Phosphonucleosides useful in the treatment of viral disorders
AssigneesUniversity College Cork, Katholieke Universiteit Leuven
InventorsWim Dehaen, Jan Balzarini, Anita Maguire, Sarah Jane Keane, Alan Ford, Nuala Maguire, Nicholas D. Mullins
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Abstract
A first aspect of the invention relates to a compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof, wherein the groups are as defined in the claims. Further aspects of the invention relate to pharmaceutical compositions comprising compounds of formula (I), and the use of compounds of formula (I) in the preparation of a medicament for treating a viral disorder.
Claims33
A compound of formula (I), or a pharmaceutically acceptable salt or prodrug thereof,
- wherein:
- X is selected from O and NR9;
- Y is C═CH2 or (CR8R8′)n, where n is 1 or 2;
- Z is a direct bond, or (CR2R2′)p, where p is 1, 2, 3 or 4;
- Q is selected from O, S, CH2, CH═CH and C≡C;
- r is 0, 1, 2 or 3;
- s is 0, 1, 2 or 3;
- t is 0 or 1;
- q is 0, 1, 2, 3, 4 or 5;
- when p is 1, 2, 3 or 4, ‘a’ is a single bond, or a double bond (in which case one of R2 and R2′ is absent, and one of R3 and R3′ is absent);
- R1, R2, R2′, R3, R3′, R4, R8 and R8′ are each independently selected from H, OR10, halogen, CN, NR11R12, N3, SR13, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl and aryl, or one of R2 and R2′ together with one of R3 and R3′ form of an epoxide;
- R5 is selected from H, P(═O)(OH)2 and P(═O)(OH)—O—P(═O)(OH)2;
- R6 is selected from H and C1-6-alkyl;
- R9-R13 are each independently selected from H and C1-6-alkyl;
- Base is a natural or non-natural nucleobase, and
- wherein the prodrug is selected from a phosphoramidate derivative, a SATE (S-acyl-2-thioethyl) ester derivative, a pivaloyloxymethyl (POM) derivative, an isopropyloxymethylcarbonyl (POC) derivative, a cyclo-saligenyl (cycloSal) derivative and an alkyloxyalkyl derivative.
A compound of formula (Ia), or a pharmaceutically acceptable salt or prodrug thereof,
- wherein:
- X is selected from O and NR9;
- R1, R2, R2′, R3, R3′, R4, R8 and R8′ are each independently selected from H, OR10, halogen, CN, NR11R12, N3, SR13, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl and aryl, or one of R2 and R2′ together with one of R3 and R3′ form of an epoxide;
- R5 is selected from H, P(═O)(OH)2 and P(═O)(OH)—O—P(═O)(OH)2;
- R6 is selected from H and C1-6-alkyl;
- R9-R13 are each independently selected from H and C1-6-alkyl;
- Base is a natural or non-natural nucleobase, and
- wherein the prodrug is selected from a phosphoramidate derivative, a SATE (S-acyl-2-thioethyl) ester derivative, a pivaloyloxymethyl (POM) derivative, an isopropyloxymethylcarbonyl (POC) derivative, a cyclo-saligenyl (cycloSal) derivative and an alkyloxyalkyl derivative.
A compound of formula (Id), or a pharmaceutically acceptable salt or prodrug thereof:
- wherein:
- X is selected from O and NR9;
- R1, R2, R2′, R3, R3′, R4, R8 and R8′ are each independently selected from H, OR10, halogen, CN, NR11R12, N3, SR13, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl and aryl, or one of R2 and R2′ together with one of R3 and R3′ form of an epoxide;
- R5 is selected from H, P(═O)(OH)2 and P(═O)(OH)—O—P(═O)(OH)2;
- R6 is selected from H and C1-6-alkyl;
- R9-R13 are each independently selected from H and C1-6-alkyl;
- Base is a natural or non-natural nucleobase, and
- wherein the prodrug is selected from a phosphoramidate derivative, a SATE (S-acyl-2-thioethyl) ester derivative, a pivaloyloxymethyl (POM) derivative, an isopropyloxymethylcarbonyl (POC) derivative, a cyclo-saligenyl (cycloSal) derivative and an alkyloxyalkyl derivative.
A compound of formula (Ie), or a pharmaceutically acceptable salt or prodrug thereof:
- wherein:
- X is selected from O and NR9;
- R1, R2, R2′, R3, R3′, R4, R8 and R8′ are each independently selected from H, OR10, halogen, CN, NR11R12, N3, SR13, C1-6-alkyl, C2-6-alkenyl, C2-6-alkynyl and aryl, or one of R2 and R2′ together with one of R3 and R3′ form of an epoxide;
- R5 is selected from H, P(═O)(OH)2 and P(═O)(OH)—O—P(═O)(OH)2;
- R6 is selected from H and C1-6-alkyl;
- R9-R13 are each independently selected from H and C1-6-alkyl;
- Base is a natural or non-natural nucleobase, and
- wherein the prodrug is selected from a phosphoramidate derivative, a SATE (S-acyl-2-thioethyl) ester derivative, a pivaloyloxymethyl (POM) derivative, an isopropyloxymethylcarbonyl (POC) derivative, a cyclo-saligenyl (cycloSal) derivative and an alkyloxyalkyl derivative.
A compound selected from the following:
- or a pharmaceutically acceptable salt or prodrug thereof
- wherein:
- R6 is selected from H and C1-6-alkyl;
- and
- Base is a natural or non-natural nucleobase, and
- wherein the prodrug is selected from a phosphoramidate derivative, a SATE (S-acyl-2-thioethyl) ester derivative, a pivaloyloxymethyl (POM) derivative, an isopropyloxymethylcarbonyl (POC) derivative, a cyclo-saligenyl (cycloSal) derivative and an alkyloxyalkyl derivative.
Dependencies are inferred from the claim text.