USRE39707EExpiredUtility
Camptothecin derivatives
Assignee: CALIFORNIA PACIFIC MED CENTERPriority: Jan 18, 2001Filed: Jan 16, 2003Granted: Jun 26, 2007
Est. expiryJan 18, 2021(expired)· nominal 20-yr term from priority
A61K 31/4745A61P 35/00C07D 491/22
50
PatentIndex Score
0
Cited by
62
References
149
Claims
Abstract
(20S) esters of camptothecin analogs are provided. The compounds are (20S) esters of an oxyalkanoic acid and camptothecin, which is are optionally substituted at the 7, 9, 10, 11, and 12 positions of the camptothecin ring. The compounds are useful for treating cancer.
Claims
exact text as granted — not AI-modified1. A compound of the formula
wherein R is R 1 —O-(CH 2 ) m —, m is an integer of 1-10 and R 1 is
phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperidino, lower alkoxycarbonyl, and lower alkylcarbonylamino;
a fused, 2-, 3-, or 4-ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino;
R 2 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore), cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, tri lower alkylsilyl, lower alkylcarbonyloxy, lower alkylcarbonylamino, lower alkylcarbonyloxymethyl, substituted vinyl, 1-hydroxy-2-nitroethyl, alkoxycarbonylethyl, aminocarbonyl, mono- or di-alkylcarbonyl, alkylcarbonyloxymethyl alkylcarbonylmethyl, benzoylmethyl, benzylcarbonyloxymethyl, or mono- or di lower alkoxymethyl;
R 3 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hyroxycarbonyl, formyl, lower alkoxycarbonyl, CH 2 NR 7 R 8 (where each of R 7 and R 8 is independently H-, alkyl of 1-6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N— represent a cyclic amino-), CH 2 R 9 (where R 9 is lower alkoxy, CN, amino lower alkoxy, mono- or di-lower alkylamino lower alkoxy, lower alkylthio, amino lower alklthio, or mono- or di-lower alkylamino lower alkylthio), or NR 10 R 11 (where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxy lower alkyl, amino lower alkyl, or mono- or di-lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino), dialkylamino alkyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino;
R 4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, amino lower alkyl, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or lower alkylcarbonylamino, or R 4 together with R 5 is methylenedioxy;
R 5 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower alkylcarbonylamino; and
R 4 is hydrogen, halo, lower alkyl, lower alkoxy, hydroxy, RC(O)O (R is defined hereinbefore) cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, or lower akylcarbonylamino.
2. The compound of claim 1 wherein m is 1, each of R 2 through R 6 is H, and R 1 is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
3. The compound of claim 2 wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkoxy, and lower alkoxy.
4. The compound of claim 3 wherein R 1 is phenyl optionally substituted with one to three halo substituents.
5. The compound of claim 4 wherein R 1 is phenyl.
6. The compound of claim 4 wherein R 1 is 4-halophenyl.
7. The compound of claim 4 wherein R 1 is 3-chlorophenyl or 2-chlorophenyl.
8. The compound of claim 4 wherein R 1 is 2,4-dichlorophenyl.
9. The compound of claim 4 wherein R 1 is 4-fluorophenyl, 4-bromophenyl, or 4-iodophenyl.
10. The compound of claim 4 wherein R 1 is 2,3-dichlorophenyl.
11. The compound of claim 4 wherein R 1 is 2,3dicoro-4-fluorophenyl.
12. The compound of claim 4 wherein R 1 is 2-bromo-4-chlorophenyl.
13. The compound of claim 4 wherein R 1 is 3-chloro-4-fluorophenyl.
14. The compound of claim 4 wherein R 1 is 2,3-difluoro-5-bromophenyl.
15. The compound of claim 4 wherein R 1 is 2-bromo-4-fluorophenyl.
16. The compound of claim 3 wherein R 1 is 3-bromomethylphenyl.
17. The compound of claim 2 wherein R 1 is 3,5-dimothyl-4-chlorophenyl; 2,5-dibromo-4-cyanophenyl; 4-benzyloxyphenyl; 4-trifluoromethoxyphenyl; or 4-hydroxycarbonylphenyl.
18. The compound of claim 3 wherein R 1 is phenyl substituted with one or two lower alkyl substituents.
19. The compound of claim 18 , wherein R 1 is 4-alkyl-substituted phenyl.
20. The compound of claim 18 , wherein R 1 is 2,4-dialkyl-substituted phenyl.
21. The compound of claim 2 , wherein R 1 is monoalkoxy-substituted phenyl.
22. The compound of claim 2 , wherein R 1 is 3,4-methylenedioxyphenyl.
23. The compound of claim 1 , wherein m is 1, each of R 2 through R 6 is H, and R 1 is a fused, 2-ring heterocyclic system.
24. The compound of claim 23 , wherein R 1 is represented by the formula
25. The compound of claim 1 , wherein m is 1, each of R 2 through R 6 is H, and R 1 is 1- or 2-naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyl and lower alkylcarbonylamino.
26. The compound of claim 25 , wherein R 1 is 2-naphthyl.
27. The compound of claim 1 , wherein m is 1, each of R 1 through R 6 is H, and R 1 is
28. The compound of claim 1 , wherein m is 1, each or R 2 through R 6 is H, and R 1 is 4-formylphenyl.
29. The compound of claim 1 , wherein m is 1, each of R 2 through is H, and R 1 is 4-nitrophenyl, 2-nitrophenyl, or 3-trifluoromethyl-4-nitrophenyl.
30. The compound of claim 1 , wherein m is an integer of 2-4, each of R 2 through R 6 is H, and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamino.
31. The compound of claim 1 , wherein R 6 is hydrogen.
32. The compound of claim 31 , wherein R 4 and R 5 together are methylenedioxy.
33. The compound of claim 1 , wherein R 2 is hydrogen.
34. The compound of claim 33 , wherein R 2 is nitro, amino, methyl, chloro, cyano, acetoxy, or acetylamino.
35. The compound of claim 31 , wherein R 3 is hydroxy.
36. The compound of claim 35 , wherein R 3 is hydrogen, R 2 is (3-chloro-n-propyl)dimethylsilyl, tert-butyldimethylsilyl, acetoxymethyl, cyano, formylethenyl, ethoxycarbonyl-ethenyl, cyanoethenyl, 2,2-dicyanoethenyl, (2-cyano-2-ethoxycarbonyl)ethenyl, ethoxycarbonyethyl, methyl, ethyl, or n-propyl; and R 4 is hydroxy, acetoxy; amino, nitro, cyano, chloro, bromo, fluoro, lower alkyl, higher alkyl, lower alkoxy, carbamoyloxy; or formyl.
37. The compound of claim 36 , wherein R 2 is ethyl and R 4 is carbamoyloxy.
38. The compound of claim 37 , wherein carbamoyloxy is 1-piperazinylcarbonyloxy, 4(-i-propylaminocarbonylmethyl)-1-piperazinyl-carbonyloxy or [4-(1-piperidinol)-1-piperidino]-carbonyloxy.
39. The compound of claim 31 , wherein R 2 and R 5 are hydrogen.
40. The compound of claim 39 , wherein R 3 is amino, nitro, cyano, halo, OH, lower alkylamino, di-lower alkylamino, lower alkyl, lower alkoxy, 1-piperidino, 1-morpholino, aminomethyl lower alkylaminomethyl, cycloalkylaminomethyl, di-lower alkylaminomethyl, cyclic aminomethyl, acetoxy, acetylamino, lower alkoxymethyl, omega-hydroxy lower alkylaminomethyl, cyanomethyl, and R 4 is hydrogen, acetoxy, cyano, nitro, amino, halo, formyl, lower alkoxy, carbamoyloxy.
41. The compound of claim 31 , wherein each of R 2 , R 3 , and R 5 is hydrogen and R 4 is —OC(O)Alkyl 1-20 .
42. The compound of claim 1 , wherein m is an integer of 1-5.
43. The compound of claim 1 , wherein m is 1.
44. The compound of claim 1 , wherein m is 1; each of R 2 , R 3 , R 5 , and R 6 is hydrogen; and R4 is R 1 —OCH 2 C(O)—.
45. A pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound as defined in claim 1 in combination with a pharmaceutically acceptable excipient.
46. The pharmaceutical composition of claim 45 , suitable for oral administration.
47. The pharmaceutical composition of claim 45 suitable for IV administration.
48. The pharmaceutical composition of claim 45 suitable for IM administration.
49. A method for treating cancer is a warm-blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 1 .
50. The method of claim 49 , wherein the compound is administered orally.
51. The method of claim 49 , wherein the compound is administered IV.
52. The method of claim 49 , wherein the compound is administered parenterally.
53. A process of preparing a compound of claim 1 , which comprises reacting
(a) a compound of the formula R—C(O)X, wherein R is R 1 —O—(CH 2 ) m , R 1 and m are defined as in claim 1 , and X is hydroxy, chloride, or R—C(O)—O (where R is defined hereinbefore) with
wherein
R 3 , R 4 , R 5 , and R 6 are defined in claim 1 .
54. The process of claim 53 wherein the reacting takes place in the presence of the coupling agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and the catalytic agent 4-(dimethylamino)pyridine.
55. A compound of the formula
wherein R is R 1 —O —( CH 2 ) m —, m is an integer of 1 - 10 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino; a fused, 2 - , 3 - , or 4 - ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkylcarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1 - or 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkyloxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkoxycarbonyloxy, and lower alkylcarbonylamino; a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; R 2 is hydrogen; R 3 is CH 2 NR 7 R 8 ( where each of R 7 and R 8 is independently H - , alkyl of 1 - 6 carbons, optionally substituted phenyl, hydroxy lower alkyl, amino lower alkyl, or mono - or dialkylamino lower alkyl, or R 7 and R 8 taken together with —N— represent a cyclic amino -) , NR 10 R 11 ( where each of R 10 and R 11 is independently hydrogen, lower alkyl, phenyl, hydroxyl lower alkyl, amino lower alkyl, or mono - or di - lower alkyl, or R 10 and R 11 taken together with —N— represent a cyclic amino ) , or dialkylamino alkyl; R 4 is lower alkoxy, hydroxy, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy, or R 4 together with R 5 is methylenedioxy; R 5 is hydrogen, or together with R 4 is methylenedioxy; and R 6 is hydrogen.
56. The compound of claim 55 , wherein R 3 is CH 2 NR 7 R 8 ( where each of R 7 and R 8 is lower alkyl), R 5 is hydrogen, and R 4 is hydroxy, alkoxy or alkylcarbonyloxy.
57. The compound of claim 56 , wherein R 3 is CH 2 N( CH 2 ) 2 and R 4 is hydroxy.
58. The compound of claim 57 , wherein m is 1 , R 1 is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
59. The compound of claim 58 , wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkyl, nitro, and lower alkoxy.
60. The compound of claim 57 , wherein m is 1 , and R 1 is a fused, 2 - ring heterocyclic system.
61. The compound of claim 57 , wherein m is 1 and R 1 is 1 - or 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
62. The compound of claim 57 , wherein m is 1 and R 1 is
63. The compound of claim 57 , wherein m is an integer of 2 - 4 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamino.
64. A pharmaceutical composition useful for treating cancer in a warm- blooded animal, which composition comprises compound as defined in claim 55 in combination with a pharmaceutically acceptable excipient.
65. The pharmaceutical composition of claim 64 suitable for oral administration.
66. The pharmaceutical composition of claim 64 suitable for IV administration.
67. The pharmaceutical composition of claim 64 suitable for IM administration.
68. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 55 .
69. The method of claim 68 , wherein the compound is administered orally.
70. The method of claim 68 , wherein the compound is administered IV.
71. The method of claim 68 , wherein the compound is administered parenterally.
72. A compound of the formula
wherein R is R 1 —O -( CH 2 ) m —, m is an integer of 1 - 10 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino; a fused, 2 - , 3 - , or 4 - ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1 - or 2 - naphthyl optionally substituted with from one to four substitutions independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; R 2 is hydrogen, lower alkyl, or halogenated lower alkyl; R 3 is hydrogen or lower alkyl; R 4 is lower alkoxy, hydroxy, halogenated lower alkoxy, carbamoyloxy, lower alkylcarbonyloxy, or R 4 together with R 5 is methylenedioxy; R 5 is hydrogen, or together with R 4 is methylenedioxy; and R 6 is hydrogen.
73. The compound of claim 72 , wherein R 3 is hydrogen, R 5 is hydrogen, and R 4 is carbamoyloxy.
74. The compound of claim 73 , wherein R 2 is lower alkyl and R 4 is 4 -( 1 - piperidino )- 1 - piperidinocarbonyloxy.
75. The compound of claim 74 , wherein m is 1 and R 2 is ethyl.
76. The compound of claim 75 , wherein m is 1 , and R 1 is optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
77. The compound of claim 76 , wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkyl, nitro, and lower alkoxy.
78. The compound of claim 75 , wherein m is 1 , and R 1 is a fused, 2 - ring heterocyclic system.
79. The compound of claim 75 , wherein m is 1 and R 1 is 1 - or 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
80. The compound of claim 75 , wherein m is 1 and R 1 is
81. The compound of claim 75 , wherein m is an integer of 2 - 4 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkoxycarbonyloxy and lower alkylcarbonylamino.
82. A pharmaceutical composition useful for treating cancer in a warm- blooded animal, which composition comprises compound as defined in claim 75 in combination with a pharmaceutically acceptable excipient.
83. The pharmaceutical composition of claim 82 suitable for oral administration.
84. The pharmaceutical composition of claim 82 suitable for IV administration.
85. The pharmaceutical composition of claim 82 suitable for IM administration.
86. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 75 .
87. The method of claim 86 , wherein the compound is administered orally.
88. The method of claim 86 , wherein the compound is administered IV.
89. The method of claim 86 , wherein the compound is administered parenterally.
90. A compound of the formula
wherein R is R 1 —O -( CH 2 ) m —, m is an integer of 1 - 10 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino; a fused, 2 - , 3 - , or 4 - ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1 - or 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; R 2 is lower alkyl; R 3 is hydrogen; R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkylcarbonyl, carbamoyloxy, lower alkylcarbonyloxy; R 5 is hydrogen; and R 6 is hydrogen.
91. The compound of claim 90 , wherein R 2 is ethyl and R 4 is hydroxy.
92. The compound of claim 91 wherein m is 1 , and R 1 is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
93. The compound of claim 92 , wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkyl, nitro, and lower alkoxy.
94. The compound of claim 91 , wherein m is 1 , and R 1 is a fused, 2 - ring heterocyclic system.
95. The compound of claim 91 , wherein m is 1 and R 1 is 1 - or 2 - napthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
96. The compound of claim 91 , wherein m is 1 and R 1 is
97. The compound of claim 91 , wherein m is an integer of 2 - 4 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamino.
98. A pharmaceutical composition useful for treating cancer in a warm-blooded animal, which composition comprises compound as defined in claim 91 in combination with a pharmaceutically acceptable excipient.
99. The pharmaceutical composition of claim 98 suitable for oral administration.
100. The pharmaceutical composition of claim 98 suitable for IV administration.
101. The pharmaceutical composition of claim 98 suitable for IM administration.
102. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 91 .
103. The method of claim 102 , wherein the compound is administered orally.
104. The method of claim 102 , wherein the compound is administered IV.
105. The method of claim 102 , wherein the compound is administered parenterally.
106. A compound of the formula
wherein R is R 1 —O ( CH 2 ) m —, m is an integer of 1 - 10 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkylcarbonyl, hydroxycarbonyl, lower alkylcarbonyloxy, benzyloxy, optionally substituted piperazine, lower alkoxycarbonyl, and lower alkylcarbonylamino; a fused, 2 - , 3 - , or 4 - ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1 - or 2 - napthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; each of R 2 , R 4 , R 5 , and R 6 is hydrogen; and R 3 is amino or nitro.
107. The compound of claim 106 , wherein R 3 is amino.
108. The compound of claim 106 , wherein R 3 is nitro.
109. The compound of claim 106 wherein m is 1 , and R 1 is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
110. The compound of claim 109 , wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkyl, nitro, and lower alkoxy.
111. The compound of claim 106 , wherein m is 1 , and R 1 is a fused, 2 - ring heterocyclic system.
112. The compound of claim 106 , wherein m is 1 and R 1 is 1 - or 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
113. The compound of claim 106 , wherein m is 1 and R 1 is
114. The compound of claim 106 , wherein m is an integer of 2 - 4 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamino.
115. A pharmaceutical composition useful for treating cancer in a warm- blooded animal, which composition comprises compound as defined in claim 106 in combination with a pharmaceutically acceptable excipient.
116. The pharmaceutical composition of claim 115 suitable for oral administration.
117. The pharmaceutical composition of claim 115 suitable for IV administration.
118. The pharmaceutical composition of claim 115 suitable for IM administration.
119. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 106 .
120. The method of claim 119 , wherein the compound is administered orally.
121. The method of claim 119 , wherein the compound is administered IV.
122. The method of claim 119 , wherein the compound is administered parenterally.
123. A compound of the formula
wherein R is R 1 —O -( CH 2 ) m —, m is an integer of 1 - 10 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, formyl, lower alkyl carbonyl, hydroxycarbonyl, lower alkoxycarbonyloxy, benzyloxy, optionally substituted piperazino, lower alkoxycarbonyl, and lower alkylcarbonylamino; a fused, 2 - , 3 - , or 4 - ring heterocyclic system optionally substituted with one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; 1 - 2 - naphthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; a 5 or 6 membered heterocyclic ring containing one or two nitrogen atoms, which ring is optionally substituted with one or two substituents selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkyl, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy, and lower alkylcarbonylamino; R 2 is tri - lower alkylsilyl; R 3 is hydrogen; R 4 is hydroxy, lower alkoxy, halogenated lower alkoxy, hydroxycarbonyl, formyl, lower alkoxycarbonyl, carbamoyloxy, lower alkylcarbonyloxy; R 5 is hydrogen; and R 6 is hydrogen.
124. The compound of claim 123 , wherein R 2 is t - butyldimethylsilyl and R 4 is hydroxy.
125. The compound of claim 124 wherein m is 1 , and R 1 is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, and benzyloxy.
126. The compound of claim 125 , wherein R 1 is phenyl optionally substituted with one to three substituents independently selected from lower alkyl, halo, halogenated lower alkyl, nitro, and lower alkoxy.
127. The compound of claim 124 , wherein m is 1 , and R 1 is a fused, 2 - ring heterocyclic system.
128. The compound of claim 124 , wherein m is 1 and R 1 is 1 - or 2 - napthyl optionally substituted with from one to four substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, hydroxycarbonyl, lower alkoxycarbonyl, lower alkylcarbonyloxy and lower alkylcarbonylamino.
129. The compound of claim 124 , wherein m is 1 and R 1 is
130. The compound of claim 124 , wherein m is an integer of 2 - 4 and R 1 is phenyl optionally substituted with from one to five substituents independently selected from the group consisting of halo, lower alkyl, lower alkoxy, hydroxy, cyano, nitro, amino, halogenated lower alkyl, halogenated lower alkoxy, carbonyl, hydroxycarbonyl, lower alkoxycarbonyl, benzyloxy, lower alkylcarbonyloxy and lower alkylcarbonylamino.
131. A pharmaceutical composition useful for treating cancer in a warm- blooded animal, which composition comprises compound as defined in claim 124 in combination with a pharmaceutically acceptable excipient.
132. The pharmaceutical composition of claim 131 suitable for oral administration.
133. The pharmaceutical composition of claim 131 suitable for IV administration.
134. The pharmaceutical composition of claim 131 suitable for IM administration.
135. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of a compound as defined in claim 124 .
136. The method of claim 135 , wherein the compound is administered orally.
137. The method of claim 135 , wherein the compound is administered IV.
138. The method of claim 135 , wherein the compound is administered parenterally.
139. A liposomal formulation that comprises a pharmaceutically acceptable liposome- forming material in combination with a compound of claim 1 .
140. The liposomal formulation of claim 139 , wherein m is 1 and each of R 2 , R 3 , R 4 , R 5 , and R 6 is hydrogen.
141. The liposomal composition of claim 139 , wherein m is 1 ; each of R 2 , R 5 , and R 6 is hydrogen; R 3 is CH 2 N ( CH 3 ) 2 ; and R 4 is hydroxy.
142. The liposomal composition of claim 139 , wherein m is 1 ; each of R 3 , R 5 , and R 6 is hydrogen; R 2 is ethyl; and R 4 is 4 -( 1 - piperazino )- 1 - piperidinocarbonyloxy.
143. The liposomal composition of claim 139 , wherein m is 1 ; each of R 3 , R 5 , and R 6 is hydrogen; R 2 is ethyl and R 4 is hydroxy.
144. The liposomal composition of claim 139 , wherein m is 1 ; each of R 2 , R 4 R 5 , and R 6 is hydrogen; and R 3 is amino.
145. The liposomal composition of claim 139 , wherein m is 1 ; each of R 2 , R 4 R 5 , and R 6 is hydrogen; and R 3 is nitro.
146. The liposomal composition of claim 139 , wherein m is 1 ; each of R 3 , R 5 , and R 6 is hydrogen; R 2 is t - butyldimethylsilyl; and R 4 is hydroxy.
147. A method for treating cancer in a warm- blooded animal, which method comprises administering a therapeutically effective amount of the liposomal formulation as defined in claim 139 .
148. The method of claim 147 , wherein the compound is administered parenterally.
149. The method of claim 147 , wherein the compound is administered intravenously.Cited by (0)
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