154323-57-6 Usage
Description
Almotriptan was first marketed in Spain as a new medicine against acute attacks of
migraine. It is the fifth agent belonging to the “triptan” class to be launched after
sumatriptan, naratriptan, zolmitriptan and rizatriptan. This close structural analog of
sumatriptan can be prepared in six steps from 4-nitrobenzylsulfonyl chloride with a Fischer
indole synthesis as the key step. Almotriptan acts as a dual 5-HT1D/1B agonist with a 35 to
51-fold selectivity versus 5-HT1A and 5-HT7 receptors respectively as well as having
insignificant affinity for the most relevant nonserotonergic receptors (K1＞1μM). Its
agonistic effect on 5-HT,n receptors of trigeminal sensory neurons turns off neurogenic
inflammation by inhibiting the release of neuropeptides such as calcitonin gene-related
peptide, neurokinin A and substance P. Concomitantly, its action on the 5-HT1B receptors
in meningeal arteries relieves the vasodilatation of these vessels associated with migraine
attacks. Almotriptan causes selective concentration-dependent vasoconstriction of human
meningeal and temporal arteries (with EC50 of 0.03 and 0.7 μM) compared to basilar (EC50
= 3.5 μM) and pulmonary arteries (EC50＞10μM) or rabbit mesenteric and renal arteries
(EC50＞100 μM). Although it is predominantly cleared by the kidneys as unchanged drug
(45%) or transformed into inactive metabolites by monoamine oxidase A (MAO-A) and
CYP3A4 enzymes in the liver, almotriptan has the highest oral bioavailability (70%) of the
triptans and has a half-life of 3.5 h. The therapeutic dose of 12.5 mg is well tolerated,
shows a rapid onset of action (30 min) and low recurrence rate compared to sumatriptan.
Originator
Almirall Prodesfarma (Spain)
Uses
Serotonin 5HT1B /1D-receptor agonist
Definition
ChEBI: An indole compound having a 2-(dimethylamino)ethyl group at the 3-position and a (pyrrolidin-1-ylsulfonyl)methyl group at the 5-position.
Manufacturing Process
To a solution of previously dried 1-[[2-carboxy-3-(2-dimethylaminoethyl)-5-
indolyl]methanesulphonyl]-pyrrolidine (1.6 g; 0.0442 moles) in anhydrous
quinoline (75 ml) and under atmosphere of nitrogen, cuprous oxide (160 mg;
0.0011 moles) was added. The reaction mixture was heated to 190°C for 15
minutes, stirred to room temperature, poured into a mixture of 1 N
hydrochloric acid (150 ml) and ethyl acetate (50 ml), shaken and decanted.
The aqueous solution was washed several times with ethyl acetate, then solid
sodium bicarbonate was added until pH = 7.8, and washed with n-hexane to
eliminate the quinoline. The aqueous solution was made alkaline with solid
potassium carbonate and extracted with ethyl acetate. The organic solution
was dried (Na2SO4), the solvent removed under reduced pressure when a
dark oil was obtained (1.3 g; yield 92%). This product was purified by column
chromatography with silica gel and methylene chloride:ethanol:ammonium
hydroxide (60:8:1) as eluent and a white foam (0.8 g) of 1-[[3-(2-
dimethylaminoethyl)-5-indolyl]methanesulphonyl]-pyrrolidine was obtained. To
a solution of the above product (0.8 g) in acetone (30 ml), a few drops of
hydrogen chloride saturated dioxan solution, were added. The precipitated
solid was collected by filtration, washed with acetone and dried to give 1-[(3-
(2-(dimethylamino)ethyl)-5-indolyl)methanesulphonyl]-pyrrolidine
hydrochloride (0.75 g). Melting point 218°-220°C.
In practice it is usually used as malate salt.
Brand name
Almogran
Therapeutic Function
Migraine therapy
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: increased risk of CNS toxicity with
citalopram - avoid; possibly increased serotonergic
effects with duloxetine or venlafaxine; increased
serotonergic effects with St John’s wort - avoid.
Antifungals: concentration increased by ketoconazole
(increased risk of toxicity).
Dapoxetine: possible increased risk of serotonergic
effects - avoid for 2 weeks after stopping 5HT1
agonists.
Ergot alkaloids: increased risk of vasospasm - avoid.
Metabolism
The major biotransformation route is via monoamine
oxidase (MAO-A) mediated oxidative deamination to
the indole acetic metabolite. Cytochrome P450 (3A4
and 2D6 isozymes) and flavin mono-oxygenase are other
enzymes involved in the metabolism of almotriptan.
None of the metabolites are significantly active
pharmacologically.
More than 75% of a dose is eliminated in urine, and the
remainder in faeces. Approximately, 50% of the urinary
and faecal excretion is unchanged almotriptan.
Check Digit Verification of cas no
The CAS Registry Mumber 154323-57-6 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,4,3,2 and 3 respectively; the second part has 2 digits, 5 and 7 respectively.
Calculate Digit Verification of CAS Registry Number 154323-57:
(8*1)+(7*5)+(6*4)+(5*3)+(4*2)+(3*3)+(2*5)+(1*7)=116
116 % 10 = 6
So 154323-57-6 is a valid CAS Registry Number.
InChI:InChI=1/C17H25N3O2S.C4H6O5/c1-19(2)10-7-15-12-18-17-6-5-14(11-16(15)17)13-23(21,22)20-8-3-4-9-20;5-2(4(8)9)1-3(6)7/h5-6,11-12,18H,3-4,7-10,13H2,1-2H3;2,5H,1H2,(H,6,7)(H,8,9)
154323-57-6Relevant articles and documents
Preparation method of anti-migraine drug almotriptan
-
, (2019/07/04)
The invention discloses a preparation method of an anti-migraine drug almotriptan. The method comprises the following steps: (1) N-protected o-haloaniline represented by formula (I) and 4-acetoxycrotonate represented by formula (II), which are used as raw materials, undergo a cascade reaction under the action of the basic skeleton of a palladium catalyst and a phosphine ligand, and an almotriptanbasic skeleton represented by formula (III) is collected from the obtained reaction product; and (2) the almotriptan basic skeleton represented by formula (III) undergoes reduction, deprotection, hydroxyl group activation and amino group substitution to obtain the product almotriptan. The preparation method has the advantages of simple and easily available raw materials and reagents, simplicity inoperation of the preparation, no harsh conditions, convenience in purification of the intermediate and the product, and high overall yield. The reaction formula is shown in the description.
Method for synthesizing almotriptan
-
Paragraph 0116; 0117; 0118; 0119; 0120, (2016/10/10)
The invention relates to the technical field of medicines, and particularly relates to a method for synthesizing almotriptan. The method comprises the following steps: drying nickel salt in vacuum under protection of argon, adding an anhydrous organic solvent and phosphine ligand, and stirring at room temperature; then, adding an alkaline substance in the mixed solution, stirring at room temperature, adding tetrahydropyrrole methyl sulfonamide and 3,5-disubstituted indole derivative; and keeping on reaction, extracting and drying after the reaction is quenched, and concentrating at reduced pressure, and purifying to obtain almotriptan. The reaction general formula is shown in the specification. The method is simple and short in synthesis route, only needs one-step reaction. The almotriptan has the characteristics of high yield, high purity and the like, has a yield of 80-92 percent and purity of 90-95 percent, and has wide industrial application.
NOVEL PROCESS
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Page/Page column 13-19, (2009/03/07)
The present invention relates to a novel process for the preparation of almotriptan and pharmaceutically acceptable salts thereof, which affords product conveniently and efficiently with commercially acceptable yields and purity. The present invention also relates to a novel synthetic intermediate used in the process.
