903576-44-3 Usage
Description
1-[3-[3-(4-Chlorophenyl)propoxy]propyl]-piperidinehydrochloride, also known as Pitolisant hydrochloride, is a first-in-class inverse agonist of the histamine H3 receptor. It was developed by Bioprojet and has orphan drug designation in the EU and US. Pitolisant hydrochloride enhances wakefulness by increasing histaminergic neuron activity and is approved in the EU for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy with or without cataplexy.
Uses
Used in Pharmaceutical Industry:
1-[3-[3-(4-Chlorophenyl)propoxy]propyl]-piperidinehydrochloride is used as a drug for the treatment of excessive daytime sleepiness (EDS) in adults with narcolepsy with or without cataplexy. It works by enhancing wakefulness through increasing histaminergic neuron activity.
Used in Sleep Disorder Treatment:
1-[3-[3-(4-Chlorophenyl)propoxy]propyl]-piperidinehydrochloride is used as a treatment for sleep disorders, specifically narcolepsy, by reducing excessive daytime sleepiness and improving overall sleep quality. It is administered once daily in the morning to ensure its waking effect is minimized at night.
Synthesis
The most likely scale preparation of pitolisant hydrochloride
consists of only four synthetic steps starting with the mesylation
of commercial 3-(4-chlorophenyl)propan-1-ol (132). Displacement of the mesylate with the sodium salt of
commercial 3-(piperidin-1-yl)propan-1-ol (133) in warm DMA
assembled the parent drug in 97% yield over two steps. Salt
formation was affected by pH adjustment to 3-4 using HCl gas
in EtOAc. Recrystallization from ethyl acetate and isopropanol
provided pitolisant hydrochloride (XII) on kilogram scale in
78% overall yield across the short four-step protocol.
in vitro
bf2.649 behaved as a competitive antagonist with a ki value of 0.16 nm. bf2.649 functioned as an inverse agonist with an ec50 value of 1.5 nm and an intrinsic activity about 50% higher than that of ciproxifan. pitolisant in vitro potency was approximately 6 times lower at the rodent receptor [1].
in vivo
pitolisant hcl was an oral bioavailable agonist. in mice, after oral and i.v. administrations of pitolisant hcl, the ratio of plasma areas under the curve was 84%. bf2.649 enhanced tele-methylhistamine levels in mouse brain, an index of histaminergic neuron activity in a dose dependent manner with an ed50 value of 1.6 mg/kg p.o. the response persisted after repeated administrations for 17 days [1]. treatment with 20-, 40-, or 60-mg doses of pitolisant showed a statistically significant suppressive effect (standardized photosensitive response [spr] reduction as measured with paired t-tests) in 9/14 (64%) patients of whom 6/14 (43%) showed abolition of the response to intermittent photic stimulation (ips) [3]. bf2.649 showed significant inhibitory activity in several mouse models of schizophrenia [4].
references
[1] ligneau x, perrin d, landais l, camelin jc, calmels tp, et al, bf2. 649 [1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride], a nonimidazole inverse agonist/antagonist at the human histamine h3 receptor: preclinical pharmacology. j pharmacol exp ther.2007 jan;320(1):365-75.[2] t a esbenshade, k e browman, r s bitner, m strakhova, m d cowart, j d brioni the histamine h3 receptor: an attractive target for the treatment of cognitive disorders. br j pharmacol. 2008 jul; 154(6): 1166–1181.[3] kasteleijn-nolst trenité d, parain d, genton p, masnou p, schwartz jc, hirsch e. efficacy of the histamine 3 receptor (h3r) antagonist pitolisant (formerly known as tiprolisant; bf2.649) in epilepsy: dose-dependent effects in the human photosensitivity model. epilepsy behav.2013 jul;28(1):66-70.[4] ligneau x, landais l, perrin d, piriou j, uguen m, denis e, robert p, parmentier r, anaclet c, lin js, burban a, arrang jm,schwartz jc. brain histamine and schizophrenia: potential therapeutic applications of h3-receptor inverse agonists studied with bf2.649. biochem pharmacol. 2007 apr 15;73(8):1215-24. a
Check Digit Verification of cas no
The CAS Registry Mumber 903576-44-3 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 9,0,3,5,7 and 6 respectively; the second part has 2 digits, 4 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 903576-44:
(8*9)+(7*0)+(6*3)+(5*5)+(4*7)+(3*6)+(2*4)+(1*4)=173
173 % 10 = 3
So 903576-44-3 is a valid CAS Registry Number.
