US2006030545A1PendingUtilityA1
Anti-proliferative compounds, compositions, and methods of use thereof
Est. expiryDec 30, 2023(expired)· nominal 20-yr term from priority
Inventors:Xiaoqin ChengGary CookManoj C. DesaiEdward DoerfflerGong-Xin HeChoung U. KimWilliam A. LeeJohn C. RohloffJianying WangZheng-Yu Yang
A61P 31/20A61P 31/12A61P 31/18A61P 31/00A61P 43/00A61P 35/00C07F 9/65616Y02P20/55C07F 9/44A61K 31/664C07F 9/6558
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Claims
Abstract
Compounds and compositions of Formula I are described, useful as anti-proliferative agents, and in particular anti-HPV, wherein: Y 1A and Y 1B are independently Y 1 ; R X1 is R X ; R X2 is alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms; Y 1 is ═O, —O(R X ), ═S, —N(R X ), —N(O)(R X ), —N(OR X ), —N(O)(OR X ), or —N(N(R X )(R X )); R X is independently R 1 , R 2 , R 4 , W 3 , or a protecting group; R 1 is independently —H or alkyl of 1 to 18 carbon atoms; R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups; R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ; R 3a is —H, —F, —Cl, —Br, —I, —CF 3 , —CN, N 3 , —NO 2 , or —OR 4 ; R 3b is ═O, —O(R 4 ), ═S, —N(R 4 ), —N(O)(R 4 ), —N(OR 4 ), —N(O)(OR 4 ), or —N(N(R 4 )(R 4 )); R 3c is —R 4 , —N(R 4 )(R 4 ), —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O)(OR 4 ), —S(O) 2 (OR 4 ), —OC(R 3b )R 4 , —OC(R 3b )OR 4 , —OC(R 3b )(N(R 4 )(R 4 )), —SC(R 3b )R 4 , —SC(R 3b )OR 4 , —SC(R 3b )(N(R 4 )(R 4 )), —N(R 4 )C(R 3b )R 4 , —N(R 4 )C(R 3b )OR 4 , —N(R 4 )C(R 3b )(N(R 4 )(R 4 )), W 3 or —R 5 W 3 ; R 3d is —C(R 3b )R 4 , —C(R 3b )OR 4 , —C(R 3b )W 3 , —C(R 3b )OW 3 or —C(R 3b )(N(R 4 )(R 4 )); R 4 is —H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms; R 5 is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms; W 3 is W 4 or W 5 ; W 4 is R 6 , —C(R 3b )R 6 , —C(R 3b )W 5 , —SO M2 R 6 , or —SO M2 W 5 , wherein R 6 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups; W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups; and M2 is 0, 1 or 2; or pharmaceutically acceptable salts thereof.
Claims
exact text as granted — not AI-modified1 . A compound of Formula I,
wherein:
Y 1A and Y 1B are independently Y 1 ;
R X1 is R X ;
R X2 is alkenyl of 2 to 18 carbon atoms or alkynyl of 2 to 18 carbon atoms;
Y 1 is ═O, —O(R X ), ═S, —N(R X ), —N(O)(R X ), —N(OR X ), —N(O)(OR X ), or —N(N(R X )(R X ));
R X is independently R 1 , R 2 , R 4 , W 3 , or a protecting group;
R 1 is independently —H or alkyl of 1 to 18 carbon atoms;
R 2 is independently R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is —H, —F, —Cl, —Br, —I, —CF 3 , —CN, N 3 , —NO 2 , or —OR 4 ;
R 3b is ═O, —O(R 4 ), ═S, —N(R 4 ), —N(O)(R 4 ), —N(OR 4 ), —N(O)(OR 4 ), or —N(N(R 4 )(R 4 ));
R 3c is —R 4 , —N(R 4 )(R 4 ), —SR 4 , —S(O)R 4 , —S(O) 2 R 4 , —S(O)(OR 4 ), —S(O) 2 (OR 4 ), —OC(R 3b )R 4 , —OC(R 3b )OR 4 , —OC(R 3b )(N(R 4 )(R 4 )), —SC(R 3b )R 4 , —SC(R 3b )OR 4 , —SC(R 3b )(N(R 4 )(R 4 )), —N(R 4 )C(R 3b )R 4 , —N(R 4 )C(R 3b )OR 4 , —N(R 4 )C(R 3b )(N(R 4 )(R 4 )), W 3 or —R 5 W 3 ;
R 3d is —C(R 3b )R 4 , —C(R 3b )OR 4 , —C(R 3b )W 3 , —C(R 3b )OW 3 or —C(R 3b )(N(R 4 )(R 4 ));
R 4 is —H, or an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is alkylene of 1 to 18 carbon atoms, alkenylene of 2 to 18 carbon atoms, or alkynylene of 2 to 18 carbon atoms;
W 3 is W 4 or W 5 ;
W 4 is R 6 , —C(R 3b )R 6 , —C(R 3b )W 5 , —SO M2 R 6 , or —SO M2 W 5 , wherein R 6 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 5 is carbocycle or heterocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups; and
M2 is 0, 1 or 2;
or pharmaceutically acceptable salts thereof.
2 . The compound of claim 1 wherein R X1 is H.
3 . The compound of claims 1 and 2 wherein R X2 is alkenyl of 2 to 18 carbon atoms.
4 . The compound of claim 1 and 2 wherein R X2 is alkenyl of 2 to 6 carbon atoms.
5 . The compound of claims 1 and 2 wherein R X2 is 2-propenyl.
6 . The compound of claim 1 of the Formula IA,
wherein Y 1A and Y 1B are as previously defined.
7 . The compound of claim 6 wherein Y 1A and Y 1B are —N(R X ).
8 . The compound of claim 7 wherein R X is R 2 .
9 . The compound of claim 8 wherein R 2 is R 4 substituted with R 3d .
10 . The compound of claim 9 wherein R 4 is ethyl substituted with R 3d .
11 . The compound of claim 10 wherein R 3d is —C(R 3b )OR 4 .
12 . The compound of claim 11 wherein R 3b is ═O.
13 . The compound of claim 12 wherein R 4 is alkyl of 1 to 18 carbon atoms.
14 . The compound of claim 13 wherein R 4 is alkyl of 1 to 6 carbon atoms.
15 . The compound of claim 14 wherein R 4 is ethyl, butyl, n-propyl, i-propyl, or hexyl.
16 . The compound of claim 15 of the formula,
17 . The compound of claim 15 of the formula,
18 . The compound of claim 15 of the formula,
19 . The compound of claim 15 of the formula,
20 . The compound of claim 15 of the formula,
21 . The compound of claim 10 wherein R 3d is —C(R 3b )OW 3 .
22 . The compound of claim 21 wherein R 3b is ═O.
23 . The compound of claim 22 wherein W 3 is W 5 .
24 . The compound of claim 23 wherein W 5 is a carbocycle.
25 . The compound of claim 24 of the formula,
26 . The compound of claim 9 wherein R 4 is propyl substituted with R 3d .
27 . The compound of claim 26 wherein R 3d is —C(R 3b )OR 4 .
28 . The compound of claim 27 wherein R 3b is ═O.
29 . The compound of claim 28 wherein R 4 is alkyl of 1 to 18 carbon atoms.
30 . The compound of claim 29 wherein R 4 is alkyl of 1 to 6 carbon atoms.
31 . The compound of claim 30 wherein R 4 is ethyl, n-butyl, n-propyl, i-propyl, or hexyl.
32 . The compound of claim 31 of the formula,
33 . The compound of claim 31 of the formula,
34 . The compound of claim 31 of the formula,
35 . The compound of claim 31 of the formula,
36 . The compound of claim 8 wherein R 2 is R 4 independently substituted with two R 3 groups.
37 . The compound of claim 36 wherein R 4 is methyl substituted with two R 3 groups.
38 . The compound of claim 37 wherein one R 3 group is R 3c .
39 . The compound of claim 38 wherein R 3c is —R 5 W 3 .
40 . The compound of claim 39 wherein R 5 is methylene.
41 . The compound of claim 40 wherein W 3 is W 5 .
42 . The compound of claim 41 wherein W 5 is phenyl.
43 . The compound of claim 42 wherein the other R 3 group is R 3d .
44 . The compound of claim 43 wherein R 3d is —C(R 3b )OR 4 .
45 . The compound of claim 44 wherein R 3b is ═O.
46 . The compound of claim 45 wherein R 4 is alkyl of 1 to 18 carbon atoms.
47 . The compound of claim 46 wherein R 4 is alkyl of 1 to 6 carbon atoms.
48 . The compound of claim 47 wherein R 4 is ethyl, n-butyl, or i-butyl.
49 . The compound of claim 48 of the formula,
50 . The compound of claim 48 of the formula
51 . The compound of claim 48 of the formula,
52 . The compound of claim 6 wherein Y 1A is —N(R X ).
53 . The compound of claim 52 wherein R X is R 2 .
54 . The compound of claim 53 wherein R 2 is R 4 substituted with R 3d .
55 . The compound of claim 54 wherein R 4 is ethyl substituted with R 3d .
56 . The compound of claim 55 wherein R 3d is —C(R 3b )OR 4 .
57 . The compound of claim 56 wherein R 3b is ═O.
58 . The compound of claim 57 wherein R 4 is propyl.
59 . The compound of claim 58 wherein R 4 is i-propyl.
60 . The compound of claim 52 wherein Y 1B is —N(R X ).
61 . The compound of claim 60 wherein R X is R 2 .
62 . The compound of claim 61 wherein R 2 is R 4 independently substituted with two R 3 groups.
63 . The compound of claim 62 wherein R 4 is methyl substituted with two R 3 groups.
64 . The compound of claim 63 wherein one R 3 group is R 3c .
65 . The compound of claim 64 wherein R 3c is —R 5 W 3 .
66 . The compound of claim 65 wherein —R 5 — is methylene.
67 . The compound of claim 66 wherein W 3 is W 5 .
68 . The compound of claim 67 wherein W 5 is phenyl.
69 . The compound of claim 68 wherein the other R 3 group is R 3d .
70 . The compound of claim 69 wherein R 3d is —C(R 3b )OR 4 .
71 . The compound of claim 70 wherein R 3b is ═O.
72 . The compound of claim 71 wherein R 4 is butyl.
73 . The compound of claim 72 wherein R 4 is i-butyl.
74 . The compound of claim 73 of the formula,
75 . The compound of claim 69 wherein R 3d is —C(R 3b )OW 3 .
76 . The compound of claim 75 wherein R 3b is ═O.
77 . The compound of claim 76 wherein W 3 is W 5 .
78 . The compound of claim 77 wherein W 5 is a carbocycle.
79 . The compound of claim 6 wherein Y 1B is —O(R X ).
80 . The compound of claim 79 wherein R X is W 3 .
81 . The compound of claim 80 wherein W 3 is W 5 .
82 . The compound of claim 81 wherein W 5 is a carbocycle.
83 . The compound of claim 82 wherein said carbocycle is phenyl.
84 . The compound of claim 83 of the formula,
85 . The compound of claim 84 wherein Y 1A is —N(R X ).
86 . The compound of claim 85 wherein R X is R 2 .
87 . The compound of claim 86 wherein R 2 is R 4 substituted with R 3d .
88 . The compound of claim 87 wherein R 4 is ethyl substituted with R 3d .
89 . The compound of claim 88 wherein R 3d is —C(R 3b )OR 4 .
90 . The compound of claim 89 wherein R 3b is ═O.
91 . The compound of claim 90 wherein R 4 is alkyl of 1 to 6 carbon atoms.
92 . The compound of claim 91 wherein R 4 is ethyl, butyl, n-propyl, or hexyl.
93 . The compound of claim 92 of the formula,
94 . The compound of claim 92 of the formula
95 . The compound of claim 92 of the formula,
96 . The compound of claim 92 of the formula,
97 . The compound of claim 88 wherein R 3d is —C(R 3b )OW 3 .
98 . The compound of claim 97 wherein R 3b is ═O.
99 . The compound of claim 98 wherein W 3 is W 5 .
100 . The compound of claim 99 wherein W 5 is a carbocycle.
101 . The compound of claim 100 of the formula,
102 . The compound of claim 87 wherein R 4 is propyl substituted with R 3d .
103 . The compound of claim 102 wherein R 4 is n-propyl substituted with R 3d .
104 . The compound of claim 103 wherein R 3d is —C(R 3b )OR 4 .
105 . The compound of claim 104 wherein R 3b is ═O.
106 . The compound of claim 105 wherein R 4 is butyl.
107 . The compound of claim 106 wherein R 4 is n-butyl.
108 . The compound of claim 107 of the formula,
109 . The compound of claim 86 wherein R 2 is R 4 substituted with R 3c and R 3d .
110 . The compound of claim 109 wherein R 4 is ethyl substituted with R 3c and R 3d .
111 . The compound of claim 110 wherein R 3c is —R 5 W 3 .
112 . The compound of claim 111 wherein —R 5 is methylene.
113 . The compound of claim 112 wherein W 3 is W 5 .
114 . The compound of claim 113 wherein W 5 is a carbocycle.
115 . The compound of claim 114 wherein said carbocycle is phenyl.
116 . The compound of claim 115 wherein R 3d is —C(R 3b )OR 4 .
117 . The compound of claim 116 wherein R 3b is ═O.
118 . The compound of claim 117 wherein R 4 is alkyl of 1 to 6 carbon atoms.
119 . The compound of claim 118 wherein R 4 is ethyl, n-butyl, or i-butyl.
120 . The compound of claim 119 of the formula,
121 . The compound of claim 119 of the formula,
122 . The compound of claim 119 of the formula,
123 . The compound of claim 6 wherein Y 1A and Y 1B are —O(R X ).
124 . The compound of claim 123 wherein R X is R 1 .
125 . The compounds of claim 124 wherein R 1 is H or i-propyl.
126 . The compound of claim 125 of the formula,
127 . The compound of claim 6 of the formula,
128 . The compound of claim 2 wherein R X1 is alkynyl.
129 . The compound of claim 128 wherein R X2 is 2-propynyl.
130 . The compound of claim 1 used as an antiproliferative agent.
131 . The compound of claim 1 used as an apoptotic agent.
132 . The compound of claim 1 used as an anti-HPV agent.
133 . The compound of claim 1 used as a topical anti-HPV agent.
134 . The compound of claim 1 used as an antiproliferative agent.
135 . The compound of claim 1 used as an apoptitic agent.
136 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
137 . The pharmaceutical composition of claim 136 , where said composition is a gel composition.
138 . The pharmaceutical composition of claim 136 , where said composition is an ointment composition.
139 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and an effective amount of at least one antiviral agent, and a pharmaceutically acceptable carrier.
140 . The pharmaceutical composition of claim 139 , where said composition is a gel composition.
141 . The pharmaceutical composition of claim 139 , where said composition is an ointment composition.Cited by (0)
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