BENZONAPHTYRIDINE COMPOUNDS AS INHIBITORS OF AUTOTAXIN

• US 20110230471A1
• Filed: 11/05/2009
• Published: 09/22/2011
• Est. Priority Date: 11/28/2008
• Status: Abandoned Application

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Schiemann, Kai, Schultz, Melanie, Kober, Ingo, Wienke, Dirk, Staehle, Wolfgang
• Application Number:
  US13/131,696
• Publication Number:
  US 20110230471A1
• Time in Patent Office: Days
• US Class Current: 514/218
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/10 of the bladder
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems

Abstract

Compounds of the formula (I), in which R¹, R², R³, R⁴, R⁵, D, Z, X, Y, m and p have the meanings indicated in Claim 1, can and be employed for the treatment of tumours.

Claims

1. Compounds of the formula I

2. Compounds according to claim 1 in which

denotes H, Hal, CN, phenyl, OA or OH,

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

3. Compounds according to claim 1 in which

R⁴ denotes H, Hal, A, OA or OH,

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

4. Compounds according to claim 1 in which

R⁵H

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

5. Compounds according to claim 1 in which

R², R³ together denotes morpholinyl, piperazinyl, 1-methylpiperazinyl, 1-ethyl-4-methylpiperazinyl, 2-(4-methylpiperazin-1-yl)ethyl, 1-methyl-4-propylpiperazinyl, 1-cyclopentyl-4-methylpiperazinyl, 1-benzyl-4-methyl-1,4-diazepanyl or 1-benzyl-4-methylpiperazinyl,

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

6. Compounds according to claim 1 in which

Het¹ particularly preferably denotes piperazyl, morpholinyl, piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, benzotriazylyl, benzofuranyl, 2,3-dihydrobenzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl, each of which is unsubstituted or mono-, di- or trisubstituted by A and/or (CH₂)_nAr.

7. Compounds according to claim 1 in which

Het² particularly preferably denotes pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, each of which is unsubstituted or mono- or di substituted by Hal, OH, OA, A and/or ═

O.

8. Compounds according to claim 1 in which

R¹ denotes H, Hal, CN, phenyl, OA or OH;

R⁴ denotes H, Hal, A, OA or OH;

R⁵ denotes H and

R², R³ together denote morpholinyl, piperazinyl, 1-methylpiperazinyl, 1-ethyl-4-methylpiperazinyl, 2-(4-methylpiperazin-1-yl)ethyl, 1-methyl-4-propylpiperazinyl, 1-cyclopentyl-4-methylpiperazinyl, 1-benzyl-4-methyl-1,4-diazepanyl or 1-benzyl-4-methylpiperazinyl,

Het¹ particularly preferably denotes piperazyl, morpholinyl, piperidinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrimidinyl, triazolyl, benzotriazylyl, benzofuranyl, 2,3-dihydrobenzoxazolyl, benzoxazolyl, dihydrobenzofuranyl or tetrazolyl, each of which is unsubstituted or mono-, di- or trisubstituted by A and/or (CH₂)_nAr,

Het² particularly preferably denotes pyrrolidinyl, morpholinyl, piperidinyl or piperazinyl, each of which is unsubstituted or mono- or disubstituted by Hal, OH, OA, A and/or ═

O,

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

9. Compounds according to claim 1 selected from the group

10. Process for the preparation of compounds of the formula I and pharmaceutically usable salts, and stereoisomers thereof, characterised in that a compound of the formula II

11. Medicaments 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.

12. A method for the treatment of diseases in which the inhibition, regulation and/or modulation of phosphodiesterase or lysophospholipase autotaxin plays a role, comprising administering to a patient an effective amount of a compound according to claim 1.

13. A method for the treatment and prophylaxis of cancer diseases, comprising administering to a patient an effective amount of a compound according to claim 1.

14. A method according to claim 13, 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.

15. A method according to claim 14, 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.

16. A method according to claim 15, where the disease to be treated is a tumour of the blood and immune system.

17. A method according to claim 16, where the tumour originates from the group of acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphatic leukaemia and/or chronic lymphatic leukaemia.

18. A method for the treatment of tumours where a therapeutically effective amount of a compound according to claim 1 is administered 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.