Trimetrexate

CI-898 · NSC249008 · NSC-249008 · Trimetrexate · CI 898 · CI898 · 5-Methyl-6-(3,4,5-trimethoxyanilinomethyl)quinazoline-2,4-diamine · 5-Methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-2,4-quinazolinediamine

https://huagongshe.com/de/chemical/5583

Identifikatoren & physikalische Daten

CAS No.	52128-35-5
Summenformel	C19H23N5O3
Durchschnittliche Molmasse	369,4 g/mol
Monoisotopische Masse	369,1800896 g/mol
SMILES	COc1cc(NCc2ccc3nc(N)nc(N)c3c2C)cc(OC)c1OC
InChIKey	NOYPYLRCIDNJJB-UHFFFAOYSA-N
PubChem CID	5583
ChEMBL	CHEMBL119
ChEBI	CHEBI:9737
DTXSID	DTXSID3023714

Chemische & physikalische Eigenschaften

XLogP	2,5
Polarare Oberfläche (TPSA)	118
H-Brücken-Donoren	3
H-Brücken-Akzeptoren	8
Frei drehbare Bindungen	6
Schwere Atome	27
Formalladung	0
Komplexität	457
Arzneimittel	Pharmaceuticals -> Listed in ZINC15
LogP (Verteilungskoeffizient)	22.55
Löslichkeit	Tan colored solidsolubility in water: > 50 mg/ml /Trimetrexate D-glucuronate/3.09e-02 g/LWater 1 - 2 (mg/mL)pH 4 Acetate buffer < 1 (mg/mL)pH 9 Acetate buffer < 1 (mg/mL)DMSO : ≥ 61.5 mg/mL (166.48 mM)
Schmelzpunkt	215-217 °C215 - 217 °C
Physical Description	Solid
Stability/Shelf Life	Bulk: A sample stored at 60 °C for 30 days showed no decomposition (UV, HPLC). Solution: A solution in 5% methanol (0.5 mg/mL) showed no decomposition after 9 days (UV). A solution in 5% dimethylacetamide /pH 4 acetate buffer showed no decomposition after 48 hours(HPLC).
Dissociation Constants	8.0
Other Experimental Properties	Crystals from aqueous acetic acidmp: 215-217 °Cpoorly sol in water. /Trimetrexate monoacetate monohydrate/
Siedepunkt	647.0±65.0 °C(Predicted)
Dichte	1.305±0.06 g/cm3(Predicted)
Lagerbedingungen	2-8°C(protect from light)
Aggregatzustand	Solid
pKa (Säurekonstante)	8.09±0.30(Predicted)
Farbe	Light yellow to green yellow

Sicherheit & Vorschriften

Weitere Sicherheitsinformationen	IMAP assessments - 2,4-Quinazolinediamine, 5-methyl-6-[[(3,4,5-trimethoxyphenyl)amino]methyl]-: Environment tier I assessment
FDA-Anforderungen	Manufacturers, packers, and distributors of drug and drug products for human use are responsible for complying with the labeling, certification, and usage requirements as prescribed by the Federal Food, Drug, and Cosmetic Act, as amended (secs 201-902, 52 Stat. 1040 et seq., as amended21 U.S.C. 321-392).
Hazardous Reactivities and Incompatibilities	Trimetrexate is incompatible with solutions containing chloride ions. Only dextrose 5% in water is recommended for intravenous infusion.Trimetrexate and leucovorin must be administered separately, as a precipitate forms instantly when these 2 drugs added together.
Treatment	In the event of overdose, Trimetrexate should be stopped and leucovorin should be administered at a dose of 40 mg/m2 every 6 hours for 3 days. (L1712)
Gesundheitliche Auswirkungen	Antibiotic resistance
Hepatotoxicity	When given without leucovorin protection, trimetrexate therapy is associated with a moderate rate of serum enzyme elevations, serum ALT or AST elevations above 5 times ULN in up to 20% of patients. When given with leucovorin, however, trimetrexate has fewer side effects although serum enzyme elevations can still occur. In clinical trials in patients with HIV infection and Pneumocystis jirovecii pneumonia, ALT elevations above 5 times ULN occurred in 1% to 8% of patients, but were usually no more frequent than with standard therapy using trimethoprim with sulfamethoxazole. The elevations were typically transient, without accompanying symptoms or jaundice and resolved or improved despite continuation of therapy. No instances of clinically apparent acute liver injury attributed to trimetrexate have been reported in the literature. In addition, trimetrexate has not been linked to sinusoidal obstruction syndrome or to reactivation of hepatitis B. Nevertheless, trimetrexate probably has hepatotoxic potential, but because it has limited use, is given for short periods of time and is administered with leucovorin, it has not been convincingly linked to cases of clinically apparent liver injury with jaundice.
Expositionspfade	Intravenous injection
Toxizitätsübersicht	In vitro studies have shown that trimetrexate is a competitive inhibitor of dihydrofolate reductase (DHFR) from bacterial, protozoan, and mammalian sources. DHFR catalyzes the reduction of intracellular dihydrofolate to the active coenzyme tetrahydrofolate. Inhibition of DHFR results in the depletion of this coenzyme, leading directly to interference with thymidylate biosynthesis, as well as inhibition of folate-dependent formyltransferases, and indirectly to inhibition of p.r.n. biosynthesis. The end result is disruption of DNA, RNA, and protein synthesis, with consequent cell death.
Signs and Symptoms	The most common side effects from antibiotics are diarrhea, nausea, vomiting. Fungal infections of the mouth, digestive tract and vagina can also occur with antibiotics
Human Toxicity Excerpts	Side effects have been noted to occur less often with trimetrexate than with methotrexate. Hematologic toxicity has been the primary as well as the dose-limiting side effect seen to date in clinical studies in patients being treated for pneumocystis carinii pneumonia. These patients have had manageable decreases in neutrophil and platelet counts. Adverse effects reported in AIDS patients have included nausea, vomiting, diarrhea, reversible liver function abnormalities, skin rash, and fever. In cancer patients treated with trimetrexate (without leucovorin), hematologic toxicities have also been observed. Mild to moderate mucositis and stomatitis have occurred in some cancer patients, but this is rare in pneumocystis carinii pneumonia patients.
Carcinogen Classification	No indication of carcinogenicity to humans (not listed by IARC).
Antidote and Emergency Treatment	Recommended method to remove /methotrexate/: charcoal hemoperfusion. /Methotrexate/Leucovorin preferably should be given within the first hour after overdosetherefore, the initial route should be iv using a dose equal to amount of folic acid antagonist consumed. Thereafter, oral doses (15 mg) should be given every 6 hr for methotrexate. /Methotrexate/Inadvertent intrathecal overdosage of methotrexate constitutes a medical emergency, requiring prompt treatment and management. Although data are limited, management may be guided by the dose administered, time elapsed since administration, and anticipated severity of neurotoxicity. Regardless of the dose administered, as soon as the overdose is recognized, a repeat lumbar puncture should be performed immediately and CSF allowed to drain to gravity. The efficacy of CSF drainage alone as a means for removing the drug is a function of the dose administered and time elapsed since administration, and decreases as these factors increase. If the dose exceeds 100 mg, prompt neurosurgical intervention with ventriculolumbar perfusion following immediate CSF drainage should be consideredcontinuous CSF drainage or multiple CSF exchanges may also be considered but are not likely to be as effective. Other treatment measures may include high-dose parenteral leucovorin calcium therapy to minimize systemic toxicity, corticosteroids to minimize CNS inflammatory reactions, and other supportive therapy as necessary. While the addition of leucovorin to the ventriculolumbar perfusion fluid has been suggested and employed, its value is not known and the possibility that it may be epileptogenic via this route of administration should be considered. The possible benefits of prophylactic anticonvulsant therapy are probably outweighed by the potential for obscuring acute neurologic symptoms and causing additional adverse effects. /Methotrexate/In cases of overdosage of methotrexate, leucovorin calcium, a potent folic acid antagonist antidote, should be administered as soon as possible, preferably within the first hr. Use of leucovorin calcium after an hr's delay is much less effective. In general, the dose of leucovorin calcium should be equal to or greater than that of methotrexate. When large doses or overdoses of methotrexateare given, leucovorin calcium may be administered by iv infusion in doses up to 75 mg within 12 hr, followed by 12 mg im every 6 hr for 4 doses. Other leucovorin calcium dosage regimens are also recommended. When average doses of methotrexate appear to have an adverse effect, 6-12 mg of leucovorin calcium may be given im every 6 hr for 4 doses. Leucovorin calcium has been administered several hr following high-dose methotrexate therapy in an effort to control the duration of exposure of sensitive cells to methotrexate ("leucovorin rescue")the manufacturers warn that this procedure is considered investigational and hazardous. /Methotrexate/
Toxicity Data	LD50: 62 mg/kg (Intravenous, Mouse) (A308)
Gefahrstoffdaten	52128-35-5(Hazardous Substances Data)

Anwendungen & Verwendung

Beschreibung

Trimetrexate (TMQ) has been approved for the treatment of Pneumocystis carinii in patients with AIDS and also exhibits antiprotozoal activity against Trypanosoma cruzi . The drug is available as a single-ingredient medication, but it can be administered along with folinic acid in much the same way that methotrexate is administered with calcium leucovorin in cancer chemotherapy. Trimetrexate is a derivative of methotrexate.

Verwenden

Trimetrexate is an FDA-approved drug which selectively inhibits Streptococcus mutans through targeting dihydrofolate reductase (DHFR).