Pyrrolidinone, Pyrrolidine-2, 5-Dione, Pyrrolidine and Thiosuccinimide Derivatives, Compositions and Methods for Treatment of Cancer

• US 20100178291A1
• Filed: 06/19/2008
• Published: 07/15/2010
• Est. Priority Date: 06/22/2007
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Hill, Jason, Ashwell, Mark A., Liu, Yanbin, Wang, Jianqiang, Ali, Syed M., Kelleher, Eugene
• Granted Patent: US 8,304,425 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 403/14 containing three or more hetero rings

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.

Claims

1. A compound of formula I, II, III, or IV, or pharmaceutically acceptable salts thereof:

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, —

CH₂R6, —

CONHR9, —

COR10, and SO₂R11;

R6 is selected from the group consisting of —

O—

P(═

O)(OH)₂, —

O—

P(═

O)(—

OH)(—

O—

(C1-C6) alkyl), —

O—

P(═

O)(—

O—

(C1-C6) alkyl)₂, —

O—

P(═

O)(—

OH) (—

O—

(CH₂)-phenyl), —

O—

P(═

O)(—

O—

(CH₂)-phenyl)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, H₂;

when both V and Z are O, R4 is —

(C1-C4) alkyl, or —

(C1-C4) substituted alkyl;

when both Z and V are not H₂, R5 is H, —

(C1-C6) alkyl, or —

CH₂R6;

X is selected from the group consisting of —

CH₂—

, —

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(═

O)—

O—

(C1-C6) alkyl, and —

C(═

O)—

O—

(C1-C6) substituted alkyl;

W is selected from the group consisting of —

CH₂—

, 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, —

(C₁-C₆) alkyl, —

(C₁-C₆)fluoro-substituted alkyl, —

(C₃-C₉) cycloalkyl, —

(C₃-C₉) fluoro-substituted cycloalkyl, —

O—

(C₁-C₆) alkyl, —

O—

(C₁-C₆) fluoro-substituted alkyl, —

O—

(C₃-C₉) cycloalkyl, and —

O—

(C₃-C₉) fluoro-substituted cycloalkyl, -aryl, —

O-aryl, —

O—

(C₁-C₄) alkyl-aryl, —

O—

(C₁-C₄) alkyl-heterocycle, and —

S(═

O)₂—

(C₁-C₆) alkyl.

3. The compound of claim 1 wherein V is O.

4. The compound of claim 3 wherein Z is O, and R4 is —

(C1-C4) alkyl, or —

(C1-C4) substituted alkyl.

5. The compound of claim 3 wherein Z is S or H₂.

6. The compound of claim 1 wherein V is S.

7. The compound of claim 6 wherein Z is O or H₂.

8. The compound of claim 1 wherein V is H₂.

9. The compound of claim 8 wherein Z is O, S, or H₂.

10. The compound of claim 1 wherein W is —

CH₂—

.

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)-pyrrolidin-2-one, (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-pyrrolidin-2-one, (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-2-one, (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-pyrrolidin-2-one, (3R,4R)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-3-(1H-indol-3-yl)-5-thioxo-pyrrolidin-2-one, (3R,4R)-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-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-yl)-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-trifluoromethyl-phenyl)-pyrrolidin-2-one, (±

)-trans-3-(5,6-Dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(3-methoxy-phenyl)-pyrrolidin-2-one, 1-[(3R,4R)-1-benzenesulfonyl-4-(1H-indol-3-yl)-pyrrolidin-3-yl]-5,6-dihydro-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.

18. A method of treating a cell proliferative disorder, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula I, II, III, IV as defined in claim 1, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, in combination with a pharmaceutically acceptable carrier, wherein said cell proliferative disorder is treated.

19. The method of claim 18, wherein said cell proliferative disorder is a precancerous condition.

20. The method of claim 18, wherein said cell proliferative disorder is a cancer.

21. The method of claim 20, wherein said cancer is lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, or ovarian cancer.

22. The method of claim 18, wherein said cell proliferative disorder is a cell proliferative disorder of the breast.

23. The method of claim 22, wherein said cell proliferative disorder of the breast is a precancerous condition of the breast.

24. The method of claim 23, wherein said precancerous condition of the breast is selected from the group consisting of atypical hyperplasia of the breast, ductal carcinoma in situ, and lobular carcinoma in situ.

25. The method of claim 22, wherein said cell proliferative disorder of the breast is breast cancer.

26. The method of claim 25, wherein said breast cancer is an estrogen-receptor negative breast cancer.

27. The method of claim 18, wherein said compound of formula I, II, III, IV, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered in combination with a second chemotherapeutic agent.

28. The method of claim 27, 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 or idarubicin.

29. The method of claim 18, wherein said treating cancer comprises a reduction in tumor size.

30. The method of claim 20, wherein the cancer is metastatic cancer.

31. The method of claim 30, wherein said treating cancer comprises inhibition of metastatic cancer cell invasion.

32. The method of claim 18 wherein the cells with proliferative order contains DNA encoding c-Met.

33. The method of claim 32 wherein the cells have a constitutively enhanced c-Met activity.

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.