Tetracycline compounds for treatment of cryptosporidium parvum related disorders
View Patent ↗Methods and compositions for treating Cryptosporidium parvum related disorders in a mammal are discussed. Several novel tetracycline compounds useful for treating Cryptosporidium parvum related disorders are also included.
1. A method for controlling Cryptosporidium parvum in a mammal, comprising administering to said mammal an effective amount of a tetracycline compound, wherein the tetracycline compound is of formula I:
wherein:
X is CHC(R 13 Y′Y) or CHR 6 ;
R 2 , R 4 and R 4 ′ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic;
R 2 ′, R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 5 is hydroxy, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 6 , R 7 , R 8 and each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 9 is hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and pharmaceutically acceptable salts thereof, such that Cryptosporidium parvum is controlled in said mammal.
2. The method of claim 1 , wherein R 2 , R 2 ′, R 3 , R 10 , R 11 , and R 12 are each hydrogen.
3. The method of claim 1 , wherein R 4 and R 4 ′ are each alkyl.
4. The method of claim 1 , wherein R 4 and R 4 ′ are each methyl.
5. The method of claim 1 , wherein R 5 is alkanoyl.
6. The method of claim 4 , wherein R 5 is an ester.
7. The method of claim 6 , wherein R 5 is a propanoic ester.
8. The method of claim 1 , wherein R 5 is hydroxyl.
9. The method of claim 1 , wherein R 5 is hydrogen.
10. The method of claim 1 , wherein X is CHR 6 .
11. The method of claim 10 , wherein R 6 is alkyl.
12. The method of claim 11 , wherein R 6 is methyl.
13. The method of claim 1 , wherein R 6 comprises a heteroatom.
14. The method of claim 13 , wherein R 6 comprises a sulfur atom.
15. The method of claim 14 , wherein R 6 is a thioether.
16. The method of claim 15 , wherein R 6 is a cyclopentylthio ether.
17. The method of claim 1 , wherein R 9 is alkyl or alkenyl.
18. The method of claim 17 , wherein R 9 is cyclopentenyl.
19. The method of claim 17 , wherein R 9 is t-butyl.
20. The method of claim 1 , wherein R 9 is alkynyl.
21. The method of claim 20 , wherein R 9 is 2-cyclohexenyl-ethynyl.
22. The method of claim 1 , wherein said tetracycline compound is of the formula:
23. The method of claim 1 , wherein said tetracycline compound is of the formula:
24. The method of claim 1 , wherein said tetracycline compound is of the formula:
25. The method of claim 1 , wherein said mammal is immunocompetent.
26. The method of claim 1 , wherein said mammal is immunocompromised.
27. The method of claim 1 , wherein said mammal is a human.
28. The method of claim 27 , wherein said human has an immunodeficiency.
29. The method of claim 28 , wherein said human has AIDS.
30. The method of claim 28 , wherein said human has undergone chemotherapy.
31. The method of claim 1 , wherein said tetracycline compound inhibits more than 70% of Cryptosporidium parvum at a concentration less than 100 μg/ml.
32. The method of claim 1 , wherein said tetracycline compound inhibits more than 70% of Cryptosporidium parvum at a concentration less than 10 μg/ml.
33. The method of claim 32 , wherein said tetracycline compound inhibits more than 70% of Cryptosporidium parvum at a concentration less than 1 μg/ml.
34. A method for treating a Cryptosporidium parvum related disorder in a mammal, comprising administering to said mammal an effective amount of a tetracycline compound, wherein the tetracycline compound is of formula I:
wherein:
X is CHC(R 13 Y′Y) or CHR 6 ;
R 2 , R 4 and R 4 ′ are each hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, arylalkyl, aryl, heterocyclic, or heteroaromatic;
R 2 ′, R 3 , R 10 , R 11 and R 12 are each hydrogen;
R 5 is hydroxy, hydrogen, thiol, alkanoyl, aroyl, alkaroyl, aryl, heteroaromatic, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 6 , R 7 , and R 8 each independently hydrogen, hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 9 is hydroxyl, halogen, thiol, alkyl, alkenyl, alkynyl, aryl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
R 13 is hydrogen, hydroxy, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl;
Y′ and Y are each independently hydrogen, halogen, hydroxyl, cyano, sulfhydryl, amino, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, or an arylalkyl; and pharmaceutically acceptable salts thereof, such that said mammal is treated for said disorder.
35. The method of claim 34 , wherein R 2 , R 2 ′, R 3 , R 10 , R 11 , and R 12 are each hydrogen.
36. The method of claim 35 , wherein R 4 and R 4 ′ are each methyl.
37. The method of claim 36 , wherein R 5 is alkanoyl, an ester group, a hydroxyl group or hydrogen.
38. The method of claim 36 , wherein X is CHR 6 .
39. The method of claim 38 , wherein R 6 is alkyl.
40. The method of claim 38 , wherein R 6 comprises a heteroatom.
41. The method of claim 40 , wherein R 6 is a thioether.
42. The method of claim 34 , wherein R 9 is alkyl, alkenyl, or alkynyl.
43. The method of claim 42 , wherein R 9 is cyclopentenyl.
44. The method of claim 42 , wherein R 9 is t-butyl.
45. The method of claim 42 , wherein R 9 is 2-cyclohexenyl-propynyl.
46. The method of claim 34 , wherein said tetracycline compound is selected from the group consisting of 5-propionyl-9-tert-butyl-doxycycline; 9-tert-butyl doxycycline; and 9-cyclohex-1-enylethynyl minocycline.
47. The method of claim 34 , wherein said mammal is immunocompetent.
48. The method of claim 34 , wherein said mammal is immunocompromised.
49. The method of claim 34 , wherein said mammal is a human.
50. The method of claim 49 , wherein said human is immunodeficient.
51. The method of claim 50 , wherein said human has AIDS.
52. The method of claim 50 , wherein said human has undergone chemotherapy.
53. The method of claim 34 , wherein said Cryptosporidium parvum related disorder is diarrhea.
54. The method of claim 34 , wherein said Cryptosporidium parvum related disorder is cryptosporidiosis.
55. The method of claim 34 , further comprising the administration of a pharmaceutically acceptable carrier.
56. The method of claim 34 , further comprising the administration of a supplementary anti- Cryptosporidium parvum agent.
57. The method of claim 34 , wherein said supplementary agent is paromomycin.