KNOWN OXIDATION OF 10,11 DOUBLE BOND OF PROTRIPTYLINE IN MAN, MINIATURE PIG, & DOG... 2 METABOLITES HAVE BEEN DETECTED WHICH DEMONSTRATE EPOXIDE INTERMEDIATE, NAMELY, DIHYDRODIOL & REARRANGEMENT PRODUCT WHOSE FORMATION IS...CATIONIC INTERMEDIATE...REARRANGING TO DIHYDROANTHRACENIC STRUCTURE.
IN DOGS, MINIATURE PIGS, & MAN, 3 URINARY METABOLITES HAVE NOW BEEN FOUND 10-HYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE, 10,11-DIHYDROXY-N-METHYL-5H-DIBENZO(AD)CYCLOHEPTENE-5-PROPYLAMINE & 5,10-DIHYDRO-10-FORMYLANTHRACENE-5-PROPYLAMINE.
IN URINE OF RATS TREATED WITH PROTRIPTYLINE...2 METABOLITES HAVE BEEN IDENTIFIED...AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-M ETHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE & 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE.
来源:Hazardous Substances Data Bank (HSDB)
代谢
消除途径：在16天的时间里，累积尿排泄约占药物的50%。粪便排泄途径似乎并不重要。
Route of Elimination: Cumulative urinary excretion during 16 days accounted for approximately 50% of the drug. The fecal route of excretion did not seem to be important.
来源:Toxin and Toxin Target Database (T3DB)
毒理性
毒性总结
丙米嗪通过减少去甲肾上腺素和血清素（5-HT）的再摄取发挥作用。
Protriptyline acts by decreasing the reuptake of norepinephrine and serotonin (5-HT).
Liver test abnormalities have been reported to occur in 10% to 12% of patients on tricyclic antidepressants, but elevations are uncommonly above 3 times the upper limit of normal. The aminotransferase abnormalities are usually mild, asymptomatic and transient, reversing even with continuation of medication. The rate of serum enzyme elevations specifically during protriptyline therapy has not been well defined. Rare instances of clinically apparent acute liver injury have been reported in patients on tricyclic antidepressants, but there have been no specific reports related to protriptyline. In typical tricyclic antidepressant acute liver injury, the latency to onset has ranged from 1 to 14 months. The pattern of serum enzyme elevations was typically cholestatic, but hepatocellular cases have also been reported including an acute hepatitis-like syndrome with acute liver failure. Instances of acute cholestatic hepatitis and prolonged jaundice compatible with vanishing bile duct syndrome have been linked to other tricyclic antidepressants, mostly amitriptyline and imipramine, the two most commonly used agents in this class. Signs or symptoms of hypersensitivity (rash, fever and eosinophilia) are frequent in reported cases, but these symptoms are usually mild and transient. Autoantibody formation is rare. Protriptyline is a rarely used tricyclic antidepressant but is suspected of having a profile of adverse effects similar to that of imipramine and amitriptyline.
Protriptyline is reported to undergo cumulative urinary excretion during 16 days, which accounts for approximately 50% of the total drug administered. The fecal excretion pathway seems to play a minimal role in drug elimination.
来源:DrugBank
吸收、分配和排泄
分泌...是迅速的，与药物起效的长时间潜伏期形成对比。/三环类抗抑郁药/
EXCRETION...IS RAPID, IN CONTRAST TO LONG LATENCY OF ONSET OF ACTION OF DRUGS. /TRICYCLIC ANTIDEPRESSANTS/
来源:Hazardous Substances Data Bank (HSDB)
吸收、分配和排泄
...从胃肠道吸收良好。...通过脱甲基化、氧化和芳香羟基化迅速分布和代谢。/丙咪嗪/
...WELL ABSORBED FROM GI TRACT. ... RAPIDLY DISTRIBUTED & METABOLIZED BY DEMETHYLATION, OXIDATION, & AROMATIC HYDROXYLATION. /IMIPRAMINE/
IN URINE OF RATS TREATED WITH PROTRIPTYLINE... THERE WAS TWICE AS MUCH 10,11-DIHYDRO-10,11-EPOXY-5-(3-METHYLAMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE AS 10,11-DIHYDRO-10,11-EPOXY-5-(3-AMINOPROPYL)-5H-DIBENZO[A,D]CYCLOHEPTENE EXCRETED &.../BOTH/ ACCOUNTED FOR 40% OF DOSE OF PROTRIPTYLINE.
MEAN PLASMA LEVELS FOR PROTRIPTYLINE IN PT ALSO ADMIN NITRAZEPAM INDISTINGUISHABLE FROM PT RECEIVING NO NITRAZEPAM. MEAN PLASMA LEVELS FOR PT RECEIVING SODIUM AMYLOBARBITONE SIGNIFICANTLY DECR. EARLY VALUES MAY BE OF PREDICTIVE IMPORTANCE TO PERMIT EARLY DOSE ADJUSTMENT.
[EN] COMPOUNDS AND THEIR USE AS BACE INHIBITORS<br/>[FR] COMPOSÉS ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE BACE
申请人：ASTRAZENECA AB
公开号：WO2016055858A1
公开（公告）日：2016-04-14
The present application relates to compounds of formula (I), (la), or (lb) and their pharmaceutical compositions/preparations. This application further relates to methods of treating or preventing Αβ-related pathologies such as Down's syndrome, β- amyloid angiopathy such as but not limited to cerebral amyloid angiopathy or hereditary cerebral hemorrhage, disorders associated with cognitive impairment such as but not limited to MCI ("mild cognitive impairment"), Alzheimer's disease, memory loss, attention deficit symptoms associated with Alzheimer's disease, neurodegeneration associated with diseases such as Alzheimer's disease or dementia, including dementia of mixed vascular and degenerative origin, pre-senile dementia, senile dementia and dementia associated with Parkinson's disease.
[EN] METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS<br/>[FR] MÉTHYLOXAZOLES ANTAGONISTES DU RÉCEPTEUR DE L'OREXINE
申请人：MERCK SHARP & DOHME
公开号：WO2016089721A1
公开（公告）日：2016-06-09
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
Heterobicyclic compounds of Formula (I):
or a pharmaceutically-acceptable salt, tautomer, or stereoisomer thereof, as defined in the specification, and compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, Huntington's Disease, and the like.
Formula (I)的杂环化合物：
或其药用可接受的盐、互变异构体或立体异构体，如规范中所定义，并含有它们的组合物，以及制备这种化合物的方法。本文还提供了通过抑制PDE10来治疗由此可治疗的疾病或疾病的方法，如肥胖症、非胰岛素依赖型糖尿病、精神分裂症、躁郁症、强迫症、亨廷顿病等。
[EN] NAPHTHALENE CARBOXAMIDE M1 RECEPTOR POSITIVE ALLOSTERIC MODULATORS<br/>[FR] COMPOSÉS DE NAPHTHALÈNE CARBOXAMIDE, MODULATEURS ALLOSTÉRIQUES POSITIFS DU RÉCEPTEUR M1
申请人：MERCK SHARP & DOHME
公开号：WO2011149801A1
公开（公告）日：2011-12-01
The present invention is directed to naphthalene carboxamide compounds of formula (I) which are M1 receptor positive allosteric modulators and that are useful in the treatment of diseases in which the M1 receptor is involved, such as Alzheimers disease, schizophrenia, pain or sleep disorders. The invention is also directed to pharmaceutical compositions comprising the compounds and to the use of the compounds and compositions in the treatment of diseases mediated by the M1 receptor.
[EN] QUINAZOLINE DERIVATIVES, COMPOSITIONS, AND USES RELATED THERETO<br/>[FR] DÉRIVÉS DE QUINAZOLINE, COMPOSITIONS ET UTILISATIONS ASSOCIÉES
申请人：UNIV EMORY
公开号：WO2013181135A1
公开（公告）日：2013-12-05
The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.
