HETEROCYCLIC COMPOUNDS AS AUTOTAXIN INHIBITORS

• US 20120015959A1
• Filed: 03/03/2010
• Published: 01/19/2012
• Est. Priority Date: 04/02/2009
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Staehle, Wolfgang, Schiemann, Kai, Schultz, Melanie
• Granted Patent: US 8,841,324 B2
• Time in Patent Office: Days
• US Class Current: 514/254.02
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 209/08 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
• CPC Class Codes: C07D 231/56 Benzopyrazoles; Hydrogenated benzopyrazoles
• CPC Class Codes: C07D 249/18 Benzotriazoles
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links

Abstract

Compounds of the formula (I), in which Het, R, X, Y, R¹ and p have the meanings indicated in claim 1, are autotaxin inhibitors and can be employed for the treatment of tumours.

Claims

1. Compounds of the formula I

2. Compounds according to claim 1 in which

R¹ denotes Hal,

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

3. Compounds according to claim 1 in which

X denotes O or CH₂,

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

4. Compounds according to claim 1 in which

Y denotes CH₂ or CH₂O,

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

5. Compounds according to claim 1 in which

A denotes unbranched or branched alkyl having 1-10 C atoms, in which 1-7 H atoms may be replaced F and/or Cl,

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

6. Compounds according to claim 1 in which

p denotes 1, 2 or 3,

and pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios.

7. Compounds according to claim 1 in which

R¹ denotes Hal,

X denotes O or CH₂,

Y denotes CH₂ or CH₂O,

R denotes

8. Compounds according to claim 1 selected from the group

9. Process for the preparation of compounds of the formula I according to claim 1 and pharmaceutically usable salts and stereoisomers thereof, characterised in that

a) for the preparation of compounds of the formula I in which

R denotes

10. A pharmaceutical composition comprising at least one compound of the formula I according to claim 1 and/or pharmaceutically usable salts and stereoisomers thereof, including mixtures thereof in all ratios, and optionally excipients and/or adjuvants.

11. A method for the treatment of cancer diseases comprising administering to a patient a therapeutically effective amount of a compound accord to claim 1.

12. The method according to claim 11, where the cancer diseases are associated with a tumour from the group of tumours of the squamous epithelium, of the bladder, of the stomach, of the kidneys, of head and neck, of the oesophagus, of the cervix, of the thyroid, of the intestine, of the liver, of the brain, of the prostate, of the urogenital tract, of the lymphatic system, of the stomach, of the larynx and/or of the lung.

13. The method according to claim 12, where the tumour originates from the group monocytic leukaemia, lung adenocarcinoma, small-cell lung carcinomas, pancreatic cancer, ovarian carcinoma, glioblastomas and breast carcinoma and colon carcinoma.

14. The method according to claim 13, where the disease to be treated is a tumour of the blood and immune system.

15. The method according to claim 14, where the tumour originates from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

16. A method for the treatment of tumours comprising administering to a patient a therapeutically effective amount of a compound according to claim 1 in combination with radiotherapy and a compound from the group 1) oestrogen receptor modulator, 2) androgen receptor modulator, 3) retinoid receptor modulator, 4) cytotoxic agent, 5) antiproliferative agent, 6) prenyl-protein transferase inhibitor, 7) HMG-CoA reductase inhibitor, 8) HIV protease inhibitor, 9) reverse transcriptase inhibitor and 10) other angiogenesis inhibitors.