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Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators

a technology of gamma secretase and heterocyclic compounds, which is applied in the direction of heterocyclic compound active ingredients, drug compositions, biocides, etc., can solve the problems of low cns penetration, unwanted side effects, and no effective treatment of ad

Inactive Publication Date: 2015-04-02
CELLZOME LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The compounds effectively modulate gamma-secretase activity in vitro and in vivo, providing a potential therapeutic approach for Alzheimer's disease and other beta-amyloid related disorders with enhanced CNS penetration and reduced side effects.

Problems solved by technology

There is currently no effective treatment for AD.
AD does not have a simple etiology, however, it has been associated with certain risk factors including (1) age, (2) family history and (3) head trauma; other factors include environmental toxins and low levels of education.
Potential limitations for the use of NSAIDs to prevent or treat AD are their inhibition activity of COX enzymes, which can lead to unwanted side effects, and their low CNS penetration (Peretto et al., 2005, J. Med. Chem. 48, 5705-5720).

Method used

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  • Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators
  • Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators
  • Novel substituted bicyclic heterocyclic compounds as gamma secretase modulators

Examples

Experimental program
Comparison scheme
Effect test

examples

[0435]Hereinafter, the term “DCM” means dichloromethane; “MeOH” means methanol; “LCMS” means Liquid Chromatography / Mass spectrometry; “aq.” means aqueous; “sat.” means saturated; “sol.” means solution; “HPLC” means high-performance liquid chromatography; “r.t.” means room temperature; “AcOH” means acetic acid; “m.p.” means melting point; “Et2O” means diethyl ether; “BDS” means base deactivated silica; “RP” means reversed phase; “min” means minute(s); “h” means hour(s); “I.D.” means internal diameter; “Pd(OAc)2” means palladium(II) acetate; “LiHMDS” means lithium hexamethyldisilazane; “HBTU” means 1-[bis(dimethylamino)methylene]-1H-benzotriazol-1-ium 3-oxide hexafluorophosphate; “Xantphos” means (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine]; “X-Phos” means dicyclohexyl[2′,4′,6′-tris(1-methylethyl)[1,1′-biphenyl]-2-yl]-phosphine; “NH4OAc” means ammonium acetate; “NMP” means 1-methyl-2-pyrrolidinone; “SFC” means Supercritical Fluid Chromatography; “iPrNH2” means isopropylam...

example a1

a) Preparation of Intermediate 1

[0436]

[0437]K2CO3 (9.6 g, 69.5 mmol) and 1-methyl-1-tosylmethylisocyanide (8 g, 38.2 mmol) were added to a sol. of 2-formyl-5-nitroanisole (6.29 g, 34.7 mmol) in MeOH (150 ml) and the r.m. was refluxed for 4 h. The r.m. was concentrated under reduced pressure, the residue was dissolved in DCM and the organic phase was washed with H2O, dried (MgSO4), filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography over Silica gel (eluent: n-heptane / EtOAc from 100 / 0 to 50 / 50). The product fractions were collected and the solvent was evaporated. Yield: 6.24 g of intermediate 1 (77%).

b) Preparation of Intermediate 2

[0438]

[0439]MeOH (150 ml) was added to Pd / C 10% (1 g) under a N2 atmosphere. Subsequently, a 0.4% thiophene sol. in DIPE (1 ml) and intermediate 1 (6.24 g, 26.6 mmol) were added. The r.m. was stirred at 25° C. under a H2 atmosphere until 3 eq of H2 was absorbed. The catalyst was filtered off over diatomaceous e...

example a2

a) Preparation of Intermediate 3

[0440]

[0441]Iodobenzene diacetate (5.49 g, 18.44 mmol) and trifluoromethanesulfonic acid (6.08 ml, 69.17 mmol) were stirred in CH3CN (100 ml) at r.t. for 1 h under N2. 2′-Methoxy-4′-nitro-acetophenone (3.0 g, 15.37 mmol) was added at once at r.t. to the sol. and the r.m. was then refluxed for 2 h, then cooled to r.t. and carefully added to a stirred sat. aq. sol. of Na2CO3 (500 ml). The product was extracted with DCM and the organic phase was dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting dark brown oil was purified by flash column chromatography over Silica gel (eluent: DCM / MeOH isocratic 95 / 5). The product fractions were collected and the solvent was evaporated under reduced pressure. Yield: 3.0 g of intermediate 3 (75%).

b) Preparation of Intermediate 4

[0442]

[0443]MeOH (50 ml) was added to Pd / C 10% (0.250 g) under a N2 atmosphere. Subsequently, a 0.4% thiophene sol. in DIPE (2 ml) and intermediate 3 (0.9...

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PUM

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Abstract

The present invention is concerned with substituted bicyclic heterocyclic compounds of Formula (I)wherein Het1, Het2, A1, A2, A3 and A4 have the meaning defined in the claims. The compounds according to the present invention are useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.

Description

CROSS REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation of U.S. Ser. No. 13 / 144,554 (now allowed), which was filed on Jul. 4, 2011 as a national stage application of Patent Application No. PCT / EP2010 / 051244, filed Feb. 2, 2010, which in turn claims the benefit of EPO Patent Application No. 09152254.0 filed Feb. 6, 2009. The complete disclosures of the aforementioned related patent applications are hereby incorporated herein by reference for all purposes.FIELD OF THE INVENTION[0002]The present invention is concerned with novel substituted bicyclic heterocyclic compounds useful as gamma secretase modulators. The invention further relates to processes for preparing such novel compounds, pharmaceutical compositions comprising said compounds as an active ingredient as well as the use of said compounds as a medicament.BACKGROUND OF THE INVENTION[0003]Alzheimer's Disease (AD) is a progressive neurodegenerative disorder marked by loss of memory, cognition, and behavi...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D487/04C07D401/12C07D413/14C07D413/12C07D471/04C07D403/12
CPCC07D487/04C07D471/04C07D401/12C07D413/14C07D413/12C07D403/12C07D403/10C07D413/10A61P25/00A61P25/16A61P25/28A61P43/00A61K31/437C07D401/10
Inventor GIJSEN, HENRICUS JACOBUS MARIAVELTER, ADRIANA INGRIDMACDONALD, GREGOR JAMESBISCHOFF, FRANCOIS PAULWU, TONGFEIVAN BRANDT, SVEN FRANCISCUS ANNASURKYN, MICHELZAJA, MIRKOPIETERS, SERGE MARIA ALOYSIUSBERTHELOT, DIDIER JEAN-CLAUDEDE CLEYN, MICHEL ANNA JOZEFOEHLRICH, DANIEL
Owner CELLZOME LTD
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