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Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators

A compound, C1-C6 technology, applied in anti-inflammatory agents, drug combinations, non-central analgesics, etc., can solve problems such as risk reduction

Active Publication Date: 2011-03-23
MERCK PATENT GMBH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

HMGCoA reductase inhibitors (statins) are effective in normalizing LDL-C levels but only reduce the risk of cardiovascular events such as stroke and myocardial infarction by about 30%

Method used

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  • Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators
  • Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators
  • Benzofurane, benzothiophene, benzothiazol derivatives as fxr modulators

Examples

Experimental program
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preparation example Construction

[0457] The process for the preparation of the compounds of formula (I) according to the invention is another object of the invention.

[0458] According to a first aspect, compounds of formula (I) according to the invention can be prepared according to a process comprising reacting a compound of formula (II):

[0459]

[0460] where R 1 , Y, A, M, Q, R 3 , X, J, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , x and y are as defined in formula (I), U is H or an amine protecting group.

[0461]"Amine protecting group" refers to a readily removable group known in the art that is capable of protecting an amino group from unwanted reactions and that can be selectively removed during synthetic procedures. The use of amine protecting groups as protecting groups to avoid undesired reactions during synthesis is well known in the art, and a variety of such protecting groups are known, for example, from T.H. Greene and P.G.M. Wuts, Organic Synthesis Protective Groups in...

Embodiment approach

[0464] According to a first embodiment, compounds of formula (II) can be prepared by reacting compounds of formula (III) with compounds of formula (IV):

[0465]

[0466] where R 1 , Y, A, M, Q, R 3 , X, J, R 5 , R 5a , R 6 , R 6a , R 7 , R 7a , R 8 , R 8a , x, y and U are as defined in formula (II), and Hal is a halogen atom.

[0467] Often, especially in the presence of palladium catalysts, such as Pd(OAc) 2 The aromatic substitution of the Hal group of the compound of formula (III) by the compound of formula (IV) is carried out in the presence of and BINAP.

[0468] In a particular aspect, compounds of formula (III) can be prepared according to a process comprising reacting compounds of formula (V):

[0469]

[0470] where M, Q, R 3 , Hal as defined in formula (III), Alk is C 1 -C 6 alkyl.

[0471] In general, the cyclization of compounds of formula (III) is carried out in the presence of a suitable base, for example an alkali metal alcoholate, such as ...

Embodiment 1

[0509] Example 1: {5-[4-(2,6-dichlorobenzyl)piperazin-1-yl]-4-methyl-benzofuran-2-yl}-morpholin-4-yl-methanol ketone

[0510]

[0511] 2-methoxy-6-methylbenzaldehyde

[0512]

[0513]Potassium peroxodisulfate (89.31g, 0.33mol) and copper (II) sulfate pentahydrate (27.22g, 0.11mol) were added to 2,3-dimethylanisole (15g, 0.11mol) in acetonitrile water mixture (750ml , 1:1) solution, the reaction mixture was stirred under reflux for 15 min until no raw material was detected by TLC (thin layer chromatography), the reaction mixture was cooled to room temperature, the product was extracted with dichloromethane (2 × 225ml), and water (2×100ml) and brine solution (100ml) washed the organic layer, dried the organic layer over sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Column chromatography, eluting with 4 / 96 ethyl acetate / hexane, gave 2 - Methoxy-6-methylbenzaldehyde (7.32 g, 44.2%). 1 H NMR (300MHz, CDCl 3 ), δ2.60 (3H, s), 3.90 (3H...

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Abstract

The present invention relates to compounds of formula (I) wherein the substituents are as defined in the claims, including pharmaceutical compositions thereof and for their use in the treatment and / or prevention and / or amelioration of one or more symptoms of disease or disorders related to the activity of FXR. The invention is also directed to intermediates and to a method of preparation of compounds of formula (I).

Description

technical field [0001] The present invention relates to chemical compositions, processes for their preparation and uses of the compositions. In particular, the invention relates to compositions of compounds of formula (I): [0002] [0003] and their use in modulating the activity of FXR receptors and their use in treating, preventing or ameliorating the symptoms of one or more diseases or disorders associated with the activity of these receptors, including but not limited to hypercholesterolemia, hypercholesterolemia, Lipoproteinemia, hypertriglyceridemia, dyslipidemia, lipodystrophy, cholestasis / fibrosis, cholelithiasis, gastrointestinal disease or condition, hyperglycemia, diabetes mellitus, type II diabetes, insulin resistance, metabolic rigidity , kidney disease, liver disease, atherosclerosis, cancer, inflammatory disease, obesity, osteoporosis, skin aging, hair growth regulation and pigment abnormalities, Parkinson's disease and / or Alzheimer's disease. Background ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/85C07D405/04C07D405/12A61K31/343A61P3/00
CPCC07D307/85C07D405/12C07D405/04A61P1/00A61P1/04A61P1/16A61P13/12A61P17/00A61P17/14A61P17/18A61P19/10A61P25/16A61P25/28A61P29/00A61P3/00A61P3/10A61P35/00A61P3/04A61P3/06A61P3/08A61P9/10
Inventor D·罗切G·莫蒂诺I·克贝尔F·孔塔尔S·克里斯特曼-弗兰克S·森古普塔R·斯特拉G·万卡特施沃尔拉奥
Owner MERCK PATENT GMBH
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