+17～+24°(D/20℃)(c=1,Na2CO3 soln.)(calculated on the dehydrous basis)
沸点：
561.26°C (rough estimate)
密度：
1.4080 (rough estimate)
闪点：
11℃
溶解度：
不溶于水
物理描述：
Methotrexate is an odorless yellow to orange-brown crystalline powder. (NTP, 1992) It is a chemotherapy drug that interferes with DNA and RNA synthesis.
颜色/状态：
Orange-brown, crystalline powder
蒸汽压力：
2.1X10-19 mm Hg at 25 °C /Estimated/
旋光度：
Specific optical rotation: 20.4 + or - 0.6 deg at 21 °C/589 D (concentration by 0.1 N sodium hydroxide) maximum absorption: 243nm, A1= 388;307 nm, A1 = 475 (in 0.1 n hydrogen chloride). 258 nm, A1= 544; 303 nm, A1= 546; 372 nm, A1= 177 (in 0.1 N sodium hydroxide)
分解：
When heated to decomposition it emits toxic fumes including /nitrogen oxides/.
Methotrexate is metabolized by folylpolyglutamate synthase to methotrexate polyglutamate in the liver as well as in tissues. Gamma-glutamyl hydrolase hydrolyzes the glutamyl chains of methotrexate polyglutamates converting them back to methotrexate. A small amount of methotrexate is also converted to 7-hydroxymethotrexate.
After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora.
After absorption, methotrexate undergoes hepatic and intracellular metabolism to form methotrexate polyglutamate, metabolites which by hydrolysis may be converted back to methotrexate. Methotrexate polyglutamates inhibit dihydrofolate reductase and thymidylate synthetase. Small amounts of these polyglutamate metabolites may remain in tissues for extended periods; the retention and prolonged action of these active metabolites vary among different cells, tissues, and tumors. In addition, small amounts of methotrexate polyglutamate may be converted to 7-hydroxymethotrexate; accumulation of this metabolite may become substantial following administration of high doses of methotrexate, since the aqueous solubility of 7-hydroxymethotrexate is threefold to fivefold lower than that of the parent compound. Following oral administration of methotrexate, the drug also is partially metabolized by the intestinal flora. Renal excretion is the primary route of elimination, and is dependent upon dosage and route of administration (A620).
Route of Elimination: Renal excretion is the primary route of elimination and is dependent upon dosage and route of administration. IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose.
Half Life: Low doses (less than 30 mg/m^2): 3 to 10 hours; High doses: 8 to 15 hours.
Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.
Methotrexate is well known to cause serum aminotransferase elevations and long term therapy has been linked to development of fatty liver disease, fibrosis and even cirrhosis. The literature on methotrexate is extensive, but with great variability in rates of liver test and biopsy abnormalities at different doses, dose regimens and durations of therapy.
With high dose intravenous methotrexate, serum ALT levels can rise to 10 to 20 times the upper limit of normal (ULN) within 12 to 48 hours, but levels then fall rapidly to normal with only rare instances of jaundice or symptoms of liver injury. With long term, low-to-moderate dose methotrexate therapy, elevations in serum ALT or AST values occur in 15% to 50% of patients, but are usually mild and self-limiting. Approximately 5% of patients have elevations greater than twice normal and these abnormalities resolve rapidly with discontinuation or dose modification, but can resolve even with continuation at the same dose level. The reported rate of ALT elevations during therapy has varied considerably, perhaps because of differences in frequency of determinations (every month vs every 3, 6 or 12 months) and due to the timing of the blood sampling (whether just before or soon after the once weekly dose). Finally, coadministration of folic acid has been shown to decrease the frequency of serum enzyme elevations and now is commonly used.
Long term therapy with methotrexate has been associated with development of fatty liver and hepatic fibrosis and, in rare instances, portal hypertension and symptomatic cirrhosis. Symptoms are usually absent until cirrhosis is present, and liver tests are typically normal or minimally and transiently elevated. Routine monitoring of patients with regular liver biopsies done at 1 to 2 year intervals or with cumulative methotrexate doses of 1 to 10 grams demonstrates that approximately 30% of patients develop mild-to-moderate histological abnormalities (fat, cellular unrest, mild inflammation, nuclear atypical) and 2 to 20% of patients develop some degree of hepatic fibrosis. Well documented cases of cirrhosis arising during long term methotrexate therapy have been reported, but cirrhosis is rare in prospective series, even with routine histological monitoring. Patients who develop fibrosis on long term methotrexate therapy often have other risk factors for fatty liver disease, including excessive alcohol use, obesity, diabetes and concurrent administration of other potentially hepatotoxic agents. Use of high doses and daily methotrexate dosing is particularly associated with development of hepatic fibrosis and rates of cirrhosis of greater than 20% after 5 to 10 years of treatment. With more modern dose regimens (5 to 15 mg in one dose weekly with folate supplementation), fibrosis and clinically apparent liver disease are rare even with long term use. The hepatic fibrosis and cirrhosis due to methotrexate typically arise after 2 to 10 years of treatment and can present with ascites, variceal hemorrhage or hepatosplenomegaly. Some patients present with signs and symptoms of portal hypertension, yet have only moderate degrees of fibrosis, suggesting that methotrexate may also cause nodular regeneration. Patients who develop portal hypertension and cirrhosis usually have had minimal or no elevations in serum aminotransferase or alkaline phosphatase levels, and monitoring using serum enzymes appears to be poorly predictive of fibrosis development. Noninvasive markers of hepatic fibrosis, such as serial platelet counts, serum procollagen III aminoterminal peptide (PIIIP), serum bile acids, hepatic ultrasound, advanced imaging techniques and transient elastography may be more efficient in screening for fibrosis in patients on long term methotrexate, but the reliability and accuracy of these approaches has not been documented prospectively. Patients with cirrhosis due to methotrexate are often asymptomatic and the condition tends to be non-progressive, even in those who restart low dose therapy. Rare instances of hepatocellular carcinoma have been reported in patients with suspected methotrexate induced cirrhosis.
Low dose, long term methotrexate therapy has also been implicated in rare instances of reactivation of hepatitis B in patients with rheumatoid arthritis or psoriasis who were HBsAg carriers, without HBeAg and with normal ALT levels and no detectable or low levels of HBV DNA before starting methotrexate. The frequency of reactivation with methotrexate is unknown, but is probably low. Reactivation typically presents after years of therapy with methotrexate and most published cases were also receiving corticosteroids. The clinical presentation is characterized by insidious onset of fatigue, nausea and jaundice accompanied by marked elevations in serum ALT and HBV DNA levels. In some instances, the acute injury is severe and progressive resulting in liver failure. In many case reports, reactivation occurred when methotrexate was withdrawn, perhaps as a result of restoration of immune reactivity in those in whom HBV DNA levels have risen during treatment. Reactivation has also been described in patients with antibodies to HBV without HBsAg (reverse seroconversion) treated with methotrexate and prednisone. The cases of reactivation of hepatitis B published in the literature have mostly resulted in death or emergency liver transplantation, perhaps reflecting publication bias for more severe cases. These cases have led to recommendations for routine screening for HBsAg before starting long term methotrexate therapy and prophylaxis with antiviral agents or careful monitoring for rises in HBV DNA levels if methotrexate is used. However, whether methotrexate on its own, without prednisone, can cause reactivation of hepatitis B is not clear.
Likelihood score: A (well known cause of chronic, clinically significant liver injury, portal hypertension and cirrhosis).
Methotrexate has a bioavailability of 64-90%, though this decreases at oral doses above 25mg due to saturation of the carrier mediated transport of methotrexate.. Methotrexate has a Tmax of 1 to 2 hours. oral doses of 10-15µg reach serum levels of 0.01-0.1µM.
Methotrexate is >80% excreted as the unchanged drug and approximately 3% as the 7-hydroxylated metabolite. Methotrexate is primarily excreted in the urine with 8.7-26% of an intravenous dose appearing in the bile.
Methotrexate clearance varies widely between patients and decreases with increasing doses. Currently, predicting clearance of methotrexate is difficult and exceedingly high serum levels of methotrexate can still occur when all precautions are taken.
In adults, oral absorption of methotrexate appears to be dose dependent. Peak serum levels are reached within one to two hours. At doses of 30 mg/sq m or less, methotrexate is generally well absorbed with a mean bioavailability of about 60%. The absorption of doses greater than 80 mg/sq m is significantly less, possibly due to a saturation effect.
[EN] ACC INHIBITORS AND USES THEREOF<br/>[FR] INHIBITEURS DE L'ACC ET UTILISATIONS ASSOCIÉES
申请人：GILEAD APOLLO LLC
公开号：WO2017075056A1
公开（公告）日：2017-05-04
The present invention provides compounds I and II useful as inhibitors of Acetyl CoA Carboxylase (ACC), compositions thereof, and methods of using the same.
Heterocyclic derivatives for the treatment of cancer and other proliferative diseases
申请人：——
公开号：US20020143182A1
公开（公告）日：2002-10-03
The invention relates to certain heterocyclic compounds useful for the treatment of cancer and other diseases, having the Formula (I):
1
wherein:
(a) m is an integer 0 or 1;
(b) R
12
is an alkyl, a substituted alkyl, a cycloalkyl, a substituted cycloalkyl, a heterocyclic, a substituted heterocyclic, a heteroaryl, a substituted heteroaryl, an aryl or a substituted aryl residue;
(c) Ar
3
is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue;
(d) Ar
4
is an aryl, a substituted aryl, a heteroaryl or a substituted heteroaryl residue;
(e) R
5
is hydrogen, hydroxy, alkyl or substituted alkyl;
(f) - - - - - represents a bond present or absent; and
(g) W, X, Y and Z are independently or together C(O)—, C(S), S, O, or NH; or a pharmaceutically acceptable salt thereof.
[EN] COMPOUNDS AND COMPOSITIONS COMPRISING CDK INHIBITORS AND METHODS FOR THE TREATMENT OF CANCER<br/>[FR] COMPOSÉS ET COMPOSITIONS COMPRENANT DES INHIBITEURS DES CDK ET MÉTHODES DE TRAITEMENT DU CANCER
申请人：UNIV GEORGIA STATE RES FOUND
公开号：WO2010129858A1
公开（公告）日：2010-11-11
Disclosed herein are compounds suitable for use as antitumor agents, methods for treating cancer wherein the disclosed compounds are used in making a medicament for the treatment of cancer, methods for treating a tumor comprising, administering to a subject a composition comprising one or more of the disclosed cytotoxic agents, and methods for preparing the disclosed antitumor agents.
The present invention provides a cobalamin-drug conjugate suitable for the treatment of tumor related diseases. Cobalamin is indirectly covalently bound to an anti-tumor drug via a cleavable linker and one or more optional spacers. Cobalamin is covalently bound to a first spacer or the cleavable linker via the 5′-OH of the cobalamin ribose ring. The drug is bound to a second spacer of the cleavable linker via an existing or added functional group on the drug. After administration, the conjugate forms a complex with transcobalamin (any of its isoforms). The complex then binds to a receptor on a cell membrane and is taken up into the cell. Once in the cell, an intracellular enzyme cleaves the conjugate thereby releasing the drug. Depending upon the structure of the conjugate, a particular class or type of intracellular enzyme affects the cleavage. Due to the high demand for cobalamin in growing cells, tumor cells typically take up a higher percentage of the conjugate than do normal non-growing cells. The conjugate of the invention advantageously provides a reduced systemic toxicity and enhanced efficacy as compared to a corresponding free drug.
[EN] 2-QUINOLONE DERIVED INHIBITORS OF BCL6<br/>[FR] INHIBITEURS DE BCL6 DÉRIVÉS DE 2-QUINOLONE
申请人：CANCER RESEARCH TECH LTD
公开号：WO2018215798A1
公开（公告）日：2018-11-29
The present invention relates to compounds of formula I that function as inhibitors of BCL6(B- cell lymphoma 6) activity: Formula I wherein X1, X2, X3, R1, R2, R3, R4 and R5 are each as defined herein. The present invention also relates to processes for the preparation of these compounds, to pharmaceutical compositions comprising them, and to their use in the treatment of proliferative disorders, such as cancer,as well as other diseases or conditions in which BCL6 activity is implicated.
