PLASMINOGEN ACTIVATOR INHIBITOR-1 INHIBITOR

摘要

The present invention provides a novel compound having plasminogen activator inhibitor-1 inhibitory activity, and an inhibitor of PAI-1 comprising the compound as an active ingredient. The present invention also provides a pharmaceutical composition having an inhibitory action on PAI-1 activity and being efficacious in the prevention and treatment of various diseases whose onset is associated with PAI-1 activity.

主权项

1. A method for treating or preventing a disease whose development is attributed to PAI-1 activity, the method comprising administering a subject being affected or potentially affected with the disease an effective amount of the compound represented by Formula (I), a salt, or a solvate thereof in a combination with a pharmacologically acceptable carrier or additive thereof: wherein —R1 and R2 are the same or different, and each represents hydrogen, halogen, C1-6-alkyl, C3-8-cycloalkyl, C3-8-cycloalkyl-C1-6-alkyl, C3-8-cycloalkenyl, C2-6-alkynyl, C3-8-cycloalkyl-C2-6-alkynyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; —X represents —CH═CH—; -A represents a group shown in any of the following (a) to (e): (a) a group represented by the following Formula (II): wherein R3 and R4 are the same or different, and each represents hydrogen, substituted or unsubstituted C1-6-alkyl, or CF3; T represents a single bond, substituted or unsubstituted C1-3-alkylene, oxygen, —CO—, —O—C1-3-alkylene, or C2-6-alkynylene; D represents substituted or unsubstituted aryl, heteroaryl, or benzo-condensed heteroaryl; substituted or unsubstituted C3-8-cycloalkyl or heterocycloalkyl; substituted or unsubstituted C3-8-cycloalkenyl or heterocycloalkenyl; or adamantyl; q is an integer 1; provided that when, in Formula (I), L is substituted or unsubstituted C1-6-alkylene-NHCO— and T is a single bond, D is not unsubstituted phenyl; (b) a group represented by any of the Following Formulae (III) to (V) wherein, in Formulae (III) to (V) above, R5 represents hydrogen or halogen; R6 represents hydrogen, C1-6-alkyl, or C1-6-hydroxyalkyl; E represents a single bond or —O—C1-6-alkylene; Ar represents substituted or unsubstituted aryl or heteroaryl; and q is an integer 1; (c) a group represented by the following Formula (VI) wherein Y represents sulfur or oxygen, and E and Ar are as defined above; (d) a group represented by the following Formula (VII) wherein G represents hydrogen or C1-6-alkyl; -L represents a single bond, substituted or unsubstituted C1-6-alkylene (some carbon atoms in the alkylene optionally form a cycloalkyl ring), substituted or unsubstituted C1-6-alkylene —O-(some carbon atoms in the alkylene optionally form a cycloalkyl ring), substituted or unsubstituted C2-6-alkenylene, substituted or unsubstituted C2-6-alkynylene, —CO—, 1,4-piperazidinyl, C1-6-alkylene-1,4-piperazidinyl, adamantylene, or a group represented by the following Formula (IX): wherein, in (CH2)n one or more carbons are optionally substituted and may form cycloalkyl with a substituent of the carbon, provided that m is an integer 0 or 1, and n is an integer 0 to 2); —B is COOR9 wherein R9 represents hydrogen; or a group converted to hydrogen in vivo, which is selected from the group consisting of C1-6-alkyl, aryl, aralkyl, —CH(R10)—O—CO—R11, —CH(R10)—O—CO—OR11, and a (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl group represented by the following formula: wherein R10 is hydrogen or C1-6-alkyl, R11 is C1-6-alkyl or C3-8-cycloalkyl, and R12 is C1-6 alkyl; or a heterocyclic group represented by any of the following Formulae (XI)-(XIII): wherein Z represents oxygen or sulfur.