Dual action 2',5'-oligoadenylate antiviral derivatives and uses thereof
AssigneeTemple University of the Commonwealth System of Higher Education
InventorsRobert J. Suhadolnik, Wolfgang Pfleiderer
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Abstract
Viral infection is inhibited in mammals by administration of metabolically stable, non-toxic 2', 5'-oligoadenylate (2-5A) derivatives that have a dual therapeutic effect. The compounds activate the intracellular latent 2-5A dependent endoribonuclease RNase L and also inhibit the action of viral DNA polymerases. Conjugates of the 2-5A derivatives for therapeutic delivery are also described.
Claims31
A compound according to the formula ##STR11## wherein n is a whole positive integer from 1 to 8,
- m is 0, 1, 2 or 3,
- R is hydrogen,
- X is selected from the group consisting of C1 to C6 alkyl and C1 to C6 alkoxy, or
- a pharmaceutically acceptable salt thereof.
A conjugate comprising a compound according to the formula ##STR12## wherein A is ##STR13## X is NH.sub.2 or CH.sub.2 ;
- m is zero, 1 2 or 3;
- n is an integer from 1 to 8;
- each R.sub.1 is independently selected from the group consisting of O, S, sulfate, Se, C.sub.1 to C.sub.8 alkyl and C.sub.1 to C.sub.8 alkoxy;
- each R.sub.2 is independently selected from the group consisting of O, S-, sulfate, Se, C.sub.1 to C.sub.8 alkyl and C1 to C.sub.8 alkoxy;
- each R.sub.3 is independently selected from hydrogen, hydroxyl, amino and --OSi(CH.sub.3).sub.2 C(CH.sub.3).sub.3 ;
- R.sub.4 and R.sub.5 are independently selected from the group consisting of hydrogen;
- hydroxyl;
- amino;
- C.sub.1 to C.sub.8 alkyl;
- C.sub.1 to C.sub.8 alkoxy;
- C.sub.1 to C.sub.8 alkylamino, alkylcarbonyl, alkylcarboxyl and alkylhalide;
- and C.sub.1 to C.sub.8 alkoxyamino, alkoxycarbonyl, alkoxycarboxyl and alkoxyhalide;
- or pharmaceutically acceptable salts thereof,
- provided the compound is not authentic 2', 5'-oligoadenylate or a salt thereof,
- said compound being covalently linked through an optional linker to an adduct through a hydroxyl oxygen at the 2'- or 3'-position of the 2'-terminal nucleotide of said compound, which adduct is selected from the group consisting of vitamin B.sub.12, biotin, folic acid, riboflavin, cholesterol and an acyl group of the formula ##STR14## wherein x is an integer from 1 to 20.
A method of antiviral treatment comprising administering to a mammal an effective amount of a compound according to the formula ##STR18## wherein n is a whole positive integer from 1 to 8,
- m is 0, 1, 2 or 3,
- X is selected from the group consisting of C1 to C6 alkyl and C1 to C6 alkoxy, or
- a pharmaceutically acceptable salt thereof.
A pharmaceutical composition comprising a compound according to the formula ##STR19## wherein n is a whole positive integer from 1 to 8,
- m is 0, 1, 2 or 3,
- X is selected from the group consisting of C1 to C6 alkyl and C1 to C6 alkoxy, or
- a pharmaceutically acceptable salt thereof, and a pharmaceutical carrier.
Dependencies are inferred from the claim text.