Compositions and methods for treatment of cancer

• US 7,713,969 B2
• Filed: 02/09/2006
• Issued: 05/11/2010
• Est. Priority Date: 02/09/2005
• Status: Active Grant

• Current Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Original Assignee: ArQule, Inc. (Merck & Co., Inc.)
• Inventors: Hill, Jason, Ashwell, Mark A., Li, Chiang J., Moussa, Magdi M., Munshi, Neru
• Primary Examiner(s): COLEMAN, BRENDA LIBBY
• Application Number:
  US11/350,335
• Publication Number:
  US 20060223760A1
• Time in Patent Office: 1,552 Days
• Field of Search: 514/233.2, 514/294, 544/126, 546/94
• US Class Current: 514/233.2
• 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 compound 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.

2. A compound:

(−

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

3. A pharmaceutical composition comprising a compound 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 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carriers or excipients.

4. A pharmaceutical composition comprising the compound (−

)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl) pyrrolidine-2,5-dione together with one or more pharmaceutically acceptable carriers or excipients.

5. A method of treating a cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound formula 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, in combination with a pharmaceutically acceptable carrier, wherein said cancer is treated, wherein said cancer is lung cancer, colon cancer, breast cancer, pancreatic cancer, prostate cancer, chronic myelogenous leukemia, melanoma, or ovarian cancer.

6. The method of claim 5, wherein said cancer is breast cancer.

7. The method of claim 6, wherein said breast cancer is an estrogen-receptor negative breast cancer.

8. The method of claim 5, wherein said treating cancer comprises a reduction in tumor size.

9. The method of claim 5, wherein the cancer is metastatic cancer.

10. The method of claim 9, wherein said treating cancer comprises inhibition of metastatic cancer cell invasion.

11. The method of claim 5 wherein the cancer contains DNA encoding c-Met.

12. The method of claim 11 wherein the cancer has a constitutively enhanced c-Met activity.

13. A method of treating a cancer, said method comprising administering to a subject in need thereof a therapeutically effective amount of a compound having a formula 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, in combination with a pharmaceutically acceptable carrier, wherein said cancer is treated, wherein said cancer is renal carcinoma, hepatoma, brain cancer, or multiple myeloma.