Repeated dosing of female rats reduced systemic exposure to tolvaptan. Analysis of the serum samples for metabolites DM-4103 and DM-4107 revealed increases in the concentrations of these metabolites following repeated dosing, and explained the reduction in serum tolvaptan concentrations. Furthermore, tolvaptan was shown to induce hepatic drug-metabolising enzymes (cytochrome b5 content and aminopyrine N-demethylase activity) in female rats after 7 days dosing at 300 mg/kg/day. Tolvaptan was both a substrate for, and inhibitor of, MDR1-mediated transport.
Tolvaptan is extensively metabolized in all species investigated. In vitro studies with rat liver supernatant produced a number of metabolites of tolvaptan. Hydroxylation of the benzazepine ring produced metabolites DM-4110, DM-4111 and DM-4119. Cleavage of the bond between the 1 and 2 positions of the benzazepine ring produced metabolites DM-4103, DM-4104, DM-4105 and DM- 4107. Oxidation of the hydroxyl group at the 5 position in the benzazepine ring produced MOP-21826.
Tolvaptan is mainly, if not exclusively, metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; the drug also is a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared with tolvaptan, metabolites of the drug have little or no antagonist activity for human V2 receptors.
Tolvaptan is metabolized extensively in humans by the CYP3A4/5 system with seven metabolites (DM-4103, DM-4104, DM-4105, DM-4107, DM-4110, DM-4111, DM-4119) detected in the plasma, urine, and faeces of all subjects in a 14C mass balance study. After administration of (14)C-tolvaptan, 13 metabolites were identified in human plasma. Tolvaptan and identified metabolites accounted for about 70% of administered radioactivity. The predominant metabolite, with >50% of the total dose using the mass balance approach was DM-4103. The terminal elimination half-life of DM-4103 is approximatley 183 hours and after multiple dosing DM-4103 shows accumulation by day 28, but this appears pharmacologically inactive in the concentrations achieved using clinically relevant doses. Only 3% of the radioactivity was due to unchanged tolvaptan in the plasma.
IDENTIFICATION AND USE: Tolvaptan is a white crystalline powder that is formulated into oral tablets. Tolvaptan is an antagonist of arginine vasopressin (antidiuretic hormone) V2 receptors. It is used to treat low sodium levels in the blood. HUMAN EXPOSURE AND TOXICITY: Tolvaptan was well tolerated in healthy subjects at single oral doses up to 480 mg and multiple doses up to 300 mg once daily for 5 days. There is no specific antidote for tolvaptan intoxication. The signs and symptoms of an acute overdose can be anticipated to be those of excessive pharmacologic effect: a rise in serum sodium concentration, polyuria, thirst, and dehydration/hypovolemia. However, chronic administration of tolvaptan can cause serious and potentially fatal liver injury. In 2013, the U.S. Food and Drug Administration (FDA) determined that the drug should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially requiring liver transplant or death. In a placebo-controlled and open label extension study of chronically administered tolvaptan in patients with autosomal dominant polycystic kidney disease, cases of serious liver injury attributed to tolvaptan were observed. Tolvaptan therapy should be initiated or reinitiated only in a hospital setting, where serum sodium concentrations and therapeutic response can be monitored closely. Too rapid correction of hyponatremia may cause osmotic demyelination syndrome, resulting in dysarthria, mutism, dysphagia, lethargy, affective changes, spastic quadriparesis, seizures, coma, or death. Slower rates of correction may be advisable in susceptible patients, including those with severe malnutrition, alcoholism, or advanced liver disease. Patients with syndrome of inappropriate secretion of antidiuretic hormone or very low baseline serum sodium concentrations may be at increased risk for too rapid correction of serum sodium concentration. Tolvaptan is contraindicated in patients who are unable to sense or appropriately respond to thirst and in those with hypovolemic hyponatremia. Tolvaptan is mainly, if not exclusively, metabolized in the liver by cytochrome P-450 (CYP) isoenzyme 3A; the drug also is a weak inhibitor of CYP3A and a substrate and inhibitor of the P-glycoprotein transport system. Compared with tolvaptan, metabolites of the drug have little or no antagonist activity for human V2 receptors. ANIMAL STUDIES: Tolvaptan had low acute toxicity when administered to rats and dogs. In repeated dose studies in rats and dogs, findings were generally related to the pharmacological effect of tolvaptan and consisted of increased urine volume, decreased urine osmolality and increased water consumption. Decreased body weight and alterations in hematological and clinical chemistry parameters were also seen but were reversible during a recovery period. Up to two years of oral administration of tolvaptan to male and female rats did not increase the incidence of tumors. In a fertility study in male and female rats, tolvaptan was associated with fewer corpora lutea and implants compared to controls. Oral administration of tolvaptan to pregnant rabbits during organogenesis was associated with reductions in maternal body weight gain and food consumption. Abortions, increased incidences of embryo-fetal death, fetal microphthalmia, open eyelids, cleft palate, brachymelia, and skeletal malformations were also observed. Tolvaptan tested negative for genotoxicity in in vitro (bacterial reverse mutation assay and chromosomal aberration test in Chinese hamster lung fibroblast cells) and in vivo (rat micronucleus assay) test systems.
In prelicensure clinical trials, tolvaptan was not implicated in causing serum enzyme elevations or clinically apparent liver injury. However, instances of worsening of hepatic failure and complications of portal hypertension were reported in a small proportion of patients with cirrhosis treated with tolvaptan. These complications included variceal hemorrhage, hepatic encephalopathy and worsening of jaundice. In many trials, however, the frequency of these complications was not significantly greater than in placebo treated controls. More recently, in large registration trials of long term therapy in patients with ADPKD, serum aminotransferase elevations occurred in 4% to 5% of patients on tolvaptan, compared to only 1% of controls. Furthermore, clinically apparent liver injury occurred in approximately 0.1% of treated patients. The time to onset of illness ranged from 3 to 9 months (Case 1), but occasionally arose during long term therapy (Case 2). The clinical presentation was with the insidious development of fatigue, nausea and abdominal pain followed by dark urine, jaundice and pruritus. The pattern of serum enzyme elevations was typically hepatocellular or mixed, and liver biopsy showed an acute hepatitis with mild cholestasis. All patients recovered after stopping therapy, generally within 1 to 3 months of stopping therapy without evidence of residual injury. Immunoallergic features and autoantibodies were not found. Rapid recurrence on rechallenge was demonstrated in several patients with marked serum enzyme elevations during therapy, but patients with jaundice were not reexposed. The frequency of clinically apparent liver injury during therapy was one reason for the delay of formal approval of long term tolvaptan therapy for ADPKD. Since its approval and more wide-spread use, occasion reports of clinically apparent liver injury have continued to appear, at least one of which led to liver transplantation. Interestingly, most instances of liver injury have been reported with its use in autosomal dominant polycystic kidney disease rather than hyponatremia. Reasons for this are probably the duration of therapy, but also may relate to the slightly higher doses used to decrease progress in polycystic kidney disease.
In a study in patients with creatinine clearances ranging from 10-124 mL/min administered a single dose of 60 mg tolvaptan, AUC and Cmax of plasma tolvaptan were less than doubled in patients with severe renal impairment relative to the controls. The peak increase in serum sodium was 5-6 mEq/L, regardless of renal function, but the onset and offset of tolvaptan's effect on serum sodium were slower in patients with severe renal impairment.
In healthy subjects the pharmacokinetics of tolvaptan after single doses of up to 480 mg and multiple doses up to 300 mg once daily have been examined. Area under the curve (AUC) increases proportionally with dose. After administration of doses > or = 60 mg, however, Cmax increases less than proportionally with dose. The pharmacokinetic properties of tolvaptan are stereospecific, with a steady-state ratio of the S-(-) to the R-(+) enantiomer of about 3. The absolute bioavailability of tolvaptan is unknown. At least 40% of the dose is absorbed as tolvaptan or metabolites. Peak concentrations of tolvaptan are observed between 2 and 4 hours post-dose. Food does not impact the bioavailability of tolvaptan. In vitro data indicate that tolvaptan is a substrate and inhibitor of P-gp. Tolvaptan is highly plasma protein bound (99%) and distributed into an apparent volume of distribution of about 3 L/kg. Tolvaptan is eliminated entirely by non-renal routes and mainly, if not exclusively, metabolized by CYP 3A. After oral dosing, clearance is about 4 mL/min/kg and the terminal phase half-life is about 12 hours. The accumulation factor of tolvaptan with the once-daily regimen is 1.3 and the trough concentrations amount to > or = 16% of the peak concentrations, suggesting a dominant half-life somewhat shorter than 12 hours. There is marked inter-subject variation in peak and average exposure to tolvaptan with a percent coefficient of variation ranging between 30 and 60%.
In patients with hyponatremia of any origin the clearance of tolvaptan is reduced to about 2 mL/min/kg. Moderate or severe hepatic impairment or congestive heart failure decrease the clearance and increase the volume of distribution of tolvaptan, but the respective changes are not clinically relevant. Exposure and response to tolvaptan in subjects with creatinine clearance ranging between 79 and 10 mL/min and patients with normal renal function are not different.
In healthy subjects receiving a single dose of Samsca 60 mg, the onset of the aquaretic and sodium increasing effects occurs within 2 to 4 hours post-dose. A peak effect of about a 6 mEq increase in serum sodium and about 9 mL/min increase in urine excretion rate is observed between 4 and 8 hours post-dose; thus, the pharmacological activity lags behind the plasma concentrations of tolvaptan. About 60% of the peak effect on serum sodium is sustained at 24 hours post-dose, but the urinary excretion rate is no longer elevated by this time. Doses above 60 mg tolvaptan do not increase aquaresis or serum sodium further. The effects of tolvaptan in the recommended dose range of 15 to 60 mg once daily appear to be limited to aquaresis and the resulting increase in sodium concentration.
[EN] INTERMEDIATES AND PROCESSES FOR THE PREPARATION OF TOLVAPTAN AND ITS DERIVATIVES [FR] INTERMÉDIAIRES ET PROCÉDÉS POUR LA PRÉPARATION DE TOLVAPTAN ET DE SES DÉRIVÉS
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.
[EN] PROCESS FOR PREPARING TOLVAPTAN INTERMEDIATES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'INTERMÉDIAIRES DE TOLVAPTAN
申请人：HETERO RESEARCH FOUNDATION
公开号：WO2012046244A1
公开（公告）日：2012-04-12
The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
The present invention provides a novel process for the preparation of 7-chloro-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one. The present invention also provides an improved process for the preparation of 7-chloro-1-(2-methyl-4-nitrobenzoyl)-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine. The present invention further provides an improved process for the preparation of 7-chloro-1-[2-methyl-4-[(2-methylbenzoyl)amino]benzoyl]-5-oxo-2,3,4,5-tetrahydro-1H-1-benzazepine.
[EN] VASOPRESSIN RECEPTOR ANTAGONISTS AND PRODUCTS AND METHODS RELATED THERETO<br/>[FR] ANTAGONISTES DU RÉCEPTEUR DE LA VASOPRESSINE, PRODUITS ET PROCÉDÉS ASSOCIÉS
申请人：BLACKTHORN THERAPEUTICS INC
公开号：WO2019050988A1
公开（公告）日：2019-03-14
Compounds are provided that antagonize vasopressin receptors, particularly the V1a receptor products containing such compounds, as well as to methods of their use and synthesis. Such compounds have the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: (I) wherein Q1, Q2, Q3, R2a, R2b, R3 and X are as defined herein.
The invention relates to novel substituted bipiperidinyl derivatives, to processes for their preparation, to their use 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 the treatment and/or prevention of diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.
