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Claims for Patent: 9,827,329

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Summary for Patent: 9,827,329
Title:Compounds and compositions for immunotherapy
Abstract: Provided are compounds for targeted immunotherapy. The compounds are useful in the treatment of diseases such as cancer. Also provided are compositions comprising the compounds.
Inventor(s): Li; Lixin (Beijing, CN)
Assignee: BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY)
Application Number:15/110,685
Patent Claims:1. A compound having the structure of Formula (Ib): TM-L-AM (Ib), wherein TM is a targeting moiety that comprises an immunoglobulin that specifically binds to a tumor antigen on a tumor cell, wherein the tumor antigen is selected from the group consisting of CD2, CD19, CD20, CD22, CD27, CD33, CD37, CD38, CD40, CD44, CD47, CD52, CD56, CD70, CD79, CD137, 4-1BB, 5T4, AGS-5, AGS-16, Angiopoietin 2, B7.1, B7.2, B7DC, B7H1, B7H2, B7H3, BT-062, BTLA, CAIX, Carcinoembryonic antigen, CTLA4, Cripto, ED-B, ErbB1, ErbB2, ErbB3, ErbB4, EGFL7, EGFR, EpCAM, EphA2, EphA3, EphB2, FAP, Fibronectin, Folate Receptor, Ganglioside GM3, GD2, glucocorticoid-induced tumor necrosis factor receptor (GITR), gp100, gpA33, GPNMB, Her2, ICOS, IGF1R, Integrin, KIR, LAG-3, Lewis Y, Mesothelin, c-MET, MN Carbonic anhydrase IX, MUC1, MUC16, Nectin-4, NKGD2, NOTCH, OX40, OX40L, PD-1, PD-L1, PSCA, PSMA, RANKL, ROR1, ROR2, SLC44A4, Syndecan-1, TACI, TAG-72, Tenascin, TIM3, TRAILR1, TRAILR2, VEGFR-1, VEGFR-2, and VEGFR-3, L is a linker, and AM is an activating moiety that is represented by structure of formula (I): ##STR00065## wherein dashed line represents bond or absence of bond, is the point to be connected to the linker; X is S or --NR.sub.1, R.sub.1 is --W.sub.0-W.sub.1-W.sub.2-W.sub.3-W.sub.4, W.sub.0 is a bond, alkyl, alkenyl, alkynyl, alkoxy, or -alkyl-S-alkyl-, W.sub.1 is a bond, --O--, or --NR.sub.2--, wherein R.sub.2 is hydrogen, alkyl or alkenyl, W.sub.2 is a bond, --O--, --C(O)--, --C(S)--, or --S(O).sub.2--, W.sub.3 is a bond, --NR.sub.3--, wherein R.sub.3 is hydrogen, alkyl or alkenyl, W.sub.4 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, aryl, aryloxy, heteroaryl, or heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, --NH.sub.2, nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, --O--R.sub.4, --O-alkyl-R.sub.4, -alkyl-O--R.sub.4, --C(O)--R.sub.4, -alkyl-C(O)--R.sub.4, -alkyl-C(O)--O--R.sub.4, --C(O)--O--R.sub.4, --S--R.sub.4, --S(O).sub.2--R.sub.4, --NH--S(O).sub.2--R.sub.4, -alkyl-S--R4, -alkyl-S(O).sub.2--R.sub.4, --NHR.sub.4, --NR.sub.4R.sub.4, --NH-alkyl-R.sub.4, halogen, --CN, --NO.sub.2, and --SH, wherein R.sub.4 is independently hydrogen, alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; Z is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, aryl, haloalkyl, heteroaryl, heterocyclyl, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, halogen, cyano, nitro, --N(R.sub.5).sub.2, -alkoxy-alkyl, -alkoxy-alkenyl, --C(O)-alkyl, --C(O)--O-alkyl, --O--C(O)-alkyl, --C(O)--N(R.sub.5).sub.2, aryl, heteroaryl, --CO-aryl, and --CO-heteroaryl, wherein each R.sub.5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl; R is hydrogen, alkyl, alkoxy, haloalkyl, halogen, aryl, heteroaryl, heterocyclyl, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, --NH.sub.2, nitro, -alkyl-hydroxyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, --O--R.sub.4, --O-alkyl-R.sub.4, -alkyl-O--R.sub.4, --C(O)--R.sub.4, --C(O)--NH--R.sub.4, --C(O)--NR.sub.4R.sub.4, -alkyl-C(O)--R.sub.4, -alkyl-C(O)--O--R.sub.4, --C(O)--O--R.sub.4, --O--C(O)--R.sub.4, --S--R.sub.4, --C(O)--S--R.sub.4, --S--C(O)--R.sub.4, --S(O).sub.2--R.sub.4, --NH--S(O).sub.2--R.sub.4, -alkyl-S--R.sub.4, -alkyl-S(O).sub.2--R.sub.4, --NHR.sub.4, --NR.sub.4R.sub.4, --NH-alkyl-R.sub.4, halogen, --CN, and --SH, wherein R.sub.4 is independently hydrogen, alkyl, alkenyl, alkoxy, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl; n is 0, 1, 2, 3, or 4; Y is --NR.sub.6R.sub.7, --CR.sub.6R.sub.7R.sub.8, or -alkyl-NH.sub.2, each of which can be optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, --NH.sub.2, halogen, --N(R.sub.5).sub.2, -alkoxy-alkyl, -alkoxy-alkenyl, --C(O)-alkyl, --C(O)--O-alkyl, --C(O)--N(R.sub.5).sub.2, aryl, heteroaryl, --CO-aryl, and --CO-heteroaryl, wherein R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, alkyl, alkenyl, alkoxy, alkylamino, dialkylamino, alkylthio, arylthio, -alkyl-hydroxyl, -alkyl-C(O)--O--R.sub.9, -alkyl-C(O)--R.sub.9, or -alkyl-O--C(O)--R.sub.9, wherein each R.sub.5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl, wherein R.sub.9 is hydrogen, alkyl, alkenyl, halogen, or haloalkyl; X and Z taken together may optionally form a (5-9)-membered ring; or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein L is represented by structure of formula (II): D-(D).sub.b-(D).sub.b.sub.m (II) m is 1, 2, 3, 4, 5, or 6, each b independently is 0 or 1, and D is independently represented by structure of formula (III): ##STR00066## wherein each i independently is 0 or 1; each j independently is 0, 1, 2, 3, 4, 5, or 6; each A independently is S, O, or N--Ra, wherein Ra is hydrogen, alkyl, alkenyl, or alkoxy; each B independently is alkyl, alkenyl, --O-alkyl-, -alkyl-O--, --S-alkyl-, -alkyl-S--, aryl, heteroaryl, heterocyclyl, or peptide, each of which is optionally substituted by one or more substituents selected from the group consisting of hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, -alkyl-aryl, -alkyl-heteroaryl, -alkyl-heterocyclyl, --O--R.sub.4, --O-alkyl-R.sub.4, --C(O)--R.sub.4, --C(O)--O--R.sub.4, --S--R.sub.4, --S(O).sub.2--R.sub.4, --NHR.sub.4, --NH-alkyl-R.sub.4, halogen, --CN, --NO.sub.2, and --SH, wherein R.sub.4 is alkyl, alkenyl, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl.

3. The compound of claim 1, wherein X is --NR.sub.1, R.sub.1 is alkyl, -alkyl-W.sub.4, -alkyl-O--W.sub.4, -alkyl-NH--C(O)--W.sub.4, -alkoxy-NH--C(O)--W.sub.4, -alkyl-NH--C(O)--NH--W.sub.4, -alkoxy-NH--C(O)--NH--W.sub.4, -alkyl-S(O).sub.2--W.sub.4, or -alkyl-NH--C(S)--W.sub.4.

4. The compound of claim 1, wherein X is S.

5. The compound of claim 1, wherein Z is hydrogen, alkyl, alkoxy, aryl, heteroaryl, haloalkyl, each of which is optionally substituted by one to three substituents selected from the group consisting of hydroxyl, alkyl, aryl, heteroaryl, heterocyclyl, cyano, -alkoxy-alkyl, nitro, and --N(R.sub.5).sub.2, wherein each R.sub.5 is independently hydrogen, alkyl, haloalkyl, -alkyl-aryl, or -alkyl-heteroaryl.

6. The compound of claim 1, wherein n is 1 or 2, R is aryl or heteroaryl each of which is optionally substituted by one to three substituents selected from the group consisting of hydroxyl, alkoxy, -alkyl-hydroxyl, --O--R.sub.4, --O-alkyl-R.sub.4, -alkyl-O--R.sub.4, --C(O)--R.sub.4, --C(O)--NH--R.sub.4, --C(O)--NR.sub.4R.sub.4, -alkyl-C(O)--R.sub.4, -alkyl-C(O)--O--R.sub.4, --C(O)--O--R.sub.4, --O--C(O)--R.sub.4, --S--R.sub.4, --C(O)--S--R.sub.4, --S--C(O)--R.sub.4, --S(O).sub.2--R.sub.4, --NH--S(O).sub.2--R.sub.4, -alkyl-S--R.sub.4, -alkyl-S(O).sub.2--R.sub.4, --NHR.sub.4, --NR.sub.4R.sub.4, --NH-alkyl-R.sub.4, halogen, --CN, and --SH, wherein R.sub.4 is independently hydrogen, alkyl, alkenyl, alkoxy, -alkyl-hydroxyl, aryl, heteroaryl, heterocyclyl, or haloalkyl.

7. The compound of claim 1, wherein Y is --NH.sub.2, -alkyl-NH.sub.2, each of which is optionally substituted by one to three substituents selected from the group consisting of alkyl, alkoxy, alkenyl, and alkynyl.

8. The compound of claim 1, wherein AM is a compound selected from the group consisting of: 2-propylthiazolo[4,5-c]quinolin-4-amine, 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine, 4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethan- ol, 1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpro- pan-2-ol, N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl-]meth- anesulfonamide, 4-amino-2-ethoxymethyl-aa-dimethyl-6,7,8,9-tetrahydro-1h-imidazo[4,5-c]qu- inoline-1-ethanol, 4-amino-aa-dimethyl-2-methoxyethyl-1h-imidazo[4,5-c]quinoline-1-ethanol, 1-{2-[3-(benzyloxy)propoxy]ethyl}-2-(ethoxymethyl)-1H-imidazo[4,5-c]quino- lin-4-amine, N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)butyl]-n'-b- utylurea, N1-[2-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5] naphthyridin-1-yl)ethyl]-2-amino-4-methylpentanamide, N-(2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy- }ethyl)-n'-phenylurea, 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-a- mine, 1-{4-[(3,5-dichlorophenyl)sulfonyl]butyl}-2-ethyl-1H-imidazo[4,5-c]q- uinolin-4-amine, N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}e- thyl)-n'-cyclohexylurea, N-{3-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propyl}-n'-- (3-cyanophenyl)thiourea, N-[3-(4-amino-2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)-2,2-dimethylpropyl]- benzamide, 2-butyl-1-[3-(methylsulfonyl)propyl]-1H-imidazo[4,5-c]quinolin-- 4-amine, N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,- 1-dimethylethyl}-2-ethoxyacetamide, 1-[4-amino-2-ethoxymethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl- ]-2-methylpropan-2-ol, 1-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-- yl]-2-methylpropan-2-ol, N-{3-[4-amino-1-(2-hydroxy-2-methylpropyl)-2-(methoxyethyl)-1H-imidazo[4,- 5-c]quinolin-7-yl]phenyl}methanesulfonamide, 1-[4-amino-7-(5-hydroxymethylpyridin-3-yl)-2-(2-methoxyethyl)-1H-imidazo[- 4,5-c]quinolin-1-yl]-2-methylpropan-2-ol, 3-[4-amino-2-(ethoxymethyl)-7-(pyridin-3-yl)-1H-imidazo[4,5-c]quinolin-1-- yl]propane-1,2-diol, 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethyl- ethyl]-3-propylurea, 1-[2-(4-amino-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)-1,1-dimethyl- ethyl]-3-cyclopentylurea, 1-[(2,2-dimethyl-1,3-dioxolan-4-yl)methyl]-2-(ethoxymethyl)-7-(4-hydroxym- ethylphenyl)-1H-imidazo[4,5-c]quinolin-4-amine, 4-[4-amino-2-ethoxymethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]q- uinolin-7-yl]-N-methoxy-N-methylbenzamide, 2-ethoxymethyl-N1-isopropyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline- -1,4-diamine, 1-[4-amino-2-ethyl-7-(pyridin-4-yl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-met- hylpropan-2-ol, N-[4-(4-amino-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfona- mide, and N-[4-(4-amino-2-butyl-1H-imidazo[4,5-c][1,5]naphthyridin-1-yl)bu- tyl]-n'-cyclohexylurea.

9. The compound of claim 2, wherein D in the linker moiety is selected from the structures of formula (V)-(VII) ##STR00067## wherein A, B, i and j are defined above.

10. The compound of claim 1, wherein TM binds to a tumor cell specifically or preferably in comparison to a non-tumor cell.

11. The compound of claim 1, wherein the immunoglobulin comprises an antibody or a functional fragment thereof.

12. The compound of claim 11, wherein the immunoglobulin comprises Rituxan (rituximab), Herceptin (trastuzumab), Erbitux (cetuximab), Vectibix (Panitumumab), Arzerra (Ofatumumab), Benlysta (belimumab), Yervoy (ipilimumab), Perjeta (Pertuzumab), Tremelimumab, Nivolumab, Dacetuzumab, Urelumab, MPDL3280A, Lambrolizumab, Blinatumomab, or a functional fragment thereof.

13. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 and one or more pharmaceutically acceptable carriers.

14. The pharmaceutical composition of claim 13, further comprising an effective amount of an additional therapeutic agent.

15. The pharmaceutical composition of claim 14, wherein the additional therapeutic agent is an anticancer agent selected from an antimetabolite, an inhibitor of topoisomerase I and II, an alkylating agent, a microtubule inhibitor, an antiandrogen agent, a GNRh modulator, and mixtures thereof.

16. A method of treating a disease in a subject comprising administering to the subject the compound of claim 1.

17. The method of claim 16, wherein the disease is a cancer selected from stomach, colon, rectal, liver, pancreatic, lung, breast, cervix uteri, corpus uteri, ovary, testis, bladder, renal, brain/Central Nervous System, head and neck, throat, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, leukemia, melanoma, non-melanoma skin cancer, acute lymphocytic leukemia, acute myelogenous leukemia, Ewing's sarcoma, small cell lung cancer, choriocarcinoma, rhabdomyosarcoma, Wilms' tumor, neuroblastoma, hairy cell leukemia, mouth/pharynx, oesophagus, larynx, or lymphoma.

18. The compound of claim 8, wherein the AM is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine.

19. The compound of claim 8, wherein the AM is 4-amino-2-(ethoxymethyl)-a,a-di-methyl-1H-imidazo[4,5-c]quinoline-1-ethan- ol.

20. The compound of claim 8, wherein the AM is 1-(4-amino-2-ethylaminomethylimidazo-[4,5-c]quinolin-1-yl)-2-methylpropan- -2-ol.

21. The compound of claim 1, wherein the tumor antigen is PD-L1.

22. The compound of claim 1, wherein the tumor antigen is CD20.

23. The compound of claim 1, wherein the tumor antigen is Her2.

24. The compound of claim 1, wherein the tumor antigen is EGFR.

Summary for Patent:   Start Trial

Foriegn Application Priority Data
Foreign Country Foreign Patent Number Foreign Patent Date
China2014 1 0011262Jan 10, 2014
China2014 1 0011324Jan 10, 2014
China2014 1 0011362Jan 10, 2014
PCT Information
PCT FiledJanuary 08, 2015PCT Application Number:PCT/CN2015/070379
PCT Publication Date:July 16, 2015PCT Publication Number:WO2015/103989

Details for Patent 9,827,329

Applicant Tradename Biologic Ingredient Dosage Form BLA Number Approval Date Patent No. Assignee Estimated Patent Expiration Status Orphan Source
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 001 1997-11-26   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX search
Genentech RITUXAN rituximab SOLUTION;INTRAVENOUS 103705 002 1997-11-26   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX search
Genentech HERCEPTIN trastuzumab VIAL; INTRAVENOUS 103792 001 1998-09-25   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX Orphan search
Imclone ERBITUX cetuximab VIAL; INTRAVENOUS 125084 001 2004-06-18   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX Orphan search
Amgen VECTIBIX panitumumab INJECTABLE; IV (INFUSION) 125147 001 2006-09-27   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX search
Amgen VECTIBIX panitumumab INJECTABLE; IV (INFUSION) 125147 002 2006-09-27   Start Trial BIRDIE BIOPHARMACEUTICALS, INC. (Grand Cayman, KY) 2034-01-10 RX search
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Number >Approval Date >Patent No. >Assignee >Estimated Patent Expiration >Status >Orphan >Source

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