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Metalloprotease inhibitors containing a heterocyclic moiety

a heterocyclic moiety and metaloprotease technology, applied in the field of new heterocyclic moiety containing pharmaceutical agents, can solve the problems of effective mmp inhibiting compounds, and achieve the effect of treating or preventing metalloprotease—especially

Inactive Publication Date: 2008-09-11
ALANTOS PHARMA HLDG INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The heterocyclic 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, glaucoma, 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, burn 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, chronic periodontitis, periodontitis, peritonitis associated with continous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hy...

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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  • Metalloprotease inhibitors containing a heterocyclic moiety
  • Metalloprotease inhibitors containing a heterocyclic moiety
  • Metalloprotease inhibitors containing a heterocyclic moiety

Examples

Experimental program
Comparison scheme
Effect test

example 2

Preparative Example 2

Step A

5-Amino-3-phenylisoxazole (995 mg) was suspended in dry pyridine (20 mL) and ethyloxalyl chloride (830 μL) was added under ice cooling. The ice bath was removed and the mixture was stirred for 2 d at room temperature and evaporated. The residue was diluted with ethyl acetate and subsequently washed with 10% aqueous citric acid and brine, dried and concentrated. The residue was recrystallized from ethyl acetate / cyclohexane to give the title compound (969 mg, 60%) as colourless needles. [MH]+=261.

Step B

The title compound from Step A above (548 mg) and PtO2 (115 mg) were suspended in EtOH (20 mL) and hydrogenated at atmospheric pressure for 2 h at 50° C., filtered over celite and refluxed for further 2 h, evaporated and purified by flash chromatography (cyclohexane / ethyl acetate 6:4 to 4:6) to afford the title compound as a colourless solid. [MH]+=245.

Step C

To a solution of the title compound from Step B above (105 mg) in THF (20 mL) was added 1M aqueous LiOH...

examples 3a to 3b

Preparative Examples 3a to 3b

Following a similar procedure as described in the Preparative Example 3, except using the aminoalcohols indicated in Table I.3 below, the following compounds were prepared.

TABLE I.3Prep. Ex. #aminealcoholproductyield3an.d.[MH]+ = 246 / 483b19%[MH]+ = 246 / 48

Preparative Example 4

Step A

A suspension of the title compound from the Preparative Example 3, Step B (567 mg) and CuCN (230 mg) in dry N-methyl-pyrrolidin-2-one (15 mL) was degassed under Argon and heated under microwave irradiation to 200° C. for 2 h. The mixture was concentrated, diluted with 1N HCl (100 mL) and extracted with EtOAc (200 mL). The organic layers were washed with H2O (2×200 mL) and brine (200 mL), dried (MgSO4), filtered, absorbed on silica and purified by flash chromatography (cyclohexane / ethyl acetate 7:3 to 6:5) to give the title compound as a colourless solid. [MH]+=211.

Step B

To an ice cooled solution of the title compound from Step A above in dry MeOH (20 mL) were added di-tert-buty...

examples 4a to 4d

Preparative Examples 4a to 4d

Following a similar procedure as described in the Preparative Example 4, Step A except using the educt indicated in Table I.4 below, the following compounds were prepared.

TABLE I.4Prep. Ex. #eductproductyield4an.d.[MH]+= 1934b93%[MH]+ = 1934cn.d.[MH]+ = 1934d55%[MH]+ = 211

Preparative Examples 5a to 5f

Following a similar procedure as described in the Preparative Example 4, Step B except using the educt indicated in Table I.5 below, the following compounds were prepared.

TABLE I.5Prep. Ex. #eductproductyield5a32% (3 steps)[MNa]+ = 3195b56%[MNa]+ = 3195c28% (2 steps)[MNa]+ = 3195dn.d.[MNa]+ = 3255e58%[MNa]+ = 3015f64%[MNa]+ = 337

Preparative Examples 6a to 6h

Following a similar procedure as described in the Preparative Example 4, Step C except using the educt indicated in Table I.6 below, the following compounds were prepared.

TABLE I.6Prep. Ex. #eductproductyield6aquant.[M − Cl]+ = 1976bquant.[M − Cl]+ = 1956cquant.[M − Cl]+ = 1976dquant.[M − Cl]+ = 1976e66% ...

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PUM

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Abstract

The present invention relates generally to pharmaceutical agents containing a heterocyclic moiety, and in particular, to heterocyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of heterocyclic MMP-3, MMP-8 and / or MMP-13 inhibiting compounds with a squaramide or benzoxazinone moiety, that exhibit an increased potency and selectivity in relation to currently known MMP-13, MMP-8 and MMP-3 inhibitors.

Description

FIELD OF THE INVENTIONThe present invention relates to a new class of heterocyclic moiety containing pharmaceutical agents which inhibits metalloproteases. In particular, the present invention provides a new class of metalloprotease inhibiting compounds containing a benzoxazinone moiety that exhibit potent inhibiting activity towards metalloproteases, in particular towards MMP-13, MMP-3, MMP-8, and more particulary towards MMP-13.BACKGROUND OF THE INVENTIONMatrix 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 development, reproduction, and tissue remodelling. Over-expression of MMPs and aggrecanases or an imbalance between extracellular matrix synthesis and degradation has been suggested as factors in inflammatory, malignant and degenera...

Claims

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Application Information

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IPC IPC(8): A61K31/538C07D239/36A61K31/513A61P19/02C07D413/12
CPCC07D487/02C07D519/00C07D498/02A61P1/02A61P1/04A61P1/16A61P1/18A61P11/00A61P11/02A61P11/06A61P11/14A61P13/00A61P13/02A61P13/12A61P15/00A61P15/06A61P17/00A61P17/02A61P17/04A61P17/06A61P17/10A61P17/16A61P19/00A61P19/02A61P19/06A61P19/08A61P19/10A61P21/00A61P25/00A61P25/04A61P25/16A61P25/18A61P25/28A61P27/02A61P27/06A61P27/16A61P29/00A61P29/02A61P3/10A61P31/04A61P31/12A61P31/18A61P33/06A61P35/00A61P35/04A61P37/06A61P37/08A61P39/06A61P43/00A61P7/00A61P7/02A61P9/00A61P9/10A61P9/12A61P9/14
Inventor GEGE, CHRISTIANCHEVRIER, CARINEGALLAGHER, BRIAN M.TAVERAS, ARTHUR
Owner ALANTOS PHARMA HLDG INC
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