Compositions and Methods for Treatment of Cancer

• US 20100221251A1
• Filed: 03/11/2010
• Published: 09/02/2010
• Est. Priority Date: 02/09/2005
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Moussa, Magdi M., Munshi, Neru, Hill, Jason, Ashwell, Mark A., Li, Chiang J.
• Granted Patent: US 8,377,927 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/337 having four-membered rings, e.g. taxol
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5517 condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/683 Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 38/08 Peptides having 5 to 11 amino acids A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/12 Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• 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: C07D 455/00 Heterocyclic compounds containing quinolizine ring systems, e.g. emetine alkaloids, protoberberine; Alkylenedioxy derivatives of dibenzo [a, g] quinolizines, e.g. berberine
• CPC Class Codes: C07D 471/06 Peri-condensed systems
• CPC Class Codes: C07D 487/06 : Peri-condensed systems
• CPC Class Codes: C07F 9/65583 : each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 : containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07K 2/00 : Peptides of undefined number of amino acids; Derivatives thereof

Abstract

The present invention relates to pyrroloquinolinyl-pyrrole-2,5-dione compounds and pyrroloquinolinyl-pyrrolidine-2,5-dione compounds, and methods of preparation of these compounds. The present invention also relates to pharmaceutical compositions comprising pyrroloquinolinyl-pyrrole-2,5-dione compounds and pyrroloquinolinyl-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 pyrroloquinolinyl-pyrrole-2,5-dione compound or pyrroloquinolinyl-pyrrolidine-2,5-dione compound of the present invention.

Claims

1. A pyrroloquinolinyl-pyrrolidine-2,5-dione compound of formula IVa, IVb, Va, or Vb, or pharmaceutically acceptable salts thereof:

where;

R1, R2 and R3 are independently selected from the group consisting of hydrogen, F, Cl, Br, I, —

NR5R6, —

(C₁-C₆) alkyl, —

(C₁-C₆) substituted alkyl, —

(C₃-C₉) cycloalkyl, —

(C₃-C₉) substituted cycloalkyl, —

O—

(C₁-C₆) alkyl, —

O—

(C₁-C₆) substituted alkyl, —

O—

(C₃-C₉) cycloalkyl, and —

O—

(C₃-C₉) substituted cycloalkyl, aryl, heteroaryl, heterocyclyl;

R4 is independently selected from the group consisting of hydrogen, —

(C₁-C₆) alkyl, —

CH₂R7;

R5, R6 are independently selected from the group consisting of hydrogen, and —

(C₁-C₆) alkyl;

R7 is independently 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;

Q is selected from the group consisting of aryl, heteroaryl, —

O-aryl, —

S-aryl, —

O-heteroaryl, and —

S-heteroaryl;

X is —

(NR8)-;

R8 is independently selected from the group consisting of hydrogen, —

(C₁-C₆) alkyl, —

(C₁-C₆) substituted alkyl, —

(C₃-C₉) cycloalkyl, —

(C₃-C₉) substituted cycloalkyl, and —

O—

(C₁-C₆) alkyl, —

C(═

O)—

O—

(C₁-C₆) alkyl and —

C(═

O)—

O—

(C₁-C₆) substituted alkyl;

Y is (CH₂)—

;

wherein said aryl, heteroaryl, —

O-aryl, —

S-aryl, —

O-heteroaryl, and —

S-heteroaryl groups may be substituted with one or more substituents independently selected from the group consisting of F, Cl, Br, I, —

NR5R6, —

(C₁-C₆) alkyl, —

(C₁-C₆) substituted alkyl, —

(C₃-C₉) cycloalkyl, —

(C₃-C₉) substituted cycloalkyl, —

O—

(C₁-C₆) alkyl, —

O—

(C₁-C₆) substituted alkyl, —

O—

(C₃-C₉) cycloalkyl, —

O—

(C₃-C₉) substituted cycloalkyl, -aryl, -aryl-(C₁-C₆) alkyl, -aryl-O—

(C₁-C₆) alkyl, —

O-aryl, —

O—

(C₁-C₄) alkyl-aryl, heteroaryl, heterocyclyl, —

O—

(C₁-C₄) alkyl-heterocycle, and —

(S(═

O)₂)—

(C₁-C₆) alkyl; and

m is 1.

2. The compound of claim 1, where 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 R4 is —

CH₂R7, and R7 is —

O—

P(═

O)(—

OH)₂, —

O—

P(═

O)(—

OH)(—

O—

(C₁-C₆) alkyl), —

O—

P(═

O)(—

O—

(C₁-C₆) alkyl)₂, a carboxylic acid group, an amino carboxylic acid group or a peptide.

4. The compound of claim 3, wherein R7 is —

O—

P(═

O)(OH)₂, —

O—

P(═

O)(—

OH)(—

O—

(C₁-C₆) alkyl), or —

O—

P(═

O)(—

O—

(C₁-C₆) alkyl)₂.

5. The compound of claim 3, wherein R7 is a carboxylic acid group, an amino carboxylic acid group or a peptide.

6. The compound of claim 5, where R7 is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

7. The compound of claim 6, where R7 is L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L histidine, L-isoleucine, L-leucine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, or L-valine.

8. The compound of claim 5, where R7 is a peptide.

9. The compound of claim 8, wherein said peptide is comprised of two or more imino or amino acids selected from the group consisting of:

L-alanine, L-arginine, L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid, L-glycine, L histidine, L-isoleucine, L-leucine, L-methionine, L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, and L-valine.

11. The compound of claim 1, where m is 2.

14. A pharmaceutical composition comprising a compound of formula IVa, IVb, Va, or Vb 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 14 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 IVa, IVb, Va, or Vb 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 IVa, IVb, Va, or Vb, 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, imatinib, paclitaxel, cyclophosphamide, lovastatin, mimosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vinctristine, vinblastine, nocodazole, teniposide, etoposide, gemcitabine, epothilone, navelbine, camptothecin, daunorubicin, 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 compound is selected from the group consisting of (+)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione, (−

)-cis-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione, (+)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione, and (−

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

33. The method of claim 18 wherein the compound is (−

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

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

35. The method of claim 34 wherein the cells have a constitutively enhanced c-Met activity.

10. (canceled)

12-13. -13. (canceled)

15. (canceled)

17. The pharmaceutical composition of 16, wherein said second chemotherapeutic agent is selected from the group consisting of tamoxifen, raloxifene, anastrozole, exemestane, letrozole, trastuzumab, imatinib, paclitaxel, cyclophosphamide, lovastatin, mimosine, gemcitabine, araC, 5-fluorouracil, methotrexate, docetaxel, goserelin, vinctristine, vinblastine, nocodazole, teniposide, etoposide, gemcitabine, epothilone, navelbine, camptothecin, daunorubicin, dactinomycin, mitoxantrone, amsacrine, doxorubicin, epirubicin or idarubicin.