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Last Updated: October 16, 2019

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Claims for Patent: 10,085,983

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Summary for Patent: 10,085,983
Title:Azabicyclo derivatives, process for preparation thereof and medical use thereof
Abstract: Azabicyclo derivatives, a preparation process, and medical use thereof are provided. In particular, azabicyclo derivatives of formula (I), pharmaceutically acceptable salts, stereoisomers, solvates and prodrugs thereof are described. The azabicyclo derivatives of formula (I) are useful as Epidermal Growth Factor Receptor (EGFR) inhibitors. The definitions of the variable R groups in the azabicyclo derivatives of formula (I) are described in the specification. ##STR00001##
Inventor(s): Jin; Yunzhou (Pudong New Area Shanghai, CN), Bu; Ping (Pudong New Area Shanghai, CN), He; Qi (Pudong New Area Shanghai, CN), Lan; Jiong (Pudong New Area Shanghai, CN), Zhou; Fusheng (Pudong New Area Shanghai, CN), Zhang; Liang (Pudong New Area Shanghai, CN), He; Xiangyu (Pudong New Area Shanghai, CN)
Assignee: Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN)
Application Number:15/515,767
Patent Claims:1. A compound represented by formula (I), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ##STR00126## wherein; each of Z.sub.1 and Z.sub.2 is independently N or CR.sub.0, wherein R.sub.0 is selected from the group consisting of H, halogen, C.sub.1-10 alkyl, and C.sub.1-10 haloalkyl; each of R.sub.1 and R.sub.2 is independently H, halogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, C.sub.1-10 alkoxy, or C.sub.3-8 cycloalkoxy; R.sub.3 is C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, substituted or unsubstituted C.sub.3-10 cycloalkyl, substituted or unsubstituted C.sub.6-10 aromatic ring, or substituted or unsubstituted C.sub.4-10 cycloalkenyl, ##STR00127## wherein "substituted" means 1-6 hydrogen atoms on a ring atom are substituted with a substituent selected from the group consisting of hydroxy, CN, NO.sub.2, halogen, C.sub.1-10 alkyl, C.sub.1-10 haloalkyl, --CON(C.sub.1-10 alkyl).sub.2, --C(O)OC.sub.1-10 alkyl, --OC(O)C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-10 alkyl, and --S(O)-phenyl, --N(C.sub.1-10 alkyl).sub.2 and wherein the phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of halogen and C.sub.1-10 alkyl; Z.sub.11 is CR.sub.15 or N; Z.sub.21 is CR.sub.26 or N; Z.sub.31 is CR.sub.37 or N; Z.sub.41 is CR.sub.44 or N; n.sub.1 is 1, 2 or 3; n.sub.2 is 1 or 2; each of R.sub.12, R.sub.13, R.sub.14, R.sub.15, R.sub.22, R.sub.23, R.sub.24, R.sub.25, R.sub.26, R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, R.sub.37, R.sub.42, R.sub.43, R.sub.44, R.sub.51, R.sub.52, R.sub.53, R.sub.54, and R.sub.61 is independently H, hydroxy, CN, NO, halogen, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, --CON(C.sub.1-10 alkyl).sub.2, --N(C.sub.1-10 alkyl).sub.2, --C(O)OC.sub.1-10 alkyl, --OC(O)C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, --SO.sub.2-phenyl, --S(O)C.sub.1-10 alkyl, or --S(O)-phenyl, wherein the alkyl or phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, C1, and methyl; each of R.sub.11, R.sub.21, and R.sub.41 is independently H, C.sub.1-10 haloalkyl, C.sub.1-10 alkyl, --COC.sub.1-10 alkyl, --CO-phenyl, --SO.sub.2C.sub.1-10 alkyl, or --SO.sub.2-phenyl, wherein the phenyl is unsubstituted or substituted with 1-3 substituents selected from the group consisting of F, Cl, and methyl; R.sub.4 is selected from the group consisting of: ##STR00128## R.sub.5 is methoxy; and each of R.sub.6 and R.sub.7.

2. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein R.sub.3 is methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, substituted or unsubstituted phenyl, substituted or unsubstituted C.sub.4-8 cycloalkenyl, ##STR00129##

3. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein, Z.sub.11 is N; each of R.sub.12, R.sub.13, and R.sub.14 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.11 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; Z.sub.21 is CR.sub.26; each of R.sub.22, R.sub.23, R.sub.24, R.sub.25, and R.sub.26 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.21 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; Z.sub.31 is N; each of R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, and R.sub.36 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; Z.sub.41 is N or CR.sub.44; each of R.sub.42, R.sub.43, and R.sub.44 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; R.sub.41 is H, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl; each of R.sub.51, R.sub.52, R.sub.53, and R.sub.54 is independently H, halogen, C.sub.1-3 haloalkyl, or C.sub.1-3 alkyl; n.sub.1 is 2; n.sub.2 is 2; and R.sub.61 is H, halogen, C.sub.1-3 haloalkyl, C.sub.1-3 alkyl, --COC.sub.1-3 alkyl, or --SO.sub.2C.sub.1-3 alkyl.

4. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 3, wherein, Z.sub.11 is N; each of R.sub.12, R.sub.13, and R.sub.14 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.11 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; Z.sub.21 is CR.sub.26; each of R.sub.22, R.sub.23, R.sub.24, R.sub.25, and R.sub.26 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.21 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; Z.sub.31 is N; each of R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, and R.sub.36 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; Z.sub.41 is N or CR.sub.44; each of R.sub.42, R.sub.43, and R.sub.44 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; R.sub.41 is H, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3; each of R.sub.51, R.sub.52, R.sub.53, and R.sub.54 is independently H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, or trifluoromethyl; n.sub.1 is 2; n.sub.2 is 2; and R.sub.61 is H, F, Cl, Br, methyl, ethyl, propyl, isopropyl, monofluoroethyl, difluoromethyl, trifluoromethyl, --COCH.sub.3, or --SO.sub.2CH.sub.3.

5. The compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, wherein the compound of formula (I) is a compound of formula (II), formula (III), formula (IV), formula (V), formula (VI), formula (VII), formula (VIII), or formula (IX), or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof: ##STR00130## wherein R.sub.11, R.sub.12, R.sub.13, R.sub.14, Z.sub.11, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00131## wherein R.sub.21, R.sub.22, R.sub.23, R.sub.24, R.sub.25, Z.sub.21, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00132## wherein R.sub.31, R.sub.32, R.sub.33, R.sub.34, R.sub.35, R.sub.36, Z.sub.31, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00133## wherein R.sub.41, R.sub.42, R.sub.43, Z.sub.41, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00134## wherein R.sub.51, R.sub.52, R.sub.53, R.sub.54, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00135## wherein R.sub.61, n.sub.1, n.sub.2, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00136## wherein R.sub.41, R.sub.42, R.sub.43, Z.sub.41, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1; ##STR00137## wherein R.sub.51, R.sub.52, R.sub.53, R.sub.54, R.sub.0, R.sub.1, R.sub.2, and R.sub.4 are defined as in claim 1.

6. A compound selected from the group consisting of: ##STR00138## ##STR00139## ##STR00140## ##STR00141## ##STR00142## ##STR00143## ##STR00144## ##STR00145## ##STR00146## ##STR00147## ##STR00148## ##STR00149## ##STR00150## ##STR00151## or a pharmaceutically acceptable salt, solvate or stereoisomer thereof.

7. A pharmaceutical composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1, and a pharmaceutically acceptable carrier.

8. A method for treating an EGFR-related disease in a subject, the method comprising administering to the subject the pharmaceutical composition of claim 7, wherein the EGFR-related disease is non-small cell lung cancer.

9. A medicinal composition comprising the compound, or the pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 1 and an additional medicament, wherein the additional medicament is at least one medicament selected from the group consisting of gefitinib, erlotinib, icotinib, lapatinib, XL647, NVP-AEE-788, ARRY-334543, EKB-569, BIBW2992, HKI272, BMS-690514, CI-1033, vandetanib, PF00299804, WZ4002, cetuximab, trastuzumab, panitumumab, matuzumab, nimotuzumab, zalutumumab, pertuzumab, MDX-214, CDX-110, IMC-11F8, Zemab, Her2 vaccine PX 1041, HSP90 inhibitors, CNF2024, tanespimycin, alvespimycin, IPI-504, SNX-5422, and NVP-AUY922.

10. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt, solvate, or stereoisomer thereof according to claim 6, and a pharmaceutically acceptable carrier.

11. A method for treating an EGFR-related disease in a subject, the method comprising administering to the subject the pharmaceutical composition according to claim 10, wherein the EGFR-related disease is non-small cell lung cancer.

12. The method according to claim 8, wherein the non-small cell lung cancer is caused by mutations of EFGR comprising L858R and T790M.

13. The method according to claim 11, wherein the non-small cell lung cancer is caused by mutations of EGFR comprising L858R and T790M.

Summary for Patent:   Request a Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
China2014 1 0520700Sep 30, 2014
PCT Information
PCT FiledSeptember 24, 2015PCT Application Number:PCT/CN2015/090568
PCT Publication Date:April 07, 2016PCT Publication Number:WO2016/050165

Details for Patent 10,085,983

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech HERCEPTIN trastuzumab VIAL; INTRAVENOUS 103792 001 1998-09-25   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX Orphan search
Imclone ERBITUX cetuximab VIAL; INTRAVENOUS 125084 001 2004-06-18   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX Orphan search
Amgen VECTIBIX panitumumab INJECTABLE; IV (INFUSION) 125147 001 2006-09-27   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX search
Amgen VECTIBIX panitumumab INJECTABLE; IV (INFUSION) 125147 002 2006-09-27   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX search
Amgen VECTIBIX panitumumab INJECTABLE; IV (INFUSION) 125147 003 2006-09-27   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX search
Genentech PERJETA pertuzumab VIAL; SINGLE-USE 125409 001 2012-06-08   Request a Trial Shanghai Haiyan Pharmaceutical Technology Co., Ltd. (Shanghai, CN) Yangtze River Pharmaceutical Group Co., Ltd. (Jiangsu, CN) 2034-09-30 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

International Patent Family for US Patent 10,085,983

Country Patent Number Publication Date
World Intellectual Property Organization (WIPO) 2016050165 Apr 07, 2016
United States of America 2017296537 Oct 19, 2017
Japan 2017530136 Oct 12, 2017
Japan 6342069 Jun 13, 2018
European Patent Office 3202767 Apr 03, 2019
European Patent Office 3202767 Aug 09, 2017
European Patent Office 3202767 Mar 14, 2018
>Country >Patent Number >Publication Date

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