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Alosetron hydrochloride

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Alosetron hydrochloride Basic information
Alosetron hydrochloride Chemical Properties
  • Melting point:288-291°C
  • storage temp. 2-8°C
  • solubility H2O: ≥5mg/mL at warmed
  • form powder
  • color white to beige
  • CAS DataBase Reference122852-69-1(CAS DataBase Reference)
Safety Information
Alosetron hydrochloride Usage And Synthesis
  • DescriptionLotronex (alosetron) was developed for the treatment of severe irritable bowel syndrome (IBS), and was approved for use by the US Food and Drug Administration (FDA) in 2000. Although Lotronex had a relatively high improvement rate in patients taking the drug for IBS, it was voluntarily pulled from the market by GlaxoWellcome that same year due to reports of severe adverse side effects, some resulting in death.
    In 2002, Lotronex was reapproved in a supplemental New Drug Application for use under more restrictive conditions. Now with a risk management program to be consulted prior to administration of the drug, Lotronex is designated to be prescribed only when its medical benefits outweigh the risks of toxic effects; women with severe diarrhea-predominant IBS are now the focal point of prescriptions for Lotronex.
  • Chemical PropertiesAlosetron hydrochloride is Crystalline Solid
  • OriginatorAlosetron hydrochloride,GlaxoSmithKline
  • UsesAlosetron hydrochloride is used in treatment of irritable bowel syndrome
  • UsesLotronex is used for severe diarrhea-predominant IBS in women. There are other potential uses, as animal models have shown at least some evidence for the ability of Lotronex to mitigate the effects of psychosis, anxiety, cognitive impairment, emesis, and drug withdrawal. These possibilities have not been verified in humans, however.
  • DefinitionChEBI: The hydrochloride salt of alosetron.
  • Manufacturing Process4-(Chloromethyl)-1-(triphenylmethyl)-1H-imidazole.
    Thionyl chloride (0.829 g) was added over 1 min to a stirred suspension of 1- (triphenylmethyl)-1H-imidazole-4-methanol (1.3 g) in a mixture of dichloromethane (50 ml) and DMF (1.0 ml) at 23°C. The solution so obtained was stirred for 15 min. and extracted with 8% sodium bicarbonate solution (80 ml). The organic phase was washed with water (50 ml), dried and evaporated to give an oil which solidified. The solid was slurried in hexane and filtered to give the title compound (1.28 g), m.p. 139-141°C.
    3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime.
    3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one (1.7 g) and hydroxylamine hydrochloride (1.925 g) in pyridine were heated at 60°C for 18 h and cooled. The reaction mixture was evaporated in vacuo to a residue to which was added 8% sodium bicarbonate (150 ml). Extraction with ethyl acetate (300 ml) produced a suspension in the organic layer; this layer and associated solid was separated from the aqueous layer. The aqueous layer was re-extracted with ethyl acetate (250 ml). The combined organic extracts (and suspended solid) were evaporated to a residue, boiled with a mixture of ethanol (150 ml) and methanol (150 ml) and cooled to 50°C. The residue was adsorbed from this solution on to FCC silica and applied to an FCC column. Elution with ethyl acetate/3-10% methanol provided the title compound (1.69 g), m.p. 219- 224°C (decomp.).
    2,3,4,5-Tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one.
    3,4-Dihydro-4-methylcyclopent[b]indol-1(2H)-one oxime (1.53 g), polyphosphoric acid (409 g) and dioxan (15 ml) were heated at 110-120°C for 2.2 h under nitrogen. The reaction mixture was cooled, and treated with 2 N sodium carbonate solution (1 L). The suspension was extracted with ethyl acetate (4x400 ml) and the combined extracts were dried. Evaporation gave a solid (1.43 g) which was recrystallised from ethyl acetate/cyclohexane. This solid was purified by FCC, eluting with dichloromethane:ethanol:ammonia solution (200:10:1) to give a solid (1.26 g) which was recrystallised from ethanol to provide the title compound (960 mg), m.p. 234-238°C.
    2,3,4,5-Tetrahydro-5-methyl-2-[(5-methyl-1H-imidazol-4-yl)methyl]-1Hpyrido[ 4,3-b]indol-1-one maleate.
    A mixture of 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one (0.6 g) and 78% sodium hydride dispersion in mineral oil (0.109 g) in dry DMF (15 ml) was stirred under nitrogen at 50°C until hydrogen evolution ceased (ca. 1.5 h). The mixture was cooled to 40°C and a solution of 4-(chloromethyl)-5- methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The reaction was then stirred at 40°C for 3 h, at 20°C for 16 h and a further portion of 4-(chloromethyl)-5-methyl-1-(triphenylmethyl)-1H-imidazole (1.12 g) in dry THF (15 ml) was added. The resulting mixture was heated at 40°C for 3 h, quenched with water (20 ml) and acetic acid (20 ml), and heated at 100°C for 2 h. The mixture was then concentrated in vacuo to ca. 60 ml, diluted with 1 M hydrochloric acid (40 ml) and washed with ethyl acetate (3x50 ml). The organic phase was discarded and the acidic aqueous phase was basified (pH=9) with potassium carbonate and extracted with ethyl acetate:ethanol (20:1; 3x100 ml). The extracts were combined, dried and evaporated to give a brown gum (ca. 1 g). This gum was adsorbed onto silica and purified by FCC eluting with dichloromethane:ethanol:ammonia solition (100:8:1) to give a pale brown solid (0.8 g); m.p. 238-240°C (decomp.). This solid was dissolved in a mixture of (hot ethanol and methanol (1:1; 100 ml) and treated with an ethanolic solution of maleic acid (3.18 g). The resulting solution was concentrated to ca. 20 ml and diluted with dry diethyl ether (ca. 8 ml) to precipitate the title compound (0.75 g) as an off-white solid melting point 160-162°C. Hydrochloride may be prepared by treating the above solid with an equivalent of an ethanolic solution of HCl.
  • brand nameLotronex (GlaxoSmithKline).
  • Therapeutic FunctionAntidiarrheal
  • Environmental FateThe environmental fate and behavior of Lotronex is uncertain, as formal studies regarding its release into the environment are virtually nonexistent in the literature. Limited water solubility (61 mg ml-1) may lead to persistence in soils, and in sediment following aquatic release, although specific fates with regard to degradation, bioaccumulation, and transport are unknown.
  • Toxicity evaluationA highly potent and selective 5-HT3 receptor agonist, Lotronex rapidly binds to cation channels that exist on enteric neurons in the human gastrointestinal tract in addition to other central and peripheral locations. Lotronex inhibits the activation of these channels, resulting in effects to the enteric nervous system whereas the activation of these channels regulates (promotes) colonic transit, visceral pain pathways, and gastrointestinal secretions – all of which are processes related to the pathophysiology of IBS. The binding of Lotronex to 5-HT3 receptors reduces the rate at which fecal matter moves through the large intestine and increases water absorption. The toxic effects of Lotronex are related to the relative activation/inactivation of the cation channels responsible for mediating these processes.
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