Compounds for use in the treatment or prophylaxis of pain, inflammation and/or autoimmunity
An autoimmune and compound technology, applied in anti-inflammatory agents, drug combinations, organic chemistry, etc., can solve the problems of patients with no pain relief and low curative effect
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Embodiment 1
[0085] Example 1——(S, S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxylbenzene)-3-phenylpropylamide preparation
[0086] (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxyphenyl)-3-benzene was prepared as described in WO 2013 / 084238 and US 2011 / 0086910 propyl amide.
[0087] In a first step, 2 g of methyl lactate were reacted with an excess of benzyl bromide to obtain 880 mg of (S)-benzyloxymethyl lactate. The reaction was performed by slurrying sodium hydride in THF and cooling to about -15°C. Then, the reaction mixture was slowly warmed to room temperature and stirred for about 1-2 hours. The reaction was quenched with saturated ammonium chloride solution and extracted twice with MTBE, then the solvent was removed on a rotary evaporator to give a crude oil. The crude product was purified by column chromatography to obtain pure (S)-2-benzyloxymethyl lactate. The (R)-2-benzyloxymethyl lactate isomer was only present at 0.93%. The yield of this step can be increased by avoiding...
Embodiment 2
[0092] Example 2 - Preparation of Polymorph 2
[0093] Suspend (S,S)-2-N(3-O-(propan-2-ol)-1-propyl-4-hydroxyphenyl)-3-phenylpropylamide (500 mg) in water (5 mL) The resulting suspension was neutralized and shaken and temperature cycled between 40°C and 25°C every 4 hours for 72 hours. Excess water was drained as far as practicable using a syringe and needle. Thereafter, the product was dried first by evaporating water at ambient temperature and then drying under vacuum at 50° C. until constant weight was reached.
[0094] Methods for Analyzing Polymorphs
[0095] X-ray powder diffraction (XRPD)
[0096] Approximately 5 mg of sample was gently compressed on an XRPD zero background single beveled silica sample holder. Then, the samples were loaded into a Philips X-Pert MPD diffractometer and analyzed using the following experimental conditions.
[0098] Generator tension: 40kV
[0099] Tube current: 40mA
[0100] Wavelength α1:
[01...
Embodiment 3
[0129] Example 3 - Bioavailability of polymorphs 1 and 2
[0130] The aim of this study was to obtain plasma samples to compare the bioavailability and pharmacokinetics of two different polymorphs 1 and 2 following single oral dose administration to 6 dogs. A crossover design was used with three dogs treated in sequence 1 (polymorph 1 followed by polymorph 2) and three dogs treated in sequence 2 (polymorph 2 followed by polymorph 1), The washout period between treatments was one week.
[0131] The post-treatment concentration-time curves for both polymorphs were characterized by rapid absorption with a sharp drop in concentration after reaching peak concentrations; at 4 hours and beyond, a second hump in the curves suggested enterohepatic recirculation.
[0132]Measures of drug exposure, maximum observed concentration (Cmax) and area under the plasma concentration-time curve (AUC) appeared to be higher following polymorph 2 administration compared to polymorph 1 administrat...
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