Benzonaphthyridinamines as autotaxin inhibitors

• US 9,029,387 B2
• Filed: 02/28/2011
• Issued: 05/12/2015
• Est. Priority Date: 03/26/2010
• Status: Expired due to Fees

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Staehle, Wolfgang, Schultz, Melanie, Schiemann, Kai
• Primary Examiner(s): JEAN-LOUIS, SAMIRA JM
• Application Number:
  US13/637,161
• Publication Number:
  US 20130012505A1
• Time in Patent Office: 1,534 Days
• Field of Search: 514/292, 514/253.03, 514/232.08, 546/81, 544/361, 544/236
• US Class Current: 514/292
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• 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 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems

Abstract

The present invention relates to benzonaphthyridinamines of the formula (I) as autotaxin inhibitors and to the use thereof in the treatment and/or prophylaxis of physiological and/or pathophysiological conditions in which the inhibition, regulation and/or modulation of phosphodiesterase or lysophospholipase autotaxin plays a role, in particular of various types of cancer and autoimmune and inflammatory diseases.

Claims

1. A compound of formula (I)

2. A compound according to claim 1 in which

D denotes Ar,

Ar denotes unsubstituted or mono- or polysubstituted phenyl,

X, Y each, independently of one another, denote —

CH₂—

, —

C(O)—

or —

CH₂OC(O)—

,

R¹ in each case, independently of one another, denote F, Cl, OA or OCH₃,

R², R³ each, independently of one another, denote H, Ar, Ar monosubstituted by OA, Het, Het monosubstituted by A, CH₂-Het, A, A monosubstituted by OH or by NRR or by CO—

NRR or by Het or by CO—

R, or each, independently of one another, denote 1-methylpiperidin-4-yl, 2-hydroxyethyl, 2-dimethylaminoethyl, methylcarbamoylmethyl, dimethylcarbamoylmethyl, 1H-benzimidazol-2-ylmethyl, 2-oxo-2-pyrrolidin-1-yl-ethyl, 2-oxo-2-piperidin-1-ylethyl, 2-morpholin-4-yl-2-oxoethyl, cyclohexylcarbamoylmethyl, 2-(4-methylpiperazin-1-yl)-2-oxo-ethyl, 2-(4-isopropylpiperazin-1-yl)-2-oxoethyl, diethylcarbamoylmethyl, 2-(4-benzylpiperazin-1-yl)-2-oxoethyl, 3-oxo-3-piperidin-1-ylpropyl, pyridin-4-yl, pyridin-3-yl, phenyl, pyridin-2-yl or 4-methoxyphenyl, where R² and R³ may alternatively together also form 4-(2-hydroxyethyl)-piperazin-1-yl,

m denotes 2,

n denotes 0,

p denotes 0,

q denotes 0 or 1,

Het, R, R⁶, A and Cyc have the meanings indicated in claim 1,

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

3. A compound according claim 1,

4. A process for preparation of compounds of the formula (I) according to claim 1 or pharmaceutically usable salts, solvates or stereoisomers thereof, comprising reacting a compound of formula (II)

5. A method of inhibiting an autotaxin comprising inhibiting said autotaxin with a compound according to claim 1.

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

7. A method for treating physiological and/or pathophysiological conditions in which inhibition, regulation and/or modulation of phosphodiesterase or lysophospholipase autotaxin plays a role, comprising administering an effective amount of a compound according to claim 1.

8. A method for treating glioblastomas, neuroblastomas, kidney cell carcinomas, prostate carcinomas, thyroid cancer, lung cancer, breast cancer, lymphomas or angiogenesis, mediated by autotaxin, said method comprising administering an effective amount of a compound according to claim according to claim 1.

9. A pharmaceutical composition according to claim 6, further comprising at least one additional pharmacologically active substance.

10. A method according to claim 7, wherein said compound is administered before and/or during and/or after the treatment with at least one additional pharmacologically active substance.

11. A kit comprising a therapeutically effective amount of at least one compound according to claim 1 and a therapeutically effective amount of at least one additional pharmacologically active substance which does not correspond to a compound according to claim 1.