122852-42-0

Basic information

• Product Name: ALOSETRON
• Synonyms: ALOSETRON;ALOSETRON 2,3,4,5-Tetrahydro-5-methyl-2-((5-methyl-1H-imidazol-4-yl)methyl)-1H-pyrido(4,3-b)indol-1-one;5-Methyl-2-[(4-methyl-1H-imidazol-5-yl)methyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-1-one
• CAS NO: 122852-42-0
• Molecular Formula: C17H18N4O
• Molecular Weight: 294.35
• Mol File: 122852-42-0.mol
• Article Data: 9

Chemical Properties

• Melting Point: 238-240 °C
• Boiling Point: 648.136 °C at 760 mmHg
• Flash Point: 345.781 °C
• Appearance: crystalline powder
• Density: 1.346 g/cm³
• Vapor Pressure: 1.1E-16mmHg at 25°C
• Refractive Index: 1.706
• PKA: 14.10±0.10(Predicted)
• CAS DataBase Reference: ALOSETRON(CAS DataBase Reference)
• NIST Chemistry Reference: ALOSETRON(122852-42-0)
• EPA Substance Registry System: ALOSETRON(122852-42-0)

Safety Data

• Hazard Codes: Xi
• Statements: 36/37/38
• Safety Statements: 26-36
• Hazardous Substances Data: 122852-42-0(Hazardous Substances Data)

Usage

Chemical Properties

crystalline powder

Originator

Alosetron hydrochloride,GlaxoSmithKline

Uses

Anti-emetic.

Indications

Alosetron (Lotronex) is a 5-HT3 receptor antagonist. Blocking this receptor results in decreased GI motility. Alosetron received FDA approval in February 2000 for the treatment of women with diarrhea-predominant IBS. In November 2000, at the request of the FDA, the drug was voluntarily withdrawn due to reported cases of ischemic colitis, including some fatalities.

Definition

ChEBI: A pyrido[4,3-b]indole compound having a 5-methyl-1H-imidazol-4-ylmethyl group at the 2-position.

Manufacturing Process

4-(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 name

Lotronex (GlaxoSmithKline).

Therapeutic Function

Antidiarrheal

InChI:InChI=1/C17H18N4O/c1-11-13(19-10-18-11)9-21-8-7-15-16(17(21)22)12-5-3-4-6-14(12)20(15)2/h3-6,10H,7-9H2,1-2H3,(H,18,19)

Upstream product

• 38585-62-5 4-hydroxymethyl-5-methylimidazole hydrochloride 
• 144-55-8 sodium hydrogencarbonate 
• 122852-75-9 2,3,4,5-tetrahydro-5-methyl-1H-pyrido[4,3-b]indol-1-one 
• 106147-85-7 4-chloromethyl-5-methyl-1-tritylimidazole 
• 550340-81-3 N₃-BOC-5-(hydroxymethyl)-4-methylimidazole 
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• 615-43-0 2-iodophenylamine 

Relevant articles and documents

Cyclic Anti-Azacarboxylation of 2-Alkynylanilines with Carbon Dioxide

Direct anti-azacarboxylation of 2-alkynylanilines with CO2 mediated by ZnEt2 was observed to afford indole-3-carboxylic acids, a class of important compounds for the synthesis of many biologically active compounds, efficiently under 1 atm of CO2. The readily available nature of the different starting materials and tolerance of various functional groups provide vast opportunities for the efficient construction of diversified libraries for bioactive compounds listed in Figure 1. As an example, this methodology has been applied to the synthesis of Lotronex, a drug molecule used for the treatment of irritable bowel syndrome.

INDOLONE MODULATORS OF 5-HT3 RECEPTOR

The present invention relates to new indolone modulators of 5-HT3 receptor, pharmaceutical compositions thereof, and methods of use thereof.

Medicaments

The invention relates to the use of compounds of formula (I) STR1 wherein Im represents an imidazolyl group of formula: STR2 and R1 represents a hydrogen atom or a group selected from C1-6 alkyl, C3-6 alkenyl, C3-10 alkynyl, C3-7 cycloalkyl, C3-7 cycloalkylC1-4 alkyl, phenyl, phenylC1-3 alkyl, phenylmethoxymethyl, phenoxyethyl, phenoxymethyl, --CO2 R5, --COR5, --CONR5 R6 or --SO2 R5 (wherein R5 and R6, which may be the same or different, each represents a hydrogen atom, a C1-6 alkyl or C3-7 cycloalkyl group, or a phenyl or phenylC1-4 alkyl group, in which the phenyl group is optionally substituted by one or more C1-4 alkyl, C1-4 alkoxy or hydroxy groups or halogen atoms, with the proviso that R5 does not represent a hydrogen atom when R1 represents a group --CO2 R5 or --SO2 R5); one of the groups represented by R2, R3 and R4 is a hydrogen atom or a C1-6 alkyl, C3-7 cycloalkyl, C3-6 alkenyl, phenyl or phenylC1-3 alkyl group, and each of the other two groups, which may be the same or different, represents a hydrogen atom or a C1-6 alkyl group; and n represents 2 or 3, and physiologically acceptable salts and solvates thereof for the manufacture of a medicament for the treatment of depression.