4-amino-5H-pyrrolo[3,2-d]pyrimidine inhibitors of nucleoside phosphorylases and nucleosidases
View Patent ↗The invention provides a compound of the formula: wherein A is selected from N, CH and CR; R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3 ; R 1 , R 2 and R 3 are each optionally substituted alkyl, aralkyl or aryl groups; B is selected from NH 2 and NHR 4 ; R 4 is an optionally substituted alkyl, aralkyl or aryl group; X is selected from H, OH and halogen; Z is selected from H, Q, SQ and OQ; Q is an optionally substituted alkyl, aralkyl or aryl group; or a tautomer, a pharmaceutically acceptable salt, an ester, or a prodrug thereof; with the proviso that the stereochemistry of the aza-sugar moiety is D-ribo or 2′-deoxy-D-erythro-; pharmaceutical compositions comprising said compound; and methods of treatment using said compound.
1. A compound of the formula (I):
wherein:
A is selected from CH and CR,
where R is selected from halogen, alkyl, aralkyl, aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3,
where R 1, R 2 and R 3 are each alkyl, aralkyl or aryl groups;
B is selected from NH 2 and NHR 4,
where R 4 is an alkyl, aralkyl or aryl group;
X is selected from H, OH and halogen; and
Z is SQ, where Q is a C 2 –C 5 alkyl group; a C 2 –C 5 alkyl group substituted with a halogen; a phenyl group; or a phenyl group substituted with a halogen or a methyl;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof;
with the proviso that the stereochemistry of the aza-sugar moiety is D-ribo or 2′-deoxy-D-erythro-.
2. A compound as claimed in claim 1 , where A is CH.
3. A compound as claimed in claim 1 , where B is NH 2 .
4. A compound as claimed in claim 1 , where Q is C 2 –C 5 alkyl.
5. A compound as claimed in claim 1 where X is OH.
6. A compound as claimed in claim 1 , where Q is selected from phenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-methylphenyl, and 4-methylphenyl.
7. A compound as claimed in claim 1 , selected from:
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-5-ethylthio-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-phenylthio-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-(4-methylphenyl)thio-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-(3-methylphenyl)thio-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-5-(4-chlorophenyl)thio-1,4-dideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-5-(3-chlorophenyl)thio-1,4-dideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-5-(4-fluorophenyl)thio-1,4-imino-D-ribitol; and
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-5-(2-fluoroethyl)thio-1,4-imino-D-ribitol;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 1 and a carrier.
9. A compound of the formula (I):
wherein:
A is selected from CH and CR,
where R is selected from halogen, alkyl, aralkyl, aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3 ,
where R 1 , R 2 and R 3 are each alkyl, aralkyl or aryl groups;
B is selected from NH 2 and NHR 4 ,
where R 4 is an alkyl, aralkyl or aryl group;
X is selected from H, OH and halogen; and
Z is Q, where Q is an alkyl, aralkyl or aryl group;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof;
with the proviso that the stereochemistry of the aza-sugar moiety is D-ribo or 2′-deoxy-D-erythro-.
10. A compound as claimed in claim 9 , where A is CH.
11. A compound as claimed in claim 9 , where B is NH 2 .
12. A compound as claimed in claim 9 , where X is OH.
13. A compound as claimed in claim 9 , selected from:
(1S)-1-(9-deazaadenin-9-yl)-1,4,5-trideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4,5-trideoxy-5-ethyl-1,4-imino-D-ribitol;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 9 and a carrier.
15. A compound as claimed in claim 1 , where Q is a C 2 –C 5 alkyl group substituted with a fluoro, or a phenyl group substituted with a chloro or a fluoro.
16. A compound selected from:
(1S)-1-(9-deazaadenin-9-yl)-1,4,5-trideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-5-benzylthio-1,4-dideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-5-(2-hydroxyethyl)thio-1,4-imino-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-(1-naphthyl)thio-D-ribitol;
(1S)-1-(9-Deazaadenin-9-yl)-1,4,5-trideoxy-5-ethyl-1,4-imino-D-ribitol; and
(1S)-1-(9-deazaadenin-9-yl)-1,4-dideoxy-1,4-imino-5-O-methyl-D-ribitol;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof.