Iron binding agents
View Patent ↗Composition, article of manufacture for and method of treating malaria in a human having an infestation of Plasmodium protozoans are described. The method comprises administering a therapeutically-effective amount of a compound of formula (I) or (IV), i.e. sufficient quantity to reduce the population of Plasmodium. The composition of the invention is a compound of formula (I) or (IV) with a pharmaceutical excipient. The article of manufacture is the composition in combination with labeling for treating malaria. The substituents are detailed in the specification.
1. A pharmaceutical composition comprising a compound represented by formula (I) or (V), in combination with a pharmaceutically acceptable excipient, wherein formulas (I) and (V) are
where:
R is OH, OR 7 , or N(OH)R 8 ;
R 1 is H, CH 3 or absent;
R 2 is H, CH 3 or absent, provided that R 1 and R 2 are not both absent;
R 3 is H or CH 3 , or R 3 is absent when one of R 1 or R 2 is absent forming a double bond between the R 1 /R 2 carbon and the R 3 carbon;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is ((CH 2 ) a (R 10 )) b (CH 2 ) a R 10 ((CH 2 ) a (R 10 )) b X;
R 6 is H, OH, alkyl of 1-6 carbons or a halogen, or R 6 is —C═C—C═C—, which, together with R 11 forms a fused ring system as follows:
R 7 is alkyl of one to four carbons or optionally substituted benzyl;
R 8 is H, alkyl of one to four carbons, optionally substituted benzyl, or
R 9 is H, alkyl of one to tour carbons or optionally substituted benzyl;
R 10 is O or CH 2 ;
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons or R 11 is part of a fused ring system when R 6 is —C═C—C═C—;
A is CH or C(OH);
B is S, O, N or CH 2 ;
a is 2 or 3;
b is 0 or 1;
m is an integer from 1 to 8;
n is 0 or 1;
p is 0, 1 or 2; and
X is
wherein each of the substituents shown is defined above,
or a pharmaceutically acceptable salt of the compound represented by formula (I) or (V)
or a stereoisomer of the compound or mixture of stereoisomers.
2. The composition of claim 1 , wherein A is CH.
3. The composition of claim 2 , wherein B is S, and n and p each is 0.
4. The composition of claim 3 , wherein R 4 is H.
5. The composition of claim 4 , wherein R is OH.
6. The composition of claim 5 , wherein R 11 is H.
7. The composition of claim 5 , wherein R 11 is OH.
8. The composition of claim 5 , wherein R 11 is OH, and each of R 1 and R 2 is H.
9. The composition of claim 8 , wherein a is 2 and each of R 3 and R 6 is H.
10. The composition of claim 9 , wherein R 10 is CH 2 and b is 0.
11. The composition of claim 9 , wherein R 10 is CH 2 and b is 1.
12. The composition of claim 9 , wherein R 10 is O and b is 0.
13. The composition of claim 9 , wherein R 10 is O and b is 1.
14. A pharmaceutical composition comprising a compound represented by formula (I) or (V), in combination with a pharmaceutically acceptable excipient, wherein formulas (I) and (V) are
where:
R is N(OH)R 8 ;
R 1 is H, CH 3 or absent;
R 2 is H, CH 3 or absent, provided that R 1 and R 2 are not both absent;
R 3 is H or CH 3 , R 3 is absent when one of R 1 or R 2 is absent forming a double bond between the R 1 /R 2 carbon and the R 3 carbon;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
R 6 is H, OH, alkyl of 1-6 carbons or a halogen, or R 6 is —C═C—C═C—, which, together with R 11 forms a fused ring system as follows:
R 8 is
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons or R 11 is part of a fused ring system when R 6 is —C═C—C═C—;
A is CH or C(OH);
B is S, O, N or CH 2 ;
n is 0 or 1;
p is 0, 1 or 2; and
Z is
wherein each of the substituents shown is defined above,
or a pharmaceutically acceptable salt of the compound represented by formula (I) or (V) or a stereoisomer of the compound or mixture of stereoisomers.
15. The composition of claim 14 , wherein A is CH.
16. The composition of claim 15 , wherein B is S, and n and p each is 0.
17. The composition of claim 15 , wherein
each of R 1 , R 2 , R 3 and R 4 is H or CH 3 ,
each of R 5 and R 11 , is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons, and
R 6 is H, OH, alkyl of 1-6 carbons or a halogen.
18. The composition of claim 17 , wherein R 4 is H.
19. A pharmaceutical composition comprising a compound represented by formula (I) or (V), in combination with a pharmaceutically acceptable excipient, wherein formulas (I) and (V) are
where:
R is OH, OR 7 , or N(OH)R 8 ;
R 1 is H, CH 3 or absent;
R 2 is H, CH 3 or absent, provided that R 1 and R 2 are not both absent;
R 3 is H or CH 3 , or R 3 is absent when one of R 1 or R 2 is absent forming a double bond between the R 1 /R 2 carbon and the R 3 carbon;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
R 6 is (CH 2 ) a R 10 (CH 2 ) r R 10 Y;
R 7 is alkyl of one to four carbons or optionally substituted benzyl;
R 8 is H, alkyl of one to four carbons, optionally, substituted benzyl, or
R 9 is H, alkyl of one to four carbons or optionally substituted benzyl;
R 10 is O or CH 2 ;
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
A is CH or C(OH);
B is S, O, N or CH 2 ;
a is 2 or 3;
m is an integer from 1 to 8;
n is 0 or 1;
p is 0, 1 or 2;
r is 2 or 3; and
Y is
wherein each of the substituents shown is defined above,
or a pharmaceutically acceptable salt of the compound represented by formula (I) or (V) or a stereoisomer of the compound or mixture of stereoisomers.
20. The composition of claim 19 , wherein A is CH.
21. The composition of claim 20 , wherein B is S, and n and p each is 0.
22. The composition of claim 21 , wherein R 4 is H.
23. The composition of claim 22 , wherein R is N(OH)R 8 .
24. The composition of claim 22 , wherein R 11 is OH and each of R 1 and R 2 is H.
25. The composition of claim 24 , wherein a is 3, and each of R 3 and R 5 is H.
26. The composition of claim 25 , wherein R 10 is CH 2 and r is 2.
27. The composition of claim 25 , wherein R 10 is CH 2 and r is 3.
28. The composition of claim 25 , wherein R 10 is O and r is 2.
29. The composition of claim 25 , wherein R 10 is O and r is 3.
30. The composition of claim 3 , wherein R is N(OH)R 8 .
31. The composition of claim 23 , wherein R 11 is OH and each of R 1 and R 2 H.
32. The composition of claim 31 , wherein a is 3 and each of R 3 and R 5 is H.
33. The composition of claim 32 , wherein R 8 is CH 3 , R 10 is O and r is 3.
34. The composition of claim 18 , wherein R 11 is OH.
35. The composition of claim 34 , wherein each of R 1 and R 2 is H.
36. The composition of claim 35 , wherein each of R 3 , R 5 and R 6 is H.
37. A compound of the formula:
wherein:
R is N(OH)R 8 ;
each of R 1 , R 2 and R 3 is H or CH 3 ;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
R 6 is H, OH, alkyl of 1-6 carbons or halogen;
R 8 is
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
A is CH;
B is S, O, N or CH 2 ;
n and p each is 0;
z is
wherein each of the substitutes shown is described above, or a pharmaceutically-acceptable salt of the compound of formula (I) or a stereoisomer of the compound or mixture of stereoisomers.
38. The compound of claim 37 , wherein A is CH and B is S.
39. The compound of claim 38 , wherein R 4 is H.
40. The compound of claim 39 , wherein each of R 1 and R 2 is H.
41. The compound of claim 40 , wherein R 11 is OH, and each of R 3 , R 5 and R 6 is H.
42. A compound of the formula:
wherein:
R is OH or N(OH)R 8 ;
each of R 1 , R 2 and R 3 is H or CH 3 ;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is ((CH 2 ) a (R 10 )) b (CH 2 ) a R 10 ((CH 2 ) a (R 10 )) b X;
R 6 is H, OH, alkyl of 1-6 carbons or halogen;
R 8 is H, alkyl of 1-4 carbons, optionally substituted benzyl or (CH 2 ) m N(OH)C(O)R 9 ;
R 9 is H, alkyl of 1-4 carbons or optionally substituted benzyl;
R 10 is O or CH 2 ;
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
A is CH;
B is S, O, N or CH 2 ;
a is 2 or 3;
b is 0 or 1;
n and p each is 0; and
X is
wherein each of the substituents shown is described above,
or a pharmaceutically acceptable salt of the compound of formula (I) or a stereoisomer of the compound or mixture of stereoisomers.
43. The compound of claim 42 , wherein A is CH and B is S.
44. The compound of claim 43 , wherein R 4 is H, each of R and R 11 is OH, and each of R 1 and R 2 is H.
45. The compound of claim 44 , wherein a is 2 and R 3 and R 6 are H.
46. The compound of claim 45 , wherein R 10 is CH 2 and b is 0.
47. The compound of claim 45 , wherein R 10 is CH 2 and b is 1.
48. The compound of claim 45 , wherein R 10 is O and b is 0.
49. The compound of claim 45 , wherein R 10 is O and b is 1.
50. A compound of the formula:
wherein:
R is OH or N(OH)R 8 ;
each of R 1 , R 2 and R 3 is H or CH 3;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
R 6 is (CH 2 ) a R 10 (CH 2 ) r R 10 Y;
R 8 is H, alkyl of 1-4 carbons, optionally substituted benzyl or (CH 2 ) m N(OH)C(OH)R 9 ;
R 9 is H, alkyl of 1-4 carbons, or optionally substituted benzyl;
R 10 is O or CH 2 ;
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
A is CH;
B is S, O, N or CH 2 ;
a is 2 or 3;
n and p each is 0;
r is 2 or 3;
Y is
wherein each of the substituents shown is described above,
or a pharmaceutically acceptable salt of the compound of formula (I) or a stereoisomer of the compound or a mixture of stereoisomers.
51. The compound of claim 50 , wherein A is CH and B is S.
52. The compound of claim 51 , wherein a is 3, each of R 1 , R 2 , R 3 , R 4 and R 5 is H, and each of R and R 11 is OH.
53. The compound of claim 52 , wherein R 10 is CH 2 and r is 2.
54. The compound of claim 52 , wherein R 10 is CH 2 and r is 3.
55. The compound of claim 52 , wherein R 10 is O and r is 2.
56. The compound of claim 52 , wherein R 10 is O and r is 3.
57. A compound of the formula:
wherein:
R 1 is H or CH 3 ;
R 2 is H or CH 3 ;
R 3 is H or CH 3 ;
R 4 is H, acyl of 1-4 carbons or alkyl of 1-4 carbons;
R 5 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
R 11 is H, OH, O-acyl of 1-4 carbons or O-alkyl of 1-4 carbons;
A is CH;
B is S, O, N or CH 2 ;
a is 1, 2 or 3;
b is an integer from 2 to 8;
n is 0 or 1;
p is 0, 1 or 2;
r is 1, 2 or 3; and
s is 1, 2 or 3,
or a pharmaceutically acceptable salt of the compound or a stereoisomer of the compound or a mixture of stereoisomers.
58. The compound of claim 57 , wherein A is CH.
59. The compound of claim 58 , wherein B is S.
60. The compound of claim 59 , wherein R 4 is H.
61. The compound of claim 60 , wherein R 11 is OH, R 1 , R 2 and R 5 are H, and n and p are 0.
62. The compound of claim 61 , wherein r and s are 3, a is 2, and b is 2.