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2 -substituted- 3 -phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

Inactive Publication Date: 2011-01-27
ALBIREO
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0616]The formation of a radioligand / PPAR complex can be measured in a scintillation counter. Affinities of test compounds can be determined by incorporating increasing concentrations of unlabelled test compound into the assay which will lead to displacement of the radiolabelled ligand from the complex which is detected as loss of radioactive signal. Competition curves can be generated by plotting % binding versus concentration and equilibrium dissociation constants determined.

Problems solved by technology

In addition GCR agonist treatment suppresses life saving immuno-activation upon infection by virus, bacteria or other pathogenic microbes, which further reduces patient quality of life and increases risk for secondary disease.
Non-Steroidal Anti-Inflammatory Drugs (NSAID) and antibiotics (e.g. 5-ASA, Sulfasalazine, and Metronidazole) are also commonly used, however with limited effect.

Method used

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  • 2 -substituted- 3 -phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease
  • 2 -substituted- 3 -phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease
  • 2 -substituted- 3 -phenylpropionic acid derivatives and their use in the treatment of inflammatory bowel disease

Examples

Experimental program
Comparison scheme
Effect test

example 1

4-Methanesulfonyloxy-benzoic acid 4-{2-carboxy-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-ethyl}-benzyl ester

[0531]

[0532]Step 1: To a solution of 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (70 mg, 0.15 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (32.5 mg, 0.15 mmol) in anhydrous DCM (3.0 mL) was added EDCxHCl (37.5 mg, 0.195 mmol) and DMAP (0.18 mg, 0.002 mmol) under nitrogen atmosphere at 0° C. After complete addition the cooling bath was removed and the homogenous mixture was stirred at ambient temperature until no starting material was left. The mixture was diluted with water and 2N aq. HCl and extracted with DCM. The combined organic layers were dried (MgSO4) and the solvent subsequently evaporated under reduced pressure to afford the desired ester intermediate which was used in the next step without further purification.

[0533]Step 2: The crude 2,2,2-trichloro ethyl ester derivative (68.7 mg, 0.10 mmol) was diss...

example 2

2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-{4-[2-(4-methanesulfonyloxy-phenyl)-acetoxymethyl]-phenyl}-propionic acid

[0534]

[0535]The title compound was prepared from 2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-3-(4-hydroxymethyl-phenyl)-propionic acid 2,2,2 trichloro-ethyl ester (33 mg, 0.072 mmol) and (4-methanesulfonyloxy-phenyl)-acetic acid (15 mg, 0.065 mmol) in the same manner as described for example 1. The crude product was purified by flash chromatography (yield: 2.0 mg, 5.6%). Mass Spectrum: M+H+547.10.

example 3

2-[2-(4-Fluoro-phenyl)-ethylsulfanyl]-3-[4-(4-trifluoromethyl-benzyloxycarbonylmethyl)-phenyl]-propionic acid

[0536]

[0537]The title compound was prepared from 3-(4-carboxymethyl-phenyl)-2-[2-(4-fluoro-phenyl)-ethylsulfanyl]-propionic acid 2,2,2-trichloro ethyl ester (30 mg, 0.061 mmol) and 4-trifluoromethylbenzyl alcohol (12 mg, 0.067 mmol) in the same manner as described for example 1. The crude product was purified by HPLC (yield: 3.0 mg, 9.4%). 1H NMR (400 MHz, CDCl3): δ 7.56 (d, 2H), 7.36 (d, 2H), 7.08-7.19 (m, 6H), 6.90-7.04 (m, 2H), 5.14 (s, 2H), 3.63 (s, 2H), 3.45 (dd, 2H), 3.15 (dd, 2H), 2.80-2.92 (m, 3H).

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Abstract

The present invention relates to 2-(substituted sulphur, sulphone or sulphoxide)-3-(substituted phenyl) propionic acid derivatives, 2-(substituted oxygen)-3-(substituted phenyl) propionic acid derivatives, benzoic acid derivatives, and derivatives of 2-methyl-2-(phenoxy or phenylthio)propanoic acid and 2-(methylor ethyl)-2-(phenoxy or phenylthio)butanoic acid, to processes for preparing such compounds, to their use in the treatment of inflammatory conditions, and to pharmaceutical compositions containing them.

Description

FIELD OF THE INVENTION[0001]The present invention relates to 2-(substituted sulphur, sulphone or sulphoxide)-3-(substituted phenyl) propionic acid derivatives, 2-(substituted oxygen)-3-(substituted phenyl) propionic acid derivatives, benzoic acid derivatives, and derivatives of 2-methyl-2-(phenoxy or phenylthio)propanoic acid and 2-(methyl or ethyl)-2-(phenoxy or phenylthio)butanoic acid, to processes for preparing such compounds, to their use in the treatment of inflammatory conditions, and to pharmaceutical compositions containing them.BACKGROUND OF THE INVENTION[0002]Inflammatory Bowel Disease (IBD) includes conditions where the patients suffer from inflammation in the gastrointestinal (GI)-tract. Several of those are considered to be of chronic nature, e.g. Crohn's disease and ulcerative colitis, and the medical need is large. The patients suffer from fevers, pain, diarrhoea or constipation and in addition hemorrhagic stool. Treatment is constrained to symptom relief, inflammato...

Claims

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Application Information

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IPC IPC(8): A61K31/216C07C309/66C07C303/30C07C321/20C07C319/20C07C69/612C07C67/28C07C69/614C07D213/55C07D295/185C07D263/32C07C317/44C07C315/04A61K31/255A61K31/435A61K31/495A61K31/421A61P1/00A61P1/04A61P29/00
CPCC07C271/28C07C309/66C07C317/44C07C323/56C07C323/62C07C327/28C07D295/04C07D231/12C07D263/32C07D263/34C07D277/24C07D277/30C07D213/55A61P1/00A61P1/04A61P29/00C07C323/66A61K31/255
Inventor BROO, ANDERSGOTTFRIES, JOHANKOSSENJANS, MICHAELLANNA, LILINDSTEDT-ALSTERMARK, EVA-LOTTENILSSON, KRISTINA A.OHLSSON, BENGTTHORSTENSSON, MARIABOIJE, MARIASJOGREN, OLOF
Owner ALBIREO
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