Dinucleoside polyphosphate compositions and their therapeutic use

1. A compound of Formula II, or the pharmaceutically acceptable non-toxic esters, amides, ureas, carbamates, ethers, acetals, ketals and/or salts thereof:

wherein:

D=O or CH 2 ;

X is oxygen, methylene, dihalomethylene, or imido;

n=0, 1 or 2;

m=0, 1 or 2;

n+m=0, 1, 2, 3 or 4;

Z=OH or H;

Z′=OH or H;

Y=OH or H;

Y′=OH or H; and

B and B′ are each independently a purine residue or a pyrimidine residue, as defined in Formula IIa′ or IIb, linked through the 9- or 1-position, respectively; and provided that at least one of B and B′ is an 8-azapurine;

R 1 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, wherein the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;

R 2 is hydroxy, alkenyl, oxo, amino, mercapto, thione, alkylthio, arylthio, aralkylthio, acylthio, alkyloxy, aryloxy, aralkyloxy, acyloxy, monosubstituted alkylamino, heterocyclic, monosubstituted cycloalkylamino, monosubstituted aralkylamino, monosubstituted arylamino, diaralkylamino, diarylamino, dialkylamino, acylamino, or diacylamino;

R x is O, H or is absent;

R 2 and R x are optionally taken together to form a 5-membered fused imidazole ring of 1,N 6 -etheno adenine derivatives, optionally substituted on the 4- or 5-positions of the etheno moiety with alkyl, aryl or aralkyl moieties as defined below;

R 3 is absent, or is hydrogen, azido, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio as defined below; or T(C 1-6 alkyl)OCONH(C 1-6 alkyl)W wherein T and W are independently amino, mercapto, hydroxy or carboxyl, or pharmaceutically acceptable esters, amides or salts thereof;

J is nitrogen or carbon;

provided that when J is nitrogen, R 3 is absent;

wherein:

R 4 is selected from the group consisting of: oxo, hydroxy, mercapto, thione, amino, cyano, C 7-12 arylalkoxy, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkylamino, and diC 1-4 alkylamino, wherein the alkyl groups are optionally linked to form a heterocycle;

R 5 is selected from the group consisting of hydrogen, oxo, acetyl, benzoyl, C 1-6 alkyl, C 1-5 alkanoyl, aroyl, and absent;

R 6 is selected from the group consisting of: hydroxy, oxo, mercapto, thione, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-6 alkylthio, amino, S-phenyl, arylthio, arylalkylthio, C 1-5 disubstituted amino, triazolyl, C 1-6 alkylamino, and di-C 1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle or linked to form a substituted ring; or

R 5 and R 6 taken together form a 5-membered fused imidazole ring of 3,N 4 -ethenocytosine derivatives between positions 3 and 4 of the pyrimidine ring, wherein said etheno moiety is optionally substituted on the 4- or 5-positions with C 1-4 alkyl, phenyl, or phenyloxy; wherein at least one hydrogen of said C 1-4 alkyl, phenyl, or phenyloxy is optionally substituted with a moiety selected from the group consisting of: halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 6-10 aryl, C 7-12 arylalkyl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino, C 1-4 alkylamino, and di-C 1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle;

R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-6 alkyl, phenyl, substituted C 2-8 alkynyl, halogen, substituted C 1-4 alkyl, CF 3 , C 2-3 alkenyl, C 2-3 alkynyl, allylamino, bromovinyl, ethyl propenoate, propenoic acid, and C 2-8 alkenyl; or

R 6 and R 7 together form a 5 or 6-membered saturated or unsaturated ring bonded through N or O or S at R 6 , such ring optionally contains functional substituents; and

R 8 is selected from the group consisting of: hydrogen, amino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-4 alkylthio, C 7-12 arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy and phenylthio; provided that when R 8 is amino or substituted amino, R 7 is hydrogen;

wherein the alkyls are straight-chain, branched or cyclic;

wherein the alkyl and aryl groups are optionally substituted with lower alkyl, aryl, amino, mono- or dialkylamino, NO 2 , N 3 , cyano, carboxylic, amido, sulfonamido, sulphonic acid, phosphate, or halo groups.

2. A compound of Formula III, or the pharmaceutically acceptable non-toxic esters, amides, ureas, carbamates, ethers, acetals, ketals and/or salts thereof:

wherein:

D=O or CH 2 ;

X is oxygen, methylene, dihalomethylene, or imido;

n=0, 1 or 2;

m=0, 1 or 2;

n+m=0, 1, 2, 3 or 4;

Z=OH or H;

Z′=OH or H;

Y=OH or H;

Y′=OH or H; and

B and B′ are each independently a purine residue or a pyrimidine residue, as defined in Formula IIIa or IIIb, linked through the 9- or 1-position, respectively; and provided that at least one of B and B′ is a purine:

R 1 is hydrogen, chlorine, amino, monosubstituted amino, disubstituted amino, alkylthio, arylthio, or aralkylthio, wherein the substituent on sulfur contains up to a maximum of 20 carbon atoms, with or without unsaturation;

R 2 is mercapto, thione, alkylthio, arylthio, aralkylthio, acylthio, alkyloxy, aryloxy, aralkyloxy, acyloxy, monosubstituted cycloalkylamino, or di-substituted amino;

R x is O, H or is absent;

R 3 is hydrogen, azido, alkoxy, aryloxy, aralkyloxy, alkylthio, arylthio, or aralkylthio as defined below; or T(C 1-6 alkyl)OCONH(C 1-6 alkyl)W wherein T and W are independently amino, mercapto, hydroxy or carboxyl, or pharmaceutically acceptable esters, amides or salts thereof;

J is carbon or nitrogen, with the provision that when J is nitrogen, R 3 is not present;

wherein:

R 4 is selected from the group consisting of: oxo, hydroxy, mercapto, thione, amino, cyano, C 7-12 arylalkoxy, C 1-6 alkylthio, C 1-6 alkoxy, C 1-6 alkylamino, and diC 1-4 alkylamino, wherein the alkyl groups are optionally linked to form a heterocycle;

R 5 is selected from the group consisting of: hydrogen, oxo, acetyl, benzoyl, C 1-6 alkyl, C 1-5 alkanoyl, aroyl, and absent;

R 6 is selected from the group consisting of: hydroxy, oxo, mercapto, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-6 alkylthio, amino, S-phenyl, arylthio, arylalkylthio, C 1-5 disubstituted amino, triazolyl, C 1-6 alkylamino, and di-C 1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle or linked to form a ring; or

R 5 and R 6 taken together form a 5-membered fused imidazole ring between positions 3 and 4 of the pyrimidine ring and form a 3,N 4 -ethenocytosine derivative, wherein said etheno moiety is optionally substituted on the 4- or 5-positions with C 1-4 alkyl, phenyl or phenyloxy, wherein at least one hydrogen of said C 1-4 alkyl, phenyl or phenyloxy is optionally substituted with a moiety selected from the group consisting of: halogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 6-10 aryl, C 7-12 arylalkyl, carboxy, cyano, nitro, sulfonamido, sulfonate, phosphate, sulfonic acid, amino, C 1-4 alkylamino, and di-C 1-4 alkylamino wherein said dialkyl groups are optionally linked to form a heterocycle;

R 7 is selected from the group consisting of hydrogen, hydroxy, cyano, nitro, C 1-6 alkyl, phenyl, substituted C 2-8 alkynyl, halogen, substituted C 1-4 alkyl, CF 3 , C 2-3 alkenyl, C 2-3 alkynyl, allylamino, bromovinyl, ethyl propenoate, and propenoic acid, and C 2-8 alkenyl; or

R 6 and R 7 together form a 5 or 6-membered saturated or unsaturated ring bonded through N or O or S at R 6 , such ring optionally contains functional substituents that themselves contain functionalities; and

R 8 is selected from the group consisting of hydrogen, amino, di-C 1-4 alkylamino, C 1-4 alkoxy, C 7-12 arylalkoxy, C 1-4 alkylthio, C 7-12 arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy and phenylthio provided that when R 8 is amino or substituted amino, R 7 is hydrogen;

wherein the alkyls are straight-chain, branched or cyclic;

wherein the aryl groups are optionally substituted with lower alkyl, amino, monoalkylamino, dialkylamino, NO 2 , N 3 , cyano, carboxylic, amido, sulfonamido, sulphonic acid, phosphate, or halo groups.

3. The compound according to claim 1 or 2 , wherein said compound is selected from the group consisting of P 1 -[(N6-phenyl)-8-azaadenosine 5′-]P 4 -(uridine 5′-) tetraphosphate; P 1 -[(N6-phenyl)-8-azaadenosine 5′]-P 4 -(2′-deoxyuridine 5′-) tetraphosphate; P 1 -[(N6-phenyl)-8-aza-2-chloroadenosine 5′-]P 4 -(uridine 5′-) tetraphosphate; P 1 -(2′-deoxyadenosine 5′-)P 4 -[(N6-phenyl)-8-azaadenosine 5′-]tetraphosphate; P 1 -[4-{7-(anilino)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl}-cyclopentane-2,3-dihydroxy-1-methoxy-]P 4 -(uridine 5′-) tetraphosphate; and tetraphosphoric acid P,P′″-bis-(4-{7[2-(3,4-difluorophenyl)-cyclopropylamino]-5-propylsulfanyl-1,2,3-triazolo[4,5-d]pyrimidin-3-yl}-2,3-dihydroxy-cyclopentylmethyl} ester.

4. A pharmaceutical formulation comprising the compound or the pharmaceutically acceptable non-toxic esters, amides, ureas, carbamates, ethers, acetals, ketals, or salt thereof according to claim 1 or 2 , in a pharmaceutically acceptable carrier, in the form of an aqueous, a gel, a gel-like, or a solid formulation.

5. The pharmaceutical formulation according to claim 4 , wherein the pharmaceutical formulation is in the form of an aqueous solution and comprises physiologically safe excipients formulated to osmolarity between 250-350 mOsm and pH 5-9.

6. The pharmaceutical formulation according to claim 4 , wherein said pharmaceutically acceptable carrier is a physiologically compatible vehicle selected from the group consisting of: aqueous electrolyte solutions, polyethers, polyvinyls, polymers of acrylic acid, lanolin, and glucosaminoglycans.

7. A method of treating a disease associated with a disorder of mucous hydration, secretion and clearance in a mammal in need thereof, comprising:

administering to said mammal a therapeutic effective amount of the compound according to claim 1 or 2 .

8. A method of treating a disease associated with platelet activation, platelet aggregation or degranulation, in a mammal in need thereof, comprising:

administering to said mammal a therapeutic effective amount of the compound according to claim 1 or 2 .