Acetyl 2-hydroxy-1, 3-diaminoalkanes

An alkyl, radical technology, applied in the field of acetyl 2-hydroxy-1, which can solve the problem of effective treatment methods that do not suspend, prevent or reverse the progression of Alzheimer's disease, etc.

Inactive Publication Date: 2005-11-09
ELAN PHARM INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] Currently, there are no effective treatments to h...

Method used

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  • Acetyl 2-hydroxy-1, 3-diaminoalkanes

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0854] Embodiment 1: the preparation of 7-bromo-1-tetralinone

[0855]

[0856] 7-Bromo-1-tetralinone was prepared following the procedure described in Cornelius, L.A.M.; Combs, D.W. Synthetic Communications 1994, 24, 2777-2788. The above isomers were separated using flash chromatography on silica gel (BiotageFlash 75, eluent solvent 20 / 1 hexane:MTBE) to yield 5-bromo-1-tetralinone (11.59 g, 51%) and 7-bromo-1 - Tetralinone (9.45 g, 42%).

Embodiment 2

[0858] Embodiment 2: the preparation of (R)-7-ethyltetralin-1-alcohol

[0859]

[0860] See generally: Jones, T.K.; Mohan, J.J.; Xavier, L.C.; Blacklock, T.J.; Mathre, D.J.; Sohar, P.; , 56, 763-769. More specifically, 7-ethyl-1-tetralinone (2.29 g, 13.1 mmol) was placed in a 100 mL round bottom flask and dissolved in anhydrous THF (40 mL). Activated 4mm molecular sieves were added and the mixture was aged for 2 hours before cannula transfer to a 250 mL three necked round bottom flask equipped with a dropping funnel, thermometer and nitrogen inlet. The solution was cooled to -25°C and 1M (S)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrollo[1 ,2-c][1,3,2]oxazaborole. The source of oxazoborole is Aldrich, cat. No. 45, 770-1, "(S)-2-Methyl-CBS-oxazaborolidine". The use of S-promoters generates R-alcohols. According to the aforementioned references, the use of 5 mol% oxazaborolidine catalyst gave comparable results.

[0861] A solution of borane-dimethylsulfide (0.70 g, 0.8...

Embodiment 3

[0862] Example 3: (S)-7-ethyl-1,2,3,4-tetrahydro-1-naphthylamine hydrochloride

[0863]

[0864] See generally: Rover, S.; Adam. G..; Cesura, A.M.; Galley, G.; Jenck, F.; -1338. Their authors reported a slight decrease in yield by partial formation of dihydronaphthalene through removal of the hydroxyl moiety.

[0865] More specifically, a solution of (R)-7-ethyltetralin-1-ol (1.77 g, 10.1 mmol) in toluene (25 mL) was cooled in an ice bath and treated with diphenylphosphoryl azide ( DPPA, 3.3 g, 2.7 mL, 12 mmol). A solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 1.8 g, 1.8 mL, 12 mmol) in toluene (8 mL) was added over 20 minutes, and the mixture was heated at 0° C. Stir for 2 hours and 16 hours at room temperature. The mixture was filtered through a pad of silica gel (elution 6:1 hexane / ethyl acetate) to remove the precipitate and the volatiles were removed in vacuo to give crude S-azide as an oily residue. This material was used directly in the next step without f...

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Abstract

The invention discloses compounds of chemical formula (I), wherein variable Z, X, R 15 , R 2 , R 3 , R c defined in this article. The compounds disclosed herein are inhibitors of β-secretase and are therefore useful in the treatment of Alzheimer's disease and other diseases in mammals characterized by the deposition of β-peptides.

Description

technical field [0001] This invention relates to acetyl 2-hydroxy-1,3-diaminoalkanes and compounds useful in the treatment of Alzheimer's disease and related diseases. More specifically, the present invention relates to compounds that can inhibit β-secretase, an enzyme that cleaves amyloid precursor protein to generate amyloid β peptide (Aβ), which is the major component of amyloid plaques found in Background technique [0002] Alzheimer's disease (AD) is a progressive degenerative disease of the brain mainly related to aging. The clinical manifestations of AD are characterized by loss of memory, cognition, reasoning, judgment, and orientation. As the disease progresses, motor, sensory, and language abilities are also affected, until there is generalized impairment of multiple cognitive functions. These cognitive losses develop gradually, but usually lead to severe impairment and eventual death within 4 to 12 years. [0003] Alzheimer's disease is characterized by two ma...

Claims

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Application Information

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IPC IPC(8): A61KC07D215/38
Inventor M·马亚尔E·T·鲍德温J·T·贝克R·休斯V·约翰S·R·普利R·滕布林克
Owner ELAN PHARM INC
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