地西泮通过CYP3A4和2C19去甲基化为活性代谢物N-去甲基地西泮，并且通过CYP3A4羟基化为活性代谢物替马西泮。N-去甲基地西泮和替马西泮都会进一步代谢为奥沙西泮。替马西泮和奥沙西泮主要通过葡萄糖醛酸化反应与葡萄糖醛酸结合而被大量消除。此外，地西泮的氧化主要由细胞色素P450同工酶介导；去甲基地西泮主要由CYP2C19和CYP3A形成，而3-羟基地西泮（替马西泮）和奥沙西泮由CYP3A形成。因为CYP2C19具有多态性，可以区分地西泮的广泛代谢者（EMs）和不良代谢者（PMs）。在单次口服剂量后，地西泮的不良代谢者显示出显著较低的清除率（12 vs 26 mL/min）和更长的消除半衰期（88 vs 41小时） than EMs。此外，不良代谢者对去甲基地西泮的清除率较低，AUC较高，消除半衰期较长。
Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are further largely eliminated by way of conjugation to glucuronic acid via glucuronidation. Furthermore, oxidation of diazepam is mediated by cytochrome P450 isozymes; formation of desmethyl-diazepam mainly by CYP2C19 and CYP3A and 3-hydroxy-diazepam (temazepam) and oxazepam by CYP3A. Because CYP2C19 is polymorphic, extensive metabolizers (EMs), and poor metabolizers (PMs) of diazepam can be distinguished. PMs of diazepam showed significantly lower clearance (12 vs 26 mL/min) and longer elimination half-life (88 vs 41 h) of diazepam than EMs after a single oral dose. Also, PMs had lower clearance, higher AUC and longer elimination half-life of desmethyl-diazepam.
Diazepam is N-demethylated by CYP3A4 and 2C19 to the active metabolite N-desmethyldiazepam, and is hydroxylated by CYP3A4 to the active metabolite temazepam. N-desmethyldiazepam and temazepam are both further metabolized to oxazepam. Temazepam and oxazepam are largely eliminated by glucuronidation.
/Investigators/ observed variations in the metabolism of diazepam in Wistar rats. /The authors/ studied these variations carefully, and found that the variations are dimorphic and about 17% of male Wistar rats examined showed two times higher diazepam metabolic activities in their liver microsomes than the rest of animals at the substrate concentrations less than 5 uM. /They were/ classified as extensive metabolizer and poor metabolizer of diazepam. No sex difference was observed in the frequency of appearance of extensive metabolizer. Activities of the primary metabolic pathways of diazepam were examined to elucidate the cause of this polymorphism in male Wistar rats. No significant differences were observed in activities of neither diazepam 3-hydroxylation or N-desmethylation between extensive metabolizer and poor metabolizer rats, while activity of diazepam p-hydroxylation was markedly (more than 200 times) higher in extensive metabolizer rats, indicating that this reaction is responsible for the polymorphism of diazepam metabolism in Wistar rats. We examined the expression levels of CYP2D1, which was reported to catalyze diazepam p-hydroxylation in Wistar rats to find no differences in the expression levels of CYP2D1 between extensive metabolizer and PM rats. The kinetic study on diazepam metabolism in male Wistar rats revealed that extensive metabolizer rats had markedly higher V(max) and smaller K(m) in diazepam p-hydroxylation than those of poor metabolizer rats, indicating the presence of high affinity high capacity p-hydroxylase enzyme in extensive metabolizer rats. As a consequence, at low concentrations of diazepam, major pathways of diazepam metabolism were p-hydroxylation and 3-hydroxylation in male extensive metabolizer rats, while in male poor metabolizer rats, 3-hydroxylation followed by N-desmethylation. Due to this kinetic nature of p-hydroxylase activity, extensive metabolizer rats had markedly higher total CL(int) of diazepam than that of poor metabolizer rats. Polymorphism in diazepam metabolism in humans is well documented, but this is the first report revealing the presence of the polymorphism in diazepam metabolism in rats. The current results infer polymorphic expression of new diazepam p-hydroxylating enzyme with lower K(m) than CYP2D1 in extensive metabolizer Wistar rats.
来源:Hazardous Substances Data Bank (HSDB)
代谢
地西泮已知的人类代谢物包括替马西泮和去甲地西泮。
Diazepam has known human metabolites that include Temazepam and nordiazepam.
Hepatic via the Cytochrome P450 enzyme system. The main active metabolite is desmethyldiazepam, in addition to minor active metabolites including temazepam and oxazepam.
Route of Elimination: Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates.
Half Life: Biphasic 1-2 days and 2-5 days, active metabolites with long half lives.
IDENTIFICATION: Diazepam is classified as a psycholeptic, anxiolytic benzodiazepine derivative. Diazepam is a crystalline solid. Diazepam is very slightly soluble in water, soluble in alcohol and freely soluble in chloroform. Indications: Treatment of anxiety disorders, seizures and status epilepticus. Symptoms of drug withdrawal associated with the chronic abuse of ethanol, benzodiazepines, barbiturates, and other CNS depressants. Skeletal muscle spasticity and acute muscular spasms, including tetanus and cerebral palsy. Treatment of insomnia: Anxiety and/or desire for producing amnesia prior to surgery, dental, and endoscopic procedures. Conscious sedation for short anesthesia, alone or in combination with an opioid. Continuous infusion for sedation or seizures in the intensive care setting. HUMAN EXPOSURE: Main risks and target organs: Central nervous system, causing depression of respiration and consciousness. Summary of clinical effects: Central nervous system (CNS) depression and coma, or paradoxical excitation, but deaths are rare when benzodiazepines are taken alone. Deep coma and other manifestations of severe CNS depression are rare. Sedation, somnolence, diplopia, dysarthria, ataxia and intellectual impairment are the most common adverse effects of benzodiazepines. Overdose in adults frequently involves co-ingestion of other CNS depressants, which act synergistically to increase toxicity. Elderly and very young children are more susceptible to the CNS depressant action. Intravenous administration of even therapeutic doses of benzodiazepines may produce apnea and hypotension. Dependence may develop with regular use of benzodiazepines, even in therapeutic doses for short periods. If benzodiazepines are discontinued abruptly after regular use, withdrawal symptoms may develop. Contraindications: The primary absolute contraindication is an allergy to diazepam or other benzodiazepines, or the constituents of the parenteral formulation. There are relative contraindications, which require more careful monitoring of patients after receiving diazepam, and stronger consideration of alternative drug therapy. In these patients, the initial dose should be decreased: Chronic obstructive respiratory disease; neonates and infants up to 6 months of age; myasthenia gravis patients, close angle glaucoma, poisoning by other CNS depressants; breast feeding; geriatric patients, patients with severe liver failure and pregnancy. Routes of entry: Oral: This is the most frequent route of diazepam administration for therapeutic use as well as accidental poisonings, intentional overdoses, and abuse. Inhalation: The administration of diazepam solution into the lungs via an endotracheal tube has been demonstrated to produce therapeutic serum diazepam concentrations in animal models. Histologic examination of the lung demonstrated pneumonitis. These results suggest adequate absorption, however, the increased pulmonary toxicity indicates that this route should not be used in clinical practice. Dermal: Diazepam is absorbed through the skin, however, this route of administration is not used clinically. Parenteral: The preferred route of parenteral administration is intravenous. Indications include severe anxiety, excitation, alcohol and drug withdrawal syndrome, and seizures. The intramuscular route of diazepam administration should be avoided because absorption is erratic, and may be significantly delayed. Parenteral diazepam is irritating, and intravenous administration should be into a large peripheral vein. The rate of administration should be no faster than 5 mg per minute, and be followed by a saline flush to decrease local venous irritation. Significant adverse effects of intravenous diazepam include coma, hypotension, bradycardia, and respiratory failure. Such effects usually occur in the setting of rapid administration, administration of excessive doses, or administration to high-risk patients (the elderly, infants, patients with chronic respiratory disease) Other: Administration of diazepam rectally as either suppositories or solution results in good absorption. This route of administration is primarily used in convulsing children with no route of parenteral access. Absorption by route of exposure: Oral: Diazepam is absorbed rapidly following oral administration; with peak plasma concentrations generally being achieved within 1.0 hour (range 0.08 to 2.5 hours). The absorption rate is slowed by food and antacids. Absorption is almost complete with bioavailability. Parenteral: Intramuscular: Absorption is poor and erratic after intramuscular injection; plasma levels attained are equal to 60% of those reached after the same oral dose. The use of intramuscular diazepam has been described, however, this route should only be considered when other routes of administration or benzodiazepines are not available. Intravenous: Blood concentrations of 400 ng/mL and 1,200 ng/mL were measured 15 minutes after intravenous bolus doses of 10 and 20 mg, respectively Chronic administration of daily doses ranging from 2 mg to 30 mg result in plasma diazepam concentrations of 20 ng/mL to 1,010 ng/mL, and concentrations of desmethyldiazepam, an active metabolite, of 55 ng/mL to 1,765 ng/mL. Distribution by route of exposure: In human volunteers, the plasma protein binding of diazepam is greater than 95%. The concentration in the CSF appears to approximately correlate with the plasma free fraction. Patients with low serum albumin concentrations may have greater CNS effects secondary to an increased free fraction of diazepam. Following intravenous administration, diazepam concentrations can be described by a 2 compartment kinetic model. An initial rapid decline in serum concentrations associated with distribution into tissue, is followed by a slower decline reflecting the terminal elimination half-life. Due to its high lipid solubility diazepam passes rapidly into the brain, and other well perfused organs, and is afterwards redistributed to muscle and adipose tissue. Enterohepatic circulation is minimal. Diazepam crosses the placental barrier to the fetus and is present in breast milk. Biological half-life by route of exposure: The terminal elimination half-life of diazepam ranges from approximately 24 hours to more than two days. With chronic dosing, steady state concentrations of diazepam are achieved between 5 days to 2 weeks. The half-life is prolonged in the elderly and in patients with cirrhosis or hepatitis. It is shortened in patients taking drugs which induce hepatic enzymes, included anticonvulsants. The active metabolite desmethyldiazepam has a longer half-life than diazepam, and takes longer to reach steady state concentrations. Metabolism: Diazepam is primarily metabolized by hepatic enzymes, with very little unchanged drug eliminated in the urine. The hepatic cytochrome enzyme isozyme responsible for S- mephenytoin hydroxylation polymorphism is most likely the hepatic enzyme species responsible for diazepam metabolism. Hepatic n-demethylation results in the formation of the active metabolite desmethyldiazepam (also known as nordiazepam). This metabolite is hydroxylated to form oxazepam, which is conjugated to oxazepam glucuronide. A minor active metabolite is temazepam. The main active substances found in blood are diazepam and desmethyldiazepam. Elimination and excretion: A two-compartment open model is usually used to describe elimination kinetics of diazepam, after a single intravenous dose has been determined. Urinary excretion of diazepam is primarily in the form of sulphate and glucuronide conjugates, and accounts for the majority of the ingested dose. There is some evidence that the disposition of diazepam is slowed by chronic dosing and by plasma desmethyldiazepam levels. There is some evidence for species differences in biliary excretion. Studies suggest that biliary excretion of diazepam is probably clinically unimportant in man. Mode of action: Toxicodynamics: The toxic and therapeutic effects of diazepam are a result of its effect on CNS GABA activity. GABA (gamma-aminobutyric acid) is an important inhibitory neurotransmitter which mediates pre- and post-synaptic inhibition in all regions of the central nervous system. Diazepam and the other benzodiazepines appear to either enhance or facilitate GABA activity by binding to the benzodiazepine receptor, which is part of a complex including an aminobutyric acid receptor, benzodiazepine receptor, and barbiturate receptor. Binding at the complex results in increased CNS inhibition by GABA. The anticonvulsant and other effects of diazepam are believed to be produced by a similar mechanism, possibly involving various subtypes of the receptor. Pharmacodynamics: The pharmacodynamic effects of diazepam are also produced primarily by its actions with the result being enhancement of the inhibitory effects of GABA on the CNS. Two different zones have been described for the benzodiazepine binding at receptor sites and they have been classified as type I (chloride independent) and type II (chloride dependent. Type I receptor stimulation is believed to be responsible for anxiolysis, and Type II receptors responsible for sedation and ataxia. Similar to other sedative hypnotic drugs, preanesthetic doses of diazepam produce anterograde amnesia in the presence of therapeutic concentrations of diazepam, probably by impairing the establishment of the memory trace in the CNS. Tolerance to its anticonvulsant effects of diazepam generally develop within the first 6 to 12 months of therapy, which result in loss of anticonvulsant effects. For this reason diazepam is not commonly utilised for the chronic treatment of seizure disorders. The neonate is very sensitive to the effects of benzodiazepine. Teratogenicity: There is a some evidence that diazepam and other benzodiazepines are teratogenic in humans, increasing the risk of congenital malformations when ingested by the mother during the first trimester of pregnancy. Metabolic interactions: Diazepam does not induce or inhibit hepatic enzyme activity, and does not alter the metabolism of other agents. As diazepam is primarily dependent on hepatic metabolism for elimination, numerous agents which either induce or inhibit hepatic cytochrome P450 pathways or conjugation can alter the rate of diazepam metabolism. Agents inhibiting diazepam metabolism: Cimetidine, oral contraceptives, disulfiram, erythromycin, isoniazid, probenecid, propranolol, fluvoxamine, imipramine, fluoxetine and ciprofloxacin. Agents inducing diazepam metabolism: Rifampin, phenytoin, carbamazepine and phenobarbital. The major dynamic interactions with diazepam involve the synergistic increase in CNS depression (including central respiratory depression and hemodynamic depression) associated with other CNS depressant agents, including ethanol, non-benzodiazepine sedative hypnotics, barbiturates, drugs with CNS anticholinergic effects such as the antihistamines and tricyclic antidepressants, and opioids. These interactions increase synergistically the CNS depression, respiratory depression, and hemodynamic depression produced by each agent involved. Diazepam can decrease the efficacy of L-dopa used for the treatment of Parkinsonism. The effect is reversible. The anticonvulsant action of diazepam antagonizes the pro-convulsant activity of certain agents, including cocaine and strychnine. The primary adverse effects are secondary to the pharmacologic action of enhanced CNS GABA activity. Cognitive and psychomotor abilities may be impaired at therapeutic doses. Additional adverse effects include dizziness and prolonged reaction time, motor incoordination, ataxia, mental confusion, dysarthria, anterograde amnesia, somnolence, vertigo, and fatigue. Dysarthria and dystonia occur much less frequently. Paradoxical reactions of CNS hyperactivity occur rarely and manifest primarily as aggressive behaviour, irritability, and anxiety. Intravenous injection can produce local phlebitis and thrombophlebitis. Intra-articular injection may produce arterial necrosis. Diazepam and other benzodiazepines can cause physical and psychological dependence when administered at high doses for prolonged periods of time. The clinical manifestations of the withdrawal syndrome are similar to those associated with withdrawal of other sedative hypnotic and CNS depressants drugs. The long half-life and presence of active metabolites result in delayed onset of symptoms. The symptoms include anxiety, insomnia, irritability, confusion, anorexia, nausea and vomiting, tremors, hypotension, hyperthermia, and muscular spasm. Severe withdrawal symptoms include seizures and death. The treatment to prevent withdrawal and minimize any symptoms is to slowly reduce the dose of diazepam over 2 to 4 weeks. ANIMAL/PLANT STUDIES: A number of repeated dose studies have been carried out. In general, toxic effects have not been remarkable. In a three-month study in rats and a six-month study in dogs, some increase in liver size was seen, together with an increase in blood cholesterol; in the dogs an elevation of plasma alanine aminotransferase activity was observed. There was no increase in tumour frequency after feeding diazepam to rats and mice for 104 and 80 weeks, respectively. There is no evidence of carcinogenicity in humans. Mutagenicity: Diazepam has been reported to have mutagenic activity in the Salmonella typhimurium tester train TA100 in the Ames test, and to be genotoxic in a mouse bone marrow micronucleus test. Little or no effect was seen in an assay for chromosomal aberrations, performed in Chinese hamster cells in vitro.
Benzodiazepines bind nonspecifically to benzodiazepine receptors which mediate sleep, affects muscle relaxation, anticonvulsant activity, motor coordination, and memory. As benzodiazepine receptors are thought to be coupled to gamma-aminobutyric acid-A (GABA<sub>A</sub>) receptors, this enhances the effects of GABA by increasing GABA affinity for the GABA receptor. Binding of GABA to the site opens the chloride channel, resulting in a hyperpolarized cell membrane that prevents further excitation of the cell.
After oral administration, it is considered that diazepam is rapidly and completely absorbed from the gastrointestinal tract as >90% of diazepam is absorbed and the average time to achieve peak plasma concentrations is 1 – 1.5 hours with a range of 0.25 to 2.5 hours. Absorption is delayed and decreased when administered with a moderate fat meal. In the presence of food mean lag times are approximately 45 minutes as compared with 15 minutes when fasting. There is also an increase in the average time to achieve peak concentrations to about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in an average decrease in Cmax of 20% in addition to a 27% decrease in AUC (range 15% to 50%) when administered with food.
来源:DrugBank
吸收、分配和排泄
消除途径
地西泮及其代谢物主要通过尿液排出，主要是以它们的葡萄糖苷酸结合物形式。
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their glucuronide conjugates.
来源:DrugBank
吸收、分配和排泄
分布容积
在年轻健康的男性中，稳态下的分布体积为0.8至1.0升/公斤。
In young healthy males, the volume of distribution at steady-state is 0.8 to 1.0 L/kg.
来源:DrugBank
吸收、分配和排泄
清除
地西泮在年轻成年人中的清除率为20至30毫升/分钟。
The clearance of diazepam is 20 to 30 mL/min in young adults.
Diazepam rectal gel is well absorbed following rectal administration, reaching peak plasma concentrations in 1.5 hours. The absolute bioavailability of Diazepam rectal gel relative to Valium injectable is 90%. The volume of distribution of Diazepam rectal gel is calculated to be approximately 1 L/kg. ... Both diazepam and its major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).
Concentration-dependent metabolism of diazepam in mouse liver
摘要：
Previous mouse liver studies with diazepam (DZ), N-desmethyldiazepam (NZ), and temazepam (TZ) confirmed that under first-order conditions, DZ formed NZ and TZ in parallel. Oxazepam (OZ) was generated via NZ and not TZ despite that performed NZ and TZ were both capable of forming OZ. In the present studies, the concentration-dependent sequential metabolism of DZ was studied in perfused mouse livers and microsomes, with the aim of distinguishing the relative importance of NZ and TZ as precursors of OZ. In microsomal studies, the K(m)s and V(max)s, corrected for binding to microsomal proteins, were 34 mu M and 3.6 nmole/min per mg and 239 mu M and 18 nmole/min per mg, respectively, for N-demethylation and C-3-hydroxylation of DZ. The K(m)s and V(max)s for N-demethylation and C-3-hydroxylation of TZ and NZ, respectively, to form OZ, were 58 mu M and 2.5 nmole/min per mg and 311 mu M and 2 nmole/min per mg, respectively. The constants suggest that at low DZ concentrations, NZ formation predominates and is a major source of OZ, whereas at higher, DZ concentrations, TZ is the important source of OZ. In livers perfused will DZ at input concentrations of 13 to 35 mu M, the extraction ratio of DZ (E{DZ}) decreased from 0.83 to 0.60. NZ was the major metabolite formed although its appearance was less than proportionate with increasing DZ input concentration. By contrast, the formation of TZ increased disproportionately with increasing DZ concentration, whereas that for OZ decreased and paralleled the behavior of NZ. Computer simulations based on a tubular flow model and the in vitro enzymatic parameters provided a poor in vitro-organ correlation. The E{DZ}, appearance rates of the metabolites, and tire extraction ratio of formed NZ (E{NZ, DZ}) were poorly predicted; TZ was incorrectly identified as the major precursor of OZ. Simulations with optimized parameters improved the correlations and identified NZ as the major contributor of OZ. Saturation of DZ N-demethylation at higher DZ concentrations increased the role of TZ in the formation of OZ. The poor aqueous solubility (limiting the concentration range of substrates used in vitro), avid tissue binding mid the coupling of enzymatic reactions in liver favoring sequential metabolism, are possible explanations for the poor in vitro-organ correlation. This work emphasizes tire complexity of tire hepatic intracellular milieu for drug metabolism and the need for additional modeling efforts to adequately describe metabolite kinetics.
[EN] S-NITROSOMERCAPTO COMPOUNDS AND RELATED DERIVATIVES<br/>[FR] COMPOSÉS DE S-NITROSOMERCAPTO ET DÉRIVÉS APPARENTÉS
申请人：GALLEON PHARMACEUTICALS INC
公开号：WO2009151744A1
公开（公告）日：2009-12-17
The present invention is directed to mercapto-based and S- nitrosomercapto-based SNO compounds and their derivatives, and their use in treating a lack of normal breathing control, including the treatment of apnea and hypoventilation associated with sleep, obesity, certain medicines and other medical conditions.
The present invention is concerned with novel hydroxy-methyl isoxazole derivatives of formula I
wherein R
1
, R
2
and R
3
are as described herein, as well as pharmaceutically acceptable salts and esters thereof. The active compounds of the present invention have affinity and selectivity for GABA A α5 receptor. Further the present invention is concerned with the manufacture of the active compounds of formula I, pharmaceutical compositions containing them and their use as pharmaceuticals.
本发明涉及一种新型的羟甲基异噁唑衍生物，其化学式为I，其中R1、R2和R3如本文所述，以及其药学上可接受的盐和酯。本发明的活性化合物具有对GABA A α5受体的亲和力和选择性。此外，本发明涉及制备化学式I的活性化合物、含有它们的药物组合物以及它们作为药物的用途。
The present invention is concerned with novel isoxazole derivatives of formula (I), wherein X, R1, R2, R3, R4 and R5 are as described herein, as well as pharmaceutically acceptable salts and esters thereof. The active compounds of the present invention have affinity and selectivity for GABA A α5 receptor. Further the present invention is concerned with the manufacture of the active compounds of formula I, pharmaceutical compositions containing them and their use as medicaments.
本发明涉及式(I)的新异噁唑衍生物，其中X、R1、R2、R3、R4和R5如本文所述，以及其药学上可接受的盐和酯。本发明的活性化合物具有对GABA A α5受体的亲和力和选择性。此外，本发明涉及制备式I的活性化合物、含有它们的药物组合物以及它们作为药物的用途。
[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] ISOXAZOLE-THIAZOLE DERIVATIVES AS GABA A RECEPTOR INVERSE AGONISTS FOR USE IN THE TREATMENT OF COGNITIVE DISORDERS<br/>[FR] DÉRIVÉS D'ISOXAZOLE-THIAZOLE COMME AGONISTES INVERSES DU RÉCEPTEUR GABA A, UTILES DANS LE TRAITEMENT DE TROUBLES COGNITIFS
申请人：HOFFMANN LA ROCHE
公开号：WO2010127974A1
公开（公告）日：2010-11-11
The present invention is concerned with isoxazole-thiazole derivatives of formula I, having affinity and selectivity for GABA A α5 receptor, their manufacture, pharmaceutical compositions containing them and their use as therapeutically active substances. The active compounds of the present invention are useful as cognitive enhancer or for the therapeutic and/or prophylactic treatment of cognitive disorders like Alzheimer's disease.
本发明涉及式I的异恶唑-噻唑衍生物，具有对GABA A α5受体的亲和力和选择性，其制备、含有它们的药物组合物以及它们作为治疗活性物质的用途。本发明的活性化合物可用作认知增强剂或用于治疗和/或预防认知障碍，如阿尔茨海默病。
