阅读说明：本技术 用于治疗寄生虫病的化合物和方法 (Compounds and methods for treating parasitic diseases ) 是由 E·科默 N·加藤 M·莫宁斯塔 B·梅利洛 于 2018-03-20 设计创作，主要内容包括：本文提供可用于治疗多种寄生虫病的化合物。这些化合物及其药学可接受的盐可配制为药物组合物、兽药组合物,且可用于治疗和/或预防通过寄生虫扩散的疾病,包括疟疾和隐孢子虫病。(Provided herein are compounds useful for the treatment of various parasitic diseases. These compounds and their pharmaceutically acceptable salts can be formulated as pharmaceutical, veterinary compositions, and can be used to treat and/or prevent diseases that spread by parasites, including malaria and cryptosporidiosis.)

1. A compound having the structure of formula (I):

wherein the "dotted" bond may be a single or double bond;

R₁is an optionally substituted aryl or heteroaryl group;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclyl group;

R₃is hydrogen or-CH₂-X；

R₄And R₅Independently is hydrogen, -X or-CH₂-X，R₄And R₅May together form a 5-or 6-membered fused ring, and R₄And R₅At least one of which is not hydrogen;

R₆and R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR, -N (R) -C (O) -R or-N (R); and

r is independently at each occurrence selected from optionally substituted C₁-C₁₂An alkyl group;

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, having the structure of formula (II):

3. the compound of claim 1 or 2, wherein R₇Is hydrogen.

4. The compound of claim 1, having the structure of formula (IIb):

5. the compound of claim 1, having the structure of formula (IIa):

6. a compound according to any one of claims 1 to 5, wherein R₄And R₅Is selected from-X or-CH₂-the same functional group of X.

7. A compound according to any one of claims 1 to 5, wherein R₅Is hydrogen and R₄is-X or-CH₂-X。

8. A compound according to any one of claims 1 to 5, wherein R₄Is hydrogen and R₅is-X or-CH₂-X。

9. A compound according to any one of claims 6 to 8, wherein R₄Or R₅of-X or-CH₂In the-X group-X is-OH, -NH₂or-N (R).

10. A compound according to any one of claims 1 to 5, wherein R₄And R₅Is independently selected from-OH and-OR, and R₄And R₅Together form a 6-membered fused ring.

11. The compound according to any one of claims 1 to 10, wherein R₆Is C_1-4Linear or branched hydrocarbons.

12. The compound according to any one of claims 1 to 10, wherein R₆Is hydrogen.

13. The compound of any one of claims 1 to 11, wherein R at each occurrence is C_1-4Linear or branched hydrocarbons.

14. The compound according to any one of claims 1 to 13, wherein R₁Is optionally substituted C₆Aryl or heteroaryl.

15. The compound according to any one of claims 1 to 14, wherein R₁Is phenyl, fluorophenyl, difluorophenyl or pyridyl.

16. The compound according to any one of claims 1 to 15, wherein R₂Is C_1-4Linear or branched alkoxy.

17. The compound according to any one of claims 1 to 16, wherein R₂Is methoxy, ethoxy, propoxy or isopropoxy.

18. The compound according to any one of claims 1 to 15, wherein R₂Is C substituted by one or more fluorine_1-4Linear or branched alkoxy.

19. The compound according to any one of claims 1 to 15, wherein R₂is-OCF₃、-OCHF₂or-OCH₂F。

20. The compound according to any one of claims 1 to 15, wherein R₂Is C_3-6Heterocyclic groups (e.g., aziridinyl, oxiranyl, thietanyl, oxetanyl, azetidinyl, thietanyl, diazacyclobutanyl, dioxacyclobutanyl, dithiacyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, oxazolyl, etc.).

21. The compound according to any one of claims 1 to 15, wherein R₂Is an oxetanyl or azetidinyl group.

22. The compound according to any one of claims 1 to 15, wherein R₂Is C_3-6A cycloalkoxy group.

23. The compound of claim 22, wherein R₂Is cyclopropoxy.

24. The compound of any one of claims 1 or 6 to 23, wherein z₁To z₄One of them is N and the others are CH.

25. The compound of any one of claims 1 or 6 to 24, wherein z₅To z₈One of them is N and the others are CH.

26. The compound of any one of claims 1,6 to 23 or 25, wherein z₁And z₄Each is N, and z₃And z₂Each is CH.

27. The compound of any one of claims 1,6 to 23 or 26, wherein z₅And z₇Each is N, and z₆And z₈Each is CH.

28. A compound having the structure of formula (III):

wherein the "dotted" bond may be a single or double bond;

R₁is an optionally substituted aryl or heteroaryl group;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclic radical；

R₃Is hydrogen or-CH₂-X；

R₆And R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR, -N (R) -C (O) -R or-N (R); and

r is independently at each occurrence C₁-C₁₂An alkyl group;

provided that at R₆In the case of hydrogen, R₃is-CH₂-N (R) and the "dotted" bond is a double bond.

29. The compound of claim 28, having the structure of formula (IV):

30. the compound of claim 28 or 29, wherein the "dashed" bond is a double bond.

31. The compound of claim 28 or 29, wherein R₆Is C_1-4Linear or branched hydrocarbons.

32. The compound of any one of claims 28 to 31, wherein R₁Is optionally substituted C₆Aryl or heteroaryl.

33. The compound according to any one of claims 28 to 32, wherein R₁Is phenyl, fluorophenyl, difluorophenyl or pyridyl.

34. The compound of any one of claims 28 to 33, wherein R₂Is C_1-4Linear or branched alkoxy.

35. The compound of any one of claims 28 to 23, wherein R₂Is methoxy, ethoxy, propoxy or isopropoxy.

36. The compound of claim 35, wherein R₂Is C_3-6A cycloalkoxy group.

37. The compound of claim 35, wherein R₂Is cyclopropoxy.

38. The compound according to any one of claims 1 to 15, wherein R₂Is C substituted by one or more fluorine_1-4Linear or branched alkoxy.

39. The compound according to any one of claims 1 to 15, wherein R₂is-OCF₃、-OCHF₂or-OCH₂F。

40. The compound according to any one of claims 1 to 15, wherein R₂Is C_3-6Heterocyclic groups (e.g., aziridinyl, oxiranyl, thietanyl, oxetanyl, azetidinyl, thietanyl, diazacyclobutanyl, dioxacyclobutanyl, dithiacyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, oxazolyl, etc.).

41. The compound according to any one of claims 1 to 15, wherein R₂Is an oxetanyl group.

42. The compound of any one of claims 28 or 30 to 37, wherein z₁To z₄One of them is N and the others are CH.

43. Root of herbaceous plantThe compound of any one of claims 28 or 30 to 42, wherein z₅To z₈One of them is N and the others are CH.

44. The compound of any one of claims 28, 30-37 or 43, wherein z₁And z₄Each is N, and z₃And z₂Each is CH.

45. The compound of any one of claims 28, 30-37 or 44, wherein z₅And z₇Each is N, and z₆And z₈Each is CH.

46. The compound of claim 1 or 28, wherein the compound is selected from the group consisting of compounds E1-E38.

47. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of any one of claims 1-46.

48. The pharmaceutical composition of claim 47, wherein the compound is present in an effective amount.

49. The pharmaceutical composition of claim 47, formulated as a veterinary composition.

50. The pharmaceutical composition of any one of claims 47-49, wherein the compound is present in an effective amount to treat malaria.

51. The pharmaceutical composition of any one of claims 47-49, wherein the compound is present in a therapeutically effective amount to treat a disease caused by a parasite from the genus Cryptosporidium.

52. The pharmaceutical composition of claim 51, wherein the disease is cryptosporidiosis.

53. A method of treating or preventing a parasitic disease in a subject, comprising the step of administering to the subject an effective amount of a compound of claims 1-46.

54. The method of claim 53, wherein the parasitic disease is malaria.

55. The method of claim 53, wherein the malaria is drug-resistant malaria.

56. The method of claim 55, wherein the drug-resistant malaria is resistant to chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof.

57. The method of claim 53, wherein the malaria is liver stage malaria.

58. The method of claim 57, wherein the liver of the subject is infected with a malaria-causing parasite and the treatment prevents spread of the infection from its liver.

59. The method of claim 53, wherein the malaria is blood-stage malaria.

60. The method of claim 53, wherein the malaria is transmission stage malaria.

61. The method of claim 53, wherein the malaria is carried in a mosquito selected from the group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium knowlesi, Plasmodium berghei, Plasmodium schlegelii, Plasmodium venorum, or Plasmodium yoelii.

62. The method of claim 61, wherein the mosquito is Plasmodium falciparum.

63. The method of claim 53, wherein the parasitic disease is cryptosporidiosis.

64. The method of claim 63, wherein the cryptosporidiosis is carried by Cryptosporidium parvum.

65. The method of claim 53, wherein the subject is a human.

66. The method of claim 53, wherein the subject is not a human.

67. The method according to claim 66, wherein the subject is a mouse, rat, rabbit, non-human primate, lizard, gecko, cow, calf, sheep, lamb, horse, foal, pig, or piglet.

68. A method of treating or preventing a parasitic disease in a subject, comprising the step of administering to the subject a pharmaceutical composition according to claims 47-52.

69. The method of claim 68, wherein the parasitic disease is malaria.

70. The method of claim 68, wherein the malaria is drug-resistant malaria.

71. The method of claim 70, wherein the drug-resistant malaria is resistant to chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof.

72. The method of claim 68, wherein the malaria is liver stage malaria.

73. The method of claim 72, wherein the liver of the subject is infected with a malaria-causing parasite and the treatment prevents spread of the infection from its liver.

74. The method of claim 68, wherein the malaria is blood-stage malaria.

75. The method of claim 68, wherein the malaria is transmission stage malaria.

76. The method of claim 68, wherein the malaria is carried in a mosquito selected from the group consisting of Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Plasmodium knowlesi, Plasmodium berghei, Plasmodium schlegelii, Plasmodium venorum, or Plasmodium yoelii.

77. The method of claim 68, wherein the mosquito is Plasmodium falciparum.

78. The method of claim 68, wherein the parasitic disease is cryptosporidiosis.

79. The method of claim 78, wherein said cryptosporidiosis is carried by Cryptosporidium parvum.

80. The method of claim 68, wherein the subject is a human.

81. The method of claim 68, wherein the subject is not a human.

82. The method according to claim 81, wherein the subject is a mouse, rat, rabbit, non-human primate, lizard, gecko, cow, calf, sheep, lamb, horse, foal, pig, or piglet.

Background

Malaria is an insect-borne infectious disease caused by protozoan parasites and is widely spread in tropical and subtropical regions including parts of america, asia and africa. Of the five plasmodium species that can infect humans (p.falciparum, p.vivax, p.ovale, p.malariae and p.knowlesi), the most severe forms of the disease are caused by p.falciparum and p.vivax. In addition, many plasmodium species infect mammals other than humans. For example, plasmodium berghei (p.berghei), plasmodium schlegeli (p.chabaudi), plasmodium venorum (p.vinckei), and plasmodium yoelii (p.yoelii) can cause malaria in certain rodents.

Approximately 51,500 million people suffer from malaria each year, with 100 to 300 of these people dying from the disease. Currently, most antimalarial drugs target the asexual blood stage of replication, when the parasite survives red blood cells. Even if the liver and the transmitting stage parasites do not cause malaria symptoms, preventive and transmission-blocking drugs are necessary to actively prevent the prevalence of the disease and to protect vulnerable population. Currently approved anti-malarial drug weapons such as chloroquine (chloroquine), atovaquone (atovaquone), pyrimethamine (pyrimethamine), and sulfadoxine (sulfadoxine) are only used for limited targets within the spectrum of human malaria parasites, and increasing broad drug resistance is driving the development of new anti-malarial drugs with new biological templates.

Cryptosporidiosis is another parasitic disease caused by cryptosporidium of the genus protozoon of the phylum apicomplexa. The most common causes of cryptosporidiosis are the intracellular apicomplexan parasites cryptosporidium parvum (c. Cryptosporidiosis may also be caused by cryptosporidium caninum (c.canis), cryptosporidium felis (c.felis), cryptosporidium turkey (c.meleagris) and cryptosporidium murine (c.muris). Cryptosporidiosis affects the distal small intestine and may affect the respiratory tract of immunocompetent and immunocompromised individuals. Cryptosporidiosis is one of the most common waterborne diseases and is found worldwide. Cryptosporidiosis may also be transmitted to other animals, including cattle, sheep, pigs, horses, goats, and geckoes. Nitazoxanide (nitazoxanide) is the standard drug currently used for the care of cryptosporidiosis, but this drug only shows partial efficacy in children, and is not as effective as placebo in AIDS patients.

Disclosure of Invention

Disclosed herein are compounds, pharmaceutical compositions and methods for the treatment and prevention of parasitic diseases, including malaria and cryptosporidiosis, including/using the compounds described above and elsewhere herein.

In some embodiments, these pharmaceutical compositions are formulated as veterinary compositions for use in subjects other than humans.

The compound may have the structure of formula (I):

wherein the "dotted" bond may be a single or double bond;

R₁is an optionally substituted aryl or heteroaryl group;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclyl group;

R₃is hydrogen or-CH₂-X；

R₄And R₅Independently is hydrogen, -X or-CH₂-X，R₄And R₅May together form a 5-or 6-membered fused ring, and R₄And R₅At least one of which is not hydrogen;

R₆and R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR、-N(R)-C(O) -R or-N (R); and

r is independently at each occurrence selected from optionally substituted C₁-C₁₂An alkyl group;

or a pharmaceutically acceptable salt thereof. X at each occurrence may be independently selected from-OH, -NH₂or-N (R). In some embodiments, R₄And/or R₅The group-X in (including when R is₄And/or R₅is-CH₂the-X group in the case of-X) may be selected from-OH, NH₂or-N (R). In addition, R at each occurrence can be independently selected from C_1-4Linear or branched hydrocarbons.

In some embodiments, R₆And R₇Each is hydrogen. In some embodiments, R₄And R₅May be selected from-X or-CH₂The same functional group of-X (e.g., R)₄is-OH and R₅is-OH, R₄is-NH₂And R is₅is-NH₂，R₄is-OCH₃And R is₅is-OCH₃Etc.). In other embodiments, R₅Is hydrogen and R₄is-X or- (CH)₂) -X. In other embodiments, R₄Is hydrogen and R₅is-X or- (CH)₂) -X. In some embodiments, R₄And R₅Independently selected from-OH and-OR, and R₄And R₅Together form a 6-membered fused ring. In some embodiments, R₆Is C_1-4Linear or branched hydrocarbons. In other embodiments, R₆Is hydrogen. R₁May be optionally substituted C₆Aryl or heteroaryl (e.g., phenyl, fluorophenyl, difluorophenyl, pyridyl, etc.). In some embodiments, R₂Is C_1-4Linear or branched alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, and the like). In some embodiments, R₂Is C substituted by one or more F_1-4Linear or branched alkoxy (e.g., -OCF)₃、-OCHF₂or-OCH₂F) In that respect In other embodiments, R₂Is C_3-6Heterocyclic radicals (e.g. aziridinyl, oxiranyl, epithiiranyl, oxy)Heterocycloalkyl, azetidinyl, thietanyl, diazacyclobutanyl, dioxacyclobutyl, dithianobutyl, pyrrolidinyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, oxazolyl, and the like). In a preferred embodiment, R₂Is an oxetanyl or azetidinyl group. In other embodiments, R₂Is C_3-6Cycloalkoxy (e.g., cyclopropoxy). In some embodiments, R₃is-CH₂-X and-X is N (R).

z₁To z₈May each be CH. In some embodiments, z₁To z₄One of them is N, and the others are CH. In some embodiments, z₅To z₈One of them is N, and the others are CH. In some embodiments, z₁And z₄Each is N, and z₃And z₂Each is CH. In some embodiments, z₅And z₇Each is N, and z₆And z₈Each is CH.

Any stereocenter in the structure of formula (I) may be in any configuration, or may exist as a racemic mixture of the respective stereocenters (e.g., stereoisomers, diastereomers, etc.). In some embodiments, the compound has the structure of formula (II):

in some embodiments, the compound has the structure of formula (IIb):

in some embodiments, the compound has the structure of formula (IIa):

the compound may also have the structure of formula (III):

wherein the "dotted" bond may be a single or double bond;

R₁is an optionally substituted aryl or heteroaryl group;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclyl group;

R₃is hydrogen or-CH₂-X；

R₆And R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR, -N (R) -C (O) -R or-N (R); and

r is independently at each occurrence selected from optionally substituted C₁-C₁₂An alkyl group;

provided that at R₆In the case of hydrogen, R₃is-CH₂-N (R) and the "dotted" bond is a double bond. In some embodiments, the "dashed" bond is a double bond. In other embodiments, the "dashed" bond is a single bond. X at each occurrence may be independently selected from-OH, -NH₂or-N (R). In addition, R at each occurrence can be independently selected from C_1-4Linear or branched hydrocarbons.

z₁To z₈May each be CH. In some embodiments, z₁To z₄One of them is N, and the others are CH. In some embodiments, z₅To z₈One of them is N, and the others are CH. In some embodiments, z₁And z₄Each is N, and z₃And z₂Each is CH. In some embodiments, z₅And z₇Each is N, and z₆And z₈Each is CH.

At one endIn some embodiments, R₆And R₇Each is hydrogen. In some embodiments, R₆Is lower alkyl (e.g., methyl, ethyl, etc.). In some embodiments, R₆Is C_1-4Linear or branched hydrocarbons. In other embodiments, R₆Is hydrogen. R₁May be optionally substituted C₆Aryl or heteroaryl (e.g., phenyl, fluorophenyl, difluorophenyl, pyridyl, etc.). In some embodiments, R₂Is C_1-4Linear or branched alkoxy (e.g., methoxy, ethoxy, propoxy, isopropoxy, and the like). In some embodiments, R₂Is C substituted by one or more F_1-4Linear or branched alkoxy (e.g., -OCF)₃、-OCHF₂or-OCH₂F) In that respect In other embodiments, R₂Is C_3-6Heterocyclic groups (e.g., aziridinyl, oxiranyl, thietanyl, oxetanyl, azetidinyl, thietanyl, diazacyclobutanyl, dioxacyclobutanyl, dithiacyclobutanyl, pyrrolidinyl, tetrahydrofuranyl, imidazolyl, pyrazolyl, oxazolyl, etc.). In a preferred embodiment, R₂Is an oxetanyl or azetidinyl group. In other embodiments, R₂Is C_3-6Cycloalkoxy (e.g., cyclopropoxy).

In some embodiments, the compound may have the structure of formula (IV):

in some embodiments, the compound is any one of compounds E1-E38 or a pharmaceutically acceptable salt thereof.

Any of the above compounds may be used in pharmaceutical compositions. In some embodiments, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient and a compound having the structure of formula (I):

wherein the "dotted" bond may be a single or double bond;

R₁is an optionally substituted aryl or heteroaryl group;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclyl group;

R₃is hydrogen or-CH₂-X；

R₄And R₅Independently is hydrogen, -X or-CH₂-X，R₄And R₅May together form a 5-or 6-membered fused ring, and R₄And R₅At least one of which is not hydrogen;

R₆and R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR, -N (R) -C (O) -R or-N (R); and

r is independently at each occurrence selected from optionally substituted C₁-C₁₂An alkyl group;

or a pharmaceutically acceptable salt thereof. X at each occurrence may be independently selected from-OH, -NH₂or-N (R). In some embodiments, R₄And/or R₅The group-X in (including when R is₄And/or R₅is-CH₂the-X group in the case of-X) may be selected from-OH, NH₂or-N (R). In addition, R at each occurrence can be independently selected from C_1-4Linear or branched hydrocarbons.

In some embodiments, the pharmaceutical composition may comprise a pharmaceutically acceptable excipient and a compound having the structure of formula (III):

wherein the "dotted" bond may be a single or double bond;

R₁is optionally viaSubstituted aryl or heteroaryl;

R₂is an optionally substituted alkoxy, cycloalkoxy or heterocyclyl group;

R₃is hydrogen or-CH₂-X；

R₆And R₇Independently hydrogen or R; and

z₁to z₈Independently at each occurrence, selected from CH or N; wherein

-X is independently selected at each occurrence from-OH, -OR, -S (O) R, -S (O)₂R、-N(R)-S(O)₂R、-S(O)₂-N(R)(R)、-S(O)₂-NHR, -N (R) -C (O) -R or-N (R); and

r is independently at each occurrence selected from optionally substituted C₁-C₁₂An alkyl group;

provided that at R₆In the case of hydrogen, R₃is-CH₂-N (R) and the "dotted" bond is a double bond. In some embodiments, the "dashed" bond is a double bond. In other embodiments, the "dashed" bond is a single bond. X at each occurrence may be independently selected from-OH, -NH₂or-N (R). In addition, R at each occurrence can be independently selected from C_1-4Linear or branched hydrocarbons. In some embodiments, the compound is present in the pharmaceutical composition in an effective amount. For example, the compound can be present in an amount effective for treating or preventing malaria. In some embodiments, the compound can be present in an amount effective for treating or preventing a disease caused by a parasite from the genus cryptosporidium (e.g., cryptosporidiosis). In some embodiments, the pharmaceutical composition can be formulated for the treatment of malaria and cryptosporidiosis.

Related methods of treating or preventing a disease in a subject are also disclosed. In some embodiments, a method of treating or preventing a parasitic disease in a subject comprises the step of administering to the subject an effective amount of a compound disclosed herein. In some embodiments, an effective amount of the compound is formulated in a pharmaceutical composition (e.g., a veterinary composition, etc.).

The parasitic disease may be malaria. In some embodiments, the malaria is resistant malaria (e.g., malaria resistant to chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, or any combination thereof, and the like). In some embodiments, the malaria is blood-stage malaria. In some embodiments, the malaria is stage of transmission malaria. In some embodiments, the malaria is liver stage malaria. In some embodiments, the subject is infected with a parasite responsible for malaria, and the treatment prevents the spread of the infection from their liver. In some embodiments, malaria is carried in a mosquito selected from the group consisting of plasmodium falciparum, plasmodium vivax, plasmodium ovale, plasmodium malariae, plasmodium knowlesi, plasmodium berghei, plasmodium shawini, plasmodium venorum, or plasmodium yoelii. In a preferred embodiment, the mosquitoes carry plasmodium falciparum (especially when the subject is a human).

The parasitic disease may be cryptosporidiosis. In some embodiments, the cryptosporidiosis is carried by cryptosporidium parvum.

In some embodiments, the subject is a human. In other embodiments, the subject is not a human (e.g., the pharmaceutical composition is formulated as a veterinary composition). In some embodiments, the subject is a mouse, rat, rabbit, non-human primate, lizard, gecko, cow, calf, sheep, lamb, horse, foal, pig, or piglet.

These and other aspects of the present invention will become apparent to those skilled in the art from the following detailed description, which, by way of example, illustrates simply various modes for carrying out the invention. It will be understood that there are additional, different, and obvious aspects of the present invention that do not depart from the present invention. Accordingly, the description is illustrative rather than limiting in nature.

Detailed Description

Definition of

It is to be understood that the technology employed herein is for the purpose of disclosing specific embodiments, and is not intended to be limiting. Moreover, although methods and materials similar or equivalent to those disclosed herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are now disclosed.

As used herein, the term "acyl" means hydrogen or an alkyl group as defined herein attached to the parent molecular group through a carbonyl group as defined herein, examples being formyl (i.e., carboxaldehyde), acetyl, trifluoroacetyl, propionyl, and butyryl. Exemplary unsubstituted acyl groups include 1 to 6, 1 to 11, or 1 to 21 carbons. In some embodiments, alkyl is further substituted with 1,2,3, or 4 substituents as described herein.

As used herein, the term "alkyl", alone or in combination with other groups, refers to a branched or straight chain monovalent saturated aliphatic hydrocarbon group of 1 to 20 carbon atoms (e.g., 1 to 16 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms, etc.).

As used herein, the term "alkylene" denotes a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by removal of two hydrogen atoms, examples being methylene, ethylene and isopropylene. In some embodiments, the alkylene is further substituted with 1,2,3, or 4 substituents as defined herein for alkyl.

As used herein, the term "alkenyl", used alone or in combination with other groups, refers to a straight or branched chain hydrocarbon residue having an ethylenic bond.

As used herein, the term "amino" refers to-N (R)^N1)₂Wherein R is^N1Each independently is H, OH, NO₂、N(R^N2)₂、SO₂OR^N2、SO₂R^N2、SOR^N2N-protecting group, alkyl, alkenyl, alkynyl, alkoxy, aryl, alkaryl, cycloalkyl, alkylcycloalkyl, carboxyalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any carboxyalkyl group described herein), sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, orOther acyl groups described herein), alkoxycarbonylalkyl (e.g., optionally substituted with an O-protecting group, such as optionally substituted arylalkoxycarbonyl or any alkoxycarbonylalkyl described herein), heterocyclyl (e.g., heteroaryl), or heterocyclylalkyl (e.g., heteroarylalkyl) wherein these recited R' s^N1Each of the groups may be optionally substituted, as defined herein for each group; or two R^N1Combine to form a heterocyclic group or an N-protecting group, and, wherein R^N2Each independently is H, alkyl or aryl. The amine group may be an unsubstituted amino group (i.e., -NH)₂) Or substituted amino groups (i.e., -N (R)^N1)₂). In a preferred embodiment, the amine group is-NH₂or-NHR^N1Wherein R is^N1Independently OH, NO₂、NH₂、NR^N2 ₂、SO₂OR^N2、SO₂R^N2、SOR^N2Alkyl, carboxyalkyl, sulfoalkyl, acyl (e.g., acetyl, trifluoroacetyl, or other acyl groups described herein), alkoxycarbonylalkyl (e.g., tert-butoxycarbonylalkyl), or aryl, and R^N2May each be H, C_1-20Alkyl (e.g. C)_1-6Alkyl), or C_6-10And (4) an aryl group.

The term "aryl" refers to an aromatic monocyclic or polycyclic group of 6 to 12 carbon atoms having at least one aromatic ring. Examples of such groups include, but are not limited to, phenyl, naphthyl, 1,2,3, 4-tetrahydronaphthyl, 1, 2-dihydronaphthyl, indanyl, and 1H-indenyl.

As used herein, "arylalkyl" means an aryl group, as defined herein, appended to the parent molecular group through an alkylene group, as defined herein. Exemplary unsubstituted arylalkyl groups are 7 to 30 carbon atoms (e.g., 7 to 16 or 7 to 20 carbon atoms, such as C)_6-10Aryl radical C_1-6Alkyl radical, C_6-10Aryl radical C_1-10Alkyl, or C_6-10Aryl radical C_1-20Alkyl groups). In some embodiments, each of the alkylene and aryl groups can be further substituted with 1,2,3, or 4 substituents as defined herein for each group.

The alkyl, carbocyclyl, and aryl groups may be substituted or unsubstituted. When they are substituted, typically 1 to 4 substituents will be present. These substituents may optionally form a ring with the alkyl, carbocyclyl or aryl to which they are attached. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g., substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g., trifluoromethyl); oxygen-containing groups such as alcohols (e.g., hydroxy, hydroxyalkyl, aryl (hydroxy) alkyl), ethers (e.g., alkoxy, cycloalkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl, more preferably, for example, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, etc.), aldehydes (e.g., formaldehyde), ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g., carboxy, carboxyalkyl), acid derivatives such as esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g., aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, arylaminocarbonyl), Carbamates (e.g., alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, arylaminocarbonyloxy) and ureas (e.g., monoalkylaminocarbonylamino, dialkylaminocarbonylamino, or arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g., amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl), azides, nitriles (e.g., cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides, and sulfones (e.g., alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); a heterocyclic heteroalkyl group; and heterocyclic groups containing one or more hetero atoms (e.g., thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidinyl, hexahydroazepinyl, piperazinyl, morpholinyl, thioindenyl, benzofuranyl, isobenzofuranyl, indolyl, oxindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl (coumarinyl), isocoumarinyl, quinolyl, isoquinolyl, dihydronaphthyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, etc.), Chromenyl (chromenyl), chromanyl (chromanyl), isochromanyl, phthalazinyl and carbolinyl groups).

The term "azido" denotes-N₃And may also be represented by-N ═ N.

As used herein, the terms "carbocycle" and "carbocyclyl" refer to an optionally substituted non-aromatic C_3-12A monocyclic, bicyclic or tricyclic ring structure, wherein the ring is formed from carbon atoms. Carbocyclic structures include cycloalkyl, cycloalkenyl, and cycloalkynyl.

The term "cycloalkyl" refers to a monovalent mono-or poly-carbocyclic group of 3 to 10, preferably 3 to 6, carbon atoms. This term is further exemplified by groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, adamantyl, and indanyl. In preferred embodiments, a "cycloalkyl" moiety may be optionally substituted with 1,2,3, or 4 substituents. Unless explicitly specified, the substituents may each independently be alkyl, alkoxy, halogen, amino, hydroxy, or oxygen. Examples of cycloalkyl moieties include, but are not limited to, optionally substituted cyclopropyl, optionally substituted cyclobutyl, optionally substituted cyclopentyl, optionally substituted cyclopentenyl, optionally substituted cyclohexyl, and optionally substituted cycloheptyl, or those specifically exemplified herein.

As used herein, the term "cyano" denotes a-CN group.

As used herein, the term "halo" or "halogen" means a fluoro (fluoro), chloro (chloro), bromo (bromo) or iodo (iodo) group.

The term "heteroalkyl," as used herein, refers to an alkyl group, as defined herein, in which one or more structural carbon atoms have each been replaced with nitrogen, oxygen, or sulfur. In some embodiments, the heteroalkyl is further substituted with 1,2,3, or 4 substituents as defined herein for alkyl. An example of heteroalkyl is "alkoxy," as used herein, which refers to alkyl-O-; and "alkanoyl," as used herein, refers to alkyl-CO-. An alkoxy substituent or alkyl-containing substituent may be substituted, for example, with one or more alkyl groups.

The term "heteroaryl" refers to an aromatic monocyclic or polycyclic group of 5 to 12 atoms having at least one aromatic ring containing 1,2 or 3 ring heteroatoms selected from N, O and S and the remaining ring atoms being C. One or two ring carbon atoms of a heteroaryl group may be replaced by a carbonyl group. Examples of heteroaryl groups are pyridyl, benzoxazolyl, benzimidazolyl and benzothiazolyl.

The term "heterocycle" or "heterocyclyl" denotes a monocyclic or multicyclic alkyl ring in which 1,2 or 3 of the carbon ring atoms are replaced by a heteroatom such as N, O or S. Examples of heterocyclyl groups include, but are not limited to, oxetanyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, and 1, 3-dioxane groups. A heterocyclyl group may be unsubstituted or substituted, and may be suitably attached through its carbon frame or through its heteroatom.

The term "heterocycloalkylene" means that a heterocyclyl group, as defined herein, is attached to the parent molecular group through a heteroalkyl group (e.g., ether or alkoxy). An example of a heterocyclic heteroalkyl group is-OCH₂CH₂The group (morpholinyl).

The above heterocyclic group and heteroaryl group may be independently substituted with 1,2,3 or more substituents. Substituents may include, for example: carbon-containing groups such as alkyl, aryl, arylalkyl (e.g., substituted and unsubstituted phenyl, substituted and unsubstituted benzyl); halogen atoms and halogen-containing groups such as haloalkyl (e.g., trifluoromethyl); oxygen-containing groups such as alcohols (e.g., hydroxyl, hydroxyalkyl, aryl (hydroxyl) alkyl), ethers (e.g., alkoxy, aryloxy, alkoxyalkyl, aryloxyalkyl), aldehydes (e.g., formaldehyde), ketones (e.g., alkylcarbonyl, alkylcarbonylalkyl, arylcarbonyl, arylalkylcarbonyl, arylcarbonylalkyl), acids (e.g., carboxyl, carboxyalkyl), acid derivatives such as esters (e.g., alkoxycarbonyl, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylcarbonyloxyalkyl), amides (e.g., aminocarbonyl, monoalkylaminocarbonyl, dialkylaminocarbonyl, aminocarbonylalkyl, monoalkylaminocarbonylalkyl, dialkylaminocarbonylalkyl, arylaminocarbonyl), carbamates (e.g., alkoxycarbonylamino, aryloxycarbonylamino, aminocarbonyloxy, carboxyalkylamino, Monoalkylaminocarbonyloxy, dialkylaminocarbonyloxy, arylaminocarbonyloxy) and ureas (e.g., monoalkylaminocarbonylamino, dialkylaminocarbonylamino, or arylaminocarbonylamino); nitrogen-containing groups such as amines (e.g., amino, monoalkylamino, dialkylamino, aminoalkyl, monoalkylaminoalkyl, dialkylaminoalkyl), azides, nitriles (e.g., cyano, cyanoalkyl), nitro; sulfur-containing groups such as thiols, thioethers, sulfoxides, and sulfones (e.g., alkylthio, alkylsulfinyl, alkylsulfonyl, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylthio, arylsulfinyl, arylsulfonyl, arylthioalkyl, arylsulfinylalkyl, arylsulfonylalkyl); and heterocyclic groups containing one or more hetero atoms (e.g., thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiadiazolyl, aziridinyl, azetidinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, tetrahydrofuranyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, piperidyl, hexahydroazepinyl, piperazinyl, morpholinyl, thioindenyl, benzofuranyl, isobenzofuranyl, indolyl, oxindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl, benzopyranyl, coumarinyl, isocoumarinyl, quinolyl, isoquinolyl, dihydronaphthyl, cinnolinyl, quinazolinyl, pyridopyridyl, benzoxazinyl, quinoxalinyl, chromenyl, chromanyl, and the like), Chromanyl, isochromanyl, phthalazinyl, benzothiazolyl, and carbolinyl).

As used herein, the term "hydroxy" denotes an-OH group. In some embodiments, the hydroxyl group may be substituted with an O-protecting group as defined herein.

As used herein, the term "N-protecting group" refers to those groups intended to protect an amine group from unwanted antisense during synthesis. Commonly used N-protecting Groups are disclosed in Protective Groups in organic Synthesis (third Edition), "Protective Groups in organic Synthesis," 3rd Edition (John Wiley & Sons, New York,1999), by Green (Greene), which is incorporated herein by reference. As used herein, the term "O-protecting group" refers to those groups intended to protect oxygen-containing groups (e.g., phenol, hydroxyl, or carbonyl) from undesired antisense during synthesis. Common O-protecting Groups are disclosed in Protective Groups in Organic Synthesis (third Edition), "Protective Groups in Organic Synthesis," 3rd Edition (John Wiley & Sons, New York,1999), by Green (Greene), which is incorporated herein by reference. As used herein, the term "perfluoroalkyl" denotes an alkyl group, as defined herein, which has been substituted with fluorine for each hydrogen bonded to the alkyl group. Examples of perfluoroalkyl groups are, for example, trifluoromethyl and pentafluoroethyl.

As used herein, the term "sulfonyl" refers to-S (O)₂-a group.

A "substituted" hydrocarbon may have as a substituent one or more hydrocarbyl groups, a substituted hydrocarbyl group, or may contain one or more heteroatoms. Examples of substituted hydrocarbyl groups include, without limitation, heterocycles such as heteroaryl. Unless specifically excluded, a hydrocarbon substituted with one or more heteroatoms will contain from 1 to 20 heteroatoms. In other embodiments, the hydrocarbon substituted with one or more heteroatoms will comprise 1 to 12, or 1 to 8, or 1 to 6, or 1 to 4, or 1 to 3, or 1 to 2 heteroatoms. Examples of heteroatoms include, but are not limited to, oxygen, nitrogen, sulfur, phosphorus, halogens (F, Cl, Br, I, etc.), boron, silicon, and the like. In some embodiments, the heteroatoms will be selected from the group consisting of oxygen, nitrogen, sulfur, phosphorus, and halogens (F, Cl, Br, I, etc.). In some embodiments, a heteroatom or group may be substituted for carbon. In some embodiments, a heteroatom or group may be substituted for hydrogen. In some embodiments, a substituted hydrocarbon may include one or more heteroatoms (e.g., interposed between two carbon atoms, as in "oxa") in the backbone or chain of the molecule. In some embodiments, a substituted hydrocarbon may include one or more heteroatoms located in the molecular backbone or side chains of a chain (e.g., covalently bonded to a carbon atom in the chain or backbone to replace a hydrogen in the backbone or chain, as in "oxo," etc.).

The term "substituent" means a group that is "substituted" at any atom, e.g., alkyl, haloalkyl, cycloalkyl, heterocyclyl, heterocycloalkenyl, cycloalkenyl, aryl, or heteroaryl, in place of one or more hydrogen atoms in the group. In one aspect, a substituent on a group is located at any one atom independently, or at any combination of two or more of the permissible atoms or groups of atoms designated for that substituent. Alternatively, the substituent may itself be substituted with any of the above substituents. Also, as used herein, the phrase "optionally substituted" means unsubstituted (e.g., substituted with H) or substituted. It is understood that substitution at a given atom is limited by valence. Common substituents include halo, C_1-12Straight or branched alkyl, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-12Cycloalkyl radical, C_6-12Aryl radical, C_3-12Heteroaryl group, C_3-12Heterocyclic group, C_1-12Alkylsulfonyl, nitro, cyano, -COOR, -C (O) NRR ', -OR, -SR, -NRR', and oxo, such as with trifluoromethoxy, chloro, bromo, fluoro, methyl, methoxy, pyridyl, furyl, tris(iii) mono-, di-, or tri-substitution in moiety oxazolyl, piperazinyl, pyrazolyl, imidazolyl, etc., each of which optionally contains one or more heteroatoms such as halogen, N, O, S, and P. R and R' are independently hydrogen, C_1-12Alkyl radical, C_1-12Haloalkyl, C_2-12Alkenyl radical, C_2-12Alkynyl, C_3-12Cycloalkyl radical, C_4-24Cycloalkylalkyl radical, C_6-12Aryl radical, C_7-24Aralkyl radical, C_3-12Heterocyclic group, C_3-24Heterocyclylalkyl radical, C_3-12Heteroaryl, or C_4-24A heteroarylalkyl group. Unless expressly excluded, all groups described herein optionally contain one or more conventional substituents to the extent permitted by the valency. Also, as used herein, the phrase "optionally substituted" means unsubstituted (e.g., substituted with H) or substituted. As used herein, the term "substituted" means that a hydrogen atom is removed and replaced with a substituent (e.g., a commonly used substituent). Those skilled in the chemical arts understand that substitution at a given atom is limited to valence states. The use of a substituent (group) prefix name without the modifier "optionally substituted" or "substituted" such as alkyl is understood to mean that the particular substituent is unsubstituted. However, the use of "haloalkyl" without the modifier "optionally substituted" or "substituted" is still understood to mean alkyl in which at least one hydrogen atom is replaced with a halogen.

It is to be understood that the description of compounds herein is limited by chemical bonding principles known to those skilled in the art. Accordingly, if a group can be substituted with one or more of a number of substituents, such substitution is selected to comply with chemical bonding principles relating to valence and the like, and to give compounds that are not inherently unstable.

The compounds provided herein can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates, or mixtures of diastereomeric racemates. For example, the optically active form can be obtained by resolution of the racemate, asymmetric synthesis or asymmetric chromatography (chromatography using a chiral adsorbent or eluent). In other words, certain disclosed compounds can exist in a variety of stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Enantiomers are a pair of stereoisomers whose mirror images can coincide, the most common reason being that they contain an asymmetrically substituted carbon atom as a chiral center. "an enantiomer" means one of a pair of molecules that are mirror images of each other and that do not coincide. Diastereomers are stereoisomers with no linkage between mirror images, the most common reason being that they contain two or more asymmetrically substituted carbon atoms and exhibit a substituent configuration around one or more chiral carbon atoms. For example, enantiomers of a compound can be prepared by separating one enantiomer from a racemate using one or more well-known techniques and methods, such as chiral chromatography and chiral chromatography-based separation methods. Techniques and/or methods suitable for isolating one enantiomer of a compound described herein from a racemic mixture may be readily determined by one of skill in the art. By "racemate" or "racemic mixture" is meant a mixture containing two enantiomers wherein such mixture does not exhibit optical activity, i.e., they do not rotate the plane of polarized light. "geometric isomers" means isomers that differ in the orientation of the substituent atoms (e.g., with respect to the orientation of a carbon-carbon double bond, with respect to the orientation of a cycloalkyl ring, with respect to the orientation of a bridged bicyclic ring system, etc.). The atoms (other than H) located on each side of the carbon-carbon double bond may be in an E (substituent located on the opposite side of the carbon-carbon double bond) configuration or a Z (substituent located on the same side) configuration. "R", "S", "R", "E", "Z", "cis" and "trans" indicate the configuration relative to the core molecule. Some of the disclosed compounds may exist in atropisomeric forms. Rotation-blocking isomers are stereoisomers resulting from the hindered rotation about a single bond, wherein the steric strain barrier to rotation is sufficiently high that conformational isomers can be separated. The compounds disclosed herein can be prepared as individual isomers by isomer-specific synthesis or by resolution from a mixture of isomers. Conventional resolution techniques include the formation of a salt of the free base of each of a pair of isomers using an optically active acid (followed by fractional crystallization and regeneration of the free base); forming a salt of the free acid of each of the pair of isomers using an optically active amine (followed by fractional crystallization and regeneration of the free acid); forming an ester or amide of each of a pair of isomers using an optically pure acid, amine or alcohol (followed by chromatographic separation and removal of the chiral auxiliary); or resolving isomeric mixtures of the starting materials or the final product using a variety of well-known chromatographic methods. When the stereochemistry of the disclosed compounds is named or indicated by structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight relative to the other stereoisomer. When individual enantiomers are named or indicated by structure, the optical purity of the indicated or named stereoisomer is at least 60%, 70%, 80%, 90%, 99% or 99.9% by weight. When individual diastereomers are named or indicated by structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure by weight. Percent optical purity is the ratio of the weight of the enantiomer to the sum of the weight of the enantiomer plus the weight of its optical isomer. Diastereomeric purity by weight is the ratio of the weight of one diastereomer to the sum of the weights of all diastereomers. When the stereochemistry of a disclosed compound is named or indicated by a structure, the named or indicated stereoisomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% relative to the other stereoisomer, in terms of mole fraction purity. When individual enantiomers are named or specified by structure, the specified or named enantiomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure in mole fraction. When individual diastereomers are named or indicated by structure, the indicated or named diastereomer is at least 60%, 70%, 80%, 90%, 99%, or 99.9% pure, in mole fraction. The percent mole fraction purity is the ratio of the number of moles of the enantiomer to the sum of the number of moles of the enantiomer plus the number of moles of its optical isomer. Likewise, percent mole fraction purity is the ratio of the number of moles of the diastereomer to the sum of the number of moles of the diastereomer plus the number of moles of its isomer. When a disclosed compound is named or specified by structure without specifying stereochemistry and the compound has at least one chiral center, it is understood that the name or structure encompasses one enantiomer of the compound free of the corresponding optical isomer, a racemic mixture of the compound, or an enriched mixture of one enantiomer relative to its corresponding optical isomer. When a disclosed compound and structure is named or specified without the knowledge of stereochemistry and the compound has two or more chiral centers, it is understood that the name or structure encompasses one enantiomer free of other diastereomers, multiple diastereomers free of other diastereomeric pairs, mixtures of diastereomers, mixtures of diastereomeric pairs, mixtures of diastereomeric mixtures wherein one diastereomer is enriched relative to the other diastereomer, or mixtures of diastereomers wherein one or more diastereomers are enriched relative to the other diastereomer. The present disclosure encompasses all of these forms.

As used herein, the term "effective amount" or "therapeutically effective amount" of an agent means an amount sufficient to produce a beneficial or desired result, such as a clinical result, and thus the "effective amount" depends on the context in which it is administered. For example, in the context of administering an anti-malarial agent, an effective amount of the agent is, for example, an amount sufficient to achieve: alleviation, amelioration, prevention, or prophylaxis of one or more symptoms or conditions as compared to the response obtained without administration of the agent, and whether detectable or undetectable; attenuation of the extent of the disease, disorder or condition; stabilization (i.e., not worsening) of the state of the disease, disorder, or condition; preventing spread of the disease, pathology, or condition (e.g., preventing spread of plasmodium infection beyond the liver, preventing systemic disease, preventing the symptomatic phase of malaria, preventing establishment of plasmodium infection, and/or preventing further spread of the disease by preventing transmission back to the mosquito, etc.); delay or slow the progression of the disease, disorder or condition; amelioration or palliation of the disease, disorder or condition; and mitigation (whether in part or in whole).

As used herein, the term "pharmaceutical composition" means a composition comprising a compound described herein, in combination with a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is manufactured and marketed under approval by a governmental regulatory agency as part of a therapeutic regimen for the treatment of a disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., tablets, capsules, caplets, or syrups); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution without a particulate plug or in a solvent system suitable for intravenous use); or any other formulation described herein (see below).

Pharmaceutical carriers useful in preparing the compositions herein can be solid, liquid or gaseous. Thus, the compositions may be in the form of tablets, pills, capsules, suppositories, powders, enteric coated or other protective formulations (e.g., incorporated on ion exchange resins or encapsulated in lipid-protein vehicles), sustained release formulations, solutions, suspensions, elixirs and aerosols. The carrier may be selected from a variety of oils, including those of petroleum, animal, vegetable or synthetic origin, for example, peanut oil, soybean oil, mineral oil and sesame oil. Water, saline, aqueous dextrose, and glycols are preferred liquid carriers, particularly for injectable solutions (when isotonic with blood). For example, formulations for intravenous administration comprise a sterile aqueous solution of the active ingredient prepared by dissolving the solid active ingredient in water to produce an aqueous solution and sterilizing the solution. Suitable pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, talc, gelatin, malt, rice, flour, chalk, silica, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene glycol, water and ethanol. The composition may contain conventional pharmaceutical additives such as preservatives, stabilizers, wetting or emulsifying agents, salts for regulating osmotic pressure, and buffers. Suitable Pharmaceutical carriers and formulations thereof are disclosed in Remington's Pharmaceutical Sciences, by E.W. Martin. In any event, such compositions will contain an effective amount of the active compound together with a suitable carrier to prepare a suitable dosage form for administration to a recipient.

As used herein, the term "pharmaceutically acceptable salt" refers to any salt of a compound described herein that is within the scope of sound medical judgment, is suitable for use in contact with the tissues of human beings and animals without toxicity, irritation, allergic response, and at a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in the following documents: berge et al, j. pharmaceutical Sciences 66:1-19,1977; and "pharmaceutically acceptable salts: properties, Selection and uses (Pharmaceutical Salts: Properties, Selection, and Use, (eds. P. H. Stahl and C.G.Wermuth), Wiley-VCH, 2008). Salts can be prepared from pharmaceutically acceptable non-toxic acids and bases including inorganic acids, organic acids, inorganic bases and organic bases. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, dichloroacetate, bisgluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glutamate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hippurate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, isethionate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, mucate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, acetate, salicylate, and the like, Palmitate, pamoate, pantothenate, pectate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, stearate, succinate, sulfate, tartrate, thiocyanate, tosylate, undecanoate, and valerate. Representative basic salts include alkali or alkaline earth metal salts, including sodium, lithium, potassium, calcium, magnesium and aluminum salts; and non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, caffeine, and ethylamine.

As used herein, the term "subject" refers to any organism to which a composition according to the present disclosure may be administered, e.g., for experimental, diagnostic, prophylactic and/or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans, lizards, geckos, etc.). The subject can be a domesticated animal (e.g., cow, calf, sheep, lamb, horse, foal, pig, piglet, etc.), or a murine animal (e.g., rat, mouse, etc.). A subject may seek treatment or have a need for treatment, require treatment, be undergoing treatment, may be undergoing treatment in the future, or be in the care of a human or animal being trained for a particular disease or condition.

As used herein and as understood in the art, "to treat" or "treating" a disorder (e.g., a disorder described herein such as malaria) is a way to obtain a beneficial or desired result such as a clinical result. Beneficial or desired results may include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions; attenuation of the extent of the disease, disorder or condition; stabilization (i.e., not worsening) of the state of the disease, disorder, or condition; preventing spread of the disease, disorder, or condition (e.g., preventing spread of plasmodium infection beyond the liver or preventing transmission of mosquitoes, preventing systemic disease, preventing the symptomatic phase of malaria, and/or preventing establishment of plasmodium infection); delay or slow the progression of the disease, disorder or condition; amelioration or palliation of the disease, disorder or condition; and mitigation (whether in part or in total), whether detectable or undetectable. By "alleviating" a disease, disorder, or condition is meant that the extent and/or time course of the undesired clinical manifestation of the disease, disorder, or condition is reduced and/or slowed or prolonged as compared to the extent or time course of no treatment.

The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with any suitable pharmaceutical excipient or excipients. Exemplary, non-limiting unit dosage forms include tablets (e.g., chewable tablets), caplets, capsules (e.g., hard or soft), troches, films, long tablets, caplets, and syrups (also see below).

Other features and advantages of the disclosure are described in the following detailed description and claims.

Compound (I)

The present disclosure provides novel compounds and pharmaceutical compositions useful for the treatment of malaria. The present disclosure also provides methods of using these compounds and compositions.

In some embodiments, the compound may be any of the compounds listed in table 1.

TABLE 1

Each stereoisomer was isolated as described in the exemplified synthesis, incorporated below for use in any biological experiment. However, although each diastereomer (i.e., isomer 1 or isomer 2) is isolated as described and not present as a composition, stereochemistry at the C3 or C4 position cannot be determined.

It is understood that if there is any inconsistency between a chemical name and a molecular formula, both the compound having the named name and the compound having the named chemical structure are to be considered as encompassed by the present invention.

The compounds of the present invention include the compounds themselves, as well as, if applicable, their salts and their prodrugs. For example, salts can be formed between an anion and a positively charged substituent (e.g., an amine group) on a compound described herein. Suitable anions include chloride, bromide, iodide, sulfate, nitrate, phosphate, citrate, methanesulfonate, trifluoroacetate, and acetate. Likewise, salts can also be formed between a cation and a negatively charged substituent (e.g., carboxylate) on a compound described herein. Suitable cations include sodium, potassium, magnesium, calcium, and ammonium cations such as tetramethylammonium. Examples of prodrugs include C1-6 alkyl esters of carboxylic acid groups, which when administered to a subject, provide the active compound.

Pharmaceutically acceptable salts of the compounds of the present disclosure include those derived from pharmaceutically acceptable inorganic acids, inorganic bases, organic acids, and organic bases. As used herein, the term "pharmaceutically acceptable salt" refers to a salt formed by the addition of a pharmaceutically acceptable acid or base to a compound disclosed herein. The phrase "pharmaceutically acceptable" as used herein refers to a substance that is acceptable in pharmaceutical applications from a toxicological standpoint and does not adversely affect the active ingredient.

Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, bisgluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, palmitate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate, and undecanoate. Other acids, such as oxalic acid, although not pharmaceutically acceptable by themselves, may also be used to prepare salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from suitable bases include alkali metal (e.g., sodium) salts, alkaline earth metal (e.g., magnesium) salts, ammonium salts, and N- (alkyl)₄ ⁺And (3) salt. The present invention also contemplates quaternization of any basic nitrogen-containing group of the compounds disclosed herein. Water-soluble, oil-soluble or dispersible products are obtained by this quaternization. The salt form of the compound of any formula herein may be an amino acid salt of a carboxyl group (e.g., L-arginine salt, L-lysine salt, L-histidine salt).

A list of suitable salts can be found in Remington's Pharmaceutical Sciences,17th ed., Mack Publishing Company, Easton, Pa.,1985, p.1418, Journal of Pharmaceutical Science,66,2(1977), and in the handbook of Pharmaceutical salts: properties, selections, and uses (Pharmaceutical Salts: Properties, Selection, and Use A Handbook; Wermuth, C.G. and Stahl, P.H. (eds.) Verlag Helvetica Chimica Acta, Zurich,2002[ ISBN 3-906390-26-8]), each of which is incorporated by reference herein in its entirety.

The neutral form of the compound may be regenerated by contacting the salt with an acid or an acid in a conventional manner and isolating the parent compound. The parent compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the present invention, the salts are equivalent to the parent.

In addition to salt forms, the present invention also provides compounds in prodrug form. Prodrugs of the compounds described herein are those compounds which undergo chemical changes under physiological conditions to provide the compounds of the present invention. In addition, prodrugs can be converted to compounds of the present invention by chemical or biochemical means in an ex vivo environment. For example, a prodrug can be slowly converted to a compound of the invention when placed in a transdermal patch reservoir with a suitable enzyme or chemical agent. Prodrugs are generally useful because in some cases they may be easier to administer than the parent drug. For example, by oral administration, they may be more bioavailable than the parent drug. The solubility of the prodrug in the pharmacological composition may also be improved over the parent drug. Various prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. One non-limiting example of a prodrug is a compound of the present invention that is administered as an ester ("prodrug"), but is then metabolically hydrolyzed to the active entity, the carboxylic acid. Other examples include peptidyl derivatives of the compounds of the invention.

The invention also encompasses various hydrate and solvate forms of the compounds.

The compounds of the present invention may also contain unnatural proportions of isotopes at one or more of the atoms for which such compounds are constructed. For example, radioactive isotopes such as tritium(s) ((iii))³H) Iodine-125 (¹²⁵I) Or carbon-14 (¹⁴C) The compound is radiolabeled. All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.

Method of producing a composite material

Without wishing to be bound by any particular theory, it is believed that the compounds exert their desired effects by their ability to inhibit the growth or kill of the parasitic protozoa responsible for malaria (e.g., plasmodium falciparum, plasmodium vivax, plasmodium ovale, plasmodium malariae, and/or plasmodium knowlesi) and/or the parasitic protozoa of cryptosporidiosis (e.g., cryptosporidium parvum, cryptosporidium hominis, cryptosporidium caninum, cryptosporidium felis, cryptosporidium turkey, and cryptosporidium murine). In some embodiments, the treatment includes prophylaxis of etiology, such as preventing the spread of plasmodium and/or cryptosporidium infection beyond the liver, preventing systemic disease, preventing the symptomatic stage of malaria, preventing the establishment of infection, and/or further transmission of tissue (e.g., to mosquitoes). In some embodiments, treatment of malaria refers to treatment aimed at achieving a cure (e.g., vivax or malaria), e.g., a complete cure (i.e., clearance of dormant species from the liver). In various examples, the method includes the spread of a parasitic infection from the liver that the tissue caused malaria. In some embodiments, treatment of cryptosporidiosis includes prophylaxis of etiology, such as the spread of cryptosporidium histolyticum beyond the site of infection (e.g., liver, intestine, respiratory tract, etc.) in a subject.

The compounds are useful for treating drug-resistant malaria, such as malaria resistant to chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, and any combination thereof.

Pharmaceutical composition

1. Formulation of

For use in the methods described herein, the compounds may be formulated as pharmaceutical or veterinary compositions. The formulation selected may vary depending on the subject to be treated, the mode of administration, and the type of treatment desired (e.g., prevention, prophylaxis, or treatment). A summary of formulation techniques can be found in Remington: pharmaceutical Science and Practice (twenty-first Edition) (Remington: The Science and Practice of Pharmacy,21st Edition, Lippincott Williams & Wilkins, (2005)) and J.Swarbrick and J.C.Boylan, Encyclopedia of Pharmaceutical Technology, eds.J.Swarbrick and J.C.Boylan,1988-1999, Marcel Dekker, New York, each of which is incorporated herein by reference. Exemplary routes of administration and formulation are described below.

In the practice of the disclosed methods, the compound (or pharmaceutically acceptable salt thereof) or composition can be administered by any of the usual and acceptable routes and methods known in the art. For example, the compound or composition can thus be administered by enteral or gastrointestinal routes (e.g., oral or rectal), topical administration (e.g., to the skin or accessible mucosa (e.g., intraoral (e.g., sublingual or buccal), intranasal, intrarectal, or urogenital surfaces)), parenteral (e.g., intramuscular, intravenous, subcutaneous, intraarticular, intracapsular, intrathecal, intradural, intraocular, or intraaural application or injection), transdermal administration, or by inhalation (e.g., by aerosol).

The composition may be in solid, liquid or gaseous form, as determined by one skilled in the art to be suitable. Thus, as a general example, the pharmaceutical composition may be in the form of a tablet, capsule, syrup, alkyl, enteric coating or other protective formulation, sustained release formulation, elixir, powder, granule, suspension, emulsion, solution, gel (e.g., aqueous sol), paste, ointment, cream, paste, transdermal patch, drenches (drenches), suppository, enema, injection, implant, spray or aerosol.

Typically, the composition comprises an effective amount of a compound described herein and one or more pharmaceutically acceptable carriers or excipients, as is well known in the art. The composition may thus include one or more diluents, buffers, preservatives, salts, carbohydrates, amino acids, carrier proteins, fatty acids, lipids, and the like. The compounds described herein may be present in amounts ranging, for example, from 1% to 95% in total, based on the total weight of the composition and by weight.

For injection, the formulations may be prepared in conventional forms such as solutions or suspensions, solid forms suitable for forming solutions or suspensions prior to injection, or emulsions. Excipients suitable for use in these formulations include, for example, water, saline, dextrose, and glycerol. Such compositions may also contain non-toxic adjuvant materials such as wetting or emulsifying agents, and pH buffering agents such as sodium acetate, sorbitan monolaurate and the like.

Formulations for oral administration include tablets containing the compound in admixture with one or more non-toxic pharmaceutically acceptable excipients. These excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); a binder (e.g., sucrose, glucose, sorbitol, gum arabic, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating, glidants, and anti-caking agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oils, or talc). Other pharmaceutically acceptable excipients may be colorants, fragrances, plasticizers, humectants and buffers.

Formulations for oral administration may be provided as chewable tablets; or a hard gel capsule in which the active ingredient is mixed with an inert solid diluent (e.g., potato starch, lactose, microcrystalline cellulose, calcium carbonate, calcium phosphate, or kaolin); or as a softgel capsule in which the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil. Powders, granules and pellets can be prepared in a conventional manner using the above-mentioned ingredients mentioned under tablets and capsules, using, for example, mixers, fluid bed devices or spray drying equipment.

Dissolution or diffusion controlled release can be achieved by suitably coating tablets, capsules, pellets or granules of the compound, or by incorporating the compound into a suitable matrix. The controlled release coating may include one or more of the above-described coating substances and/or, for example, shellac, beeswax, sugar wax, castor wax, carnauba wax, stearyl alcohol, glycerol monostearate, glycerol distearate, glycerol palmitostearate, ethylcellulose, acrylic resins, dl-polylactic acid, cellulose acetobutyrate, polyvinyl chloride, polyvinyl acetate, acetylpyrrolidone, polyethylene, polymethacrylates, methyl methacrylate, 2-strong methacrylate, methacrylate hydrogels, 1, 3-butanediol, ethylene glycol methacrylate, and/or polyethylene glycol. In controlled release matrix formulations, the matrix material may also include, for example, hydrated methyl cellulose, hydrated carnauba wax, hydrated stearyl alcohol, carbopol 934, silicone, glyceryl tristearate, methyl acrylate-methyl methacrylate, polyvinyl chloride, polyethylene, and/or halogenated fluorocarbons.

Liquid forms in which the compounds and compositions may be incorporated for oral administration include aqueous solutions; a properly aromatized syrup; aqueous or oily suspensions; aromatized emulsions using edible oils such as cottonseed oil, sesame oil, cocoa butter or peanut oil; as well as elixirs and similar pharmaceutical vehicles.

The pharmaceutical composition may also be formulated as a veterinary composition intended for subjects other than humans. The veterinary composition according to the invention may be in any suitable form to suit the desired mode of administration, for example, nasal, oral, intradermal, dermal or parenteral. In a preferred embodiment, the composition is in a form for oral administration and is placed in the mouth directly after consumption, for example, by livestock, or mixed with food or after a meal. The veterinary composition of the invention is in the form of an intranasal, oral or injectable suspension or solution; or a solid or semi-solid form such as a powder, pellet, capsule, granule, dragee, soft capsule, spray, cachet, pill, tablet, patch, implant, or gel. In a particular embodiment, the composition is in an oral solid form, preferably a tablet. In some embodiments, the veterinary compositions can have an effective amount of the compound for a particular animal species (e.g., cattle, lamb, goat, horse, etc.).

In a preferred embodiment, the compositions of the present invention are formulated as pills or tablets for oral administration. According to this type of formulation, they contain lactose monohydrate, microcrystalline cellulose, crospovidone/povidone, aroma, compressible sugar and magnesium stearate as excipients. When the compositions are in the form of pills or tablets, they are, for example, 1mg, 2mg or 4mg of torasemide pills or tablets. Such pills or tablets are divisible so that they can be cut into a dosage form suitable for once-or twice-daily administration according to the invention. In a further preferred embodiment, the compositions of the present invention are formulated as injectable solutions or suspensions for parenteral administration. Injectable compositions are produced by mixing a therapeutically effective amount of torasemide with pH adjusting agents, buffers, suspending agents, solvating agents, stabilizing agents, tonicity agents and/or preservatives according to conventional methods and by converting the mixture into intravenous, subcutaneous, intramuscular injection or infusion form. Possibly, the injectable composition may be lyophilized according to conventional methods. Examples of suspending agents include methylcellulose, polysorbate 80, hydroxyethylcellulose, xanthan gum, sodium carboxymethylcellulose, and polyethoxylated sorbitan monolaurate. Examples of solubilizing agents include polyoxyethylene solidified castor oil, polysorbate 80, niacinamide, polyoxyethylated sorbitan monolaurate, polyethylene glycol (macrogol), and ethyl esters of castor oil fatty acids. In addition, the stabilizer includes sodium sulfite, sodium metabisulfite and ether, and the preservative includes methyl parahydroxybenzoate, ethyl parahydroxybenzoate, sorbic acid, phenol, cresol and chlorocresol. An example of a tonicity agent is mannitol. When preparing injectable suspensions or solutions, it is desirable to ensure that they are isotonic with blood.

2. Reagent kit

The compounds and compositions may be packaged in kits, optionally with one or more other agents (see below). Non-limiting examples of kits include those containing, for example, two or more pills, a pellet and powder, a suppository and a liquid in one vial, or two topical creams. The kit may include optional components to assist in administering the unit dose to the subject, such as a vial for reconstitution of powder form, a syringe for injection, a custom IV delivery system, or an inhaler. In addition, the unit dose kit may contain instructions for preparing and administering the composition. Kits can be manufactured as a single-use unit dose for one subject, multiple-use for a particular subject (used at a constant dose, or where each compound can potentially vary as treatment progresses); or the kit may contain multiple doses suitable for administration to multiple subjects ("big pack"). The kit components may be assembled in compartments, blister packs, bottles and tubes.

3. Dosage form

The dosage of the compound depends on factors such as the mode of administration, the age and weight of the subject, and the physical condition of the subject to be treated, and is ultimately at the discretion of the attendant physician or veterinarian. The amount of such a compound, as determined by the attending physician or veterinarian, is referred to herein and in the claims as a "therapeutically effective amount". For example, the dosage of a compound disclosed herein typically ranges from about 1mg to 1000mg per day. Preferably, the therapeutically effective amount is an amount of about 1mg to about 500mg per day.

As described herein, each drug may be administered independently from 1 to 4 times per day for 1 day to 1 year, and may even be administered throughout the rest of the subject's life. Chronic dosing may be indicated.

4. Combination therapy

The compounds and pharmaceutical compositions may be compatible with and used in conjunction with therapy, in other words, the compounds and pharmaceutical compositions may be compatible with or administered concurrently with, prior to, or sequentially after one or more desired therapeutic agents or procedures. The particular therapeutic (therapeutic agent or process) combination employed in the combination regimen will take into account the compatibility of the desired therapeutic agent and/or process with the desired therapeutic effect to be achieved. It will be appreciated that the therapies employed may achieve the desired effect on the same lesion, or they may achieve different effects (e.g., control of any side effects).

Examples of other drugs to be combined with the compounds described herein include drugs for the treatment of malaria (e.g., chloroquine, quinine, pyrimethamine, sulfadoxine, mefloquine, artemether, lumefantrine, artesunate, amodiaquine, dihydroartemisinin, piperaquine, proguanil, doxycycline, clindamycin, artemisinin, atovaquone, any other therapeutic agent approved for the treatment of malaria, and any combination thereof) and/or drugs for the treatment of cryptosporidiosis (e.g., nitazoxanide). Other examples of drugs to be combined with the compounds described herein include drugs for the treatment of different diseases but with associated or related symptoms or signs. The method of combination may involve the use of two (or more) agents, either together or separately, as determined to be appropriate by one skilled in the art. In one embodiment, two or more drugs are formulated together for simultaneous or near-simultaneous administration of the agents.