122852-42-0 Usage
Description
Alosetron is a pyrido[4,3-b]indole compound with a 5-methyl-1H-imidazol-4-ylmethyl group at the 2-position. It is a crystalline powder that acts as an anti-emetic agent. Alosetron is marketed under the brand name Lotronex by GlaxoSmithKline.
Uses
Used in Pharmaceutical Industry:
Alosetron is used as an anti-emetic agent for the treatment of diarrhea-predominant irritable bowel syndrome (IBS-D) in women. It works by selectively binding to and inhibiting the 5-HT3 receptors in the gastrointestinal tract, which helps to reduce the frequency and severity of diarrhea and abdominal pain associated with IBS-D.
Originator
Alosetron
hydrochloride,GlaxoSmithKline
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drug was voluntarily withdrawn due to reported cases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.
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.
Therapeutic Function
Antidiarrheal
Check Digit Verification of cas no
The CAS Registry Mumber 122852-42-0 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,2,2,8,5 and 2 respectively; the second part has 2 digits, 4 and 2 respectively.
Calculate Digit Verification of CAS Registry Number 122852-42:
(8*1)+(7*2)+(6*2)+(5*8)+(4*5)+(3*2)+(2*4)+(1*2)=110
110 % 10 = 0
So 122852-42-0 is a valid CAS Registry Number.
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)
122852-42-0Relevant articles and documents
Cyclic Anti-Azacarboxylation of 2-Alkynylanilines with Carbon Dioxide
Miao, Bukeyan,Li, Suhua,Li, Gen,Ma, Shengming
, p. 2556 - 2559 (2016/07/06)
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
-
Page/Page column 13, (2010/05/13)
The present invention relates to new indolone modulators of 5-HT3 receptor, pharmaceutical compositions thereof, and methods of use thereof.
Medicaments
-
, (2008/06/13)
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.