2′ and/or 5′ amino-acid ester phosphoramidate 3′-deoxy adenosine derivatives as anti-cancer compounds
Disclosed are chemical compounds, the compounds for use in a method of treatment, particularly in a method of prophylaxis or treatment for cancer, a process for preparation of the compounds and pharmaceutical compositions comprising the compounds. The compounds may, in particular, be useful in the treatment of leukaemia, lymphoma and/or solid tumours in Homo sapiens . The compounds are derivatives of cordycepin (3′-deoxyadenosine) having a 2′ and/or 5′-amino-acid ester phosphoramidate moiety.
1. A compound of formula (Ib):
wherein:
W 1 and W 2 are each independently selected from the group consisting of —P(═O)(U)(V) and H, with the proviso that at least one of W 1 and W 2 is —P(═O)(U)(V),
where U and V, independently for each of W 1 and W 2 , are selected from the group consisting of:
(a) U is —OAr and V is —NR 4 —CR 1 R 2 —C(═O)OR 3 ,
where Ar is selected from the group consisting of C 6-30 aryl and 5-30-membered heteroaryl, each of which is optionally substituted with one, two, or three substituents selected from halo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, nitro and cyano;
each of R 1 and R 2 is independently selected from H, and the group consisting of C 1-20 alkyl, C 6 arylC 1-6 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6 aryl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-30 aryl, C 6-30 aryloxy and 5-20-membered heterocyclyl;
R 3 is selected from H, and the group consisting of straight, branched, or cyclic butyl, pentyl, hexyl, octyl, nonyl, and dodecyl groups, C 6-30 arylC 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-30 aryl, and 5-20-membered heterocyclyl;
R 4 is selected from H, and the group consisting of C 1-20 alkyl, C 6-30 arylC 1-20 alkyl, C 2-20 alkenyl, C 1-20 alkoxy, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-30 aryl, C 6-30 aryloxy and 5-20-membered heterocyclyl;
and
(b) each of U and V is selected independently from —NR 5 R 6 ,
where R 5 is selected from the group consisting of H and C 1-6 alkyl and R 6 is —CR 7 R 8 CO 2 R 9 , where R 7 and R 8 are selected independently from the group consisting of the side chains, including H, of naturally occurring alpha amino acids and R 9 is selected from H, and the group consisting of C 1-20 alkyl, C 6-30 arylC 1-20 alkyl-, C 2-20 alkenyl, C 1-20 alkoxyC 1-20 alkyl, C 1-20 alkoxyC 6-30 aryl, C 2-20 alkynyl, C 3-20 cycloalkyl, C 6-30 aryl, and 5-20-membered heterocyclyl; or
R 5 and R 6 together with the N atom to which they are attached form a ring moiety comprising 5 to 8 ring atoms;
X is selected from the group consisting of: NR 12 R 13 , where each of R 12 and R 13 is independently selected from the group consisting of H and C 1-6 alkyl; and —SR 14 where R 14 is selected from the group consisting of H and C 1-6 alkyl;
Z is independently selected from the group consisting of H, OH, F, Cl, Br, I, C 1-6 alkyl, —NR 12 R 13 , and —SR 14 where R 14 is selected from the group consisting of H and C 1-6 alkyl; and
Y is selected from the group consisting of H, OH, F, Cl, Br, I, —OC 1-6 alkyl, C 1-6 alkyl, C 2-8 alkynyl, —NR 15 R 16 where each of R 15 and R 16 is independently selected from H and C 1-6 alkyl, and —SR 17 where R 17 is selected from the group consisting of H and C 1-6 alkyl,
or a pharmaceutically acceptable salt of the compound of formula (Ib).
2. The compound of claim 1 , wherein the compound is represented by formula (II):
wherein X is —NR 12 R 13 .
3. The compound according to claim 1 , wherein Ar is selected from the group consisting of phenyl and napthyl.
4. The compound according to claim 3 , wherein Ar is unsubstituted.
5. The compound according to claim 3 , wherein Ar is substituted with one, two, or three substituents selected from the group consisting of: halo, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, nitro and cyano.
6. The compound according to claim 1 , wherein R 2 is C 1 -C 4 -alkyl.
7. The compound according to claim 6 , wherein R 2 is methyl.
8. The compound according to claim 7 , wherein the C atom bearing R 1 and R 2 has the same absolute configuration as of L-alanine.
9. The compound according to claim 1 , wherein R 3 is selected from the group consisting of benzyl and straight, branched, or cyclic butyl, pentyl, hexyl, octyl, nonyl, and dodecyl groups.
10. The compound according to claim 9 , wherein R 3 is selected from the group consisting of benzyl and n-pentyl.
11. The compound according to claim 10 , wherein R 3 is benzyl.
12. The compound according to claim 1 , wherein X is NH 2 .
13. The compound according to claim 1 , wherein Y is H.
14. The compound according to claim 1 , wherein Z is H.
15. The compound according to claim 1 , wherein Z is F.
16. The compound according to claim 1 , wherein Z is Cl.
17. The compound according to claim 1 , wherein Z is OMe.
18. The compound of claim 1 , wherein the compound is selected from the group consisting of:
(2S)-Benzyl 2-(((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)amino)propanoate;
Benzyl 2-(((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)acetate;
(2S)-Pentyl 2-(((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphoryl)amino)-4-methylpentanoate;
(2S)-Benzyl 2-(((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(2-(3-ethoxy-3-oxopropyl)phenoxy)phosphoryl)amino)propanoate;
(2S)-Benzyl 2-(((((2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(phenoxy)phosphoryl)amino)propanoate;
Benzyl 2-(((((2S,4R,5R)-5-(6-amino-9H-purin-9-yl)-4-((((1-(benzyloxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;
(2S)-Benzyl 2-(((((2R,3R,5S)-2-(6-amino-9H-purin-9-yl)-5-(hydroxymethyl)tetrahydrofuran-3-yl)oxy)(naphthalen-1-yloxy)phophoryl)amino)proponate;
Benzyl 2-[({[5-(6-amino-9H-purin-9-yl)-4-hydroxyoxolan-2-yl]methoxy}({[1-(benzyloxy)-1-oxopropan-2-yl]amino})phosphoryl)amino]propanoate;
(2S)-Benzyl 2-((((2S,4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate;
(2S)-Benzyl 2-((((2S,4R,5R)-5-(6-amino-2-methoxy-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate;
(2S)-Benzyl 2-(((((2S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;
(2S)-Hexyl 2-(((((2S,4R,5R)-5-(6-amino-2-fluoro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate;
(2R)-Benzyl 2-((((2S,4R,5R)-5-(6-amino-2-chloro-9H-purin-9-yl)-4-hydroxytetrahydrofuran-2-yl)methoxy)(naphthalen-1-yloxy)phosphorylamino)propanoate;
2-O-Methyl-3′-deoxyadenosine-5′-O-[1-naphthyl(1-pentyloxy-L-leucinyl)] phosphate;
2-O-Methyl-3′-deoxyadenosine-5′-O-[phenyl(1-hexyloxy-L-alaninyl)] phosphate;
2-Fluoro-3′-deoxyadenosine-5′-O-[1-naphthyl(benzyloxy-L-alaninyl)] phosphate;
2-Fluoro-3′-deoxyadenosine-5′-O-[1-naphthyl(1-pentyloxy-L-leucinyl)] phosphate;
2-Chloro-3′deoxyadenosine 5′-O-[1-phenyl (2,2-dimethylpropoxy-L-alanine)] phosphate; and
2-Chloro-3′deoxyadenosine 5′-O-[1-naphtyl (2,2-dimethylpropoxy-L-alanine)] phosphate.
19. A pharmaceutical composition, comprising a compound according to claim 1 ; and a pharmaceutically acceptable excipient.