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Acetyl mimic compounds for the inhibition of isoprenyl-s-cysteinyl methyltransferase

A compound and alkenyl technology, applied in drug combination, organic chemistry, digestive system, etc., can solve problems such as edema and fluid retention

Inactive Publication Date: 2011-01-12
SIGNUM BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

NSAIDs may also cause fluid retention, leading to edema

Method used

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  • Acetyl mimic compounds for the inhibition of isoprenyl-s-cysteinyl methyltransferase
  • Acetyl mimic compounds for the inhibition of isoprenyl-s-cysteinyl methyltransferase
  • Acetyl mimic compounds for the inhibition of isoprenyl-s-cysteinyl methyltransferase

Examples

Experimental program
Comparison scheme
Effect test

example 20

[0282]

[0283] or a pharmaceutically acceptable salt, enantiomer, diastereomer or double bond isomer thereof, wherein:

[0284] R 1 is optionally substituted heteroaryl or:

[0285]

[0286]

[0287] R 2 is via one or more R 7 A radical substituted aliphatic group;

[0288] R 13 independently for H, or -NH-S(O) 2 R 14 ;

[0289] R 14 are independently H, (C1-C4) alkyl or aryl;

[0290] R 5 are independently H, alkyl, aryl, alkenyl or alkynyl, wherein R 5 Optionally one or two R 7 group substitution;

[0291] R 6 is H, alkyl, aryl, alkenyl, alkynyl or cyclic group, where R 6 Optionally one or two R 7 group substitution;

[0292] R 7 is-NHC(=O)(C 1 -C 8 ) Alkyl, -(C 1 -C 8 ) Alkyl, -(C 1 -C 8 ) alkenyl, -(C 1 -C 8 ) alkynyl, phenyl, -(C 2 -C 5 ) heteroaryl, -(C 1 -C 6 ) heterocycloalkyl, -(C 3 -C 7 ) cycloalkyl, -O-(C 1 -C 8 ) Alkyl, -O-(C 1 -C 8 ) alkenyl, -O-(C 1 -C 8 )alkynyl, -O-phenyl, -CN, -OH, oxo, halo, -C(=O)OH, -COhalo, ...

example

[0339] As described in the Examples below, in certain exemplary embodiments, compounds are prepared according to the following general procedures. It is to be understood that while the general methods describe the synthesis of certain compounds of the invention, the following general methods, and others known to those skilled in the art, are applicable to all classes, subclasses and classes of each of the described compounds disclosed herein. type.

[0340] The following general experimental procedure was used in each of the examples described below. Proton NMR ( 1 HNMR) spectrum is recorded on the Bruker 500MHz spectrometer, dimethyl sulfoxide (DMSO-d6), methanol (CD 3 0D) or chloroform (CDCl 3 ) used as 1 H-NMR solvent. The residual proton absorption of the deuterated solvent was used as an internal standard. all 1 H-NMR chemical shifts are reported as delta values ​​in parts per million (ppm). Splitting patterns are abbreviated as follows: s, singlet; d, doublet; t,...

example 1

[0342] Synthetic compounds (where R 3 = pyridine derivatives)

[0343]

[0344] 2-Bromopyridine was added to a solution of farnesylcysteine ​​methyl ester in diglyme and heated to 130°C under nitrogen for 19 hours. The reaction mixture was diluted with aqueous ammonia, and the product was extracted into chloroform. The combined organic phases were dried over anhydrous sodium sulfate and the solvent was removed in vacuo to give the crude product which could be purified using reverse phase HPLC. The protective methyl group on -COOH can be hydrolyzed under basic conditions before or after purification. Details of this method are described in Ito et al., Biological & Pharmaceutical Bulletin. 2007 30: pp. 1838-1843.

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Abstract

Among other things, the present invention provides novel compounds capable of effectively inhibiting inflammatory responses that are mediated by G-proteins or GPCRs in neutrophils, macrophages and platelets. In particular, compounds of the present invention act as inhibitors of edema, inhibitors of erythema and inhibitors of MPO (myeloperoxidase), pharmaceutical compositions containing the same compounds and the use thereof for the treatment of diseases that may benefit from edema, erythema and MPO inhibition, such as inflammation (acute or chronic), asthma, autoimmune diseases, and chronic obstructive pulmonary disease (COPD) (e.g., emphysema, chronic bronchitis and small airways disease, etc.), inflammatory responses of the immune system, skin diseases (e.g., reducing acute skin irritation for patients suffering from rosacea, atopic dermatitis, seborrheic dermatitis, psoriasis), irritable bowel syndrome (e.g., Chron's disease and ulcerative colitis, etc.), and central nervous system disorders (e.g., Parkinson's disease).

Description

[0001] Related applications [0002] This application claims priority to US Provisional Patent Application Serial No. 61 / 065,939, filed February 14, 2008, the entire disclosure of which is incorporated herein by reference. Background technique [0003] Inflammation is often the body's response to infection or injury, in which cells involved in detoxification and repair are mobilized by inflammatory mediators to the site of damage. Infection or injury may be caused by acute or chronic disease, disorder, condition or trauma, environmental conditions or aging. Examples include diseases, conditions, syndromes, conditions and injuries of the cardiovascular system, digestive system, skin system, muscular system, nervous system, reproductive system, respiratory system and urinary system, as well as diseases, conditions, syndromes of tissues and cartilage, Conditions and injuries such as atherosclerosis, irritable bowel syndrome, psoriasis, tendonitis, Alzheimer's disease and vascul...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/13C07D239/42C12P13/12
CPCC07D207/34C07D295/215C07C335/08C07D239/42C07D403/12C07D213/74C07D265/30C07D277/42C07C323/57C07D249/04C07D413/12C07D207/22C07D257/04C07C323/60C07C323/59C07D233/88C07D401/12C07D235/14C07D263/48C07C327/42C07C323/58C07D417/12C07D233/70A61P1/04A61P11/00A61P11/06A61P17/00A61P17/06A61P17/08A61P25/16A61P25/28A61P29/00A61P37/00A61P37/06A61P43/00
Inventor 李圣烨迈克尔·沃龙科夫彼得·沃兰宁
Owner SIGNUM BIOSCIENCES INC