150399-23-8 Usage
Description
Pemetrexed disodium, marketed as ALIMTA, is a novel, multi-targeted antifolate that suppresses tumor growth by impeding both DNA synthesis and folate metabolism. It is a pyrrolo[2,3-d]pyrimidine-based antifolate that disrupts cell replication by inhibiting multiple folate-dependent metabolic processes. Pemetrexed disodium has demonstrated promising clinical activity in a wide variety of solid tumors, including non-small cell lung, breast, mesothelioma, colorectal, pancreatic, gastric, bladder, cervix, and head and neck.
Uses
Used in Anticancer Applications:
Pemetrexed disodium is used as an antineoplastic agent for the treatment of malignant pleural mesothelioma in patients who cannot be treated with surgery and non-small cell lung cancer (certain types) in patients whose disease is locally advanced or has metastasized. It is also being studied in the treatment of other types of cancer.
Used in Drug Delivery Systems:
Pemetrexed disodium is used in combination therapy with cisplatin for the treatment of malignant pleural mesothelioma. The combination therapy has shown to increase the median overall survival time compared to cisplatin alone.
Used in Pharmaceutical Industry:
Pemetrexed disodium is used as an active pharmaceutical ingredient in the development of cancer treatments. It is available in a 100-mg sterile vial for intravenous use and is administered via the IV route, distributing to all tissues. Cellular activation to the more potent polyglutamated forms occurs, and the majority of the dose is excreted unchanged in the urine.
Used in Research and Development:
Pemetrexed disodium is used as a research compound for studying its effects on various types of cancer and its potential applications in combination therapies. It is also used to investigate the mechanisms of resistance and the development of new drug delivery systems to enhance its efficacy and bioavailability.
References
[1] https://www.cancer.gov/about-cancer/treatment/drugs/pemetrexeddisodium
[2] Axel-R. Hanauske, V. Chen P. Paoletti, C. Niyikiza (2001) Pemetrexed Disodium: A Novel Antifolate Clinically Active Against Multiple Solid Tumors, The Oncologist, 6, 363-373
Originator
Eli Lilly (US)
Mechanism of action
Like methotrexate, it is actively transported into tumor cells through reduced folate carriers and, in polyglutamated form, inhibits the synthesis of pyrimidine and purine-based nucletotides by disrupting folatedependent metabolic processes . In addition to DHFR, this pyrrolopyrimidine-based inhibitor binds tightly to thymidylate synthase and GAR transformylase.
Clinical Use
Pemetrexed is a novel multitarget antifolate used by the IV route for the treatment of advanced or metastatic nonsmall cell lung cancer and in combination with cisplatin in malignant pleural mesothelioma.
Side effects
Patients on pemetrexed must take folate and vitamin B12 supplements to reduce the risk of bone marrow suppression (neutropenia, thrombocytopenia, and anemia) and GI side effects. Pretreatment with corticosteroids can reduce the risk of drug-induced skin rash. Pemetrexed has a half-life of 3.5 hours and is excreted primarily unchanged via the kidneys. Significant cross-resistance has been noted between pemetrexed and other pyrimidine and folate antagonists.
Synthesis
A number of papers
outlining the syntheses of pemetrexed and related analogs have appeared. A practical and scalable synthetic
route is depicted in Scheme 9. Palladium (0) coupling
of methyl 4-bromobenzoate (57) with 3-butyn-1-ol (58) gave
crystalline 59, which was then reduced over palladium on
carbon in DCM to give alcohol 60. Filtration of the catalyst
afforded a DCM solution of alcohol 60, which was utilized
directly in a TEMPO-catalyzed sodium hypochlorite
oxidation, providing known aldehyde 61 without isolation.
Addition of 5,5-dibromobarbituric acid (DBBA) and
catalytic amount of HBr in acetic acid to the DCM solution
of 61 effected the conversion to a-bromoaldehyde 62. After
aqueous work-up, the solution was concentrated and diluted
with acetonitrile to exchange solvents. Addition of
commercially available 2,4-diamino-6-hydroxypyrimidine
(63), aqueous sodium acetate and heating to 45°C resulted in
cyclic condensation and precipitation of pyrrolo[2,3-
d]pyrimidine 64 from the reaction mixture in 67% yield
based on 60. Saponification of 64 with aqueous sodium
hydroxide followed by acidification afforded the carboxylic
acid derivative 65, which was elaborated to 66 by
chlorodimethoxytriazine active ester coupling method.
Reaction of 65 with 2-chloro-4,6-dimethoxy-1,3,5-triazine
(CDMT) in the presence of N-methylmorpholine in DMF
solution followed by reaction of the resulting dimethoxy-s-triazinyl ester with diethyl L-glutamate afforded crude 66,
which was isolated via crystallization as pTSA salt 67.
Saponification of 67 with aqueous sodium hydroxide
followed by acidification with HCl gave pemetrexed as the
free acid, which was crystallized as disodium salt form.
Drug interactions
Potentially hazardous interactions with other drugs
Antimalarials: antifolate effect increased by
pyrimethamine. Antipsychotics: avoid with clozapine, increased risk
of agranulocytosis.
Nephrotoxic agents: may reduce clearance of
pemetrexed - use with caution.
Live vaccines: avoid use; YELLOW
FEVER VACCINE ABSOLUTELY
CONTRAINDICATED.
Metabolism
Pemetrexed undergoes minimal hepatic metabolism,
and about 70-90% of a dose is eliminated unchanged in
the urine within 24 hours. In vitro studies indicate that
pemetrexed is actively secreted by OAT3 (organic anion
transporter).
Check Digit Verification of cas no
The CAS Registry Mumber 150399-23-8 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,5,0,3,9 and 9 respectively; the second part has 2 digits, 2 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 150399-23:
(8*1)+(7*5)+(6*0)+(5*3)+(4*9)+(3*9)+(2*2)+(1*3)=128
128 % 10 = 8
So 150399-23-8 is a valid CAS Registry Number.
InChI:InChI=1/C20H21N5O6.2Na.7H2O/c21-20-24-16-15(18(29)25-20)12(9-22-16)6-3-10-1-4-11(5-2-10)17(28)23-13(19(30)31)7-8-14(26)27;;;;;;;;;/h1-2,4-5,9,13H,3,6-8H2,(H,23,28)(H,26,27)(H,30,31)(H4,21,22,24,25,29);;;7*1H2/q;2*+1;;;;;;;/p-2
