Claims for Patent: 8,304,425

Summary for Patent: 8,304,425

Title:	Pyrrolidinone, pyrrolidine-2,5-dione, pyrrolidine and thiosuccinimide derivatives, compositions and methods for treatment of cancer
Abstract:	The present invention relates to pyrrolidin-2-one, pyrrolidin-2,5-dione, pyrrolidine and thiosucciniroide compounds of formulae (I)-(IV), and methods of preparation of these compounds. The present invention also relates to pharmaceutical compositions comprising pyrrolidin-2-one, pyrrolidin-2,5-dione, pyrrolidine and thiosuccinimide compounds. The present invention provides methods of treating a cell proliferative disorder, such as a cancer, by administering to a subject in need thereof a therapeutically effective amount of a compound of pyrrolidin-2-one, pyrrolidin-2,5-dione, pyrrolidine and thiosuccinimide compound of the present invention. ##STR00001##
Inventor(s):	Wang; Jianqiang (Acton, MA), Ali; Syed M. (North Andover, MA), Kelleher; Eugene (Wellesley, MA), Liu; Yanbin (Acton, MA), Hill; Jason (Auburndale, MA), Ashwell; Mark A. (Carlisle, MA)
Assignee:	ArQule, Inc. (Woburn, MA)
Application Number:	12/664,550
Patent Claims:	1. A compound of formula I, II, III, or IV, or pharmaceutically acceptable salts thereof: ##STR00038## wherein: R1, R2, and R3 are independently selected from the group consisting of H, F, Cl, Br, I, --NR7R8, --(C1-C6) alkyl, --(C1-C6) substituted alkyl, --(C3-C9) cycloalkyl, --(C3-C9) substituted cycloalkyl, --O--(C1-C6) alkyl, --O--(C3-C9) cycloalkyl, and --O--(C3-C9) substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl; R4 is selected from the group consisting of H, --(C1-C4) alkyl, and --(C1-C4) substituted alkyl; R5 is selected from the group consisting of H, --(C1-C6) alkyl, --CH.sub.2R6, --CONHR9, --COR10, and --SO.sub.2R11; R6 is selected from the group consisting of --O--P(.dbd.O)(OH).sub.2, --O--P(.dbd.O)(--OH)(--O--(C1-C6) alkyl), --O--P(.dbd.O)(--O--(C1-C6) alkyl).sub.2, --O--P(.dbd.O)(--OH) (--O--(CH.sub.2)-phenyl), --O--P(.dbd.O)(--O--(CH.sub.2)-phenyl).sub.2, a carboxylic acid group, an amino carboxylic acid group, and a peptide; R7 and R8 are independently selected from the group consisting of H and --(C1-C6) alkyl; R9, R10, and R11 are independently selected from the group consisting of H, NHR12, --(C1-C6)alkyl, --(C1-C6) substituted alkyl, --(C3-C9)cycloalkyl, --(C3-C9) substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl; Q is selected from the group consisting of indolyl, substituted indolyl, aryl, heteroaryl, heterocyclyl, and alkyl; V and Z are independently selected from the group consisting of O, S, H.sub.2; provided that at least one of V and Z is H.sub.2; X is selected from the group consisting of --CH.sub.2--, --NR12, S, O, and a bond; R12 is selected from the group consisting of H, --(C1-C6) alkyl, --(C1-C6) substituted alkyl, --(C3-C9) cycloalkyl, --(C3-C9) substituted cycloalkyl, --O--(C1-C6) alkyl, --C(.dbd.O)--O--(C1-C6) alkyl, and --C(.dbd.O)--O--(C1-C6) substituted alkyl; W is selected from the group consisting of --CH.sub.2--, CO, and a bond; and m is 0, 1 or 2. 2. The compound of claim 1, wherein Q is an indolyl group or an indolyl group substituted with one or more substituents independently selected from the group consisting of: F, Cl, Br, I, --(C.sub.1-C.sub.6) alkyl, --(C.sub.1-C.sub.6)fluoro-substituted alkyl, --(C.sub.3-C.sub.9) cycloalkyl, --(C.sub.3-C.sub.9) fluoro-substituted cycloalkyl, --O--(C.sub.1-C.sub.6) alkyl, --O--(C.sub.1-C.sub.6) fluoro-substituted alkyl, --O--(C.sub.3-C.sub.9) cycloalkyl, and --O--(C.sub.3-C.sub.9) fluoro-substituted cycloalkyl, -aryl, --O-aryl, --O--(C.sub.1-C.sub.4) alkyl-aryl, --O--(C.sub.1-C.sub.4) alkyl-heterocycle, and --S(.dbd.O).sub.2--(C.sub.1-C.sub.6) alkyl. 3. The compound of claim 1 wherein V is O. 4. The compound of claim 1 wherein Z is O, and R4 is H. 5. The compound of claim 4 wherein R1, R2. R3, and R5 are H. 6. The compound of claim 1 wherein V is S. 7. The compound of claim 5 wherein X is --CH.sub.2-- and m is 0. 8. The compound of claim 1 wherein V is H.sub.2. 9. The compound of claim 8 wherein Z is O, S, or H.sub.2. 10. The compound of claim 1 wherein W is --CH.sub.2--. 11. The compound of claim 10 wherein m is 1. 12. The compound of claim 11 wherein X is a bond. 13. The compound of claim 1 wherein R5 is H. 14. The compound of claim 1 wherein the compound is selected from the group consisting of 4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-pyrro- lidin-2-one, (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-y- l)-pyrrolidin-2-one, (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-y- l)-pyrrolidin-2-one, (.+-.)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indo- l-3-yl)-pyrrolidin-2-one, (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-y- l)-5-thioxo-pyrrolidin-2-one, (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-y- l)-5-thioxo-pyrrolidin-2-one, 1-[(3R,4R)-4-(1H-Indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-4H-pyrrolo[3,2,- 1-ij]quinoline, (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-y- l)-pyrrolidine-1-carboxylic acid ethylamide, 1-[(3R,4R)-4-(1H-indol-3-yl)-1-(propane-2-sulfonyl)-pyrrolidin-3-yl]-5,6-- dihydro-4H-pyrrolo[3,2,1-ij]quinoline, and cyclobutyl-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(- 1H-indol-3-yl)-pyrrolidin-1-yl]-methanone, (.+-.)-trans-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-trifl- uoromethyl-phenyl)-pyrrolidin-2-one, (.+-.)-trans-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-metho- xy-phenyl)-pyrrolidin-2-one, 1-[(3R,4R)-1-benzenesulfonyl-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihyd- ro-4H-pyrrolo[3,2,1-ij]quinoline, and 1-[(3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-- 3-yl)-pyrrolidin-1-yl]-3,3-dimethyl-butan-1-one. 15. A pharmaceutical composition comprising a compound of formula I, II, III, or IV as defined in claim 1 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients. 16. The pharmaceutical composition of claim 15 further comprising a second chemotherapeutic agent. 17. The pharmaceutical composition of 16, wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, trastuzumab, imatanib, paclitaxel, cyclophosphamide, lovastatin, minosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vincristin, vinblastin, nocodazole, teniposide, etoposide, gemcitabine, epothilone, navelbine, camptothecin, daunonibicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin, and idarubicin.

Details for Patent 8,304,425

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2027-06-22
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	02/10/2017		2027-06-22
Genentech, Inc.	HERCEPTIN HYLECTA	trastuzumab and hyaluronidase-oysk	Injection	761106	02/28/2019		2027-06-22