Cholesterol conjugates of 2'5'-oligoadenylate derivatives and antiviral uses thereof

• US 5,643,889 A
• Filed: 09/14/1994
• Issued: 07/01/1997
• Est. Priority Date: 07/11/1984
• Status: Expired due to Term

• Current Assignee: Temple University of The Commonwealth System of Higher Education
• Original Assignee: Temple University of The Commonwealth System of Higher Education
• Inventors: Pfleiderer, Wolfgang, Suhadolnik, Robert J.
• Primary Examiner(s): Wilson, James O.
• Application Number:
  US08/306,274
• Time in Patent Office: 1,021 Days
• Field of Search: 514/44, 514/45, 514/46, 514/47, 514/26, 514/5, 514/169, 514/61, 536/4.1, 536/5, 536/22.1, 536/23.1, 536/25.2, 47/58
• US Class Current: 514/44.00R
• CPC Class Codes: A61K 31/70 Carbohydrates; Sugars; Derivatives thereof sorbitol A61K31/047
• CPC Class Codes: A61K 31/7115 Nucleic acids or oligonucleotides having modified bases, i.e. other than adenine, guanine, cytosine, uracil or thymine
• CPC Class Codes: A61K 31/712 Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61K 47/549 Sugars, nucleosides, nucleotides or nucleic acids
• CPC Class Codes: A61K 47/551 one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid
• CPC Class Codes: A61K 47/554 the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid
• CPC Class Codes: A61K 47/557 the modifying agent being biotin
• 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
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds
• CPC Class Codes: C07J 43/003 not condensed
• CPC Class Codes: C07J 51/00 Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00

Abstract

A cholesterol-cordycepin conjugate having the formula ##STR1## wherein: n is an integer from 1 to 8; R₁ is selected from the group of consisting of T, T'"'"' and Y; T is ##STR2## T'"'"' is ##STR3## where x is an integer from 1 to 18; Y is ##STR4## where m is zero, 1, 2, or 3; each R₂ is independently selected from the group consisting of oxygen and sulfur; each R₃ is independently selected from the group consisting of hydrogen and hydroxyl; R₄ is selected from the group consisting of hydrogen, hydroxyl and T or T'"'"'; R₅ is selected from the group consisting of hydrogen, hydroxyl and T or T'"'"'; provided that all R₁, R₄ and R₅ may not be T or T'"'"'; at least one R₃ is hydrogen or R₄ is hydrogen; and at least one of R₁, R₄ and R₅ must be T or T'"'"'; or a water soluble salt thereof. The compounds possess increased antiviral activity and/or metabolic stability.

Claims

1. A compound of the formula:

##STR12## wherein;

n is an integer from 1 to 8;

R₁ is selected from the group of consisting of T, T'"'"' and Y, wherein

T is ##STR13## T'"'"' is ##STR14## where x is an integer from 1 to 18;

Y is ##STR15## where m is zero, 1, 2, or 3;

each R₂ is independently selected from the group consisting of oxygen and sulfur;

each R₃ is independently selected from the group consisting of hydrogen and hydroxyl;

R₄ is selected from the group consisting of hydrogen, hydroxyl, T and T'"'"';

R₅ is selected from the group consisting of hydrogen, hydroxyl, T and T'"'"';

provided that

all R₁, R₄ and R₅ may not be T or T'"'"';

at least one R₃ is hydrogen or R₄ is hydrogen; and

at least one of R₁, R₄ and R₅ must be T or T'"'"';

or a water soluble salt thereof.

2. A compound according to claim 1 wherein each R₃ is hydrogen and R₄ is hydrogen.

3. A compound according to claim 2 wherein each R₂ is oxygen.

4. A compound according to claim 3 where n is 1 or 2 and R₅ is T;

or a water soluble salt thereof.

5. A compound according to claim 3 where n is 1 or 2 and R₁ is T;

or a water soluble salt thereof.

6. A compound according to claim 3 where n is 1 or 2 and R₅ is T'"'"';

or a water soluble salt thereof.

7. A compound according to claim 3 where n is 1 or 2 and R₁ is T'"'"';

or a water soluble salt thereof.

8. A compound according to any of claims 4, 5, 6 or 7 wherein n is 1.

9. A compound according to claim 1 wherein R₁ is Y and m is zero.

10. A compound according to claims 6 or 7 where x is 2.

11. A compound according to claim 1 which is 3'"'"'-deoxyadenylyl-(2'"'"'→

5'"'"')-3'"'"'-deoxyadenylyl-(2'"'"'→

5'"'"')-2'"'"'-O-(2-cholesterylcarbonyl)ethylcarbonyl-3'"'"'-deoxyadenosine;

or a water soluble salt thereof.

12. A compound according to claim 1 which is 5'"'"'-O-[2-(cholesteryloxycarbonyl)ethylcarbonyl]-3'"'"'-deoxyadenylyl-(2'"'"'.fwdarw.5'"'"')-3'"'"'-deoxyadenylyl-(2'"'"'→

5'"'"')-3'"'"'-deoxyadenosine;

or a water soluble salt therof.

13. An antiviral composition comprising a compound according to claim 1 in combination with a pharmaceutical carrier.

14. A method of treating viral infection in a mammal comprising administering thereto an antiviral effective amount of a compound according to claim 1.

15. A method of treating viral infection in a plant comprising administering thereto an antiviral effective amount of a compound according to claim 1.

16. An antiviral composition comprising a compound according to claim 1 in combination with an agricultural carrier.