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Heterobicyclic metalloprotease inhibitors

a metalloprotease inhibitor and heterobicyclic technology, applied in the field of amide containing heterobicyclic metalloprotease inhibiting compounds, can solve the problems of effective mmp inhibiting compounds, and achieve the effect of treating or preventing metalloprotease, especially

Inactive Publication Date: 2007-07-05
ALANTOS PHARMA HLDG INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0014] The heterobicyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases, such as rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson's disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, chronic wound healing, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, bum therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi's sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, periodontitis, chronic periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion inju

Problems solved by technology

The difficulty in developing effective MMP inhibiting compounds comprises several factors, including choice of selective versus broad-spectrum MMP inhibitors and rendering such compounds bioavailable via an oral route of administration.

Method used

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  • Heterobicyclic metalloprotease inhibitors
  • Heterobicyclic metalloprotease inhibitors
  • Heterobicyclic metalloprotease inhibitors

Examples

Experimental program
Comparison scheme
Effect test

example 8

Preparative Example 8

[0579]

Step A

[0580] To a solution of the title compound from the Preparative Example 3, Step E (153 mg) in EtOH (10 mL) were added NEt3 (0.16 mL) and hydroxylamine hydrochloride (81 mg). The mixture was heated to reflux for 4 h, then concentrated, dissolved in THF (5 mL) and pyridine (0.19 mL) and cooled to 0° C. Trifluoroacetic anhydride (0.25 mL) was added and the mixture was stirred for 16 h. Concentration and purification by chromatography (silica, hexanes / EtOAc) afforded the title compound as a white solid (217 mg, >99%). [MNa]+=392.

example 9

Preparative Example 9

[0581]

Step A

[0582] To a solution of the title compound from the Preparative Example 4, Step A (33.7 mg) in 1,4-dioxane / H2O (1:1, 2 mL) were added NaOH (97.4 mg) and di-tert-butyl dicarbonate (68.7 mg). The resulting mixture was stirred at room temperature overnight, diluted with EtOAc, washed with IN aqueous HCl and saturated aqueous NaCl, dried (MgSO4), and concentrated to give a white solid (34.6 mg, 71%). [MNa]+=300.

Step B

[0583] To a solution of the title compound from Step A above (34.6 mg) in CH2Cl2 (1 mL) were added oxalyl chloride (33 μL) and DMF (2 μL). The mixture was stirred at room temperature for 2 h and concentrated. The remaining residue was dissolved in CH2Cl2 (1 mL) and added to a cold (−78° C.) saturated solution of NH3 in CH2Cl2 (1 mL). The mixture was stirred at −78° C. for 1 h, warmed to room temperature, concentrated, redissolved in CH2Cl2 (5 mL), filtered, and concentrated to give a white solid (25.9 mg, 75%). [MNa]+=299.

example 10

Preparative Example 10

[0584]

Step A

[0585] To mixture of the title compound from the Preparative Example 7, Step B (536 mg) and allyl bromide (1.6 mL) in CHCl3 / THF (1:1, 20 mL) were added Bu4NHSO4 (70 mg) and a 1M solution of LiOH in H2O (10 mL) and the resulting biphasic mixture was stirred at 40° C. overnight. The organic phase was separated, concentrated, diluted with CHCl3, washed with H2O, dried (MgSO4), filtered, concentrated and purified by chromatography (silica, cyclohexane / EtOAc) to afford the title compound (610 mg, >99%). [MNa]+=354.

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Abstract

The present invention relates generally to amide group containing pharmaceutical agents, and in particular, to amide containing heterobicyclic metalloprotease inhibitor compounds. More particularly, the present invention provides a new class of heterobicyclic MMP-13 inhibiting and MMP-3 inhibiting compounds, that exhibit an increased potency in relation to currently known MMP-13 and MMP-3 inhibitors.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a continuation in part of U.S. application Ser. No. 11 / 440,087, filed May 22, 2006, which claims the benefit of U.S. Provisional Application No. 60 / 734,991, filed Nov. 9, 2005, U.S. Provisional Application No. 60 / 706,465, filed Aug. 8, 2005, and U.S. Provisional Application No. 60 / 683,470, filed May 20, 2005, the contents of each of which are hereby incorporated by reference.FIELD OF THE INVENTION [0002] The present invention relates generally to amide containing heterobicyclic metalloprotease inhibiting compounds, and more particularly to heterobicyclic MMP-13 inhibiting compounds. BACKGROUND OF THE INVENTION [0003] Matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS=a disintegrin and metalloproteinase with thrombospondin motif) are a family of structurally related zinc-containing enzymes that have been reported to mediate the breakdown of connective tissue in normal physiological processes such as embryonic d...

Claims

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Application Information

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IPC IPC(8): A61K31/538A61K31/5377A61K31/519C07D491/04C07D487/04
CPCC07D487/04A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/06A61P11/14A61P13/02A61P13/12A61P15/06A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P19/02A61P19/06A61P19/10A61P21/00A61P25/00A61P25/02A61P25/08A61P25/14A61P25/16A61P25/18A61P25/28A61P27/02A61P27/16A61P29/00A61P3/02A61P31/04A61P31/12A61P31/18A61P31/22A61P33/06A61P35/00A61P37/06A61P37/08A61P39/02A61P43/00A61P7/00A61P7/02A61P9/00A61P9/04A61P9/08A61P9/10A61P9/12A61P9/14A61P3/10
Inventor STEENECK, CHRISTOPHGEGE, CHRISTIANRICHTER, FRANKKROTH, HEIKOHOCHGUERTEL, MATTHIASESSERS, MICHAELVAN VELDHUIZEN, JOSHUANOLTE, BERTGALLAGHER, BRIANFEUERSTEIN, TIMSCHNEIDER, MATTHIASARNDT, TORSTENDENG, HONGBOBIESINGER, RALFWU, XINYUANBLUHM, HARALDSUCHOLEIKI, IRVINGTAVERAS, ARTHUR
Owner ALANTOS PHARMA HLDG INC
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