US 7,018,985 B1 · Composition and method for inhibiting platelet aggregation

Abstract

The present invention provides novel compounds of dinucleotide polyphosphates and the method of preventing or treating diseases or conditions associated with platelet aggregation. The method comprises administering systemically to a patient a pharmaceutical comprising a purinergic P2τ receptor antagonist, in an amount effective to elevate its extracellular concentration to bind to P2τ receptors and inhibit P2τ receptor-mediated platelet aggregation. Methods of systemic administration include injection by intravenous, intramuscular, intrasternal and intravitreal routes, infusion, transdermal administration, oral administration, rectal administration and intra-operative instillation.

A pharmaceutical formulation comprising a compound of general formula I, or salts thereof:

wherein:
X1, X2, and X3 are independently selected from the group consisting of oxygen, methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T, W, and V are independently oxygen or sulfur;
m=0, 1 or 2;
n=0, 1, or 2;
p=0, 1, or 2;
M=H or a pharmaceutically-acceptable inorganic or organic counterion;
D1=O or C;
B′ is a purine or a pyrimidine residue according to general formulas IV and V which is linked to the 1′ position of the furanose or carbocycle via the 9- or 1-position, respectively;
A is M or alkyl;
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=O or C;
B is a purine or a pyrimidine residue according to general formulas IV and V which is linked to the sugar or carbocycle via the 9- or 1-position, respectively;
wherein when D1 and D2 are oxygen, the furanose is in the β-configuration;
Y′=H, OH, or OR1, where OR1 falls under the definition of general Formula II or III;
Z′=OH or OR2, where OR2 falls under the definition of general Formula II or III;
Z=OH or OR3, where OR3 falls under the definition of general formula II or III;
Y=H, OH, or OR4, where OR4 falls under the definition of general Formula II or III;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
wherein compounds of general Formula I are molecules whose structures fall within the definitions of Formula Ia and Formula Ib:
X1, X2, and X3=O;
T, V, and W=O;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=OH or OR2, where OR2 falls under the definition of general formula II;
Z=OH or OR3, where OR3 falls under the definition of general formula II;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula II;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2=O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m and p=0, 1 or 2;
n=0 or 1;
such that the sum of m+n+p is from 0 to 5;
or
X1, X2, and X3=O;
T, V, and W=O;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula III;
Z′=OH or OR2, where OR2 falls under the definition of general formula III;
Z=OH or OR3, where OR3 falls under the definition of general formula III;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula III;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2=O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m and p=0, 1 or 2;
n=0 or 1;
such that the sum of m+n+p is from 0 to 5;
or
X1 and X3=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T, V, and W=O;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=OH or OR2, where OR2 falls under the definition of general formula II;
Z=OH or OR3, where OR3 falls under the definition of general formula II;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula II;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2=O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m and p=0, 1 or 2;
n=1;
such that the sum of m+n+p is from 0 to 5;
or
X1 and X3=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T, V, and W=O;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula III;
Z′=OH or OR2, where OR2 falls under the definition of general formula III;
Z=OH or OR3, where OR3 falls under the definition of general formula III;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula III;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2 is O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m and p=0, 1 or 2;
n=1;
such that the sum of m+n+p is from 0 to 5;
or
X1 and X3=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T=S;
V and W=O;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=OH or OR2, where OR2 falls under the definition of general formula II;
Z=OH or OR3, where OR3 falls under the definition of general formula II;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula II;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2=O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m, n and p=1;
or
X1 and X3=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T=S;
V and W=O;
M is selected from the group consisting of H, NH4+, Na+ and other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula III;
Z′=OH or OR2, where OR2 falls under the definition of general formula III;
Z=OH or OR3, where OR3 falls under the definition of general formula III;
Y=H, OH, or OR4, where OR4 falls under the definition of general formula III;
provided that at least one of Y′, Z′, Z, and Y is OR1, OR2, OR3, or OR4, respectively;
D1=O;
D2=O or C;
B and B′ are purine or pyrimidine residues according to general formulas IV and V;
m, n, and p=1;
wherein:
A is M or alkyl;
X1 and X2=O;
T, V, and W=O;
M=H, NH4+, Na or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=H, OH or OR2, where OR2 falls under the definition of general formula II;
with the provision that at least one of Y′ and Z′ is OR1 or OR2;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
n and p are 0, 1, or 2 such that the sum of n+p is from 1 to 3;
or
A is M or alkyl;
X1 and X2=O;
T, V, and W=O;
M is selected from the group consisting of H, NH4+, Na+ and other pharmaceutically-acceptable inorganic or organic counterion;
Y′=OR1, where OR1 falls under the definition of general formula III;
Z′=OR2, where OR2 falls under the definition of general formula III;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
n and p are 0, 1, or 2 such that the sum of n+p is from 1 to 3;
or
A is M or alkyl;
X1 and X2=O;
T and V=O;
W=S;
M=H, NH4+, Na+ or other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=H, OH or OR2, where OR2 falls under the definition of general formula II;
with the provision that at least one of Y′ and Z′ is OR1 or OR2;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
p is 0, 1, or 2 such that the sum of n+p is from 1 to 3;
n=1;
or
A is M or alkyl;
X1 and X2=O;
T and V=O;
W=S;
M is selected from the group consisting of H, NH4+, Na+ and other pharmaceutically-acceptable inorganic or organic counterion;
Y′=OR1, where OR1 falls under the definition of general formula III;
Z′=OR2, where OR2 falls under the definition of general formula III;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
p is 0, 1, or 2 such that the sum of n+p is from 1 to 3;
n=1;
or
A is M or alkyl;
X1=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T, V, and W=O;
M is selected from the group consisting of H, NH4+, Na+ and other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula II;
Z′=H, OH or OR2, where OR2 falls under the definition of general formula II;
with the provision that at least one of Y′ and Z′ is OR1 or OR2;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
p is 0, 1, or 2 such that the sum of n+p is from 1 to 3;
n=1;
or
A is M or alkyl;
X1=O;
X2 is selected from the group consisting of methylene, monochloromethylene, dichloromethylene, monofluoromethylene, difluoromethylene, and imido;
T, V, and W=O;
M is selected from the group consisting of H, NH4+, Na+ and other pharmaceutically-acceptable inorganic or organic counterion;
Y′=H, OH, or OR1, where OR1 falls under the definition of general formula III;
Z′=H, OH or OR2, where OR2 falls under the definition of general formula III;
D1=O or C;
B′ is purine or pyrimidine residue according to general formulas IV and V;
p is 0, 1, or 2 such that the sum of n+p is from 1 to 3;
n=1;
wherein, for compounds according to Formula Ia or Ib, where Y′=OR1, Z′=OR2, Z=OR3 and/or Y=OR4, at least one of the four is a residue which is linked directly to the corresponding 2′ or 3′ hydroxyl oxygen of the furanose or carbocycle via a carbon atom;
wherein said residue falls within the scope of formula II or formula III:
wherein:
O is the corresponding 2′ or 3′ oxygen of the furanose or carbocycle;
R5, R6, and R7 are selected from the group consisting of H, an alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl, such that the moiety defined according to formula II is an ether;
or
R5 and R6 are taken together to be oxygen or sulfur doubly bonded to Q, and R7 is selected from the group consisting of alkyl, cycloalkyl, aralkyl, and substituted aralkyl, such that the moiety defined according to formula II is an ester or thioester;
or
R5 and R6 are taken together to be oxygen or sulfur doubly bonded to Q, and R7 is amino or mono- or disubstituted amino, where the substituents are selected from the group consisting of alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl, such that the moiety according to formula II is a carbamate or thiocarbamate;
or
R5 and R6 are taken together to be oxygen or sulfur doubly bonded to Q, and R7 is selected from the group consisting of alkoxy, cycloalkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, and substituted aryloxy, such that the moiety according to formula II is a carbonate or thiocarbonate;
or
R5 and R6 are taken together to be oxygen or sulfur doubly bonded to Q and both the 2′ and 3′ oxygens of the furanose are directly bound to Q to form a cyclical carbonate or thiocarbonate, R7 is not present;
wherein:
O is the 2′ and 3′ oxygens of the furanose or carbocycle;
and
the 2′ and 3′ oxygens of the furanose or carbocycle are linked by a common carbon atom to form a cyclical acetal, cyclical ketal, or cyclical orthoester;
and
for cyclical acetals and ketals, R8 and R9 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl;
or are joined together to form a homocyclic or heterocyclic ring composed of 3 to 8 atoms, or for cyclical orthoesters, R8 is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, aryl, substituted aralkyl, and substituted aryl, and R9 is selected from the group consisting of alkyloxy, cycloalkyloxy, aralkyloxy, aryloxy, substituted aralkyloxy, and 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, provided when D1 and D2 are oxygen, the ribosyl moieties are in the D-configuration;
wherein:
R10 and R14 are selected from the group consisting of hydroxy, oxo, amino mercapto, alkylthio, alkyloxy, aryloxy, alkylamino, cycloalkylamino, aralkylamino, arylamino, diaralkylamino, diarylamino, and dialkylamino, where the alkyl groups are optionally linked to form a heterocycle;
or
R10 and R14 are acylamino according to Formula VI, provided that they incorporate an amino residue from the C-6 position of the purine or the C-4 position of the pyrimidine;
or
when R10 in a purine or R14 in a pyrimidine has as its first atom nitrogen, R10 and R11 or R14 and R15 are taken together to form a 5-membered fused imidazole ring, optionally substituted on the etheno ring with R5-R9 selected from the group consisting of alkyl, cycloalkyl, aralkyl, or aryl moieties, as described above;
J is carbon or nitrogen, with the provision that when nitrogen, R12 is not present;
R11 is hydrogen, O or is absent;
R12 is selected from the group consisting of hydrogen, alkyl, azido, alkylamino, arylamino, aralkylamino, alkoxy, aryloxy, aralkyloxy, alkylthio, arythio, aralkylthio, and ω-A(C1-6alkyl)B- wherein A and B are selected from the group consisting of independently amino, mercapto, hydroxy and carboxyl;
R13 is selected from the group consisting of hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, and aralkylthio, where the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;
R15 is selected from the group consisting of hydrogen, and acyl, such as acetyl, benzoyl, phenylacyl, with or without substituents;
R16 is selected from the group consisting of hydrogen, methyl, alkyl, halo, alkyl, alkenyl, substituted alkenyl, alkynyl, and 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;
Q is a carbon atom;
W is oxygen or sulfur;
R17 is amino or mono- or disubstituted amino such that the moiety according to formula VI is a urea or thiourea;
or
R17 is selected from the group consisting of alkoxy, aralkyloxy, aryloxy, substituted aralkyloxy, and substituted aryloxy, such that the moiety according to formula VI is a carbamate or thiocarbamate;
or
R17 is selected from the group consisting of alkyl, cycloalkyl, aralkyl, and aryl, with or without substituents or heteroatoms, such that the moiety according to formula VI is an amide.

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Composition and method for inhibiting platelet aggregation

Life of this patent

Composition and method for inhibiting platelet aggregation

Life of this patent

Abstract

Claims38