US2006046981A1PendingUtilityA1
Anti-nonmelanoma carcinoma compounds, compositions, and methods of use thereof
Est. expiryDec 30, 2023(expired)· nominal 20-yr term from priority
Inventors:Riri Shibata
A61P 35/00A61P 31/12A61P 31/00A61P 31/18A61P 31/20A61P 43/00C07F 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-nonmelanoma carcinoma agents, wherein: Y 1A and Y 1B are independently Y 1 ; R X1 and R X2 are independently R X ; 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; and 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 and R X2 are independently R X ;
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 claim 2 wherein R X2 is W 3 .
4 . The compound of claim 3 wherein W 3 is W 5 .
5 . The compound of claim 4 wherein W 5 is cyclopropyl.
6 . The compound of claim 5 of the Formula IA,
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 propyl.
14 . The compound of claim 13 wherein R 4 is n-propyl.
15 . The compound of claim 14 of the formula,
16 . The compound of claim 13 wherein R 4 is i-propyl.
17 . The compound of claim 16 of the formula,
18 . The compound of claim 10 wherein R 3d is —C(R 3b )OW 3 .
19 . The compound of claim 18 wherein R 3b is ═O.
20 . The compound of claim 19 wherein W 3 is W 5 .
21 . The compound of claim 20 wherein W 5 is a carbocycle.
22 . The compound of claim 9 wherein R 4 is propyl substituted with R 3d .
23 . The compound of claim 22 wherein R 3d is —C(R 3b )OR 4 .
24 . The compound of claim 23 wherein R 3b is ═O.
25 . The compound of claim 24 wherein R 4 is ethyl.
26 . The compound of claim 25 of the formula,
27 . The compound of claim 24 wherein R 4 is butyl.
28 . The compound of claim 27 wherein R 4 is n-butyl.
29 . The compound of claim 28 of the formula,
30 . The compound of claim 24 wherein R 4 is propyl.
31 . The compound of claim 30 wherein R 4 is i-propyl.
32 . The compound of claim 31 of the formula,
33 . The compound of claim 8 wherein R 2 is R 4 independently substituted with two R 3 groups.
34 . The compound of claim 33 wherein R 4 is methyl substituted with two R 3 groups.
35 . The compound of claim 34 wherein one R 3 group is R 3c .
36 . The compound of claim 35 wherein R 3d is —R 5 W 3 .
37 . The compound of claim 36 wherein R 5 is methylene.
38 . The compound of claim 37 wherein W 3 is W 5 .
39 . The compound of claim 38 wherein W 5 is phenyl.
40 . The compound of claim 35 wherein the other R 3 group is R 3d .
41 . The compound of claim 40 wherein R 3d is —C(R 3b )OR 4 .
42 . The compound of claim 41 wherein R 3b is ═O.
43 . The compound of claim 42 wherein R 4 is butyl.
44 . The compound of claim 43 wherein R 4 is i-butyl.
45 . The compound of claim 44 of the formula,
46 . The compound of claim 6 wherein Y 1A is —N(R X ).
47 . The compound of claim 46 wherein R X is R 2 .
48 . The compound of claim 47 wherein R 2 is R 4 substituted with R 3d .
49 . The compound of claim 48 wherein R 4 is ethyl substituted with R 3d .
50 . The compound of claim 49 wherein R 3d is —C(R 3b )OR 4 .
51 . The compound of claim 50 wherein R 3b is ═O.
52 . The compound of claim 51 wherein R 4 is propyl.
53 . The compound of claim 52 wherein R 4 is i-propyl.
54 . The compound of claim 46 wherein Y 1B is —N(R X ).
55 . The compound of claim 54 wherein R X is R 2 .
56 . The compound of claim 55 wherein R 2 is R 4 independently substituted with two R 3 groups.
57 . The compound of claim 56 wherein R 4 is methyl substituted with two R 3 groups.
58 . The compound of claim 57 wherein one R 3 group is R 3c .
59 . The compound of claim 58 wherein R 3c is —R 5 W 3 .
60 . The compound of claim 59 wherein —R 5 — is methylene.
61 . The compound of claim 60 wherein W 3 is W 5 .
62 . The compound of claim 61 wherein W 5 is phenyl.
63 . The compound of claim 58 wherein the other R 3 group is R 3d .
64 . The compound of claim 63 wherein R 3d is —C(R 3b )OR 4 .
65 . The compound of claim 64 wherein R 3b is ═O.
66 . The compound of claim 65 wherein R 4 is butyl.
67 . The compound of claim 66 wherein R 4 is i-butyl.
68 . The compound of claim 67 of the formula,
69 . The compound of claim 63 wherein R 3d is —C(R 3b )OW 3 .
70 . The compound of claim 69 wherein R 3b is ═O.
71 . The compound of claim 70 wherein W 3 is W 5 .
72 . The compound of claim 71 wherein W 5 is a carbocycle.
73 . The compound of claim 6 wherein Y 1B is —O(R X ).
74 . The compound of claim 73 wherein Y 1B is —O(W 3 ).
75 . The compound of claim 74 wherein W 3 is W 5 .
76 . The compound of claim 75 wherein W 5 is a carbocycle.
77 . The compound of claim 76 wherein said carbocycle is phenyl.
78 . The compound of claim 77 of the formula,
79 . The compound of claim 78 wherein Y 1A is —N(R X ).
80 . The compound of claim 79 wherein R X is R 2 .
81 . The compound of claim 80 wherein R 2 is R 4 substituted with R 3d .
82 . The compound of claim 81 wherein R 4 is ethyl substituted with R 3d .
83 . The compound of claim 82 wherein R 3d is —C(R 3b )OR 4 .
84 . The compound of claim 83 wherein R 3b is ═O.
85 . The compound of claim 84 wherein R 4 is propyl.
86 . The compound of claim 85 wherein R 4 is n-propyl.
87 . The compound of claim 86 of the formula,
88 . The compound of claim 81 wherein R 4 is propyl substituted with R 3d .
89 . The compound of claim 88 wherein R 4 is n-propyl substituted with R 3d .
90 . The compound of claim 89 wherein R 3d is —C(R 3b )OR 4 .
91 . The compound of claim 90 wherein R 3b is ═O.
92 . The compound of claim 91 wherein R 4 is butyl.
93 . The compound of claim 92 wherein R 4 is n-butyl.
94 . The compound of claim 93 of the formula,
95 . The compound of claim 79 wherein R X is R 2 .
96 . The compound of claim 95 wherein R 2 is R 4 substituted with R 3c and R 3d .
97 . The compound of claim 96 wherein R 4 is ethyl substituted with R 3c and R 3d .
98 . The compound of claim 97 wherein R 3c is —R 5 W 3 .
99 . The compound of claim 98 wherein —R 5 is methylene.
100 . The compound of claim 99 wherein W 3 is W 5 .
101 . The compound of claim 100 wherein W 5 is a carbocycle.
102 . The compound of claim 101 wherein said carbocycle is phenyl.
103 . The compound of claim 102 wherein R 3d is —C(R 3b )OR 4 .
104 . The compound of claim 103 wherein R 3b is ═O.
105 . The compound of claim 104 wherein R 4 is ethyl.
106 . The compound of claim 105 of the formula,
107 . The compound of claim 6 wherein Y 1A and Y 1B are —O(R X ).
108 . The compound of claim 2 wherein R X2 is R 4 .
109 . The compound of claim 108 wherein R 4 is alkyl.
110 . The compound of claim 108 wherein R 4 is alkenyl.
111 . The compound of claim 108 wherein R 4 is alkynyl.
112 . The compound of claim 110 wherein R 4 is 2-propenyl.
113 . The compound of claim 2 wherein R X2 is R 2 .
114 . The compound of claim 113 wherein R 2 is R 4 substituted with one R 3 .
115 . The compound of claim 114 wherein R 4 is methyl substituted with one R 3 .
116 . The compound of claim 115 wherein R 3 is R 3a .
117 . The compound of claim 116 wherein R 3a is —CF 3 .
118 . The compound of claim 115 wherein R 4 is —CH 2 —CF 3 .
119 . The compound of claim 1 wherein R X1 is H.
120 . The compound of claim 119 wherein R X2 is alkenyl of 2 to 18 carbon atoms.
121 . The compound of claim 119 wherein R X2 is alkenyl of 2 to 6 carbon atoms.
122 . The compound of claims 119 wherein R X2 is 2-propenyl.
123 . The compound of claim 1 of the Formula IA,
wherein Y 1A and Y 1B are as previously defined.
124 . The compound of claim 123 wherein Y 1A and Y 1B are —N(R X ).
125 . The compound of claim 124 wherein R X is R 2 .
126 . The compound of claim 125 wherein R 2 is R 4 substituted with R 3d .
127 . The compound of claim 126 wherein R 4 is ethyl substituted with R 3d .
128 . The compound of claim 127 wherein R 3d is —C(R 3b )OR 4 .
129 . The compound of claim 128 wherein R 3b is ═O.
130 . The compound of claim 129 wherein R 4 is alkyl of 1 to 18 carbon atoms.
131 . The compound of claim 130 wherein R 4 is alkyl of 1 to 6 carbon atoms.
132 . The compound of claim 131 wherein R 4 is ethyl, butyl, n-propyl, i-propyl, or hexyl.
133 . The compound of claim 132 of the formula,
134 . The compound of claim 132 of the formula,
135 . The compound of claim 132 of the formula,
136 . The compound of claim 132 of the formula,
137 . The compound of claim 132 of the formula,
138 . The compound of claim 127 wherein R 3d is —C(R 3b )OW 3 .
139 . The compound of claim 138 wherein R 3b is ═O.
140 . The compound of claim 139 wherein W 3 is W 5 .
141 . The compound of claim 140 wherein W 5 is a carbocycle.
142 . The compound of claim 141 of the formula,
143 . The compound of claim 126 wherein R 4 is propyl substituted with R 3d .
144 . The compound of claim 143 wherein R 3d is —C(R 3b )OR 4 .
145 . The compound of claim 144 wherein R 3b is ═O.
146 . The compound of claim 145 wherein R 4 is alkyl of 1 to 18 carbon atoms.
147 . The compound of claim 146 wherein R 4 is alkyl of 1 to 6 carbon atoms.
148 . The compound of claim 147 wherein R 4 is ethyl, n-butyl, n-propyl, i-propyl, or hexyl.
149 . The compound of claim 148 of the formula,
150 . The compound of claim 148 of the formula,
151 . The compound of claim 148 of the formula,
152 . The compound of claim 148 of the formula,
153 . The compound of claim 125 wherein R 2 is R 4 independently substituted with two R 3 groups.
154 . The compound of claim 153 wherein R 4 is methyl substituted with two R 3 groups.
155 . The compound of claim 154 wherein one R 3 group is R 3c .
156 . The compound of claim 155 wherein R 3c is —R 5 W 3 .
157 . The compound of claim 156 wherein R 5 is methylene.
158 . The compound of claim 157 wherein W 3 is W 5 .
159 . The compound of claim 158 wherein W 5 is phenyl.
160 . The compound of claim 159 wherein the other R 3 group is R 3d .
161 . The compound of claim 160 wherein R 3d is —C(R 3b )OR 4 .
162 . The compound of claim 161 wherein R 3b is ═O.
163 . The compound of claim 162 wherein R 4 is alkyl of 1 to 18 carbon atoms.
164 . The compound of claim 163 wherein R 4 is alkyl of 1 to 6 carbon atoms.
165 . The compound of claim 164 wherein R 4 is ethyl, n-butyl, or i-butyl.
166 . The compound of claim 165 of the formula,
167 . The compound of claim 165 of the formula
168 . The compound of claim 165 of the formula,
169 . The compound of claim 123 wherein Y 1A is —N(R X ).
170 . The compound of claim 169 wherein R X is R 2 .
171 . The compound of claim 170 wherein R 2 is R 4 substituted with R 3d .
172 . The compound of claim 171 wherein R 4 is ethyl substituted with R 3d .
173 . The compound of claim 172 wherein R 3d is —C(R 3b )OR 4 .
174 . The compound of claim 173 wherein R 3b is ═O.
175 . The compound of claim 174 wherein R 4 is propyl.
176 . The compound of claim 175 wherein R 4 is i-propyl.
177 . The compound of claim 169 wherein Y 1B is —N(R X ).
178 . The compound of claim 177 wherein R X is R 2 .
179 . The compound of claim 178 wherein R 2 is R 4 independently substituted with two R 3 groups.
180 . The compound of claim 179 wherein R 4 is methyl substituted with two R 3 groups.
181 . The compound of claim 180 wherein one R 3 group is R 3c .
182 . The compound of claim 181 wherein R 3c is —R 5 W 3 .
183 . The compound of claim 182 wherein —R 5 — is methylene.
184 . The compound of claim 183 wherein W 3 is W 5 .
185 . The compound of claim 184 wherein W 5 is phenyl.
186 . The compound of claim 185 wherein the other R 3 group is R 3d .
187 . The compound of claim 186 wherein R 3d is —C(R 3b )OR 4 .
188 . The compound of claim 187 wherein R 3b is ═O.
189 . The compound of claim 188 wherein R 4 is butyl.
190 . The compound of claim 189 wherein R 4 is i-butyl.
191 . The compound of claim 190 of the formula,
192 . The compound of claim 186 wherein R 3d is —C(R 3b )OW 3 .
193 . The compound of claim 192 wherein R 3b is ═O.
194 . The compound of claim 193 wherein W 3 is W 5 .
195 . The compound of claim 194 wherein W 5 is a carbocycle.
196 . The compound of claim 123 wherein Y 1B is —O(R X ).
197 . The compound of claim 196 wherein R X is W 3 .
198 . The compound of claim 197 wherein W 3 is W 5 .
199 . The compound of claim 198 wherein W 5 is a carbocycle.
200 . The compound of claim 199 wherein said carbocycle is phenyl.
201 . The compound of claim 200 of the formula,
202 . The compound of claim 201 wherein Y 1A is —N(R X ).
203 . The compound of claim 202 wherein R X is R 2 .
204 . The compound of claim 203 wherein R 2 is R 4 substituted with R 3d .
205 . The compound of claim 204 wherein R 4 is ethyl substituted with R 3d .
206 . The compound of claim 205 wherein R 3d is —C(R 3b )OR 4 .
207 . The compound of claim 206 wherein R 3b is ═O.
208 . The compound of claim 207 wherein R 4 is alkyl of 1 to 6 carbon atoms.
209 . The compound of claim 208 wherein R 4 is ethyl, butyl, n-propyl, or hexyl.
210 . The compound of claim 209 of the formula,
211 . The compound of claim 209 of the formula
212 . The compound of claim 209 of the formula,
213 . The compound of claim 209 of the formula,
214 . The compound of claim 205 wherein R 3d is —C(R 3b )OW 3 .
215 . The compound of claim 214 wherein R 3b is ═O.
216 . The compound of claim 215 wherein W 3 is W 5 .
217 . The compound of claim 216 wherein W 5 is a carbocycle.
218 . The compound of claim 217 of the formula,
219 . The compound of claim 204 wherein R 4 is propyl substituted with R 3d .
220 . The compound of claim 219 wherein R 4 is n-propyl substituted with R 3d .
221 . The compound of claim 220 wherein R 3d is —C(R 3b )OR 4 .
222 . The compound of claim 221 wherein R 3b is ═O.
223 . The compound of claim 222 wherein R 4 is butyl.
224 . The compound of claim 223 wherein R 4 is n-butyl.
225 . The compound of claim 224 of the formula,
226 . The compound of claim 203 wherein R 2 is R 4 substituted with R 3c and R 3d .
227 . The compound of claim 226 wherein R 4 is ethyl substituted with R 3c and R 3d .
228 . The compound of claim 227 wherein R 3c is —R 5 W 3 .
229 . The compound of claim 228 wherein —R 5 is methylene.
230 . The compound of claim 229 wherein W 3 is W 5 .
231 . The compound of claim 230 wherein W 5 is a carbocycle.
232 . The compound of claim 231 wherein said carbocycle is phenyl.
233 . The compound of claim 232 wherein R 3d is —C(R 3b )OR 4 .
234 . The compound of claim 233 wherein R 3b is ═O.
235 . The compound of claim 234 wherein R 4 is alkyl of 1 to 6 carbon atoms.
236 . The compound of claim 235 wherein R 4 is ethyl, n-butyl, or i-butyl.
237 . The compound of claim 236 of the formula,
238 . The compound of claim 236 of the formula,
239 . The compound of claim 236 of the formula,
240 . The compound of claim 123 wherein Y 1A and Y 1B are —O(R X ).
241 . The compound of claim 240 wherein R X is R 1 .
242 . The compounds of claim 241 wherein R 1 is H or i-propyl.
243 . The compound of claim 242 of the formula,
244 . The compound of claim 123 of the formula,
245 . The compound of claim 119 wherein R X2 is alkynyl.
246 . The compound of claim 245 wherein R X2 is 2-propynyl.
247 . A compound of claim 1 used as an anti-nonmelanoma carcinoma agent.
248 . A compound of claim 1 used as a topical anti-nonmelanoma carcinoma agent.
249 . A pharmaceutical composition comprising an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
250 . The pharmaceutical composition of claim 249 , where said composition is a gel composition.
251 . The pharmaceutical composition of claim 249 , where said composition is an ointment composition.
252 . 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 anti-nonmelanoma carcinoma agent, and a pharmaceutically acceptable carrier.
253 . The pharmaceutical composition of claim 252 , where said composition is a gel composition.
254 . The pharmaceutical composition of claim 252 , where said composition is an ointment composition.Join the waitlist — get patent alerts
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