Use of TAFI inhibitors for enhanced myocardial reperfusion and facilitated PCI

A method of enhancing myocardial reperfusion and facilitating PCI comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (II) or a pharmaceutically acceptable salt thereof:

• wherein:
• R1 is hydrogen, alkyl, alkenyl, aryl or aralkenyl;
• R2 is —P(O)(OR5)2, —P(O)(O R5)R6, —P(O)(OR5)—R7—N(R6)2, —P(O)(OR5)—R7—C(O)—R8, —P(O)(OR5)—R7—N(R5)—C(O)OR8, —P(O)(OR5)—R7—N(R5)—C(O)—R7—N(R5)—C(O)OR8, —P(O)(OR5)—R7—N(R5)—S(O)2—R9, or —P(O)(OR5)—R7—N(R5)—C(S)—N(R6)2;
• R3 is tetrazole, —C(O)OR6, —C(O)O—R7—OC(O)R5, —S(O)OR5, —S(O)2OR5, —P(O)(OR5)2, —P(O)(OR5)R6, or —B(OR5)2;
• R4 is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, mercapto, alkylthio, phenyl, cycloalkyl, nitro, cyano, —OR6, —N(R6)2, —R7—N(R6)2, —N(R6)—C(O)OR8, —R7—N(R6)—C(O)OR8, —N(R6)—C(O)—R6, —R7—N(R6)—C(O)—R6, —C(O)—N(R6)2, —C(O)—R7—N(R6)2, —N(R5)—C(NR5)—N(R5)2, —N(R5)—C(O)—N(R6)2 and —N(R5)—C(O)—R7—N(R62);
• or R4 is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R6)2, —R7—N(R6)2, —N(R6)—C(O)OR8, —R7—N(R6)C(O)OR8, —N(R6)—C(O)—R6, —R7—N(R6)—C(O)—R6, —C(O)—N(R6)2, —C(O)—R7—N(R6)2, —N(R—N(R5)—C(O)—N(R6)2 or —N(R5)—C(O)—R7—N(R62), or wherein a nitrogen atom in the N-heterocyclyl may be optionally substituted by —C(NR5)—N(R5)2, —C(NR5)—R5, —C(O)—N(R6)2 or —C(O)—R7—N(R6)2;
• each R5 is independently hydrogen, alkyl or aralkyl;
• each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl;
• each R7is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R6)2, —C(O)OR6, or —C(O)N(R6)2), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R6)2, —C(O)OR6, or —C(O)N(R6)2);
• each R3 is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl;
• and
• R9 is —R7N(R6)C(O)OR8, haloalkyl, alkyl (optionally substituted by hydroxy, alkoxy, aralkoxy, haloalkoxy, cyano, nitro, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6), alkenyl (optionally substituted by hydroxy, alkoxy, haloalkoxy, cyano, nitro, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6), aryl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6), aralkyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6), aralkenyl (wherein the aryl group is optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6), or N-heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, hydroxy, alkoxy, cyano, nitro, halo, haloalkoxy, —N(R6)2, —C(O)OR6, —C(O)N(R6)2 or —N(R6)C(O)R6);
• provided that when R3 is —C(O)OH or when R4 is a substituted aryl or substituted N-heterocyclyl,
• R2 can not be —P(O)(OR5)—R7—N(H)—C(O)OR8 or
• —P(O)(OR5)—R7 —N(H)—C(O)—R7—N(R5)—C(O)OR8;
• as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers.

A method of enhancing myocardial reperfusion and facilitating PCI comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (III), or a pharmaceutically acceptable salt thereof:

• wherein:
• X is —CH2— or —O—;
• R1 is hydrogen, alkyl, alkenyl, aryl or aralkenyl;
• R2 is —P(O)(OR5)—R7—N(R5)—C(O)R6, —P(O)(OR5)—R7—N(R5)—C(O)OR8 or —P(O)(OR5)—R7—N(R5)—C(O)—R7—N(R5)—C(O)OR8,
• R3is —C(O)OH;
• R4is aryl optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, mercapto, alkylthio, phenyl, cycloalkyl, nitro, cyano, —OR6, —N(R6)2, —R7—N(R6)2, —N(R6)—C(O)OR8, —R7—N(R6)—C(O)OR8, —N(R6)—C(O)—R6, —R7—N(R6)—C(O)—R6, —C(O)—N(R6)2, —C(O)—R7—N(R6)2, —N(R5)—C(NR5)—N(R5)2, —N(R5)—C(O)—N(R6)2 and —N(R5)—C(O)—R7—N(R62);
• or R4 is N-heterocyclyl wherein a carbon atom in the N-heterocyclyl may be optionally substituted by alkyl, halo, nitro, cyano, —N(R6)2, —R7—N(R6)2, —N(R6)—C(O)OR8, —R7—N(R6)—C(O)OR8, —N(R6)—C(O)—R6, —R7—N(R6)—C(O)—R6, —C(O)—N(R6)2, —C(O)—R7—N(R6)2, —N(R5)—C(NR5)—N(R5)2, —N(R5)—C(O)—N(R6)2 or —N(R5)—C(O)—R7—N(R62), or wherein a nitrogen atom in the
• N-heterocyclyl may be optionally substituted by —C(NR5)—N(R5)2, —C(NR5)—R6, —C(O)—N(R6)2 or —C(O)—R7—N(R6)2;
• each R5 is independently hydrogen, alkyl or aralkyl;
• each R6 is independently hydrogen, alkyl, alkenyl, alkynyl, aryl, aralkyl or aralkenyl;
• each R7 is independently cycloalkylene (optionally substituted by alkyl), a straight or branched alkylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R6)2, —C(O)OR6, or —C(O)N(R6)2), or a straight or branched alkenylene chain (optionally substituted by hydroxy, mercapto, alkylthio, aryl, cycloalkyl, —N(R6)2, —C(O)OR6, or —C(O)N(R6)2);
• and
• each R8 is independently alkyl, alkenyl, aryl, aralkyl or aralkenyl;
• as a single stereoisomer, a mixture of stereoisomers, or as a racemic mixture of stereoisomers.