Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

Spiro-hydantoin compounds useful as anti-inflammatory agents

a technology of hydantoin and compounds, which is applied in the field of hydantoin compounds, can solve the problems of chronic inflammation, poor wound healing, and patients' inability to mount a normal inflammatory or immune respons

Inactive Publication Date: 2005-01-06
DHAR T G MURALI +5
View PDF5 Cites 19 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

"The present invention provides compounds that can be used to treat inflammatory or immune diseases. These compounds have a specific formula (I) and can be attached to a ring or a carbon atom. The compounds have various functional groups that can be used to create pharmaceutical compositions and methods of treating diseases such as inflammatory bowel disease, rheumatoid arthritis, and lupus erythematosus. The compounds can be administered to patients in need of treatment."

Problems solved by technology

These patients are unable to mount a normal inflammatory or immune response; they suffer from disorders such as recurrent infections, poor wound healing, granulocytosis, progressive periodontitis, and umbilical cord separation.
While sufficient levels of CD18 integrins interacting with ICAMs are needed to mount a normal immune response, significant cellular and tissue injury can result in chronic inflammatory states where there is an inappropriate influx of leukocytes to the disease site.
Continuous recruitment of leukocytes from blood vessels into inflamed tissue, as in chronic inflammatory states, can perpetuate tissue injury and lead to excessive fibrous repair and autoimmune disease.
Also, present therapies for many inflammatory and immune diseases have drawbacks.
However, β2-agonists have limited efficacy and inhaled corticosteroids raise safety concerns.
The first three of these therapies raise toxicity issues over long-term (e.g., 6-9 month) use, whereas topical treatments have limited efficacy.
Additionally, these treatments typically are applied only in response to flares and not as a prophylaxis measure.

Method used

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • Spiro-hydantoin compounds useful as anti-inflammatory agents
  • Spiro-hydantoin compounds useful as anti-inflammatory agents
  • Spiro-hydantoin compounds useful as anti-inflammatory agents

Examples

Experimental program
Comparison scheme
Effect test

examples

The following Examples illustrate embodiments of the inventive compounds and starting materials, and are not intended to limit the scope of the claims. For ease of reference, the following abbreviations are used herein:

Abbreviations

AlCl3=aluminum chloride Ac2O=acetic anhydride AcONa=sodium acetate bp=boiling point CH3CN=acetonitrile DCC=dicyclohexylcarbodiimide DCE=dichloroethane DCM=dichloromethane DMAP=4-dimethylaminopyridine DIPEA or DIEA=N,N-diisopropylethylamine DME=1,2-dimethoxyethane DMF=dimethyl formamide EDCI=1-3-dimethylaminopropyl)-3-ethylcarbodiimide Et2O=diethyl ether HOBT=1-hydroxybenzotriazole EtOAc=ethyl acetate EtOH=ethanol g=gram(s) HCl=hydrochloric acid KOH=potassium hydroxide K2CO3=potassium carbonate l=liter LiAlH4=lithium aluminum hydride MeCN=acetonitrile MeOH=methanol MgSO4=magnesium sulfate NaH=sodium hydride Na2SO4=sodium sulfate NaOH=sodium hydroxide NMP=1-methyl-2-pyrrolidinone PBr3=phosphorus tribromide (Ph3P)4Pd=tetrak...

preparation 1

4-(4-Bromophenyl)-4-oxobutyric acid

AlC3 (128.8 g, 0.97 mol) was added by portions within 20 min to a suspension of succinic anhydride (44.3 g, 0.44 mol) and bromobenzene (100 ml, 0.99 mol) in DCM (500 ml) while the reaction flask was cooled in a water bath. After 1h30 min at RT, the reaction mixture was refluxed for 2 h. After cooling, the reaction medium was slowly poured into a mixture of ice (1.5 l) and concentrated HCl (100 ml). The precipitate was washed twice with water, with isopropanol, and finally with pentane. After drying 4-(4-bromophenyl)-4-oxobutyric acid was obtained as an off-white solid (86.4 g, mp=148° C.). 1H NMR (CDCl3): 7.85 (2H, d, J=8.5 Hz), 7.62 (2H, d, J=8.5 Hz), 3.28 (2H, t, J=6.5 Hz), 2.82 (2H, t, J=6.5 Hz).

preparation 2

4-(4-Bromophenyl)-4-oxobutyric acid methyl ester

4-(4-Bromophenyl)-4-oxobutyric acid (86.4 g, 0.336 mol) (Preparation 1) in MeOH (1.7 l) containing H2SO4 (86 ml) was refluxed for 21 h. After cooling, the light precipitate was filtered off and the reaction mixture concentrated to dryness. The obtained solid was placed in water and extracted twice with EtOAc. The organic layer was washed with diluted NaOH and twice with brine, dried over Na2SO4 and concentrated to yield the desired 4-(4-bromophenyl)-4-oxobutyric acid methyl ester as a low melting point solid (87.5 g, mp=50° C.). 1H NMR (CDCl3): 7.85 (2H, d, J=8.5 Hz), 7.60 (2H, d, J=8.5 Hz), 3.71 (3H, s), 3.28 (2H, t, J=6.5 Hz), 2.76 (2H, t, J=6.5 Hz).

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
adhesive interactionsaaaaaaaaaa
adhesionaaaaaaaaaa
adhesive functionaaaaaaaaaa
Login to View More

Abstract

Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates, enantiomers, and diastereomers, and prodrugs thereof, are useful as inhibitors of LFA-1 / ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR4b; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R2, R4a, R4b, and R4c are as defined in the specification.

Description

FIELD OF THE INVENTION The present invention relates to spiro-hydantoin compounds, pharmaceutical compositions containing them, and methods of using such compounds in treating inflammatory or immune disease. BACKGROUND OF THE INVENTION Cells adhere to other cells and to substrates through specific, regulated processes that are critical to various biological functions. The proper functioning of the immune system is dependent upon adhesive interactions and cell migration. A key event in an immune response involves the migration of leukocytes to a disease site. During an inflammatory response, leukocytes are recruited to the site of injury and extravasated by a series of cellular interactions involving cell-cell and cell-substrate adhesion. One family of molecules that serves an important adhesive function is integrins. Integrins are expressed on cell surfaces and function in cell-cell and cell-substrate adhesion. Integrins are alpha-beta heterodimers: each integrin has an alpha (α)...

Claims

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4166A61K31/4184C07D233/76A61K31/4188A61K31/4192A61K31/4196A61K31/42A61K31/427A61K31/428A61K31/4439A61K31/454A61K31/4545A61K31/4709A61K31/497A61K31/498A61K31/501A61K31/506A61K31/5377A61K31/541A61P1/00A61P1/04A61P1/16A61P1/18A61P3/10A61P7/00A61P9/00A61P9/10A61P11/00A61P11/08A61P13/12A61P17/00A61P17/06A61P19/02A61P19/10A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P37/02A61P37/06A61P37/08A61P39/02C07D233/96C07D235/02C07D401/04C07D401/14C07D487/10C07D487/20C07D519/00
CPCC07D233/96C07D487/10C07D235/02A61P1/00A61P1/04A61P1/16A61P1/18A61P11/00A61P11/08A61P13/12A61P17/00A61P17/06A61P19/02A61P19/10A61P25/00A61P25/28A61P27/02A61P27/16A61P29/00A61P37/02A61P37/06A61P37/08A61P39/02A61P7/00A61P9/00A61P9/10A61P3/10
Inventor DHAR, T.G. MURALIPOTIN, DOMINIQUEBLANDINE MAILLET, MAGALI JEANNINELAUNAY, MICHELENICOLAI, ERIC ANTOINEIWANOWICZ, EDWIN J.
Owner DHAR T G MURALI
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com