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Novel heterocyclic derivatives and their use in the treatment of neurological disorders

A compound, heteroaryl technology, applied in the field of new heterocyclic derivatives and its application in the treatment of neurological diseases, can solve the problem of different substrate specificity

Active Publication Date: 2013-11-20
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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  • Novel heterocyclic derivatives and their use in the treatment of neurological disorders
  • Novel heterocyclic derivatives and their use in the treatment of neurological disorders
  • Novel heterocyclic derivatives and their use in the treatment of neurological disorders

Examples

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preparation example Construction

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

[0372] a) a compound of the following formula in free form or in 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, reacting with the following formula compound 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) making the following formula 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 a halogen, such as bromine, and PG is a protecting group,

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

[0381]

[0382] where R 2 As defined in Formula I,

[0383] c) make the following formula compound of free form or sa...

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- base)-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) solution was added ammonium carbonate (21.02 g, 219.0 mmol). The reaction mixture was stirred in an autoclave at 100°C for 17h, then water, 1Maq.NaHCO 3 soln. and EtOAc dilution. The phases were separated, and the aqueous phase was washed with EtOAc, Et 2 O and DCM re-extracted. The combined organic phases were dried over sodium sulfate, filtered and concentrated to afford the title compound as an off-white solid which was 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 ): δ10.86 (br s, 1H), 8.48 (s, 1H), 7...

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, the synthesis being accomplished using the racemic mixture obtained from Example 1, step j), which has the same analytical data.

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Abstract

The invention relates to novel heterocyclic compounds of the formula in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.

Description

technical field [0001] The present invention relates to novel heterocyclic derivatives and their pharmaceutically acceptable salts, their pharmaceutical compositions, their pharmaceutical combination products and their use as medicines, especially for the treatment of neurodegenerative diseases by inhibiting BACE-1 or by inhibiting Use of BACE-2 in the treatment of diabetes. Background technique [0002] Alzheimer's disease is a devastating neurodegenerative disease. Its sporadic-occurring form affects older populations (incidence increases sharply at >75 years of age), and there are also many familial forms, with disease onset 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 components of senescent plaques are small 4 kDa amyloid peptides. They are produced by the proteolytic processing of a large transmembrane protein...

Claims

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Application Information

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IPC IPC(8): C07D413/14C07D487/04A61K31/5377A61P25/00
CPCC07D413/14C07B2200/05C07D487/04C07D413/04A61K31/5377C07D471/04A61P25/00A61P25/28A61P3/04A61P9/12A61P3/10A61K2300/00C07B59/002
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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