Triamterene appears as odorless yellow powder or crystalline solid. Melting point 316°C. Almost tasteless at first and with a slightly bitter aftertaste. Acidified solutions give a blue fluorescence. Used as a diuretic drug.
颜色/状态：
Yellow plates from butanol
气味：
Odorless
蒸汽压力：
1.09X10-11 mm Hg at 25 °C (est)
稳定性/保质期：
Store at 25 °C (77 °F); excursions permitted to 15 deg - 30 °C (59 deg - 86 °F). Dispense in a tight, light resistant container.
分解：
When heated to decomposition it emits toxic fumes of /nitrogen oxides/.
解离常数：
pKa = 6.2
碰撞截面：
155.4 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]
Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma.
来源:DrugBank
代谢
三氨蝶吟的代谢和排泄命运尚未完全确定。据报道，该药物代谢为6-p-羟基三氨蝶吟及其硫酸结合物。
The metabolic and excretory fate of triamterene has not been fully determined. The drug is reportedly metabolized to 6-p-hydroxytriamterene and its sulfate conjugate.
The kinetics of triamterene and its active phase II metabolite were studied in 32 patients with various degrees of impaired renal function; the creatinine clearances ranged from 135 to 10 mL/min. The area under the plasma concentration-time curves (AUC) for triamterene were not influenced by kidney function, but the AUCs for the effective metabolite OH-TA-ester were significantly elevated in renal failure, indicating accumulation of the metabolite. Urinary recovery of triamterene and its metabolite over a 48 hr collection period was significantly reduced in renal failure. This is considered to be due to delayed urinary excretion, corresponding to reduced renal clearance. The renal clearance of the native drug exceeded that of the metabolite, because of their different protein binding, 55% for triamterene and 91% for the metabolite. The latter is eliminated almost exclusively via tubular secretion and extra-renal elimination is less important. ...
Patients with liver cirrhosis have reduced ability to hydroxylate triamterene, as evidenced by high plasma concentrations of triamterene and low concentrations of 4'-hydroxytriamterene sulfate. After administration of 200 mg of triamterene, peak plasma concentrations in eight patients without liver disease were 559 +/- 48 ng/mL and 2956 +/- 320 ng/mL for triamterene and 4'-hydroxytriamterene sulfate, respectively. In the seven patients with alcoholic cirrhosis, peak plasma concentrations of triamterene were increased to 1434 +/- 184 ng/mL, while the concentrations of the sulfate were reduced to 469 +/- 84 ng/mL. Renal clearance was also reduced in patients with cirrhosis: the clearance of triamterene and the sulfate were 2.8 +/- 0.7 and 38.0 +/- 6.6 mL/minute, respectively, compared with 14.4 +/- 1.5 and 116.7 +/- 11.6 mL/ minute, respectively, in patients without liver disease.
IDENTIFICATION AND USE: Triamterene is epithelial sodium channel blocker, which is used as diuretic in human patients, as well as in veterinary medicine in dogs and cats. There is little experience associated with its use in dogs or cats and it is rarely recommended. HUMAN STUDIES: Overdosage of triamterene may cause electrolyte imbalance, especially hyperkalemia. Nausea, vomiting, other GI disturbances, and weakness may also occur. Hypotension may also result, especially when the drug is used concomitantly with hydrochlorothiazide or other diuretics or hypotensive agents. Mucosal ulceration and severe bone-marrow insufficiency with marked megaloblastic transformation occurred during treatment with triamterene in a patient with decompensated alcoholic liver cirrhosis and malnutrition. Two cases of triamterene crystalline nephropathy have been reported. Acute intravascular hemolysis and renal failure developed while a patient was taking triamterene. ANIMAL STUDIES: In the first study in mice, triamterene caused significant increases in the incidences of hepatocellular adenoma in females. In a second study, survival of exposed mice was similar to that of controls. There were significant increases in the incidence of hepatocellular adenoma in males and females, and of hepatocellular adenoma or carcinoma (combined) in females. The incidence of liver foci was increased in some groups of treated mice in both the first and second studies. Treatment with triamterene also caused treatment-related thyroid follicular cell hyperplasia. Triamterene caused a significant increase in the incidence of hepatocellular adenoma in male rats. Hepatocellular adenoma was present in all three dosed groups of males and not in males in the control group. There was no significant increase in the incidence of tumors in female rats. Reproduction studies have been performed in rats without evidence of harm to the fetus due to triamterene. Triamterene was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537 with or without exogenous metabolic activation. It did not induce chromosomal aberrations in Chinese hamster ovary cells, with or without metabolic activation. Positive results were obtained for induction of sister chromatid exchanges in Chinese hamster ovary cells with and without metabolic activation.
Triamterene therapy has been associated with rare instances of idiosyncratic, clinically apparent liver injury which have invariably been mild and anicteric. The liver injury typically arises after 4 to 12 weeks of therapy and the pattern of serum enzyme elevations is usually hepatocellular or mixed. Fever is a prominent symptom and the reaction is often more typical of drug-fever than hepatotoxicity (Case 1). Rash and eosinophilia can occur, but are usually not prominent. Autoantibodies are rare. All published cases of triamterene associated liver injury have been self-limited in course and resolved rapidly upon withdrawal.
Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents.
Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide.
In a pharmacolinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Triamterene was found to cross the placental barrier and appear in the cord blood of animals.
The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers.
Earlier in vivo studies revealed a low concentration of triamterene in the brain of guinea pigs and baboons, and a transfer of the drug from the fetus to the mother. Additional investigations have been performed to characterize further the transport system(s) for triamterene in the central nervous system (CNS), placenta, and kidney. In guinea pigs a very low brain to free plasma concentration ratio (0.1) was achieved 3.5 min after drug administration and was maintained during 180 min of drug infusion. The cerebrospinal fluid (CSF) concentration was similar to the concentration of the drug in the brain. A higher brain to free plasma concentration ratio was gradually reached in dogs studied with nanogram per ml and microgram per ml concentrations of triamterene in CSF. Administration of triamterene to fetal and maternal sheep revealed a placental extraction (E) from fetal plasma to placenta 20 times greater than that from maternal plasma to placenta. The E from fetal plasma to placenta was unaffected by a triamterene concentration in the maternal circulation 10 times that in the fetus. These findings and studies of renal clearance support an active transfer of triamterene by the CNS, placenta, and kidney; the physiologic substrate for these systems is unknown.
DISUBSTITUTED TRIFLUOROMETHYL PYRIMIDINONES AND THEIR USE
申请人：BAYER PHARMA AKTIENGESELLSCHAFT
公开号：US20160221965A1
公开（公告）日：2016-08-04
The present application relates to novel 2,5-disubstituted 6-(trifluoromethyl)pyrimidin-4(3H)-one derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of cardiovascular, renal, inflammatory and fibrotic diseases.
SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS
申请人：BLUM Andreas
公开号：US20140135309A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula I
wherein Ar, R
1
and R
2
are as defined herein, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] SULFOXIMINE SUBSTITUTED QUINAZOLINES FOR PHARMACEUTICAL COMPOSITIONS<br/>[FR] QUINAZOLINES SUBSTITUÉES PAR SULFOXIMINE POUR COMPOSITIONS PHARMACEUTIQUES
申请人：BOEHRINGER INGELHEIM INT
公开号：WO2014072244A1
公开（公告）日：2014-05-15
This invention relates to novel sulfoximine substituted quinazoline derivatives of formula (I), wherein Ar, R1 and R2 are as defined in the description and claims, and their use as MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) kinase inhibitors, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment or amelioration of MNK1 (MNK1a or MNK1b) and/or MNK2 (MNK2a or MNK2b) mediated disorders.
[EN] HETEROCYCLIC COMPOUNDS FOR THE TREATMENT OF STRESS-RELATED CONDITIONS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES POUR LE TRAITEMENT D'ÉTATS LIÉS AU STRESS
申请人：OTSUKA PHARMA CO LTD
公开号：WO2010137738A1
公开（公告）日：2010-12-02
The present invention provides a novel heterocyclic compound. A heterocyclic compound represented by general formula (1) wherein, R1 and R2, each independently represent hydrogen; a phenyl lower alkyl group that may have a substituent(s) selected from the group consisting of a lower alkyl group and the like on a benzene ring and/or a lower alkyl group; or a cyclo C3-C8 alkyl lower alkyl group; or the like; R3 represents a lower alkynyl group or the like; R4 represents a phenyl group that may have a substituent(s) selected from the group consisting of a 1,3,4-oxadiazolyl group that may have e.g., halogen or a heterocyclic group selected from pyridyl group and the like; the heterocyclic group may have at least one substituent(s) selected from a lower alkoxy group and the like or a salt thereof.
PYRIMIDINYL AND 1,3,5-TRIAZINYL BENZIMIDAZOLES AND THEIR USE IN CANCER THERAPY
申请人：Rewcastle Gordon William
公开号：US20110009405A1
公开（公告）日：2011-01-13
Provided herein are pyrimidinyl and 1,3,5-triazinyl benzimidazoles of Formula I, and their pharmaceutical compositions, preparation, and use as agents or drugs for cancer therapy, either alone or in combination with radiation and/or other anticancer drugs.
