BENZONAPHTHYRIDINAMINES AS AUTOTAXIN INHIBITORS

• US 20130012505A1
• Filed: 02/28/2011
• Published: 01/10/2013
• Est. Priority Date: 03/26/2010
• Status: Active Grant

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Staehle, Wolfgang, Schultz, Melanie, Schiemann, Kai
• Granted Patent: US 9,029,387 B2
• Time in Patent Office: Days
• US Class Current: 514/232.8
• 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. Compounds of the formula (I)

2. Compounds according to claim 1 in which

D denotes Ar,

Ar denotes unsubstituted or mono- or polysubstituted phenyl, but preferably denotes mono- or polysubstituted phenyl,

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

CH₂—

, —

C(O)—

or —

CH₂OC(O)—

, X is preferably=—

C(O)— and

Y is preferably=—

CH₂—

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

3. Compounds according to claim 1, selected from the group consisting of:

4. Process for the preparation of compounds of the formula (I) according to claim 1 and pharmaceutically usable salts, solvates and stereoisomers thereof, characterised in that a compound of the 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 and 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 the 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 cancer, tumours, malignant tumours, benign tumours, solid tumours, sarcomas, carcinomas, hyperproliferative diseases, carcinoids, Ewing'"'"'s sarcomas, Kaposi'"'"'s sarcomas, brain tumours, tumours originating from the brain and/or nervous system and/or meninges, gliomas, glioblastomas, neuroblastomas, stomach cancer, kidney cancer, kidney cell carcinomas, prostate cancer, prostate carcinomas, connective tissue tumours, soft tissue sarcomas, pancreas tumours, liver tumours, head tumours, neck tumours, laryngeal cancer, oesophageal cancer, thyroid cancer, osteosarcomas, retinoblastomas, thymus gland cancer, testicular cancer, lung cancer, lung adenocarcinomas, small-cell lung carcinomas, bronchial carcinomas, breast cancer, mammacarcinomas, intestinal cancer, colorectal tumours, colon carcinomas, rectal carcinomas, gynaecological tumours, ovarian tumours, uterine cancer, cervical cancer, cervical carcinomas, corpus carcinomas, endometrial carcinomas, urinary bladder cancer, urogenital tract cancer, bladder cancer, skin cancer, epithelial tumours, squamous epithelial carcinomas, basaliomas, spinaliomas, melanomas, intraocular melanomas, leukaemias, monocytic leukaemias, chronic leukaemias, chronic myeloid leukaemias, chronic lymphatic leukaemias, acute leukaemias, acute myeloid leukaemias, acute lymphatic leukaemias, lymphomas, angiogenesis, arteriosclerosis, atherosclerosis, eye diseases, uveititis, choroidal neovascularisation, diabetic retinopathy, autoimmune diseases, inflammatory diseases, asthma, chronic obstructive pulmonary disease (COPD), chronic inflammatory bowel disease (IBD), arthritis, osteoporosis, osteoarthritis, gout, gouty arthritis, rheumatoid spondylitis, allergic rhinitis, psoriasis, neurodegenerative diseases, restenosis, wound healing, transplant rejection, autoimmune enteropathy, autoimmune hepatitis, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy syndrome type I (APECED), bullous pemphigoid, chronic gastritis, Churg-Strauss syndrome, colitis ulcerosa, dermatomyositis, type 1 diabetes mellitus, dermatitis herpetiformis Duhring, epidermolysis bullosa acquisita, glomerulonephritis, Goodpasture'"'"'s syndrome, Guillain-Barré

syndrome, Hashimoto'"'"'s thyreoiditis, lichen sclerosus, linear IgA dermatosis, lupus erythematodes, microscopic polyangiitis, Adamantiades-Behç

et disease, Basedow'"'"'s disease, Bechterew'"'"'s dissease, Crohn'"'"'s dissease, multiple sclerosis, myasthenia gravis, PANDAS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections), pelvic inflammatory disease (PID), pemphigus foliaceus, pemphigus seborrhoicus, pemphigus vulgaris, polychondritis, polymyositis, rheumatic fever, rheumatoid arthritis, SAPHO syndrome, sarcoidosis (Boeck'"'"'s disease), Sjö

gren'"'"'s syndrome, dematosclerosis, stiff person syndrome, sympathetic ophthalmia, systemic lupus erythematodes, vasculitis allergica, vitiligo, Wegener'"'"'s granulomatosis and/or celiac disease, said method comprising administering an effective amount of a compound 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.

13. 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.

14. Intermediate compound of the formula (V)

11. (canceled)

12. (canceled)