Drug-eluting stents coated with P2Y12 receptor antagonist compound

A P2Y12 receptor antagonist compound-eluting stent, wherein the stent is coated with one or more P2Y12 receptor antagonist compound of general Formula I, or a pharmaceutically acceptable salt, solvate, or hydrate thereof;

• wherein a therapeutically effective amount of the compound is eluted to the local environment when the stent is placed in a vessel,
• wherein:
• X1, X2, and X3 are independently oxygen, methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, or imido;
• T1, T2, W, and V are independently oxygen or sulfur;
• m=0, 1 or 2;
• n=0 or 1;
• p=0, 1, or 2;
• where the sum of m+n+p is from 0 to 5;
• M=H, or a pharmaceutically-acceptable inorganic or organic counterion;
• D1=O or CH2;
• Y′=H, OH, or OR1;
• Z′=H, OH, or OR2;
• with the proviso that when A=M, at least one of Y′ and Z′ is OR1, or OR2;
• A=M, or
• A is a nucleoside residue which is defined as:
• and which is linked to the phosphate chain via the 5′-position of the furanose or carbocycle;
• wherein:
• D2=0 or CH2;
• Z=H, OH, or OR3;
• Y=H, OH, or OR4;
• with the proviso that at least one of Y′, Z′, Y and Z is equal to OR1, OR2 OR4 or OR3 respectively;
• R1, R2, R3, and/or R4 are residues which are linked directly to the 2′- and/or 3′-hydroxyls of the respective furanose or carbocycle via a carbon atom according to Formula II, or linked directly to two (2′- and 3′-) hydroxyls of the respective furanose or carbocycle via a common carbon atom according to Formula III;
• wherein:
• O is the corresponding 2′- and/or 3′-oxygen of the respective furanose or carbocycle;
• C is a carbon atom;
• R5, R6, and R7 are H, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety defined according to Formula II is an ether;
• or
• R5 and R6 are H, an alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, and R7 is alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy such that the moiety defined according to Formula II is an acyclic acetal or ketal;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety defined according to Formula II is an ester or thioester;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is amino or mono- or disubstituted amino, where the substituents are alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, such that the moiety according to Formula II is a carbamate or thiocarbamate;
• or
• R5 and R6 are taken together as oxygen or sulfur doubly bonded to C, and R7 is alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula II is a carbonate or thiocarbonate;
• or
• R7 is not present and R5 and R6 are taken together as oxygen or sulfur doubly bonded to C and both the 2′- and 3′-oxygens of the respective furanose or carbocycle are directly bound to C to form a cyclical carbonate or thiocarbonate;
• wherein:
• the O atoms are the 2′- and 3′-oxygens of a furanose or carbocycle;
• and the 2′- and 3′-oxygens of the furanose or carbocycle are linked by a common carbon atom (C) to form a cyclical acetal, cyclical ketal, or cyclical orthoester;
• for cyclical acetals and ketals, R8 and R9 are independently hydrogen, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, substituted aryl, or can be joined together to form a homocyclic or heterocyclic ring composed of 3 to 8 atoms, preferably 3 to 6 atoms;
• and
• for cyclical orthoesters, R8 is hydrogen, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, or substituted aryl, R9 is alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy;
• B and B′ are independently a purine residue, as in Formula IV, linked through the 9-position, or a pyrimidine residue, as in Formula V, linked through the 1-position;
• wherein:
• R10 and R14 independently are hydroxy, oxo, amino, mercapto, alkylthio, alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino, arylamino, diaralkylamino, diarylamino, or dialkylamino, where the alkyl groups are optionally linked to form a heterocycle;
• or
• R10 and R14 independently are acylamino according to Formula VI;
• or
• when R10 in a purine or R14 in a pyrimidine has as its first atom nitrogen, R10 and R11 or R14 and R15 can be taken together to form a 5-membered fused imidazole ring to give an etheno compound, optionally substituted on the etheno ring with one or more alkyl, cycloalkyl, aralkyl, or aryl moieties;
• J is carbon or nitrogen, with the provision that when J=nitrogen, R12 is not present;
• R11 is hydrogen, oxygen, or is absent;
• R15 is hydrogen, or acyl;
• R12 is hydrogen, alkyl, bromo, azido, alkylamino, arylamino or aralkylamino, alkoxy, aryloxy or aralkyloxy, alkylthio, arythio or aralkylthio, or ω-A(C1-6alkyl)B-, wherein A and B are independently amino, mercapto, hydroxy or carboxyl;
• R13 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio;
• R16 is hydrogen, methyl, alkyl, halogen, alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl;
• wherein NH is the amino residue at the C-6 position in a purine or the amino residue at the C-4 position in a pyrimidine;
• C is a carbon atom;
• W1 is oxygen or sulfur;
• R17 is amino or mono- or disubstituted amino, with the amino substituent being alkyl, cycloalkyl, aralkyl, or aryl, such that the moiety according to Formula VI is a urea or thiourea;
• or
• R17 is alkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, or substituted aryloxy, such that the moiety according to Formula VI is a carbamate or thiocarbamate;
• or
• R17 is alkyl, cycloalkyl, aralkyl, or aryl, with or without substituents or heteroatoms, such that the moiety according to Formula VI is an amide.