halogen, OR 2.1 , oxo, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 1-6 -alkanol, C 6-10 -aryl, COOR 2.1 , CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 ,
R 2 is a mono- or polycyclic C 3-10 cycloalkyl optionally mono- or poly-bridged via C 1-3 -alkyl groups and optionally substituted by a group selected from branched or unbranched C 1-6 -alkanol, C 1-3 -fluoroalkyl, C 1-3 -alkylene-OR 2.1 , OR 2.1 , COOR 2.1 , SO 2 —NR 2.2 R 2.3 , het, C 6-10 -aryl, C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, mono- or bicyclic C 3-10 cycloalkyl, and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 ,
R 2 is a mono- or polycyclic C 6-10 -aryl optionally substituted by OH, SH, or halogen or by one or more groups selected from OR 2.1 , COOR 2.1 , NR 2.2 R 2.3 , CH 2 —NR 2.2 R 2.3 ,C 3-10 -cycloalkyl, het, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 6-10 -aryl-C 1-6 -alkylene, het-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, C 6-10 -aryl, SO 2 —CH 3 , SO 2 —CH 2 CH 3 , and SO 2 —NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 ,
R 2 is a group selected from a het and a hetaryl, each optionally substituted by one or more groups selected from halogen, OH, oxo, CF 3 , CHF 2 , and CH 2 F or by one or more groups selected from OR 2.1 , C 1-3 -alkylene-OR 2.1 , SR 2.1 , SO—R 2.1 , SO 2 —R 2.1 , COOR 2.1 , COR 2.1 , C 1-6 -alkanol, C 3-10 -cycloalkyl, C 6-10 -aryl, C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, het, hetaryl, C 1-3 -alkylene-OR 2.1 , and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 , or
NR 1 R 2 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, OR 2.1 , C 1-3 -alkylene-OR 2.1 , oxo, halogen, C 1-6 -alkyl, C 6-10 -aryl, COOR 2.1 , CH 2 —NR 2.2 —COO—R 2.1 , CH 2 —NR 2.2 —CO—R 2.1 , CH 2 —NR 2.2 —CO—CH 2 —NR 2.2 R 2.3 , CH 2 —NR 2.2 —SO 2 —C 1-3 -alkyl, CH 2 —NR 2.2 —SO 2 —NR 2.2 R 2.3 , CH 2 —NR 2.2 —CO—NR 2.2 R 2.3 , CO—NR 2.2 R 2.3 , CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 ,
R 3 is a group selected from a mono- or bicyclic C 6-10 -aryl, a het, and a hetaryl, each optionally substituted by one or more groups selected from halogen, —C 1-3 -alkyl, cyclopropyl, —C 1-3 -fluoroalkyl, —C 1-3 -alkylene-OR 2.1 , —OH, and —O—C 1-3 -alkyl,
R 4 is H, C 1-6 -alkyl, F, C 1-3 -fluoroalkyl, (C 1-6 -alkylene)-OH, (C 1-6 -alkylene)-OCH 3 , (C 1-6 -alkylene)-NH 2 , (C 1-6 -alkylene)-NH(C 1-3 -alkyl), or (C 1-6 -alkylene)-N(C 1-3 -alkyl) 2 ,
R 4′ is H or F, and
R 5 is H, F, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH 3 , C 1-6 -alkylene-NH 2 , C 1-6 -alkylene-NH(C 1-3 -alkyl), or C 1-6 -alkylene-N(C 1-3 -alkyl) 2 , and R 6 and R 7 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from —CH 3 , —OH, —F, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3 -alkyl), —N(C 1-3 -alkyl) 2 , and O—(C 1-3 -alkyl), or
R 7 is H, F, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH 3 , C 1-6 -alkylene-NH 2 , C 1-6 -alkylene-NH(C 1-3 -alkyl), or C 1-6 -alkylene-N(C 1-3 -alkyl) 2 , and R 5 and R 6 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from CH 3 , —OH, —F, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3 -alkyl), —N(C 1-3 -alkyl) 2 , and OCH 3 ,
wherein:
R 2.1 is H or a group selected from C 1-6 -alkyl, C 1-6 -alkanol, C 1-3 -fluoroalkyl, mono- or bicyclic C 3-10 cycloalkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, het-C 1-6 -alkylene, C 3-10 -cycloalkyl-C 1-6 -alkylene, a mono- or bicyclic C 6-10 -aryl, a hetaryl, and a het, each optionally substituted by one or more groups selected from OH, O—(C 1-3 -alkyl), halogen, C 1-6 -alkyl, and C 6-10 -aryl,
R 2.2 and R 2.3 are each independently H or a group selected from C 1-6 -alkyl, mono- or bicyclic C 3-10 -cycloalkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, mono- or bicyclic C 6-10 -aryl, a het, a hetaryl, CO—NH 2 , CO—NH(CH 3 ), CO—N(CH 3 ) 2 , SO 2 —(C 1-2 -alkyl), CO—R 2.1 , and COOR 2.1 , each optionally substituted by one or more groups selected from OH, halogen, C 1-6 -alkyl, C 6-10 -aryl, and COOR 2.1 ,
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.
2. A method for treating chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), rheumatoid arthritis, Crohn's disease, multiple sclerosis and atopic dermatitis 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 or SO 2 ,
R 1 is H or C 1-6 -alkyl,
R 2 is H or a group selected from C 1-10 -alkyl and C 2-6 -alkenyl, each optionally substituted by one or more groups selected from halogen and C 1-3 -fluoroalkyl or optionally substituted by one or more groups selected from OR 2.1 , COOR 2.1 , CONR 2.2 R 2.3 , SR 2.1 , SO—R 2.1 , SO 2 —R 2.1 , C 6-10 -aryl, a het, a hetaryl, a mono- or bicyclic C 3-10 -cycloalkyl, CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, halogen, OR 2.1 , oxo, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 1-6 -alkanol, C 6-10 -aryl, COOR 2.1 , CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 ,
R 2 is a mono- or polycyclic C 3-10 cycloalkyl optionally mono- or poly-bridged via C 1-3 -alkyl groups and optionally substituted by a group selected from branched or unbranched C 1-6 -alkanol, C 1-3 -fluoroalkyl, C 1-3 -alkylene-OR 2.1 , OR 2.1 , COOR 2.1 , SO 2 —NR 2.2 R 2.3 , het, C 6-10 -aryl, C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, mono- or bicyclic C 3-10 cycloalkyl, and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 ,
R 2 is a mono- or polycyclic C 6-10 -aryl optionally substituted by OH, SH, or halogen or by one or more groups selected from OR 2.1 , COOR 2.1 , NR 2.2 R 2.3 , CH 2 —NR 2.2 R 2.3 ,C 3-10 -cycloalkyl, het, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 6-10 -aryl-C 1-6 -alkylene, het-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, C 6-10 -aryl, SO 2 —CH 3 , SO 2 —CH 2 CH 3 , and SO 2 —NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 ,
R 2 is a group selected from a het and a hetaryl, each optionally substituted by one or more groups selected from halogen, OH, oxo, CF 3 , CHF 2 , and CH 2 F or by one or more groups selected from OR 2.1 , C 1-3 -alkylene-OR 2.1 , SR 2.1 , SO—R 2.1 , SO 2 —R 2.1 , COOR 2.1 , COR 2.1 , C 1-6 -alkanol, C 3-10 -cycloalkyl, C 6-10 -aryl, C 1-6 -alkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, het, hetaryl, C 1-3 -alkylene-OR 2.1 , and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, halogen, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, C 6-10 -aryl, and NR 2.2 R 2.3 , or
NR 1 R 2 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, OR 2.1 , C 1-3 -alkylene-OR 2.1 , oxo, halogen, C 1-6 -alkyl, C 6-10 -aryl, COOR 2.1 , CH 2 —NR 2.2 —COO—R 2.1 , CH 2 —NR 2.2 —CO—R 2.1 , CH 2 —NR 2.2 —CO—CH 2 —NR 2.2 R 2.3 , CH 2 —NR 2.2 —SO 2 —C 1-3 -alkyl, CH 2 —NR 2.2 —SO 2 —NR 2.2 R 2.3 , CH 2 —NR 2.2 —CO—NR 2.2 R 2.3 , CO—NR 2.2 R 2.3 , CH 2 —NR 2.2 R 2.3 , and NR 2.2 R 2.3 ,
R 3 is a group selected from a mono- or bicyclic C 6-10 -aryl, a het, and a hetaryl, each optionally substituted by one or more groups selected from halogen, —C 1-3 -alkyl, cyclopropyl, —C 1-3 -fluoroalkyl, —C 1-3 -alkylene-OR 2.1 , —OH, and —O—C 1-3 -alkyl,
R 4 is H, C 1-6 -alkyl, F, C 1-3 -fluoroalkyl, (C 1-6 -alkylene)-OH, (C 1-6 -alkylene)-OCH 3 , (C 1-6 -alkylene)-NH 2 , (C 1-6 -alkylene)-NH(C 1-3 -alkyl), or (C 1-6 -alkylene)-N(C 1-3 -alkyl) 2 ,
R 4′ is H or F, and
R 5 is H, F, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH 3 , C 1-6 -alkylene-NH 2 , C 1-6 -alkylene-NH(C 1-3 -alkyl), or C 1-6 -alkylene-N(C 1-3 -alkyl) 2 , and R 6 and R 7 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from —CH 3 , —OH, —F, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3 -alkyl), —N(C 1-3 -alkyl) 2 , and O—(C 1-3 -alkyl), or
R 7 is H, F, C 1-6 -alkyl, C 1-3 -fluoroalkyl, C 1-6 -alkylene-OH, C 1-6 -alkylene-OCH 3 , C 1-6 -alkylene-NH 2 , C 1-6 -alkylene-NH(C 1-3 -alkyl), or C 1-6 -alkylene-N(C 1-3 -alkyl) 2 , and R 5 and R 6 together form a bridge selected from methylene, ethylene, and propylene, each optionally substituted by a group selected from CH 3 , —OH, —F, —CF 3 , —CHF 2 , —CH 2 F, —NH 2 , —NH(C 1-3 -alkyl), —N(C 1-3 -alkyl) 2 , and OCH 3 ,
wherein:
R 2.1 is H or a group selected from C 1-6 -alkyl, C 1-6 -alkanol, C 1-3 -fluoroalkyl, mono- or bicyclic C 3-10 cycloalkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, het-C 1-6 -alkylene, C 3-10 -cycloalkyl-C 1-6 -alkylene, a mono- or bicyclic C 6-10 -aryl, a hetaryl, and a het, each optionally substituted by one or more groups selected from OH, O—(C 1-3 -alkyl), halogen, C 1-6 -alkyl, and C 6-10 -aryl,
R 2.2 and R 2.3 are each independently H or a group selected from C 1-6 -alkyl, mono- or bicyclic C 3-10 -cycloalkyl, C 6-10 -aryl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, mono- or bicyclic C 6-10 -aryl, a het, a hetaryl, CO—NH 2 , CO—NH(CH 3 ), CO—N(CH 3 ) 2 , SO 2 —(C 1-2 -alkyl), CO—R 2.1 , and COOR 2.1 , each optionally substituted by one or more groups selected from OH, halogen, C 1-6 -alkyl, C 6-10 -aryl, and COOR 2.1 ,
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.
3. The method according to claim 1 , wherein:
R 2 is a group selected from monocyclic, saturated three-, four-, five-, six- or seven-membered heterocyclic groups with 1, 2, or 3 heteroatoms in each case selected from N, O, and S, each optionally substituted by one or more groups selected from fluorine, OH, CF 3 , CHF 2 , CH 2 F, and oxo or by one or more groups selected from OR 2.1 , C 1-3 -alkylene-OR 2.1 , SR 2.1 , SO—R 2.1 , SO 2 —R 2.1 , COOR 2.1 , COR 2.1 , C 1-6 -alkanol, C 3-10 -cycloalkyl, phenyl, C 1-6 -alkyl, phenyl-C 1-6 -alkylene, hetaryl-C 1-6 -alkylene, het, hetaryl, and NR 2.2 R 2.3 , each optionally substituted by one or more groups selected from OH, OR 2.1 , oxo, F, Cl, CF 3 , CHF 2 , CH 2 F, C 1-6 -alkyl, phenyl, and NR 2.2 R 2.3 ,
and the pharmacologically acceptable salts thereof.
4. The method according to claim 3 , wherein:
R 2 is a group selected from a monocyclic, saturated six-membered heterocyclic group with at least one heteroatom selected in each case from N, O, and S, each optionally be substituted by one or more groups selected from F, CF 3 , CHF 2 , CH 2 F, OH, oxo, NH 2 , NHCH 3 , N(CH 3 ) 2 , methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, and ethoxy,
and the pharmacologically acceptable salts thereof.
5. The method according to claim 4 , wherein:
R 2 is a group selected from piperidine or tetrahydropyran, each optionally substituted by one or more groups selected from F, OH, CF 3 , CHF 2 , CH 2 F, NH 2 , NHCH 3 , N(CH 3 ) 2 , oxo, methyl, and methoxy,
and the pharmacologically acceptable salts thereof.
6. The method according to claim 1 , wherein:
R 3 is a group selected from the group comprising a phenyl optionally substituted by one or more groups selected from F, Cl, Br, methyl, ethyl, propyl, isopropyl, cyclopropyl, C 1-3 -fluoroalkyl, C 1-3 -alkanol, OH, and O—C 1-3 -alkyl,
and the pharmacologically acceptable salts thereof.
7. The method according to claim 1 , wherein:
R 4 is H or methyl, and
R 4 . is H,
and the pharmacologically acceptable salts thereof.
8. The method according to claim 1 , wherein:
R 6 and R 7 together form a bridge selected from among methylene and ethylene, or wherein
R 5 and R 6 together form a bridge selected from among methylene and ethylene, and the pharmacologically acceptable salts thereof.
9. The method according to claim 1 , wherein the compound of formula 1 is selected from:
and the pharmacologically acceptable salts thereof.