Composition and method for inhibiting platelet aggregation

• US 7,018,985 B1
• Filed: 08/21/2000
• Issued: 03/28/2006
• Est. Priority Date: 08/21/2000
• Status: Expired due to Fees

• Current Assignee: Inspire Pharmaceuticals Incorporated (Akorn Holdings Topco LLC), Board of Trustees of The University of Illinois
• Original Assignee: Inspire Pharmaceuticals Incorporated (Akorn Holdings Topco LLC), University of North Carolina At Chapel Hill (University of North Carolina System)
• Inventors: Boyer, José L., Douglass, James G. III, Yerxa, Benjamin R., Olins, Gillian M.
• Primary Examiner(s): LEWIS, PATRICK T
• Assistant Examiner(s): LEWIS, PATRICK T
• Application Number:
  US09/643,138
• Time in Patent Office: 2,045 Days
• Field of Search: 514/45, 514/46, 514/47, 514/48, 514/49, 514/50, 514/51, 514/81, 536/26.2, 536/26.23, 536/26.26, 544/264, 544/265
• US Class Current: 514/48
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 31/7084 Compounds having two nucleosides or nucleotides, e.g. nicotinamide-adenine dinucleotide, flavine-adenine dinucleotide
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary system
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 39/00 General protective or antinoxious agents
• CPC Class Codes: A61P 41/00 Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 7/12 : Antidiuretics, e.g. drugs for diabetes insipidus ADH A61P5/10
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/02 : Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: C07H 19/04 : Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
• CPC Class Codes: C07H 19/10 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/20 : with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: C07H 19/207 : the phosphoric or polyphosphoric acids being esterified by a further hydroxylic compound, e.g. flavine adenine dinucleotide or nicotinamide-adenine dinucleotide
• CPC Class Codes: C07H 21/00 : Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids

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 P2_τ receptor antagonist, in an amount effective to elevate its extracellular concentration to bind to P2_τ receptors and inhibit P2_τ 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.

Claims

1. 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(C_1-6alkyl)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.

2. The compound according to claim 1, wherein said compound is fluorescently labeled and used as a biochemical probe for the P2_T receptor.

3. A method of treating diseases or conditions associated with platelet aggregation comprising:

administering to a patient a pharmaceutical formulation according to claim 1, wherein said compound is effective to bind the P2_T receptors on platelets and inhibit ADP-induced platelet aggregation.

4. The method according to claim 3, wherein said pharmaceutical formulation is administered to reduce the incidence of dose-related adverse side effects of other therapeutic agents used to prevent, manage or treat platelet aggregation disorders.

5. The method according to claim 3, wherein said administering is systemic administration of said compound.

6. The method according to claim 5, wherein said systemic administration is administration of an injectable form of said compound, such that a therapeutically effective amount of said compound contacts the target platelets of said patient via systemic absorption and circulation.

7. The method according to claim 5, wherein said systemic administration is accomplished by administering an oral form of said compound, such that a therapeutically effective amount of said compound contacts the target platelets of said patient via systemic absorption and circulation.

8. The method according to claim 5, wherein said systemic administration is administration of said compound in a form of a transdermal patch or a transdermal pad, such that a therapeutically effective amount of said compound contacts the target platelets of said patient via systemic absorption and circulation.

9. The method according to claim 5, wherein said systemic administration is administration of a liquid/liquid suspension of said compound via nose drops or nasal spray, or administration of a nebulized liquid to oral or nasopharyngeal airways of said subject, such that a therapeutically effective amount of said compound inhibits platelet aggregation.

10. The method according to claim 5, wherein said systemic administration comprises infusion of said compound to target platelets via a device selected from a group consisting of a pump catheter system and a continuous or selective release device.

11. The method according to claim 5, wherein said systemic administration is administration of a suppository form of said compound, such that a therapeutically effective amount of said compound contacts the target platelets of said patient via systemic absorption and circulation.

12. The method according to claim 5, wherein said systemic administration is vaginal administration in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

13. The method according to claim 5, wherein said compound is administered to a patient by an intravitreal delivery.

14. The method according to claim 5, wherein said systemic administration is administration of an intra-operative instillation of a gel, cream, powder, foam, crystals, liposomes, spray or liquid suspension form of said compound, such that a therapeutically effective amount of said compound contracts the target platelets of said patient via systemic absorption and circulation.

15. The method according to claim 3, wherein said diseases or conditions associated with platelet aggregation are disorders or procedures characterized by thrombosis, primary arterial thrombotic complications of atherosclerotic disease, thrombotic complications of interventions of atherosclerotic disease, thrombotic complications of surgical or mechanical damage, mechanically-induced platelet activation, shunt occlusion, thrombosis secondary to vascular damage and inflammation, indications with a diffuse thrombotic/platelet consumption component, venous thrombosis, coronary arterial thrombosis, pathological effects of atherosclerosis and arteriosclerosis, platelet aggregation and clot formation in blood and blood products during storage, chronic or acute states of hyper-aggregability, reocclusion of an artery or vein following fibrinolytic therapy, platelet adhesion associated with extracorporeal circulation, thrombotic complications associated with thrombolytic therapy, thrombotic complications associated with coronary and other angioplasty, or thrombotic complications associated with coronary artery bypass procedures.

16. The method according to claim 15, wherein said disorders or procedures characterized with thrombosis are unstable angina, coronary angioplasty, or myocardial infarction.

17. The method according to claim 15, wherein said primary arterial thrombotic complications of atherosclerosis are thrombotic stroke, peripheral vascular disease, or myocardial infarction without thrombolysis.

18. The method according to claim 15, wherein said thrombotic complications of interventions of atherosclerotic disease are associated with angioplasty, endarterectomy, stent placement, coronary or other vascular graft surgery.

19. The method according to claim 15, wherein said thrombotic complications of surgical or mechanical damage are associated with tissue salvage following surgical or accidental trauma, reconstructive surgery including skin flaps, or reductive surgery such as breast reduction.

20. The method according to claim 15, wherein said mechanically-induced platelet activation is caused by cardiopulmonary bypass resulting in microthromboembolism.

21. The method according to claim 15, wherein said shunt occlusion is renal dialysis or plasmapheresis.

22. The method according to claim 15, wherein said thrombosis secondary to vascular damage and inflammation is vasculitis, arteritis, glomerulonephritis or organ graft rejection.

23. The method according to claim 15, wherein said indications with a diffuse thrombotic/platelet consumption component are disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, heparin-induced thrombocytopenia, or pre-eclampsia/eclampsia.

24. The method according to claim 15, wherein said venous thrombosis is deep vein thrombosis, veno-occlusive disease, hematological conditions, or migraine.

25. The method according to claim 24, wherein said hematological conditions are thrombocythemia or polycythemia.

26. The method according to claim 15, wherein said coronary arterial thrombosis is associated with unstable angina, coronary angioplasty or acute myocardial infarction.

27. The method according to claim 15, wherein pathological effects of atherosclerosis and arteriosclerosis are arteriosclerosis, acute myocardial infarction, chronic stable angina, unstable angina, transient ischemic attacks, strokes, peripheral vascular disease, arterial thrombosis, preeclampsia, embolism, restenosis or abrupt closure following angioplasty, carotid endarterectomy, or anastomosis of vascular grafts.

28. The method according to claim 15, wherein said chronic or acute states of hyper-aggregability is caused by DIC, septicemia, surgical or infectious shock, post-operative and post-partum trauma, cardiopulmonary bypass surgery, incompatible blood transfusion, abruptio placenta, thrombotic thrombocytopenic purpura, snake venom or immune diseases.

29. The method according to claim 15, wherein said reocclusion of an artery or vein following fibrinolytic therapy is inhibited by internal administration of said compound with a fibrinolytic agent.

30. The method according to claim 29, wherein said fibrinolytic agent is selected from the group consisting of natural or synthetic products which directly or indirectly cause lysis of a fibrin clot.

31. The method according to claim 29, wherein said fibrinolytic agent is a plasminogen activator selected from the group consisting of anistreplase, urokinase, pro-urokinase, streptokinase, tissue plasminogen activator and mutants or variants thereof, which retain plasminogen activator activity.

32. The method according to claim 31, wherein said variants are selected from the group consisting of variants which have been chemically modified, variants which one or more amino acids have been added, deleted or substituted and variants with one or more modified functional domains.

33. The method according to claim 32, wherein said modified functional domains are added, deleted or altered by combining the active site of one plasminogen activator or fibrin binding domain with another plasminogen activator or fibrin binding molecule.

34. The pharmaceutical formulation according to claim 1, wherein said formulation is sterile.

35. The pharmaceutical formulation according to claim 1, wherein said formulation further comprises a pharmaceutical carrier.

36. The pharmaceutical formulation according to claim 1, wherein said formulation further comprises a buffering agent.

38. The pharmaceutical formulation of claim 1 wherein said compound is a compound of Formula I:

wherein;

V=O;

n=m=p=0;

A=M;

M=H or a pharmaceutically-acceptable inorganic or organic counterion;

D₁=O;

wherein;

O is the 2′ and

3′

oxygens of the furanose; and

the 2′ and

3′

oxygens of the furanose are linked by a common carbon atom to form a cyclical acetal; and

R₈ is hydrogen; and

R₉ is selected from the group consisting of aralkyl, aryl, substituted aralkyl, and substituted aryl;

in which the aralkyl groups are from 1 to 5 carbons in the alkyl portion, and are;

monocyclic moieties from 4 to 8 carbons without heteroatoms in the aryl portion; and

the aryl groups are monocyclic moieties from 4 to 8 carbons, without heteroatoms;

B′

is a purine residue according to general Formula IV

wherein;

R₁₀ is acylamino, according to Formula VI;

W is oxygen; and

R₁₇ is amino or mono- or disubstituted amino such that the moiety according to Formula VI is a urea;

J=carbon;

R₁₁ is absent;

R₁₂ is hydrogen; and

R₁₃ is hydrogen.

37. 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;

wherein;

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;

D₁=O;

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;

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, aryl, substituted aralkyl, ad substituted aryl, 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 alkylthio, alkyloxy, aryloxy, cycloalkylamino, aralkylamino, arylamino, diaralkylamino, and diarylamino, 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(C_1-6alkyl)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.