103628-46-2 Usage
Uses
Used in Pharmaceutical Industry:
Sumatriptan is used as a serotonin 5HT1 receptor agonist for the acute treatment of migraine headaches with or without aura in adults. It is available in various dosage forms, including an oral tablet, a subcutaneous injection, a nasal spray formulation, and a suppository, allowing for tailored therapy to individual patient needs. Sumatriptan has a fast onset of action via subcutaneous injection or nasal spray administration. However, it is contraindicated with monoamine oxidase inhibitors because it is primarily degraded by hepatic MAO-A. Due to its short duration of action, frequent dosing may be required to prevent migraine recurrence.
Originator
Imigran,GlaxoSmithKline,UK
Manufacturing Process
A solution of (phenylthio)acetaldehyde (6.05 g) in absolute ethanol (180 ml)
was added over 10 min to a solution of 4-hydrazino-Nmethylbenzenemethanesulphonamide
hydrochloride (10 g) in water (180 ml)
with cooling. After addition of the aldehyde was complete, the mixture was
stirred at 5°C for a period of 14 h. The precipitated solid was filtered off,
washed with water (200 ml), hexane (200 ml) and dried in vacuo to give the
N-methyl-4-[2-[2-(phenylthio)ethylidene]hydrazino]benzenemethanesulphonamide
(10.95 g), melting point 110°-112°C.A solution of the N-methyl-4-[2-[2-
(phenylthio)ethylidene]hydrazino]benzenemethane-sulphonamide in absolute
ethanol (300 ml) was saturated with hydrogen chloride gas (ca. 30 min) whilst
being cooled in an ice-water bath, allowed to stir at room temperature for 3 h
and filtered. The filtrate was concentrated in vacuo and chromatographed to
afford a foam, which solidified on trituration with ether to an amorphous
powder (2.17 g). A sample was recrystallized from hexane-dichloromethane to
give the N-methyl-3-(phenylthio)-1H-indole-5-methanesulphonamide, melting
point 133°-134°C.To a solution of N-methyl-3-(phenylthio)-1H-indole-5-methanesulphonamide
(460 mg) in absolute ethanol (50 ml) was added Raney nickel [4.6 g, 50%
slurry in water, washed to neutrality with deionized water (60 ml)] and the
reaction mixture refluxed for 16 h under an atmosphere of nitrogen. On cooling to room temperature, the supernatant was removed and the Raney
nickel extracted with ethanol (2x50 ml, which was brought to a gentle reflux
for 15 min under an atmosphere of nitrogen). The combined extracts were
filtered through a sand-celite pad and concentrated in vacuo. Chromatography
of the residue, afforded an oil (87 mg) which crystallized from ether-hexane
to give the N-methyl-1H-indole-5-methanesulphonamide (90 mg), melting
point 127°-129°C.To N,N-diethyl chloroacetamide (800 mg) at 0°C was added phosphorous
oxychloride (250 μl) over a period of 30 sec. After the addition was complete,
the mixture was allowed to stir at 0°C for 15 min and then at room
temperature for 20 min. The N-methyl-1H-indole-5-methanesulphonamide
(300 mg) was added at 0°C and the mixture warmed to 65°C, whereupon it
dissolved. The mixture was stirred for 2 h at this temperature then poured
onto ice (ca. 5 g) and chloroform (5 ml) and stirred vigorously for 1 h. A solid
was filtered off, washed with water (50 ml), and hexane (100 ml) and dried in
vacuo to give the 3-(chloroacetyl)-N-methyl-1H-indole-5-
methanesulphonamide (192 mg).A solution of the 3-(chloroacetyl)-N-methyl-1H-indole-5-
methanesulphonamide (160 mg) in ethanolic dimethylamine (30 ml, 33% w/v
solution in ethanol) was heated to reflux for 2 h. On cooling to room
temperature the solvent was removed in vacuo and the residue was
chromatographed to afford the 3-[(dimethylamino)acetyl]-N-methyl-1Hindole-
5-methanesulphonamide, melting point 230°C, dec.To a suspension of the 3-[(dimethylamino)acetyl]-N-methyl-1H-indole-5-
methanesulphonamide (46.5 mg) in 1-propanol (5 ml) was added sodium
borohydride (62 mg). The reaction mixture was brought to reflux for a period
of 3 h, then an additional quantity of borohydride (60 mg) was added. After
refluxing for a further 1 h, the mixture was allowed to cool to room
temperature and quenched with 2 N HCl (10 ml). The aqueous solution was
washed with ethyl acetate (5 ml) then neutralized (NaHCO3 solution) and
extracted with ethyl acetate (3 x 15 ml). The combined extracts were
concentrated in vacuo and the residue chromatographed to give the 3-[2-
(dimethylamino)ethyl]-N-methyl 1H-indole-5-methanesulphonamide as a gum
(2 mg) which was shown by TLC.Succinic acid in hot methanol was added to a hot solution of the the 3-[2-
(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide in
absolute ethanol and the mixture was heated to reflux with stirring to give a
solution. The solution was allowed to cool with stirring to room temperature,
and the resultant suspension was farther cooled in an ice-bath for 2 h. The
solid was filtered off, washed with ethanol, and dried in vacuo to give the 3-
[2-(dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulphonamide, salt
with succinic acid (1:1).
Therapeutic Function
Serotoninergic
Clinical Use
5HT1
receptor agonist:
Acute relief of migraine
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: increased risk of CNS toxicity with
citalopram, escitalopram, fluoxetine and fluvoxamine
- avoid with citalopram; risk of CNS toxicity with
MAOIs, moclobemide, SSRIs, sertraline, St John’s
Wort - avoid; possibly increased serotonergic effects
with duloxetine and venlafaxine.
Dapoxetine: possible increased risk of serotonergic
effects - avoid for 2 weeks after stopping 5HT1
agonists.
Ergot alkaloids: increased risk of vasospasm - avoid.
Metabolism
Sumatriptan is extensively metabolised in the liver mainly
by monoamine oxidase type A and is excreted mainly in
the urine as the inactive indole acetic acid derivative and
its glucuronide.
Non-renal clearance accounts for about 80% of the
total clearance. The remaining 20% is excreted in urine,
mainly as metabolites, by active renal tubular secretion.
Sumatriptan and its metabolites also appear in the faeces.
Check Digit Verification of cas no
The CAS Registry Mumber 103628-46-2 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,0,3,6,2 and 8 respectively; the second part has 2 digits, 4 and 6 respectively.
Calculate Digit Verification of CAS Registry Number 103628-46:
(8*1)+(7*0)+(6*3)+(5*6)+(4*2)+(3*8)+(2*4)+(1*6)=102
102 % 10 = 2
So 103628-46-2 is a valid CAS Registry Number.
InChI:InChI=1/C14H21N3O2S/c1-15-10-20(18,19)12-4-5-14-13(8-12)11(9-16-14)6-7-17(2)3/h4-5,8-9,15-16H,6-7,10H2,1-3H3
103628-46-2Relevant articles and documents
Palladium-Catalyzed α-Arylation of Methyl Sulfonamides with Aryl Chlorides
Zheng, Bing,Li, Minyan,Gao, Gui,He, Yuying,Walsh, Patrick J.
supporting information, p. 2156 - 2162 (2016/07/16)
A palladium-catalyzed α-arylation of sulfonamides with aryl chlorides is presented. A Buchwald-type pre-catalyst formed with Kwong’s indole-based ligand enabled this transformation to be compatible with a large variety of methyl sulfonamides and aryl chlorides in good to excellent yields. Importantly, under the optimized reaction conditions, only mono-arylated products were observed. This method has been applied to the efficient synthesis of sumatriptan, which is used to treat migraines. (Figure presented.) .
PROCESS FOR PREPARING 3-(2-(DIMETHYLAMINO)ETHYL)-N- METHYL-1H-INDOLE-5-METHANESULFONAMIDE AND PRODUCT THEREOF
-
Page/Page column 10-11; 12-13, (2009/04/25)
The present invention relates to an improved process for the preparation of 3-(2- (dimethylamino) ethyl)-N-methyl- 1 H-indole-5-methanesulfonamide (sumatriptan) acid addition salt and the base having enhanced yield and purity. Further the present invention also provides a novel crystalline sumatriptan base.
Unanticipated acyloxymethylation of sumatriptan indole nitrogen atom and its implications in prodrug design
Rodrigues, Tiago,Moreira, Rui,Guedes, Rita C.,Iley, Jim,Lopes, Francisca
experimental part, p. 344 - 350 (2009/04/04)
Sumatriptan is a potent and selective 5-HT1B and 5-HT 1D agonist used in the symptomatic treatment of migraine; it shows poor oral bioavailability ascribed, in part, to its low lipophilicity. In an attempt to develop acyloxymethyl prodrugs of sumatriptan suitable for oral administration, we carried out the reaction of sumatriptan with chloromethyl esters. To our surprise, acyloxymethylation occurred preferentially at the indole nitrogen rather than at sulfonamide nitrogen, reflecting a difference either in product stability or in the nucleophilicities of the indole and sulfonamide anions. The hydrolysis of the corresponding N1- acyloxymethyl derivatives was studied in aqueous buffers and in human plasma, by HPLC. N1-Acyloxymethyl derivatives of sumatriptan are rapidly hydrolysed to the chemically stable N1-hydroxymethylsumatriptan at pH 1-13. Slow formation of the parent drug was observed only at high pH values. Hydrolysis of sumatriptan derivatives is slower in human plasma than in phosphate buffer and also generates N1-hydroxymethylsumatriptan rather than the parent drug. These results indicate that N1- acyloxymethyl derivatives of sumatriptan cannot be considered as true prodrugs of sumatriptan.
A NOVEL PROCESS FOR PREPARATION OF INDOLE DERIVATIVES
-
Page 10-12, (2010/02/09)
A novel process of preparation of a compound of 3-(2-Dimethylamino)-N-methyl-lH-indole-5-methane sulfonamide, which comprises of a reaction 4-hydrazino-N-methyl benzene methane sulfonamide with 4-dimethyl amino butyraldehyde diethyl acetal in a chlorinated solvent in the presence of ethyl poly phosphate and conversion of the crude product to a product of 3-(2-Dimethylamino)-N-methyl-lH-indole-5-methane sulfonamide succinate of extra high purity and colour.
3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-5-methanesulfonamide and the Succinate Thereof
-
Page 15-16, (2008/06/13)
A process for the preparation of highly pure Sumatriptan is described. A process for the preparation of novel crystalline Form I and crystalline Form II of Sumatriptan succinate is described. Sumatriptan is used for alleviating the pain of migraine headaches.
Process for the production of indole derivatives
-
, (2008/06/13)
The invention provides a process for the production of a compound of formula I, which comprises reacting a compound of formula II with a compound of formula III, in the presence of a strong base and a palladium(0) catalyst, at an elevated temperature, in a solvent which does not adversely affect the reaction. Compounds of formula I may be further processed to compounds of formula V, which are useful in the treatment of inter alia migraine.
Synthesis of 5-substituted indole derivatives, part II. Synthesis of sumatriptan through the Japp-Klingemann reaction
Pete, Bela,Bitter, Istvan,Harsanyi, Kalman,Toke, Laszlo
, p. 665 - 673 (2007/10/03)
Synthesis of selective 5-HT(1B/1D) receptor agonist, sumatriptan (1) was accomplished through decarboxylation of 2-carboxy-3-[2-(dimethylamino)ethyl]- N-methyl-1H-indole-5-methanesulfonamide (2) in quinoline with copper powder. The preparation of the acid (2) was effected through the Japp-Klingemann method thus avoiding the need for the formation of hydrazine from diazonium salt. Attempted decarboxylation in N,N-dimethylacetamide resulted in the formation of the β-carboline (16).
Simple methods for the labelling of N-methyl amines using isotopically labelled methyl iodide
Fellows, Ian,Carr, Richard M.,DeBoeck, Nigel,Montgomery, Stephen,Waterhouse, Ian,Sutherland, Derek R.
, p. 1127 - 1143 (2007/10/03)
Methods for the synthesis of isotopically labelled N-methyl amines using the target amine and isotopically labelled methyl iodide in a quaternisation/dequaternisation strategy are described. The method has been further refined to allow the synthesis of such amines without any isotopic dilution.
Synthesis of 5-substituted indole derivatives, I. An improved method for the synthesis of sumatriptan
Pete, Bela,Bitter, Istvan,Szantay Jr., Csaba,Schon, Istvan,Toke, Laszlo
, p. 1139 - 1149 (2007/10/03)
An improved synthesis of sumatriptan (1b) via Fischer cyclization was achieved by introducing the ethoxycarbonyl group on the N-atom of the sulphonamide moiety in N-methyl-4-hydrazinobenzenemethanesulphonamide (7). As a result, substitution on the benzylic carbon of the indole nucleus could be avoided; however, formation of 1,1-bis-(indol-2-yl)-4-dimethylaminobutane-type by-product (19) was observed. The indolization procedure was optimized to suppress the unwanted side reaction. The N-protection of the sulphonamide moiety was found to be beneficial regarding the purification of the 3-[2-(dimethylamino)ethyl]-N-ethoxycarbonyl-N-methyl-1H-indole-5- methanesulphonamide (18).
Indole derivative
-
, (2008/06/13)
A compound of formula (I) STR1 and its physiologically acceptable salts and solvates are described as useful in treating and/or preventing pain resulting from dilatation of the cranial vasculature in particular migraine. The compound (I) may be prepared, for example, by cyclizing a compound of formula (II) STR2
