26171-23-3 Usage
Description
An antiinflammatory, analgesic, and antipyretic that is as efficacious as
moderate doses of aspirin and better tolerated. Tolmetin produces
a number of adverse effects including epigastric pain, dyspepsia,
nausea, and vomiting. Tolmetin is approximately 99% plasma
protein bound, yet does not interfere with concurrent treatment
with oral hypoglycemics. Tolmetin has been found to be effective in the treatment of osteoarthritis and rheumatoid arthritis.
Originator
Tolectin,McNeil,US,1976
Uses
Different sources of media describe the Uses of 26171-23-3 differently. You can refer to the following data:
1. inhibits synthesis of prostaglandins and
exhibits expressed analgesic, anti-inflammatory, and fever-reducing properties. It is used
for relieving weak to moderate pain in rheumatoid arthritis and osteoarthritis.
2. Tolmetine is an NSAID.
Definition
ChEBI: A monocarboxylic acid that is (1-methylpyrrol-2-yl)acetic acid substituted at position 5 on the pyrrole ring by a 4-methylbenzoyl group. Used in the form of its sodium salt dihydrate as a nonselective nonsteroidal anti-inflammatory drug.
Indications
Tolmetin (Tolectin) is indicated for the relief of osteoarthritis,
rheumatoid arthritis, ankylosing spondylitis,
and moderate pain. It is ineffective in gouty arthritis for
unknown reasons.Tolmetin can inhibit both COX-1 and
COX-2 but has a moderate selectivity for COX-1. The
most frequently reported side effects are GI disturbance
and CNS reactions (e.g., headache, asthenia, and
dizziness). These effects are less frequently observed
than after aspirin or indomethacin use. Blood pressure
elevation, edema, and weight gain or loss have been
associated with tolmetin administration. Tolmetin metabolites
in urine have been found to produce pseudoproteinuria
in some laboratory tests.
Manufacturing Process
5-(p-Toluoyl)-1-methylpyrrole-2-acetonitrile - To a cooled suspension of 26.6 g
(0.2 mol) aluminum chloride in 80 ml dichloroethane is added dropwise 30.8 g
(0.2 mol) p-toluoyl chloride. The resulting solution is added dropwise to a
solution of 1-methylpyrrole-2-acetonitrile in 80 ml dichloroethane cooled
externally with an ice bath. After the addition, the resulting solution is stirred
at room temperature for 20 minutes and then refluxed for 3 minutes. The
solution is poured into ice acidified with dilute hydrochloric acid. The organic
and aqueous fractions are separated. The aqueous fraction is extracted once
with chloroform.
The organic fractions are combined and washed successively with N,N_x0002_dimethyl-1,3-propanediamine, dilute hydrochloric acid, saturated sodium
bicarbonate solution and saturated sodium chloride solution. The organic
fraction is dried over anhydrous magnesium sulfate. The solvent is then
evaporated off. Upon trituration of the residue with methanol, a solid
crystallizes, 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, which is removed by
filtration and purified by recrystallization from benzene.
Additional product is isolated from the mother liquors which are combined,
concentrated in vacuo and the resulting oily residue column chromatographed
on neutral alumina using hexane, benzene and ether as successive solvents.
The product is isolated by concentrating in vacuo the first few major
compound-bearing fractions (10% ether in benzene). The solids are combined
and recrystallized from methanol and then from benzene-hexane, melting
point 102°C to 105°C.
5-(p-Toluoyl)-1-methylpyrrole-2-acetic acid - A solution of 3.67 g (0.015 mol)
of 5-(p-toluoyl)-1-methylpyrrole-2-acetonitrile, 24 ml of 1 N sodium hydroxide
and 50 ml of 95% ethanol is stirred and refluxed for 24 hours.
The resulting solution is poured into ice acidified with dilute hydrochloric acid.
A white solid precipitates which is extracted into ether. The ether phase is
washed with a saturated solution of sodium chloride and dried over anhydrous
magnesium sulfate. The solvent is evaporated and a white solid, 5-(p-toluoyl)-
1-methylpyrrole-2-acetic acid is obtained which is recrystallized twice from
isopropanol, melting point 155°C to 157°C.
Therapeutic Function
Antiinflammatory
Biological Functions
Tolmetin (Tolectin) is an antiinflammatory, analgesic,
and antipyretic agent that produces the usual gastric
distress and ulceration observed with NSAIDs.
However, tolmetin is better tolerated than aspirin and
produces less tinnitus and vertigo. Tolmetin is a substitute
for indomethacin in indomethacin-sensitive patients
and is unique among such drugs in that it can be
used to treat juvenile arthritis.
General Description
Tolmetin sodium (Tolectin), is an arylacetic acid derivativewith a pyrrole as the aryl group. This drug is well absorbed and has a relatively short plasma half-life (1 hour). It is recommendedfor use in the management of acute and chronicRA. Its efficacy is similar to aspirin and indomethacin, butwith less frequency of the adverse effects and tinnitus associatedwith aspirin. It does not potentiate coumarin-likedrugs nor alter the blood levels of sulfonylureas or insulin.However, tolmetin, and especially its closely related drug,zomepirac (i.e., with a p-chlorobenzoyl group and an additionalmethyl group on the pyrrole ring), can produce a rarebut fatal anaphylactic reaction because of irreversible bindingof their unstable acyl glucuronides. Zomepirac waswithdrawn from market because it is eliminated only via theester-type, acyl glucuronide. It is possible that tolmetin isless toxic in this regard because it undergoes additional hepaticbenzylic hydroxylation via its p-methyl group and isexcreted as its stable ether glucuronide.
Synthesis
Tolmetin, 1-methyl-5-n-tolylpyrrol-2-acetic acid (3.2.61) is synthesized from 1-
methylindole, which is aminomethylated using formaldehyde and dimethylamine, forming
2-dimethylaminomethyl-1-methylindol (3.2.57). The product is methylated by methyl
iodide, giving the corresponding quaternary salt (3.2.58). Reaction of the product with
sodium cyanide gives 1-methylpyrrole-2-acetonitrile (3.2.59), which is acylated at the free α-position of the pyrrole ring by 4-methylbenzoylchloride in the presence of aluminum
chloride. The resulting 1-methyl-5-n-toluylpyrrol-2-acetonitrile (3.2.60) undergoes further
alkaline hydrolysis, giving corresponding acid, tolmetin (3.2.61) [116–118].
Check Digit Verification of cas no
The CAS Registry Mumber 26171-23-3 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,6,1,7 and 1 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 26171-23:
(7*2)+(6*6)+(5*1)+(4*7)+(3*1)+(2*2)+(1*3)=93
93 % 10 = 3
So 26171-23-3 is a valid CAS Registry Number.
InChI:InChI=1/C14H13NO3/c1-9-3-5-10(6-4-9)13(16)11-7-8-12(14(17)18)15(11)2/h3-8H,1-2H3,(H,17,18)
26171-23-3Relevant articles and documents
Design, synthesis, anticancer evaluation, and molecular modelling studies of novel tolmetin derivatives as potential VEGFR-2 inhibitors and apoptosis inducers
Doghish, Ahmed S.,Gedawy, Ehab M.,Hamed, Mohammed I. A.,Hassan, Rasha A.,Kassab, Asmaa E.
, p. 922 - 939 (2021)
Novel tolmetin derivatives 5a–f to 8a–c were designed, synthesised, and evaluated for antiproliferative activity by NCI (USA) against a panel of 60 tumour cell lines. The cytotoxic activity of the most active tolmetin derivatives 5b and 5c was examined against HL-60, HCT-15, and UO-31 tumour cell lines. Compound 5b was found to be the most potent derivative against HL-60, HCT-15, and UO-31 cell lines with IC50 values of 10.32 ± 0.55, 6.62 ± 0.35, and 7.69 ± 0.41 μM, respectively. Molecular modelling studies of derivative 5b towards the VEGFR-2 active site were performed. Compound 5b displayed high inhibitory activity against VEGFR-2 (IC50 = 0.20 μM). It extremely reduced the HUVECs migration potential exhibiting deeply reduced wound healing patterns after 72 h. It induced apoptosis in HCT-15 cells (52.72-fold). This evidence was supported by an increase in the level of apoptotic caspases-3, -8, and -9 by 7.808-, 1.867-, and 7.622-fold, respectively. Compound 5b arrested the cell cycle in the G0/G1 phase. Furthermore, the ADME studies showed that compound 5b possessed promising pharmacokinetic properties.
Synthetic method of non-steroidal antiinflammatory drug pain killing
-
Paragraph 0041; 0052-0055; 0066-0067; 0094; 0105-0105, (2021/04/17)
The invention discloses a synthesis method of non-steroidal anti-inflammatory drug tolmetin. The methodcomprises the following steps: sequentially preparing a sulfuric acid-containing acetonedicarboxylic acid crude product, 2-(2-acetoxy)-1-methyl-1H-pyrrole-3-formic acid and 2-(2-alkyl acetate)-1-methyl-1H-pyrrole-3-formic acid by taking citric acid or citric acid monohydrate as a raw material; and carrying out decarboxylation, acylation, hydrolysis and acidification to obtain tolmetin. The synthetic method provided by the invention overcomes the defect that the existing tolmetin preparation process depends on N-methylpyrrole, and is a low-cost, low-pollution and high-yield synthetic method of non-steroidal anti-inflammatory drug tolmetin.
Isotope labelling by reduction of nitriles: Application to the synthesis of isotopologues of tolmetin and celecoxib
Ellis-Sawyer, Kate,Bragg, Ryan A.,Bushby, Nick,Elmore, Charles S.,Hickey, Michael J.
, p. 213 - 220 (2017/04/10)
The aryl methyl group is found in many drug-like compounds, but there are limited ways of preparing compounds with an isotope label in this methyl position. The process of cyanation of an aryl halide followed by complete reduction of the nitrile to a methyl group was investigated as a route for preparing stable and radiolabelled isotopologues of drug-like compounds. Using this methodology, carbon-13, deuterium, carbon-14, and tritium labelled isotopologues of the nonsteroidal anti-inflammatory drug tolmetin were produced, as well as carbon-13, deuterium, and carbon-14 labelled isotopologues of another nonsteroidal anti-inflammatory drug, celecoxib. The radiolabelled compounds were produced at high specific activity and the stable isotope labelled compounds with high incorporation making them suitable for use as internal standards in mass spectrometry assays. This approach provides a common synthetic route to multiple isotopologues of compounds using inexpensive and readily available labelled starting materials.
