US2021363121A1PendingUtilityA1
Notch inhibitors for use in the treatment of t-cell acute lymphoblastic leukemia
Assignee: UNIV DEGLI STUDI ROMA LA SAPIENZAPriority: Dec 29, 2016Filed: Aug 9, 2021Published: Nov 25, 2021
Est. expiryDec 29, 2036(~10.4 yrs left)· nominal 20-yr term from priority
Inventors:Bruno BottaIsabella ScrepantiLuca TottoneNadezda ZhdanoskayaCinzia IngallinaFrancesca GiulimondiDeborah QuaglioRocco PalermoMattia MoriFrancesca Ghirga
C07D 309/32A61P 35/02C07C 49/248C07C 49/835C07D 309/12A61K 31/121C07C 49/84
41
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Claims
Abstract
Compounds of formula (I) in the capacity of compounds with anti-tumor activity for the treatment of T-cell acute lymphoblastic leukemia (T-ALL).
Claims
exact text as granted — not AI-modified1 .- 10 . (canceled)
11 . An inhibitor of Notch signaling of formula (I)
wherein
X and Y are carbon atoms bound by a single or double bond having, independently, an E or Z configuration;
R 1′ is hydrogen, halogen, OR A , C(═O)R A , C(═O)OR A , OC(═O)R A , SR A , SO 2 R A , SO 3 R A , OSO 2 R A , OSO 3 R A , N(R A ) 2 , NHC(═O)R A , C(═O)N(R A ) 2 , or C(R A ) 3 ;
R 2′ , R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: hydrogen; halogen; OR B ; C(═O)R B ; C(═O)OR B ; OC(═O)R B ; SR B ; SO 2 R B ; SO 3 R B ; OSO 2 R B ; OSO 3 R B ; N(R B ) 2 ; NHC(═O)R B ; C(═O)N(R B ) 2 ; C(R B ) 3 ; a linear or branched, saturated or unsaturated C 1-7 acyclic aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl; a C 5-7 heterocyclic group;
wherein at each occurrence R A and R B are independently selected from: hydrogen; a linear or branched, saturated or unsaturated C 1-7 aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group;
and pharmaceutically acceptable salts thereof,
with the exception of compounds of formula (I) wherein R 1′ , R 2′ , R 3′ , R 1 , R 2 , R 3 have the meanings indicated in the following table and X and Y are carbon atoms bound by a double bond:
No.
R1′
R2′
R3′
R1
R2
R3
101
H
H
H
H
H
H
102
H
H
H
OH
H
H
103
H
H
H
H
OH
H
104
H
H
H
H
H
OH
105
OH
H
H
H
H
H
106
OH
H
H
OH
H
H
107
OH
H
H
H
OH
H
108
OH
H
H
H
H
OH
109
OH
H
H
H
H
OCH 3
110
OH
H
H
H
OCH 3
OCH 3
111
OH
H
H
H
H
CH 3
112
OH
OCH 3
OCH 3
H
H
Br
113
OCH 3
H
OCH 3
H
H
Cl
114
OCH 3
H
OCH 3
H
H
Br
115
H
OCH 3
OCH 3
H
H
Cl
116
H
OCH 3
OCH 3
H
H
SCH 3
117
OCH 3
H
H
H
H
F
118
H
H
OCH 3
OCH 3
H
H
119
H
H
OCH 3
H
H
Cl
120
H
H
CH 3
H
H
N(CH 3 ) 2
121
H
H
CH 3
H
H
F
122
H
H
CH 3
H
H
Cl
123
H
H
CH 3
H
H
SCH 3
124
NH 2
H
H
H
H
H
125
NH 2
H
H
H
H
Cl
126
NH 2
H
H
H
H
OCH 3
127
H
H
NH 2
H
H
H
128
H
H
NH 2
Cl
H
H
129
H
H
NH 2
H
H
Cl
130
H
H
NH 2
Cl
H
Cl
131
OH
H
OCH 3
H
OCH 3
OCH 3
132
OCH 3
H
OCH 3
H
H
OCH 3
133
OH
H
OCH 3
H
OH
OCH 3
134
OH
H
OCH 3
H
H
OH
135
OH
H
OCH 3
H
OCH 3
H
136
OH
H
H
H
H
OH
137
OCH 3
OCH 3
OCH 3
H
OH
OCH 3
138
OCH 3
OCH 3
OCH 3
H
H
OCH 3
139
OCH 3
OCH 3
OCH 3
H
F
OCH 3
140
H
H
CH 3
H
OH
OCH 3
141
OCH 3
OCH 3
OCH 3
H
OH
OH
142
H
OCH 3
OCH 3
H
OCH 3
OCH 3
143
OCH 3
H
OCH 3
H
H
OCH 3
144
H
H
F
H
H
F
145
OH
H
OCH 3
H
H
Cl
146
H
H
OCH 3
H
H
OCH 3
147
H
OCH 3
OCH 3
H
H
OCH 3
148
H
H
CH 3
H
H
CH 3
149
H
H
OCH 3
H
H
OCH 3
150
OH
H
OCH 3
H
OCH 3
OCH 3
151
H
H
CH 3
H
H
OCH 3
152
OH
H
OH
H
H
H
153
OH
H
H
H
OH
H
154
OH
H
H
Cl
H
H
155
OH
H
H
H
H
H
156
OH
H
H
H
H
Cl
157
OH
H
H
H
H
Br
158
OH
H
H
H
H
OCH 3
159
OH
H
OH
H
H
OH
160
OCH 3
H
OCH 3
H
F
H
161
OCH 3
H
OCH 3
Cl
H
H
162
OCH 3
H
OCH 3
OCH 3
H
OCH 3
163
OH
H
OCH 3
Cl
H
H
164
OH
H
OCH 3
H
H
Cl
165
OH
H
OCH 3
Cl
H
H
166
OH
H
OCH 3
H
F
H
167
OH
H
OCH 3
H
OCH 3
H
168
OH
H
OCH 3
OCH 3
OCH 3
H
169
OH
H
OCH 3
H
OCH 3
OCH 3
170
OH
H
OCH 3
OCH 3
H
OCH 3
171
OH
H
OCH 3
OCH 3
OCH 3
OCH 3
172
H
H
H
H
H
H
173
OH
H
H
H
H
H
174
H
OH
H
H
H
H
175
H
H
OH
H
H
H
176
H
H
H
OH
H
H
177
H
H
H
H
OH
H
178
H
H
H
H
H
OH
179
H
H
OH
OH
H
H
180
H
H
OH
H
OH
H
181
H
H
OH
H
H
OH
182
H
H
H
OH
H
OH
183
OH
H
H
OH
H
OH
184
H
OH
H
OH
H
OH
185
H
H
OH
OH
H
OH
186
H
OH
OH
OH
H
OH
187
H
H
H
OH
CH 2 CH═CH 2
OH
188
H
H
OCH 3 CO
H
H
H
189
H
H
OCH 3
H
H
H
190
H
H
H
OCH 3 CO
H
H
191
H
H
H
OCH 3
H
H
192
H
H
OCH 3
OH
H
H
193
H
H
H
OH
H
OCH 3 CO
194
H
H
OH
OH
H
OH
195
H
H
H
H
H
H
196
H
H
Cl
H
H
Cl
197
H
H
CH 3
H
H
CH 3
198
H
Cl
H
CH 3
H
CH 3
199
H
H
H
CH 3
H
CH 3
200
H
H
CH(CH 3 ) 2
H
H
CH 3
201
Cl
H
Cl
H
H
CH 3
202
H
H
Cl
H
H
CH 3
203
H
H
CH 3
H
H
Cl
204
OH
H
OH
H
H
OH
205
OH
OCH 3
OH
H
OH
OH
206
OH
OH
OH
H
OH
OH
207
OH
OCH 3
OH
H
OH
OCH 3
12 . The inhibitor of Notch signaling of formula (I) according to claim 11 , wherein X and Y are carbon atoms bound by a double bond having, independently, an E or Z configuration.
13 . The inhibitor of Notch signaling of formula (I) according to claim 11 , wherein
R 1′ is hydrogen, halogen, OR A , OC(═O)R A , SR A , SO 2 R A , SO 3 R A , OSO 2 R A , OSO 3 R A , C(R A ) 3 ; R 2′ , R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: hydrogen; halogen; OR B ; C(═O)R B ; C(═O)OR B ; OC(═O)R B ; SR B ; SO 2 R B ; SO 3 R B ; OSO 2 R B ; OSO 3 R B ; N(R B ) 2 ; NHC(═O)R B ; C(═O)N(R B ) 2 ; C(R B ) 3 ; at each occurrence, R A and R B are independently selected from: hydrogen; a linear or branched, saturated or unsaturated C 1-7 aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen and sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group;
14 . The inhibitor of Notch signaling of formula (I) according to claim 11 , wherein
R 1′ is hydrogen, halogen, OR A , OC(═O)R A , SR A , SO 2 R A , SO 3 R A , OSO 2 R A , OSO 3 R A , C(R A ) 3 ; R 2′ , R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: a linear or branched, saturated or unsaturated C 1-7 acyclic aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group; and R A has the meaning indicated in claim 11 .
15 . The inhibitor of Notch signaling of formula (I) according to claim 11 , wherein
X and Y are carbon atoms bound by a double bond having, independently, an E or Z configuration; R 1′ is OR A ; R 2′ is hydrogen; R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: hydrogen and OR B ; R 3 is OR B ; and at each occurrence R A and R B are independently selected from: hydrogen; a linear or branched, saturated or unsaturated C 1-7 aliphatic group, preferably a linear or branched, saturated or unsaturated C 1-3 aliphatic group; a C 5-7 heterocyclic group.
16 . The inhibitor of Notch signaling of formula (I) according to claim 11 selected from:
2′-hydroxy-4,4′-dimethoxychalcone (3)
2′-hydroxy-4,4′-dimethoxy-3-(tetrahydropyran-2-yloxy)chalcone (5a)
2′,3-dihydroxy-4,4′-dimethoxychalcone (5)
2′-hydroxy-3,4-dimethoxy-4′-(tetrahydropyran-2-yloxy)chalcone (6a)
2′-hydroxy-3,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (7a)
2′,4-dihydroxy-3,4′-dimethoxychalcone (7)
2′-hydroxy-4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (8a)
2′,4-dihydroxy-4′-methoxychalcone (8)
2′,4-dihydroxy-4′-methoxydihydrochalcone (8b)
2′-hydroxy-4′-methoxychalcone (9)
2′-hydroxy-4′-methoxy-3-(tetrahydropyran-2-yloxy)chalcone (11a)
2′,3-dihydroxy-4′-methoxychalcone (11)
2,2′-dihydroxy-4′-methoxychalcone (12)
2′-hydroxy-2,4′-dimethoxychalcone (13)
2′-hydroxy-4-(tetrahydropyran-2-yloxy)chalcone (14a)
2′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (15a)
4-hydroxy-2′-methoxychalcone (15)
2′,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (16a)
4-hydroxy-2′,4′-dimethoxychalcone (16)
4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (17a)
4-hydroxy-4′-methoxychalcone (17).
17 . The inhibitor of Notch signaling of formula (I)
according to claim 11 selected from:
2′-hydroxy-4,4′-dimethoxychalcone (3)
2′,3-dihydroxy-4,4′-dimethoxychalcone (5)
2′-hydroxy-3,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (7a)
2′,4-dihydroxy-3,4′-dimethoxychalcone (7)
2′-hydroxy-4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (8a)
2′,4-dihydroxy-4′-methoxychalcone (8)
2′-hydroxy-4′-methoxychalcone (9)
2′-hydroxy-4′-methoxy-3-(tetrahydropyran-2-yloxy)chalcone (11a)
2′,3-dihydroxy-4′-methoxychalcone (11)
2,2′-dihydroxy-4′-methoxychalcone (12)
2′-hydroxy-2,4′-dimethoxychalcone (13)
2′-hydroxy-4-(tetrahydropyran-2-yloxy)chalcone (14a)
2′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (15a)
4-hydroxy-2′-methoxychalcone (15)
2′,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (16a)
4-hydroxy-2′,4′-dimethoxychalcone (16)
4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (17a)
4-hydroxy-4′-methoxychalcone (17).
18 . Pharmaceutical composition comprising at least one inhibitor of Notch signaling of formula (I) according to claim 11 and at least one pharmaceutically acceptable vehicle or excipient.
19 . An inhibitor of Notch signaling selected from:
2′-hydroxy-4,4′-dimethoxychalcone (3) 2′-hydroxy-4,4′-dimethoxy-3-(tetrahydropyran-2-yloxy)chalcone (5a) 2′,3-dihydroxy-4,4′-dimethoxychalcone (5) 2′-hydroxy-3,4-dimethoxy-4′-(tetrahydropyran-2-yloxy)chalcone (6a) 2′-hydroxy-3,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (7a) 2′,4-dihydroxy-3,4′-dimethoxychalcone (7) 2′-hydroxy-4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (8a) 2′,4-dihydroxy-4′-methoxychalcone (8) 2′,4-dihydroxy-4′-methoxydihydrochalcone (8b) 2′-hydroxy-4′-methoxychalcone (9) 2′-hydroxy-4′-methoxy-3-(tetrahydropyran-2-yloxy)chalcone (11a) 2′,3-dihydroxy-4′-methoxychalcone (11) 2,2′-dihydroxy-4′-methoxychalcone (12) 2′-hydroxy-2,4′-dimethoxychalcone (13) 2′-hydroxy-4-(tetrahydropyran-2-yloxy)chalcone (14a) 2′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (15a) 4-hydroxy-2′-methoxychalcone (15) 2′,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (16a) 4-hydroxy-2′,4′-dimethoxychalcone (16) 4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (17a) 4-hydroxy-4′-methoxychalcone (17).
20 . The inhibitor of Notch signaling according to claim 19 selected from:
2′-hydroxy-4,4′-dimethoxychalcone (3)
2′,3-dihydroxy-4,4′-dimethoxychalcone (5)
2′-hydroxy-3,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (7a)
2′,4-dihydroxy-3,4′-dimethoxychalcone (7)
2′-hydroxy-4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (8a)
2′,4-dihydroxy-4′-methoxychalcone (8)
2′-hydroxy-4′-methoxychalcone (9)
2′-hydroxy-4′-methoxy-3-(tetrahydropyran-2-yloxy)chalcone (11a)
2′,3-dihydroxy-4′-methoxychalcone (11)
2,2′-dihydroxy-4′-methoxychalcone (12)
2′-hydroxy-2,4′-dimethoxychalcone (13)
2′-hydroxy-4-(tetrahydropyran-2-yloxy)chalcone (14a)
2′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (15a)
4-hydroxy-2′-methoxychalcone (15)
2′,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (16a)
4-hydroxy-2′,4′-dimethoxychalcone (16)
4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (17a)
4-hydroxy-4′-methoxychalcone (17).Join the waitlist — get patent alerts
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