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Heterocyclic derivatives and their application in the treatment of neurological diseases

A technology of compound and alkyl, applied in the field of diabetes treatment, can solve the problem of different substrate specificity

Active Publication Date: 2016-08-17
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite structural and sequence similarities, the substrate specificities of BACE-1 and BACE-2 appear to differ

Method used

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  • Heterocyclic derivatives and their application in the treatment of neurological diseases
  • Heterocyclic derivatives and their application in the treatment of neurological diseases
  • Heterocyclic derivatives and their application in the treatment of neurological diseases

Examples

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preparation example Construction

[0371] In another aspect, the present invention relates to a method for preparing a compound of formula I in free form or salt form, the method comprising:

[0372] a) Make a compound of the following formula in free form or salt form:

[0373]

[0374] Where X 1 , X 3 , X 4 , X 5 , R 6 , E 1 And E 2 As defined in Formula I, PG is a protecting group that reacts with the compound of the following formula in free form or salt form:

[0375]

[0376] Where R 2 As defined in formula I, L is a leaving group, such as a hydroxyl group,

[0377] b) Make the following compound in free form or salt form:

[0378]

[0379] Where X 1 , X 3 , X 4 , X 5 , R 6 , E 1 And E 2 As defined in formula I, Hal is halogen, such as bromine, PG is a protecting group,

[0380] Reacts with compounds of the following formula in free or salt form:

[0381]

[0382] Where R 2 As defined by Formula I,

[0383] c) Make a compound of the following formula in free or salt form:

[0384]

[0385] Where X 1 , X 3 , X 4 , X 5 ,...

Embodiment 1

[0601] Example 1: 5-Bromo-pyridine-2-carboxylic acid [6-((R)-5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazine-3- (Yl)-pyridin-2-yl)-amide

[0602]

[0603] a) 5-(6-Bromo-pyridin-2-yl)-5-methyl-imidazolidine-2,4-dione

[0604] To 1-(6-bromo-pyridin-2-yl)-ethanone (CAS 49669-13-8, 8.75g, 43.7mmol) and potassium cyanide (4.27g, 65.6mmol) in ethanol / water (40.0 / 26.7 ml) was added ammonium carbonate (21.02g, 219.0mmol) to the solution. The reaction mixture was stirred in an autoclave at 100°C for 17h, and then water, 1Maq.NaHCO 3 Dilute with soln. and EtOAc. Separate the phases, use EtOAc and Et for the aqueous phase 2 O and DCM were extracted again. The combined organic phase was dried over sodium sulfate, filtered and concentrated to obtain the target compound as an off-white solid, which can be used directly in the next step without further purification.

[0605] HPLC Rt H4 =0.62min; ESIMS: 270,272[(M+H) + ]; 1 H NMR(400MHz, DMSO-d 6 ): δ 10.86 (br s, 1H), 8.48 (s, 1H), 7.81 (m, 1H),...

Embodiment 2

[0632] Example 2: 5-Bromo-pyridine-2-carboxylic acid [6-(5-amino-3-methyl-3,6-dihydro-2H-[1,4]-oxazin-3-yl)-pyridine -2-yl]-amide

[0633]

[0634] The racemate of Example 1 can be prepared according to the method used in Example 1, using the racemic mixture obtained in step j) of Example 1 to complete the synthesis, which has the same analytical data.

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Abstract

The present invention relates to a heterocyclic compound of formula (I). In formula (I), all variables are as defined in the description. The present invention also relates to its pharmaceutical composition, its combined product and their use as medicine, especially for Use for treating Alzheimer's disease or diabetes by inhibiting BACE-1 or BACE-2.

Description

Technical field [0001] The present invention relates to heterocyclic derivatives and their pharmaceutically acceptable salts, their pharmaceutical compositions, their pharmaceutical combination products and their use as medicines, in particular to the treatment of neurodegenerative diseases by inhibiting BACE-1 or by inhibiting BACE- 2 Uses for the treatment of diabetes. Background technique [0002] Alzheimer's disease is a devastating neurodegenerative disease. Its sporadic form affects the elderly population (> The incidence rate increases sharply at the age of 75). In addition, there are many familial forms, and the onset of the disease occurs in the fourth or fifth decade of life. Pathologically, it is characterized by the presence of extracellular senile plaques and intracellular neurofibrillary tangles in the patient’s brain. The nuclear composition of senile plaques is small 4kDa amyloid peptides. They are produced by proteolytic processing of a large transmembrane ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D413/14C07D487/04A61K31/5377A61P25/00
CPCC07D413/04C07D413/14C07B2200/05C07D487/04A61K31/5377C07D471/04A61P25/00A61P25/28A61P3/04A61P9/12A61P3/10A61K2300/00C07B59/002
Inventor S·巴迪格M·舍布罗鲁K·胡尔特S·雅基耶R·M·吕尔恩德R·马绍尔H·鲁伊格尔M·廷特尔诺特-布洛莱伊S·J·费恩施塔尔M·沃格特勒
Owner NOVARTIS AG
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