3-hydroxypyrrolidine inhibitors of 5′-methylthioadenosine phosphorylase and nucleosidase
View Patent ↗The present invention relates to 3-hydroxypyrrolidine compounds of the general formula (I) which are inhibitors of 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase. The invention also relates to the use of these compounds in the treatment of diseases or conditions in which it is desirable to inhibit 5′-methylthioadenosine phosphorylase or 5′-methylthioadenosine nucleosidase including cancer, and to pharmaceutical compositions containing the compounds.
1. A compound of the formula (I):
where:
X is a cycloalkyl, alkenyl, alkynyl or aryl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
or X is a butyl, isobutyl, or pent-3-yl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
or X is an alkyl group which is substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole, or NR 2 R 3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
or X is SR 1 ; or X is NR 2 R 3 ; or X is propyl;
R 1 , R 2 and R 3 are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2a R 3a group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
R 2a and R 3a are independently selected from the group consisting of alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano or thiazole group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
A is CH;
B is NH 2 or NHR 5 ;
R 5 is an alkyl, alkenyl, alkynyl, aralkyl, aralkenyl, aralkynyl, or aryl group, each of which is optionally substituted with one or more halogen or hydroxy groups; and
D is H, OH, NH 2 , or SCH 3 ;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof;
provided that when B is NH 2 , and D is H, X is not propyl, CH 2 OH, CH 2 SQ, where Q is an optionally substituted alkyl or aryl group, or CH 2 OQ, where Q is an optionally substituted alkyl group.
2. A compound as claimed in claim 1 which is a compound of the formula (Ia):
provided that when B is NH 2 and D is H, X is not propyl, CH 2 OH, CH 2 SQ, where Q is an optionally substituted alkyl or aryl group, or CH 2 OQ, where Q is an optionally substituted alkyl group;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof.
3. A compound as claimed in claim 1 which is a compound of the formula (Ib):
provided that X is not propyl, CH 2 OH, CH 2 SQ, where Q is an optionally substituted alkyl or aryl group, or CH 2 OQ, where Q is an optionally substituted alkyl group;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof.
4. A compound as claimed in claim 1 where X is an alkenyl or alkynyl group each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
5. A compound as claimed in claim 1 where X is a cycloalkyl, alkenyl, alkynyl or aryl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups;
or X is a butyl, isobutyl, or pent-3-yl group each of which is optionally substituted with one or more substituents selected from the group consisting hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
6. A compound as claimed in claim 1 where X is a cycloalkyl group which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
7. A compound as claimed in claim 1 where X is a cycloalkyl group where one or more of the ring atoms is a heteroatom.
8. A compound as claimed in claim 1 where X is an aryl group which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2 R 3 group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
9. A compound as claimed in claim 1 where X is SR 1 , where R 1 is alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2a R 3a group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
10. A compound as claimed in claim 1 where X is NR 2 R 3 , where R 2 and R 3 are independently selected from alkyl, alkenyl, alkynyl, aralkyl or aryl, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, aralkylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole or NR 2a R 3a group, where each alkylthio, arylthio and aralkylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.
11. A compound as claimed in claim 1 where B is NH 2 .
12. A compound selected from the group consisting of:
i. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-phenylpyrrolidine;
ii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-vinylpyrrolidine;
iii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-4-ethenyl-3-hydroxypyrrolidine;
iv. (±)-trans-4-Allyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
v. (±)-trans-4-Cyclopropyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
vi. (±)-trans-4-Cyclohexyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
vii. (±)-trans-4-Cyclohexylmethyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
viii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-prop-1-en-2-yl-pyrrolidine;
ix. (±)-trans-4-Butyl-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
x. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-pent-3-yl-pyrrolidine;
xi. (±)-trans-4-Cyclopentyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(1H-1,2,3-triazol-1-yl)pyrrolidine;
xiii. (±)-trans-4-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xiv. (3R,4S)-4-Butyl-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xv. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-phenylpyrrolidine;
xvi. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-vinylpyrrolidine;
xvii. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-4-ethynyl-3-hydroxy-pyrrolidine;
xviii. (3R,4S)-4-Allyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xix. (3R,4S)-4-Cyclopropyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xx. (3R,4S)-4-Cyclohexyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xxi. (3R,4S)-4-Cyclohexylmethyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xxii. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-prop-1-en-2-yl-pyrrolidine;
xxiii. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-pent-3-yl-pyrrolidine;
xxiv. (3R,4S)-4-Cyclopentyl-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xxv. (3S,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(1H-1,2,3-triazol-1-yl)pyrrolidine;
xxvi. (3R,4R)-4-(1-Benzyl-1H-1,2,3-triazol-4-yl)-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xxvii. (3R,4S)-4-(3-Benzylthiopropyl)-1-[(9-deaza-adenin-9-yl)methyl]-3-hydroxypyrrolidine;
xxvii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(2-methylpropyl)pyrrolidine;
xxix. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(2-methylpropyl)pyrrolidine;
xxx. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(thiazol-2-yl)-pyrrolidine;
xxxi. (3R,4S)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(thiazol-2yl)-pyrrolidine
xxxii. (±)-trans-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(tetrazol-5-yl)-pyrrolidine; and
xxxiii. (3R,4R)-1-[(9-Deaza-adenin-9-yl)methyl]-3-hydroxy-4-(tetrazol-5-yl)-pyrrolidine;
or a tautomer thereof, or a pharmaceutically acceptable salt thereof, or an ester prodrug form thereof.
13. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 1 .
14. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound as claimed in claim 12 .
15. A compound as claimed in claim 1 where X is an alkyl group which is substituted with one or more substituents selected from the group consisting of hydroxy, alkoxy, cycloalkyl, thiol, alkylthio, arylthio, halogen, carboxylic acid, carboxylate alkyl ester, nitro, cyano, thiazole, or NR 2 R 3 group, where each alkylthio and arylthio group is optionally substituted with one or more alkyl, halogen, amino, hydroxy, or alkoxy groups.