5H-pyrrolo[3,2-d]pyrimidine nucleoside metabolism inhibitors
View Patent ↗The present invention provides a compound of the formula (I): wherein A is selected from N, CH and CR, where R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3 , where R 1 , R 2 and R 3 are each optionally substituted alkyl, aralkyl or aryl groups; B is selected from OH, NH 2 , NHR 4 , H and halogen, where R 4 is an optionally substituted alkyl, aralkyl or aryl group; D is selected from OH, NH 2 , NHR 5 , H, halogen and SCH 3 , where R 5 is an optionally substituted alkyl, aralkyl or aryl group; X and Y are independendy selected from H, OH and halogen, with the proviso that when one of X and Y is hydroxy or halogen, the other is hydrogen; Z is OH, or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ and OQ, where Q is an optionally substituted alkyl, aralkyl or aryl group; and W is OH or H, with the proviso that when W is OH, then A is CR where R is as defined above; or a tautomer thereof; or a pharmaceutically acceptable salt thereof; or an ester thereof. The invention also provides pharmaceutical compositions comprising compounds of formula (I), methods of preparing compounds of formula (I), and methods of treatment using compounds of formula (I).
1. A compound of the formula:
wherein:
A is CH or CR, where R is selected from halogen, optionally substituted alkyl, aralkyl and aryl, OH, NH 2 , NHR 1 , NR 1 R 2 and SR 3 , where R 1 , R 2 and R 3 are each optionally substituted alkyl, aralkyl or aryl groups;
B is OH;
D is selected from OH, NH 2 , NHR 5 , H, halogen and SCH 3 , where R 5 is an optionally substituted alkyl, aralkyl or aryl group;
X and Y are independently selected from H, OH and halogen, with the proviso that when one of X and Y is hydroxy or halogen, the other is hydrogen;
Z is OH, or, when X is hydroxy, Z is selected from hydrogen, halogen, hydroxy, SQ and OQ, where Q is an optionally substituted alkyl, aralkyl or aryl group; and
W is OH or H, with the proviso that when W is OH, then A is CR where R is as defined above;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
2. A compound as claimed in claim 1 , wherein D is NHR 5 , and R 5 is C 1 –C 4 alkyl.
3. A compound as claimed in claim 1 wherein when one or more halogens are present, they are chosen from chlorine or fluorine.
4. A compound as claimed in claim 1 wherein when Z is SQ or OQ, Q is C 1 –C 5 alkyl or phenyl.
5. A compound as claimed in claim 1 wherein either D is H.
6. A compound as claimed in claim 1 wherein D is H, OH or NH 2 , X is OH or H and Y is H.
7. A compound as claimed in claim 1 wherein Z is OH, H or methylthio.
8. A compound as claimed in claim 1 wherein W is OH, Y is H, X is OH, and A is CR where R is methyl or halogen.
9. A compound as claimed in claim 1 wherein W is H, Y is H, X is OH and A is CH.
10. A compound as claimed in claim 1 selected from
(1S)-1-(9-deaza-8-fluorohypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol;
(1S)-1-(9-deaza-8-methylhypoxanthin-9-yl)-1,4-dideoxy-1,4-imino-D-ribitol; or
( 1 S)-1-(9-deazahypoxanthin-9-yl)-1,3,4trideoxy-1,4-imino-D-ribitol;
or a tautomer thereof; or a pharmaceutically acceptable salt thereof.
11. A composition comprising a compound of the formula (I) as claimed in claim 1 , and a carrier or diluent.
12. A method for preparing a compound of the formula (I) as defined in claim 1 , wherein A is CR and R is as defined in claim 1 , the method comprising reacting a compound of formula (II)
wherein R 9 is an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R 6 is an N-protecting group, B′ and D′ are independently selected from H, OR 7 and N(R 8 ) 2 , and R 7 and R 8 are O- and N-protecting groups respectively;
(i) with a strong base capable of deprotonation at C-8 of the 9-deazapurine moiety; then
(ii) with an electrophile selected from the group consisting of an alkyl halide, an aldehyde, a formylating agent and N-fluorosulfomidobenzene; and
(iii) O- and N-deprotecting the product by acid-, alkali- or fluoride ion-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis as required for the O- and N-protecting groups in use.
13. A method as claimed in claim 12 wherein the strong base comprises butyllithium.
14. A method for preparing a compound of the formula (I) as defined in claim 1 , wherein W is H, the method comprising reacting a compound of formula (III)
wherein R 9 is an alkoxycarbonyl or aralkyloxycarbonyl group, Z′ is a hydrogen or halogen atom, a group of formula SQ or OQ, or a trialkylsilyloxy, alkyldiarylsilyloxy or optionally substituted triarylmethoxy group and Q is an optionally substituted alkyl, aralkyl or aryl group, and R 6 is an N-protecting group, B′ and D′ are independently selected from H, OR 7 and N(R 8 ) 2 , R 7 and R 8 are O- and N-protecting groups, respectively, and R 10 is an O-protecting group;
(i) with a thiocarbonylating agent; then
(ii) with a radical reducing agent; and
(iii) O- and N-deprotecting the product by acid-, alkali- or fluoride ion-catalyzed hydrolysis or alcoholysis or catalytic hydrogenolysis as required for the O- and N-protecting groups in use.
15. A method as claimed in claim 14 wherein the thiocarbonylating agent is thiocarbonyl diimidazole.
16. A method as claimed in claim 14 wherein the radical reducing agent comprises tributyltin hydride.
17. The method of claim 12 , wherein the electrophile is N-fluorosulfomidobenzene.
18. The method of claim 12 , wherein the electrophile is methyl iodide, acetaldehyde or dimethylformamide.