Compositions and Methods for the Treatment of Cancer

• US 20100183603A1
• Filed: 06/19/2008
• Published: 07/22/2010
• 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., Ali, Syed, Wang, Jianqiang, Westlund, Neil, Namdev, Nivedita
• Granted Patent: US 8,513,292 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 471/06 Peri-condensed systems
• CPC Class Codes: C07D 487/06 Peri-condensed systems
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to pyrrolidine-2,5-dione compounds, and methods of preparation of these compounds. The present invention also relates to pharmaceutical compositions comprising pyrrolidine-2,5-dione 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 or pyrrolidine-2,5-dione compound of the present invention. (Ia) (Ib) (IIa) (IIIb) Where U is independently selected from: (I) or (II)

where U is independently selected from:

Claims

1. A compound of formula Ia, Ib, IIa, or IIb, or a pharmaceutically acceptable salt thereof:

Where U is independently selected from;

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, R7, and R8 are independently 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, and —

CH₂R6;

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;

R9 is selected from the group consisting of H, —

(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 aryl, heteroaryl, heterocyclyl, alkyl, substituted aryl, substituted heteroaryl, substituted heterocyclyl, and substituted alkyl;

T is —

CH₂—

, —

C(O)—

, or a bond;

when T is a bond, Y is a bond, W is bond, X is —

CH₂—

, and m=1, n=1;

V and Z are independently selected from the group consisting of O, S, and H₂;

X is independently selected from the group consisting of —

CH₂—

, —

NR8, S, O, and a bond;

Y and W are independently —

CH₂—

, or a bond;

m is 1 or 2;

n is 1 or 2;

and wherein X, Y, and W cannot all be a bond.

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 Q is selected from the group consisting of 2-chlorophenyl and 3-methoxyphenyl.

4. The compound of claim 1 wherein both V and Z are O.

5. The compound of claim 1 wherein R5 is H.

6. The compound of claim 1 wherein X is selected from the group consisting of —

(NR8)-, S, and O.

7. The compound of claim 1 wherein X is —

CH₂—

.

8. The compound of claim 7 wherein Y is a bond.

9. The compound of claim 8 wherein m is 2.

10. The compound of claim 9 wherein W is —

CH₂—

.

11. The compound of claim 10 wherein n is 1.

12. The compound of claim 1 wherein U is

13. The compound of claim 6 wherein T is —

CH₂—

.

14. The compound of claim 6 wherein T is —

C(O)—

.

15. The compound of claim 6 wherein U is

16. The compound of claim 1 wherein U is

17. The compound of claim 1, wherein the compound is selected from the group consisting of (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-ylmethyl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, (±

)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline-1-carbonyl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione, (±

)-trans-3-(5-bromo-1H-indol-3-yl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrolidine-2,5-dione, (±

)-trans-3-(2-Chloro-phenyl)-4-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-pyrrolidine-2,5-dione, (±

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-8-yl)-4-(3-methoxyphenyl)-pyrrolidine-2,5-dione, and (±

)-trans-3-(4,5-dihydro-pyrrolo[3,2,1-hi]indol-1-yl)-4-(1H-indol-3-yl)-pyrrolidine-2,5-dione.

18. A pharmaceutical composition comprising a compound of formula Ia, Ib, IIa, or IIb as defined in claim 1 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients.

19. The pharmaceutical composition of claim 18 further comprising a second chemotherapeutic agent.

21. 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 Ia, Ib, IIa, or IIb 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.

22. The method of claim 21, wherein said cell proliferative disorder is a precancerous condition.

23. The method of claim 21, wherein said cell proliferative disorder is a cancer.

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

25. The method of claim 21, wherein said compound of formula Ia, Ib, IIa, or IIb, or a pharmaceutically acceptable salt thereof, or a prodrug or metabolite thereof, is administered in combination with a second chemotherapeutic agent.

26. The method of claim 25, 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.

27. The method of claim 21, wherein said treating cancer comprises a reduction in tumor size.

28. The method of claim 21, wherein the cancer is metastatic cancer.

29. The method of claim 28, wherein said treating cancer comprises inhibition of metastatic cancer cell invasion.

30. The method of claim 21 wherein the cells with said proliferative disorder contains DNA encoding c-Met.

31. The method of claim 30 wherein the cells have a constitutively enhanced c-Met activity.

20. The pharmaceutical composition of 19, 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.