Trioxane dimer sulfur compounds
The disclosure provides novel trioxane sulfur dimers having Formula I: methods for their preparation, pharmaceutical compositions containing these compounds, and methods for treating cancer, proliferative disorders, and/or malaria using these compounds and/or compositions.
1. A compound of Formula I:
or a pharmaceutically acceptable salt or solvate thereof, wherein:
n is independently an integer from 0 to 2;
R 1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, wherein R 1 is optionally independently substituted with 1 to 5 R 2 groups;
R 2 is independently hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroarylalkyl, (CH 2 ) j CN, (CH 2 )OR 3 , (CH 2 ) q O(CH 2 ) j OR 3 , (CH 2 ) q O(CH 2 ) t O(CH 2 ) j OR 3 , (CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 , (CH 2 ) j C(O)R 3 , (CH 2 ) j C(O)OR 3 , (CH 2 ) j OC(O)R 3 , (CH 2 ) j NR 4 R 5 , (CH 2 ) j C(O)NR 4 R 5 , (CH 2 ) j OC(O)NR 4 R 5 , (CH 2 ) j NR 6 C(O)R 3 , (CH 2 ) j NR 6 C(O)OR 3 , (CH 2 ) j NR 6 C(O)NR 4 R 5 , —(CH 2 ) j S(O) m R 7 , (CH 2 ) j S(O) 2 NR 4 R 5 , (CH 2 ) j NR 6 S(O) 2 R 7 , or (CH 2 ) j OP(O)(OR 7 ) 2 , wherein q is independently an integer from 0 to 20, and j, t, and u are each independently an integer from 0 to 6, and each m is independently an integer from 0 to 2, wherein R 2 is optionally independently substituted with 1 to 5 R 8 groups;
R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, perfluoroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted heteroarylalkyl, or
R 3 , R 6 , and R 7 are as described above, and R 4 and R 5 , together with the N atom to which they are attached, form substituted or unsubstituted heterocycloalkyl, or substituted or unsubstituted heteroaryl, wherein R 3 , R 4 , R 5 , R 6 , and R 7 are each optionally independently substituted with 1 to 5 R 8 groups; and
R 8 is independently halogen, hydroxyl, cyano, nitro, alkyl, perfluoroalkyl, oxo, NH 2 , NH(alkyl), N(alkyl) 2 , O-alkyl, S-alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
2. The compound of claim 1 , wherein:
n is independently 2;
R 1 is independently substituted or unsubstituted (C 1 -C 20 )alkyl, substituted or unsubstituted (C 1 -C 20 )heteroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted (C 3 -C 7 )heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, or substituted or unsubstituted quinoxalinyl;
R 2 is independently hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )heteroalkyl, perfluoroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted (C 3 -C 7 )heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted quinoxalinyl, —(CH 2 ) j CN, —(CH 2 )OR 3 , —(CH 2 ) q O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 , —(CH 2 ) j C(O)R 3 , —(CH 2 ) j C(O)OR 3 , —(CH 2 ) j OC(O)R 3 , —(CH 2 ) j NR 4 R 5 , —(CH 2 ) j C(O)NR 4 R 5 , —(CH 2 ) j OC(O)NR 4 R 5 , —(CH 2 ) j NR 6 C(O)R 3 , —(CH 2 ) j NR 6 C(O)OR 3 , —(CH 2 ) j NR 6 C(O)NR 4 R 5 , —(CH 2 ) j S(O) m R 7 , —(CH 2 ) j S(O) 2 NR 4 R 5 , —(CH 2 ) j NR 6 S(O) 2 R 7 , or —(CH 2 ) j OP(O)(OR 7 ) 2 ;
R 3 , R 4 , R 5 , R 6 , and R 7 are each independently hydrogen, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )heteroalkyl, perfluoroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted (C 3 -C 7 )heterocycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, or substituted or unsubstituted quinoxalinyl, or
R 3 , R 6 , and R 7 are as described above, and R 4 and R 5 , together with the N atom to which they are attached, form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted imidazolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted piperazinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, substituted or unsubstituted pyrrolyl, or substituted or unsubstituted imidazolyl; and
R 8 is independently halogen, hydroxyl, cyano, nitro, perfluoroalkyl, oxo, NH 2 , NH((C 1 -C 6 )alkyl), N((C 1 -C 6 )alkyl) 2 , O(C 1 -C 6 )alkyl, S(C 1 -C 6 )alkyl, phenyl, biphenyl, naphthyl, benzyl, pyrrolyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, isooxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, indazolyl, benzimidazolyl, benzofuryl, benzothienyl, benzoxazolyl, benzoisooxazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, or quinoxalinyl.
3. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted (C 1 -C 20 )alkyl; and
R 2 is independently hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )heteroalkyl, perfluoroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, substituted or unsubstituted (C 3 -C 7 )heterocycloalkyl.
4. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted (C 1 -C 20 )alkyl; and
R 2 is independently substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, or substituted or unsubstituted quinoxalinyl.
5. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted (C 1 -C 20 )alkyl; and
R 2 is independently —(CH 2 ) j CN, —(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O (CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 , —(CH 2 ) j C(O)R 3 , —(CH 2 ) j C(O)OR 3 , —(CH 2 ) j OC(O)R 3 , —(CH 2 ) j NR 4 R 5 , —(CH 2 ) j C(O)NR 4 R 5 , —(CH 2 ) j OC(O)NR 4 R 5 , —(CH 2 ) j NR 6 C(O)R 3 , —(CH 2 ) j NR 6 C(O)OR 3 , —(CH 2 ) j NR 6 C(O)NR 4 R 5 , —(CH 2 ) j S(O) m R 7 , —(CH 2 ) j S(O) 2 NR 4 R 5 , —(CH 2 ) j NR 6 S(O) 2 R 7 , or —(CH 2 ) j OP(O)(OR 7 ) 2 .
6. The compound of claim 5 , wherein R 2 is independently —(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) j OR 3 , or —(CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 .
7. The compound of claim 6 , wherein R 3 is hydrogen.
8. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted phenyl; and
R 2 is independently hydrogen, halogen, nitro, cyano, hydroxyl, substituted or unsubstituted (C 1 -C 6 )alkyl, substituted or unsubstituted (C 1 -C 6 )heteroalkyl, perfluoroalkyl, substituted or unsubstituted (C 3 -C 7 )cycloalkyl, or substituted or unsubstituted (C 3 -C 7 )heterocycloalkyl.
9. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted phenyl; and
R 2 is independently substituted or unsubstituted phenyl, substituted or unsubstituted biphenyl, substituted or unsubstituted naphthyl, substituted or unsubstituted benzyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyrazolyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted furyl, substituted or unsubstituted thienyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted isooxazolyl, substituted or unsubstituted thiazolyl, substituted or unsubstituted pyridinyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted pyrimidinyl, substituted or unsubstituted pyrazinyl, substituted or unsubstituted indolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzofuryl, substituted or unsubstituted benzothienyl, substituted or unsubstituted benzoxazolyl, substituted or unsubstituted benzoisooxazolyl, substituted or unsubstituted benzthiazolyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted phthalazinyl, substituted or unsubstituted quinazolinyl, or substituted or unsubstituted quinoxalinyl.
10. The compound of claim 2 , wherein:
R 1 is independently substituted or unsubstituted phenyl; and
R 2 is independently —(CH 2 ) j CN, —(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O (CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 , —(CH 2 ) j C(O)R 3 , —(CH 2 ) j C(O)OR 3 , —(CH 2 ) j OC(O)R 3 , —(CH 2 ) j NR 4 R 5 , —(CH 2 ) j C(O)NR 4 R 5 , —(CH 2 ) j OC(O)NR 4 R 5 , —(CH 2 ) j NR 6 C(O)R 3 , —(CH 2 ) j NR 6 C(O)OR 3 , —(CH 2 ) j NR 6 C(O)NR 4 R 5 , —(CH 2 ) j S(O) m R 7 , —(CH 2 ) j S(O) 2 NR 4 R 5 , —(CH 2 ) j NR 6 S(O) 2 R 7 , or —(CH 2 ) j OP(O)(OR 7 ) 2 .
11. The compound of claim 10 , wherein R 2 is independently —(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) j OR 3 , —(CH 2 ) q O(CH 2 ) t O(CH 2 ) j OR 3 , or —(CH 2 ) q O(CH 2 ) t O(CH 2 ) u O(CH 2 ) j OR 3 .
12. The compound of claim 11 , wherein R 3 is hydrogen; R 4 and R 5 are (C 1 -C 6 )alkyl; and R 7 is (C 1 -C 6 )alkyl, or phenyl.
13. The compound of claim 10 , wherein R 2 is independently —(CH 2 ) j OR 3 ; R 3 is arylalkyl; and R 8 is halogen.
14. The compound of claim 1 , having formula:
15. A method of preparing the compound of Formula I of claim 1 , comprising the steps of:
a) reacting the compound of Formula II with R 1 SH and base to provide the sulfide compound of Formula I; and
b) optionally treating the sulfide compound of Formula I with an oxidizing agent to provide the sulfoxide and/or sulfone compound of Formula I:
wherein X is a leaving group.
16. The method of claim 15 , wherein X is halogen, mesylate, tosylate or triflate; and the base is 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), sodium hydride, or pyridine.
17. The compound of Formula I, prepared by the method of claim 15 .
18. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound of Formula I of claim 1 .
19. A method of treating cancer in a subject in need of such treatment, the method comprising the steps of administering to the subject a therapeutically effective amount of a compound of Formula I of claim 1 .
20. The method of claim 19 , wherein the cancer is leukemia, non-small cell lung cancer, colon cancer, central nervous system cancer, melanoma cancer, ovarian cancer, renal cancer, prostate cancer, and breast cancer.
21. A method of treating malaria in a subject in need of such treatment, the method comprising the steps of administering to the subject a therapeutically effective amount of a compound of Formula I of claim 1 .