Derivatives of gefitinib
This invention relates to novel quinazoline derivatives, their derivatives, pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are beneficially treated by inhibiting cell surface tyrosine receptor kinases.
1. A compound of the formula A
or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of the compounds depicted in the following Table:
TABLE
Cmpd
Y 1 = Y 2
Y 3 = Y 4
Y 5 = Y 6
Y 7 = Y 8
R 1
R 2
R 3
101
D
D
D
D
CD 3
CD 2 CD 2 CD 2
F
102
H
H
H
H
CD 3
CD 2 CD 2 CD 2
F
104
H
H
H
H
CD 3
CH 2 CH 2 CH 2
F
108
D
D
D
D
CD 3
CD 2 CD 2 CD 2
H
109
H
H
H
H
CD 3
CD 2 CD 2 CD 2
H
110
D
D
D
D
CD 3
CH 2 CH 2 CH 2
H
111
H
H
H
H
CD 3
CH 2 CH 2 CH 2
H
112
D
D
D
D
CD 3
CD 2 CD 2 CD 2
H
113
H
H
H
H
CD 3
CD 2 CD 2 CD 2
H
114
D
D
D
D
CD 3
CH 2 CH 2 CH 2
H
115
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OH
116
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OH
117
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OH
118
H
H
H
H
CD 3
CH 2 CH 2 CH 2
OH
119
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OH
120
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OH
121
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OH
122
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OCD 3
123
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OCD 3
124
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OCD 3
125
H
H
H
H
CD 3
CH 2 CH 2 CH 2
OCD 3
126
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OCD 3
127
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OCD 3
128
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OCD 3
129
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OCH 3
130
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OCH 3
131
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OCH 3
132
H
H
H
H
CD 3
CH 2 CH 2 CH 2
OCH 3
133
D
D
D
D
CD 3
CD 2 CD 2 CD 2
OCH 3
134
H
H
H
H
CD 3
CD 2 CD 2 CD 2
OCH 3
135
D
D
D
D
CD 3
CH 2 CH 2 CH 2
OCD 3
136
D
D
D
D
CD 3
CD 2 CD 2 CD 2
Cl
137
H
H
H
H
CD 3
CD 2 CD 2 CD 2
Cl
138
D
D
D
D
CD 3
CH 2 CH 2 CH 2
Cl
139
H
H
H
H
CD 3
CH 2 CH 2 CH 2
Cl
140
D
D
D
D
CD 3
CD 2 CD 2 CD 2
Cl
141
H
H
H
H
CD 3
CD 2 CD 2 CD 2
Cl
142
D
D
D
D
CD 3
CH 2 CH 2 CH 2
Cl
143
D
D
D
D
CD 3
CD 2 CD 2 CD 2
Br
144
H
H
H
H
CD 3
CD 2 CD 2 CD 2
Br
145
D
D
D
D
CD 3
CH 2 CH 2 CH 2
Br
146
H
H
H
H
CD 3
CH 2 CH 2 CH 2
Br
147
D
D
D
D
CD 3
CD 2 CD 2 CD 2
Br
148
H
H
H
H
CD 3
CD 2 CD 2 CD 2
Br
149
D
D
D
D
CD 3
CH 2 CH 2 CH 2
Br.
2. The compound of claim 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
3. A pyrogen-free pharmaceutical composition comprising as a first therapeutic agent a compound of claim 1 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
4. The composition of claim 3 , further comprising a second therapeutic agent useful in the treatment of a patient suffering from non-small cell lung cancer.
5. The composition of claim 4 , wherein the second therapeutic agent is selected from anastrozole, cediranib, bexarotene, calcitriol, capecitabine, carboplatin, cefixime, celecoxib, canertinib, cisplatin, dexamethasone, docetaxel, cetuximab, etoposide, everolimus, fluorouracil, fulvestrant, gemcitabine, irinotecan, leucovorin, loperamide, oxaliplatin, paclitaxel, PEG-interferon alpha, pemetrexed, raltitrexed, simvastatin, sirolimus, sunitinib, tamoxifen, temozolomide, topotecan, trastuzumab, and vinorelbine.
6. A method of treating a patient suffering from, or susceptible to, non-small cell lung cancer comprising the step of administering to the patient in need thereof a composition of claim 3 .
7. The method of claim 6 , wherein the patient is a smoker.
8. The method of claim 6 , wherein the patient is a non-smoker.
9. The method of claim 6 , further comprising the additional step of co-administering to the patient in need thereof a second therapeutic agent useful in the treatment of non-small cell lung cancer.
10. The method of claim 9 , wherein the second therapeutic agent is selected from AZD2171, bexarotene, carboplatin, celecoxib, cisplatin, docetaxel, cetuximab, everolimus, fulvestrant, gemcitabine, paclitaxel, pemetrexed, simvastatin, sirolimus, and vinorelbine.