Analogues of coformycin and their use for treating protozoan parasite infections
View Patent ↗This invention relates to compounds that are analogues of coformycin, pharmaceutical compositions containing the compounds, and methods of using the compounds for treating protozoan parasite infections, especially malaria.
1. A compound of formula (I):
where
R 1 is methyl, ethyl, propyl or phenyl;
X is selected from hydrogen, hydroxyl and halogen;
Y is selected from hydrogen and hydroxyl;
Z is an oxygen atom; and
B is the radical of formula (II):
or a pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1 which has the formula (IA):
3. The compound as claimed in claim 1 which has the formula (IB):
4. The compound as claimed in claim 1 where R 1 is methyl.
5. The compound as claimed in claim 1 where X and Y are both hydroxyl.
6. The compound as claimed in claim 1 where X is hydroxyl and Y is hydrogen.
7. The compound as claimed in claim 1 where X is hydrogen and Y is hydroxyl.
8. The compound as claimed in claim 1 which is selected from:
(i) 5′-methylthiocoformycin [(8R)-8-hydroxy-3-(5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(ii) 2′-deoxy-5′-methylthiocoformycin [(8R)-8-hydroxy-3-(2-deoxy-5-methylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(iii) 3′-deoxy-5′-methylthiocoformycin [(8R)-8-hydroxy-3-(3-deoxy-5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(iv) 2′-deoxy-5′-propylthiocoformycin [[(8R)-8-hydroxy-3-(5-propylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine]; and
(v) 2′-deoxy-5′-phenylthiocoformycin [[(8R)-8-hydroxy-3-(5-phenylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine].
9. The compound as claimed in claim 1 which is 5′-methylthiocoformycin [(8R)-8-hydroxy-3-(5-methylthio-βD-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine].
10. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of claim 1 .
11. The pharmaceutical composition as claimed in claim 10 where the compound is selected from:
(i) 5′-methylthiocoformycin [(8R)-8-hydroxy-3-(5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(ii) 2′-deoxy-5′-methylthiocoformycin [(8R)-8-hydroxy-3-(2-deoxy-5-methylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(iii) 3′-deoxy-5′-methylthiocoformycin [(8R)-8-hydroxy-3-(3-deoxy-5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine];
(iv) 2′-deoxy-5′-propylthiocoformycin [[(8R)-8-hydroxy-3-(5-propylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine]; and
(v) 2′-deoxy-5′-phenylthiocoformycin [[(8R)-8-hydroxy-3-(5-phenylthio-β-D-erythro-pentofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine].
12. The pharmaceutical composition of claim 10 comprising a pharmaceutically effective amount of 5′-methylthiocoformycin [(8R)-8 -hydroxy-3-(5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine].
13. A method of treating or preventing a protozoan parasite infection comprising administering a pharmaceutically effective amount of the compound of claim 1 to a patient requiring treatment.
14. The method as claimed in claim 13 where the infection is caused by a protozoan parasite of the genera Giardia, Trichomonas, Leishmania, Trypanosoma, Crithidia, Herpetomonas, Leptomonas, Histomonas, Eimeria, Isopora, Neospora , or Plasmodium.
15. The method as claimed in claim 13 where the infection is malaria.
16. The method as claimed in claim 13 where the infection is malaria and the compound is 5′-methylthiocoformycin [(8R)-8-hydroxy-3-(5-methylthio-β-D-ribofuranosyl)-3,6,7,8-tetrahydroimidazo[4,5-d][1,3]diazepine].
17. A process for preparing a compound of formula (I) as claimed in claim 1 comprising the following steps:
step (i) reacting a glycosyl donor compound of formula (III):
where
L is a leaving group;
X 1 is selected from hydrogen, halogen, acyloxy, and arylcarbonyloxy; and Y 1 is selected from hydrogen and acyloxy; or
X 1 and Y 1 are oxygen atoms linked together by a protecting group; and
R 1 is methyl, ethyl, propyl or phenyl;
with a compound of formula (IV) in the presence of a glycosyl donor activating reagent:
where
R 2 is a protecting group; and
R 3 is a protecting group; and
step (ii) removing the protecting groups to give hydroxyl or amine groups by any one or more of:
(a) acid- and/or base-catalyzed hydrolysis;
(b) acid- and/or base-catalyzed alcoholysis; and
(c) catalytic hydrogenolysis.
18. A process for preparing a compound of formula (I) as claimed in claim 1 comprising the following steps:
step (i) selective sulfonylation of the primary hydroxyl group of a compound of formula (V):
where
X is selected from hydrogen, hydroxyl and halogen;
Y is selected from hydrogen and hydroxyl;
Z is an oxygen atom; and
B is the radical of formula (VI)
where
R 2 is a protecting group; and
R 3 is a protecting group;
step (ii) reacting the product with a thiolate salt of formula R 1 SM, where M is a metal cation and R 1 is methyl, ethyl, propyl or phenyl; and
step (iii) removing any remaining protecting groups.
19. The process of claim 18 , further comprising preparing the compound of formula (V) by:
reacting a glycosyl donor compound of formula (III):
where
L is a leaving group;
X 1 is selected from hydrogen, halogen, acyloxy, and arylcarbonyloxy; and
Y 1 is selected from hydrogen and acyloxy; or
X 1 and Y 1 are oxygen atoms linked together by a protecting group; and
Y 2 is acyloxy;
with a compound of formula (IV) in the presence of a glycosyl donor activating reagent or a metal hydride such as sodium hydride
where
R 2 is a protecting group; and
R 3 is a protecting group; and
removing the protecting groups on the sugar moiety to give hydroxyl groups by any one or more of:
(a) acid- and/or base-catalyzed hydrolysis;
(b) acid- and/or base-catalyzed alcoholysis; and
(c) catalytic hydrogenolysis.