Vandetanib derivatives
This invention relates to novel quinazoline derivatives of the formula: wherein each variable is as defined herein, and their acceptable acid addition salts. The invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions beneficially treated by inhibitory activity against the VEGF receptor tyrosine kinase.
1. A compound of Formula I
or a pharmaceutical salt thereof; wherein:
each Z is independently selected from hydrogen or deuterium;
each R is selected from —CH 3 , —CH 2 D, —CHD 2 and CD 3 ; and
when each R is —CH 3 at least one Z is deuterium,
wherein there is at least 50.1% incorporation of deuterium at any atom designated as D or deuterium.
2. A compound of Formula A
or a pharmaceutically acceptable salt thereof; wherein:
each Z is independently selected from hydrogen and deuterium;
each R is selected from —CH 3 , —CH 2 D, —CHD 2 and CD 3 ; and
when each R is —CH 3 at least one Z is deuterium,
wherein there is at least 50.1% incorporation of deuterium at any atom designated as D or deuterium.
3. The compound of claim 2 , wherein each Z 1 is the same.
4. The compound of claim 3 , wherein each Z 2 is the same.
5. The compound of claim 4 , wherein each Z 3 is the same.
6. The compound of claim 5 , wherein R 1 is selected from CH 3 and CD 3 .
7. The compound of claim 6 , wherein R 2 is selected from CH 3 and CD 3 .
8. The compound of claim 7 wherein Z 4 is hydrogen.
9. The compound of claim 8 , selected from any one of the compounds set forth in the table:
Cmpd
R 1
R 2
Each Z 3
Each Z 1
Each Z 2
100
CD 3
CH 3
H
H
H
101
CH 3
CD 3
H
H
H
102
CH 3
CH 3
D
H
H
103
CD 3
CH 3
D
H
H
104
CH 3
CD 3
D
H
H
105
CD 3
CD 3
H
H
H
106
CD 3
CD 3
D
H
H
107
CD 3
CH 3
H
D
H
108
CH 3
CD 3
H
D
H
109
CH 3
CH 3
D
D
H
110
CD 3
CH 3
D
D
H
111
CH 3
CD 3
D
D
H
112
CD 3
CD 3
H
D
H
113
CD 3
CD 3
D
D
H
114
CD 3
CH 3
H
H
D
115
CH 3
CD 3
H
H
D
116
CH 3
CH 3
D
H
D
117
CD 3
CH 3
D
H
D
118
CH 3
CD 3
D
H
D
118
CD 3
CD 3
H
H
D
119
CD 3
CD 3
D
H
D
120
CD 3
CH 3
H
D
D
121
CH 3
CD 3
H
D
D
122
CH 3
CH 3
D
D
D
123
CD 3
CH 3
D
D
D
124
CH 3
CD 3
D
D
D
125
CD 3
CD 3
H
D
D
126
CD 3
CD 3
D
D
D.
10. The compound of claim 7 wherein Z 4 is deuterium.
11. The compound of claim 10 which is
12. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
13. A pyrogen-free pharmaceutical composition comprising a compound of claim 2 ; and a pharmaceutically acceptable carrier.
14. The composition of claim 13 further comprising a second anti-cancer agent.
15. The composition of claim 14 , wherein the second anti-cancer agent is selected from one or more of 5-fluorouracil, folinic acid, irinotecan, docetaxel, capecitabine, oxaliplatin, bevacizumab, cyclophosphamide, methotrexate, pemetrexed, cisplatin, carboplatin, irinotecan, cetuximab, vinorelbine, gemcitabine, paclitaxel, prednisolone, 13-cis retinoic acid, erlotinib, anastrozole, and leucovorin.
16. A method of inhibiting the activity of VEGFR-2/KDR tyrosine kinase in a cell, comprising the step of contacting the cell with a compound of claim 2 .
17. A method of treating a patient suffering from thyroid cancer, comprising the step of administering to the patient in need thereof a composition of claim 13 .