Claims for Patent: 10,017,492

Summary for Patent: 10,017,492

Title:	Isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof
Abstract:	Provided are an isoindoline derivative, intermediate, preparation method, pharmaceutical composition and use thereof. The isoindoline derivative and the pharmaceutical composition thereof can regulate the production or activity of immunological cytokines, thus effectively treating cancer and inflammatory disease. ##STR00001##
Inventor(s):	Ge; Chuansheng (Shanghai, CN), Lee; Wen-Cherng (Shanghai, CN), Liao; Baisong (Shanghai, CN), Zhang; Lei (Shanghai, CN)
Assignee:	KANGPU BIOPHARMACEUTICALS, LTD. (Shanghai, CN)
Application Number:	15/523,651
Patent Claims:	1. An isoindoline derivative having a structure of general formula (I), a pharmaceutically acceptable salt, a polymorph, a stereoisomer, an isotopic compound, or a metabolite thereof; ##STR00419## in the general formula (I), n1 is selected from 0 or 1; Z is ##STR00420## wherein the carbon atom labelled by * is an asymmetric center; each of R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 is independently selected from H or D; R.sub.2 is selected from H, D or a halogen; each of L.sub.1 and L.sub.2 is independently selected from CD.sub.2, CHD or CH.sub.2; X is selected from NH, ND or O; R.sub.10 is H, D or ##STR00421## wherein each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from H, D, a halogen, a cyano, a hydroxy, ##STR00422## a substituted or unsubstituted (C.sub.1-C.sub.12)alkyl, a substituted or unsubstituted (C.sub.1-C.sub.12)alkoxy, a (C.sub.2.about.C.sub.20)heterocycloalkyl or deuterated (C.sub.2.about.C.sub.20)heterocycloalkyl; wherein each of R.sup.a and R.sup.b is independently H, a (C.sub.1-C.sub.12)alkyl, or a (C.sub.1-C.sub.12)alkylacyl; each of R.sup.c and R.sup.d is independently H or a (C.sub.1-C.sub.12)alkyl; R.sup.e is ##STR00423## or a (C.sub.2.about.C.sub.20)heterocycloalkyl; each of R.sup.e1 and R.sup.e2 is independently H or a (C.sub.1-C.sub.12)alkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from the group consisting of D, a halogen, a hydroxy, a (C.sub.1-C.sub.12)alkoxy, a (C.sub.2.about.C.sub.20)heterocycloalkyl, a (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, ##STR00424## wherein each of R.sup.f and R.sup.g is independently H or a (C.sub.1-C.sub.12)alkyl; R.sup.h is a (C.sub.2.about.C.sub.20)heterocycloalkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkyl is selected from the group consisting of D, a (C.sub.2.about.C.sub.20)heterocycloalkyl, a deuterated (C.sub.2.about.C.sub.20)heterocycloalkyl, a (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, or a (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl; when more than one substituents are contained in the substituted (C.sub.1-C.sub.12)alkoxy or the substituted (C.sub.1-C.sub.12)alkyl, the substituents are the same or different; in each of the groups mentioned above, the heteroatom of the (C.sub.2.about.C.sub.20)heterocycloalkyl contained in the (C.sub.2.about.C.sub.20)heterocycloalkyl, the deuterated (C.sub.2.about.C.sub.20)heterocycloalkyl, the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl or the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl, is selected from the group consisting of O, N and S; provided that in the general formula (I), when n1 is 0, R.sub.1, R.sub.3 and R.sub.10 are H or D, X is NH or ND, R.sub.2 is a halogen; provided that in the general formula (I), when n1 is 1, R.sub.10 is ##STR00425## 2. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 1, wherein, in the general formula (I), the asymmetric center refers to an achiral carbon, (S) configuration carbon, enriched (S) configuration carbon, (R) configuration carbon, enriched (R) configuration carbon or racemate; and/or, in the general formula (I), Z is selected from the group consisting of ##STR00426## ##STR00427## 3. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 1, wherein, in the general formula (I), the (C.sub.2.about.C.sub.20)heterocycloalkyl contained in the (C.sub.2.about.C.sub.20)heterocycloalkyl, the deuterated (C.sub.2.about.C.sub.20)heterocycloalkyl, the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl, or the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is preferably a (C.sub.2-C.sub.6)heterocycloalkyl containing 1 or 2 heteroatom(s) selected from N or O; and/or, in the general formula (I), when R.sub.10 is ##STR00428## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from ##STR00429## or a substituted (C.sub.1-C.sub.12)alkoxy, each of R.sup.a and R.sup.b is independently a (C.sub.1-C.sub.12)alkyl or a (C.sub.1-C.sub.12)alkylacyl, each of R.sup.c and R.sup.d is independently a (C.sub.1-C.sub.12)alkyl; R.sup.e is ##STR00430## each of R.sup.e1 and R.sup.e2 is independently a (C.sub.1-C.sub.12)alkyl; the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is ##STR00431## and each of R.sup.f and R.sup.g is independently a (C.sub.1-C.sub.12)alkyl, the structure of the (C.sub.1-C.sub.12)alkylacyl is ##STR00432## R.sup.a1 is a (C.sub.1-C.sub.12)alkyl; in the definition of R.sup.a, R.sup.b, R.sup.a1, R.sup.c, R.sup.d, R.sup.e1, R.sup.e2, R.sup.f or R.sup.g, the (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; and/or, in the general formula (I), when R.sub.10 is ##STR00433## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from a (C.sub.1-C.sub.12)alkoxy, the (C.sub.1-C.sub.12)alkoxy is a (C.sub.1-C.sub.4)alkoxy; and/or, in the general formula (I), when R.sub.10 is ##STR00434## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent in the substituted (C.sub.1-C.sub.12)alkoxy is selected from ##STR00435## in the general formula (I), when R.sub.10 is ##STR00436## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from ##STR00437## 4. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 3, wherein, the (C.sub.2.about.C.sub.6)heterocycloalkyl is pyrrolidine, morpholinyl or piperazinyl; the (C.sub.1-C.sub.12)alkyl contained in the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl or the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; the deuterated (C.sub.2.about.C.sub.20)heterocycloalkyl is ##STR00438## the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a (C.sub.1-C.sub.12)alkyl is ##STR00439## the (C.sub.2.about.C.sub.20)heterocycloalkyl substituted with a deuterated (C.sub.1-C.sub.12)alkyl is ##STR00440## and/or, in the definition of each of R.sup.a, R.sup.b, R.sup.a1, R.sup.c, R.sup.d, R.sup.e1, R.sup.e2, R.sup.f and R.sup.g, the (C.sub.1-C.sub.12)alkyl is a (C.sub.1-C.sub.4)alkyl; the (C.sub.1-C.sub.4)alkyl is a methyl, an ethyl, a n-propyl, an iso-propyl, a n-butyl, an iso-butyl or a tert-butyl; and/or, in the general formula (I), when R.sub.10 is ##STR00441## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted (C.sub.1-C.sub.12)alkoxy, and when the substituent contained in the substituted (C.sub.1-C.sub.12)alkoxy is selected from a (C.sub.1-C.sub.4)alkoxy, the (C.sub.1-C.sub.4)alkoxy is a methoxy, an ethoxy, a n-propoxy, an isopropoxy, a n-butoxy, an isobutoxy, or a tert-butoxy. 5. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 1, wherein, in the general formula (I), when R.sub.10 is ##STR00442## each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a halogen, the halogen is F, Cl, Br or I; and/or, in the general formula (I), when R.sub.10 is ##STR00443## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.12)alkyl, the substituted or unsubstituted (C.sub.1-C.sub.12)alkyl is a substituted or unsubstituted (C.sub.1-C.sub.4)alkyl; and/or, in the general formula (I), when R.sub.10 is ##STR00444## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.12)alkoxy, the substituted or unsubstituted (C.sub.1-C.sub.12)alkoxy is a substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy; and/or, in the general formula (I), when R.sub.10 is ##STR00445## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from ##STR00446## and/or, in the general formula (I), when R.sub.10 is ##STR00447## and each of R.sub.3', R.sub.4' and R.sub.5' is independently selected from ##STR00448## and/or, in the general formula (I), when R.sub.10 is ##STR00449## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from ##STR00450## 6. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 5, wherein, in the general formula (I), when R.sub.10 is ##STR00451## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.4)alkyl, the substituted or unsubstituted (C.sub.1-C.sub.4)alkyl is a substituted or unsubstituted methyl, a substituted or unsubstituted ethyl, a substituted or unsubstituted propyl, a substituted or unsubstituted isopropyl, a substituted or unsubstituted n-butyl, a substituted or unsubstituted isobutyl, or a substituted or unsubstituted tert-butyl; the substituted (C.sub.1-C.sub.12)alkyl is ##STR00452## and/or, in the general formula (I), when R.sub.10 is ##STR00453## and each of R.sub.2', R.sub.3', R.sub.4' and R.sub.5' is independently selected from a substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy, the substituted or unsubstituted (C.sub.1-C.sub.4)alkoxy is a substituted or unsubstituted methoxy, a substituted or unsubstituted ethoxy, a substituted or unsubstituted n-propoxy, a substituted or unsubstituted n-butoxy, a substituted or unsubstituted isobutoxy, or a substituted or unsubstituted tert-butoxy, the substituted (C.sub.1-C.sub.12)alkoxy is ##STR00454## 7. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 1, wherein, in the definition of R.sub.10, the ##STR00455## ##STR00456## ##STR00457## ##STR00458## ##STR00459## ##STR00460## ##STR00461## ##STR00462## ##STR00463## ##STR00464## ##STR00465## ##STR00466## ##STR00467## 8. The isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, or the metabolite thereof according to claim 1, wherein the compound having a structure of general formula (I) is selected from the group consisting of ##STR00468## ##STR00469## ##STR00470## ##STR00471## ##STR00472## ##STR00473## ##STR00474## ##STR00475## ##STR00476## ##STR00477## ##STR00478## ##STR00479## ##STR00480## ##STR00481## ##STR00482## ##STR00483## ##STR00484## ##STR00485## ##STR00486## ##STR00487## ##STR00488## ##STR00489## ##STR00490## ##STR00491## ##STR00492## ##STR00493## ##STR00494## ##STR00495## ##STR00496## ##STR00497## ##STR00498## ##STR00499## ##STR00500## ##STR00501## ##STR00502## ##STR00503## ##STR00504## ##STR00505## ##STR00506## ##STR00507## ##STR00508## ##STR00509## ##STR00510## ##STR00511## ##STR00512## ##STR00513## ##STR00514## ##STR00515## ##STR00516## ##STR00517## ##STR00518## ##STR00519## ##STR00520## ##STR00521## ##STR00522## ##STR00523## ##STR00524## ##STR00525## ##STR00526## ##STR00527## ##STR00528## ##STR00529## ##STR00530## ##STR00531## ##STR00532## ##STR00533## ##STR00534## ##STR00535## ##STR00536## ##STR00537## ##STR00538## ##STR00539## ##STR00540## ##STR00541## ##STR00542## ##STR00543## ##STR00544## ##STR00545## ##STR00546## ##STR00547## ##STR00548## ##STR00549## ##STR00550## ##STR00551## ##STR00552## ##STR00553## ##STR00554## ##STR00555## ##STR00556## ##STR00557## ##STR00558## ##STR00559## ##STR00560## ##STR00561## ##STR00562## ##STR00563## ##STR00564## ##STR00565## ##STR00566## ##STR00567## ##STR00568## ##STR00569## ##STR00570## ##STR00571## ##STR00572## ##STR00573## ##STR00574## ##STR00575## ##STR00576## ##STR00577## ##STR00578## ##STR00579## ##STR00580## ##STR00581## ##STR00582## ##STR00583## ##STR00584## ##STR00585## ##STR00586## ##STR00587## ##STR00588## ##STR00589## ##STR00590## ##STR00591## ##STR00592## ##STR00593## ##STR00594## ##STR00595## ##STR00596## ##STR00597## ##STR00598## ##STR00599## ##STR00600## ##STR00601## ##STR00602## ##STR00603## ##STR00604## ##STR00605## ##STR00606## ##STR00607## ##STR00608## ##STR00609## ##STR00610## ##STR00611## ##STR00612## ##STR00613## ##STR00614## ##STR00615## ##STR00616## ##STR00617## ##STR00618## ##STR00619## ##STR00620## ##STR00621## ##STR00622## ##STR00623## ##STR00624## ##STR00625## ##STR00626## ##STR00627## ##STR00628## ##STR00629## ##STR00630## ##STR00631## ##STR00632## ##STR00633## ##STR00634## ##STR00635## ##STR00636## ##STR00637## ##STR00638## ##STR00639## ##STR00640## ##STR00641## 9. A process for preparing the isoindoline derivative having a structure of general formula (I) according to claim 1, comprising: conducting a deprotection reaction with compound A-06(1) to give compound A-06(a1) and thereafter an amidation reaction with compound A-06(a1) to give the compound of general formula (I); ##STR00642## wherein in compound A-06(1), compound A-06(a1) or the general formula (I), L.sub.1, L.sub.2, X, Z, *, R.sub.1-R.sub.10 and n1 are as defined in claim 1; one of R.sup.a and R.sup.b is ##STR00643## and the other is ##STR00644## and one of R.sup.a1 and R.sup.b1 is ##STR00645## and the other is ##STR00646## wherein in ##STR00647## each of R.sup.a'' and R.sup.b'' is independently H or D. 10. A process for preparing an isoindoline derivative having a structure of general formula (I) according to claim 1 where n1 is 0, comprising: conducting a reduction reaction with compound I-RS to give the compound of general formula (I); ##STR00648## wherein in compound I-RS or the general formula (I), R.sub.2 is halogen, n1 is 0, X is NH or ND, R.sub.10 is H or D, and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 1. 11. A process for preparing an isoindoline derivative having a structure of general formula (I) according to claim 1 where n1 is 1 and X is NH or HD, comprising: conducting a reductive amination reaction with compound P-01 and ##STR00649## to give the compound of general formula (I); ##STR00650## wherein in ##STR00651## R.sup.p3 is independently H or D and R.sub.10 is ##STR00652## where R.sub.2', R.sub.3', R.sub.4' and R.sub.5' are as defined in claim 1, in the compound P-01 each of R.sup.p1 and R.sup.p2 is independently H or D and L.sub.1, Z, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1, and in the general formula (I) X is NH or ND, n1 is 0, and L.sub.1, L.sub.2, Z, R.sub.1, R.sub.2 and R.sub.3 are as defined in claim 1. 12. The process according to claim 9, further comprising conducting a reduction reaction with compound A-05(1) to give the compound A-06(1); ##STR00653## wherein in compound A-05(1) L.sub.1, R.sub.1-R.sub.8, and R.sup.a and R.sup.b are as defined in claim 9 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 9, X is NH or ND, n1 is 0, and R.sub.10 is H or D. 13. The process of claim 9, further comprising conducting a reductive amination reaction with compound A-05(2) and ##STR00654## to give compound A-06(1); ##STR00655## wherein in compound A-05(2) L.sub.1, R.sub.1-R.sub.9, R.sup.a and R.sup.b are as defined in claim 9 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.9, R.sup.a and R.sup.b are as defined in claim 9, X is NH or ND and n1 is 1, and in ##STR00656## R.sup.p3 is H or D and R.sub.10 is ##STR00657## wherein R.sub.2', R.sub.3', R.sub.4' and R.sub.5' are as defined in claim 1. 14. The process of claim 9, further comprising conducting a nucleophilic substitution reaction with compound A-05(3) and ##STR00658## to give compound A-06(1); ##STR00659## wherein in compound A-05(3) L.sub.1, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 9 and in compound A-06(1) L.sub.1, L.sub.2, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 9, X is O, and n1 is 1, and in ##STR00660## R.sub.10 is ##STR00661## where R.sub.2', R.sub.3', R.sub.4' and R.sub.5' are as defined in claim 1. 15. The process of claim 10, further comprising conducting a coupling reaction with compound A-03 and compound A-04(2) or salt thereof to give compound I-RS; ##STR00662## wherein in compound A-03 L.sub.1 and R.sub.1-R.sub.3 are as defined in claim 9 and Hal is a halogen, in compound A-04(2) * and R.sub.4-R.sub.9 are as defined in claim 9, and in compound I-RS L.sub.1, Z, *, and R.sub.1-R.sub.3 are as defined in claim 9. 16. The process of claim 10, further comprising conducting a deprotection and an amidation reaction sequentially with compound A-05(1) to give compound I-RS; ##STR00663## wherein in compound A-05(1) L.sub.1, *, R.sub.1-R.sub.8, R.sup.a and R.sup.b are as defined in claim 9, in compound A-06(a2) L.sub.1 and R.sub.1-R.sub.8 are as defined in claim 9 and one of R.sup.a2 and R.sup.b2 is ##STR00664## and the other is ##STR00665## in ##STR00666## where each of R.sup.a'' and R.sup.b'' is independently H or D, and in compound I-RS L.sub.1, Z, and R.sub.1-R.sub.3 are as defined in claim 9. 17. The process of claim 11, further comprising conducting a reduction reaction with compound I-RS to give compound P-01; ##STR00667## wherein in compound I-RS R.sub.2 is H, D or a halogen and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 11 and in P-01, R.sub.2 is H, D or a halogen, each of R.sup.p1 and R.sup.p2 is independently H or D, and L.sub.1, Z, R.sub.1 and R.sub.3 are as defined in claim 11. 18. An intermediate compound A-06(1) or A-06(a1): ##STR00668## wherein in compound A-06(1) or A-06(a1), the definitions of L.sub.1, L.sub.2, X, n1, Z, R.sub.1-R.sub.10 refer to those in claim 1; in compound A-06(1), one of R.sup.a and R.sup.b is ##STR00669## the other is ##STR00670## in compound A-06(a1), one of R.sup.a1 and R.sup.b1 is ##STR00671## the other is ##STR00672## in ##STR00673## each of R.sup.a'' and R.sup.b'' is independently H or D. 19. A pharmaceutical composition, which comprises a therapeutically effective and/or prophylactically effective amount of the substance selected from the group consisting of the isoindoline derivatives having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, and the metabolite thereof according to claim 1. 20. The pharmaceutical composition according to claim 19, wherein the composition comprises other therapeutic agent(s), the other therapeutic agent(s) is selected from the group consisting of elotuzumab, palbociclib, nivolumab, pembrolizumab, panobinostat, PD-1 inhibitor, PD-L1 inhibitor, pemetrexed, topotecan, doxorubicin, bortezomib, gemcitabine, dacarbazine, dexamethasone, biaxin, vincristine, azacitidine, rituximab, trastuzumab, prednisone, docetaxel, clofarabine injection, Ublituximab, romidepsin, HDAC inhibitor, androgen receptor inhibitor, androgen biosynthesis inhibitor, BTK inhibitor, erythropoietin, eltrombopag, minocycline and melphalan. 21. A method of treating a disease, symptom or disorder caused by TNF-.alpha. or associated with abnormal regulation of TNF-.alpha. activity, wherein the method comprises administering to a subject a therapeutically or prophylactically effective amount of a substance selected from the group consisting of the isoindoline derivative having a structure of general formula (I), the pharmaceutically acceptable salt, the polymorph, the stereoisomer, the isotopic compound, and the metabolite thereof according to claim 1. 22. The method of claim 21, wherein the disease, symptom or disorder includes myelodysplastic syndrome, multiple myeloma, mantle cell lymphoma, non Hodgkin's lymphoma, papillary and follicular thyroid carcinoma, breast cancer, prostate cancer, chronic lymphocytic leukemia, amyloidosis, type I complex regional pain syndrome, malignant melanoma, radiculopathy, myelofibrosis, glioblastoma, glioma sarcomatosum, malignant glioma, refractory plasma cell tumor, chronic myelomonocytic leukemia, follicular lymphoma, ciliary and chronic melanoma, iris melanoma, recurrent ocular melanoma, extraocular extension melanoma, solid tumor, T-cell lymphoma, erythroid lymphoma, monoblastic and monocytic leukemia; myeloid leukemia, central nervous system lymphoma, brain tumors, meningiomas, spinal tumor, thyroid cancer, non-small cell lung cancer, ovarian cancer, skin cancer, renal cell carcinoma, myelofibrosis, Burkitt's lymphoma, Hodgkin's lymphoma, large cell lymphoma, diffuse large B cell lymphoma, astrocytoma, hepatocellular carcinoma, or primary macroglobulinemia. 23. A method of treating a disease, symptom or disorder caused by TNF-.alpha. or associated with abnormal regulation of TNF-.alpha. activity, wherein the method comprises administering to a subject a therapeutically or prophylactically effective amount of the pharmaceutical composition according to claim 19.

Details for Patent 10,017,492

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2034-10-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2034-10-30
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2034-10-30