一些具有局部麻醉作用的哌啶基酰基苯胺的合成

N-(β-苯硫乙基)-苯胺和N-(β-对氯苯硫乙基)-苯胺分别用氯乙酰氯、β-氯丙酰氯和γ-氯丁酰氯酰化,生成的氯代酰胺(IIIa-e)用哌啶处理,得到一系列N-(β-苯硫乙基)-哌啶基酰基苯胺(IVa-c)和N-(β-对氯苯硫乙基)-哌啶基酰基苯胺(IVd,e).药理试验表明化合物IVa—e有很强的局部麻醉作用.     

强效镇痛剂研究——Ⅱ.3-甲基芬太尼类衍生物的合成及镇痛活性

本文报道了N-[1-(β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7209)和N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)等一系列3-甲基芬太尼类衍生物的合成及镇痛活性。绝大部分该类衍生物均具有典型的吗啡样镇痛活性,是一类结构较简单、易于合成、镇痛作用极强的麻醉镇痛剂。化合物7302的ED₅₀为0.0022mg/kg(ip,小鼠,热板法),比芬太尼强28倍,竟达吗啡的6318倍,为我们至今合成该类衍生物中作用最强者。     

防治血吸虫病药物的研究 Ⅱ.2-巯基-1,3-硫氮茚及1,3-二氮茚衍生物的合成

合成2-(β-一二乙氨基乙巯基)-1,3-硫氮茚盐酸盐,2-(β-六氢吡啶基乙巯基)-1,3-硫氮茚盐酸盐,1-(β-二乙氨基乙基)-1,3-二氮茚双盐酸盐和1-(β-二乙氨基乙基)-1,3-二氮茚双盐酸盐四个化合物,经过对小白鼠进行日本血吸虫病的预防或治疗试验,证明没有作用。     

肿瘤的化学治疗ⅩⅩⅫ.N-乙酰基-N-{3-[双-(β-氯乙基)-氨基]-6-甲基(或氢)-苯基}-甘氨酸的合成

从3-硝基-6-甲基-苯胺为原料经过六步反应合成了N-乙酰基-N-{3-[双-(β-氯乙基)-氨基]-6-甲基-苯基}-甘氨酸(Ⅲ₂),并从硝基苯胺以制备Ⅲ_a相似的步骤合成N-乙酰基-N-{3-[双-(β-氯乙基)-氨基]-苯基}-甘氨酸(Ⅲ_b)和N-乙酰基-N-{4-[双-(β-氯乙基)-氨基]-苯基}-甘氨酸(Ⅲ_c).药理试验表明:化合物Ⅲ_a对小白鼠肉瘤-180有显著的抑制作用,但化合物Ⅲ_b和Ⅲ_c无明显作用.Ⅲ_a-c对体外组织培养的Hela瘤细胞都无抑制作用.     

强效镇痛剂研究 Ⅶ.1-β-羟基-3-甲基芬太尼(7302)及有关化合物非对映异构体的合成及镇痛活性

本文报道N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(简称1-β-羟基-3-甲基芬太尼,编号7302)及N-[1-苯甲酰基甲基-3-甲基-4-哌啶基]-N-丙酰苯胺(7303)非对映异构体的合成及镇痛活性。初步结果表明(小鼠,ip,热板法),7302分子中三个手性中心的构型对镇痛活性影响都至关重要。顺-A-7302的强度为顺-B-7302的5.3倍,反-A-7302为反-B-7302的2倍左右。顺-A-7302为四个非对映异构体中作用最强者,为吗啡的6000多倍,为依托芬的3倍左右。     

强效镇痛剂研究——Ⅴ.N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺(7302)酯类衍生物的合成及镇痛活性

本文报道了一系列N-[1-(β-酰氧基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺类衍生物及其化学结构与镇痛强度之间的关系,并测定了几个代表化合物的镇痛作用时间及与阿片受体亲和力。实验结果表明,7302的β-羟基酯化后,均能维持一定的镇痛强度,其镇痛作用时间与母体化合物7302相近。从受体结合试验来看,酯化后与受体亲和的能力显著下降。     

抗肿瘤药物的研究 Ⅲ.含氨基酸的氮芥磷酰胺衍生物的合成

以N-磷酰氨基酸为载体而形成的氮芥磷酰胺衍生物,可能具有较好的抗肿瘤专属性。双-(β-氯乙基)氨基磷酰二氯(Ⅰ)与二当量的甘、丙、缬、亮、笨丙、天冬及谷氨酸乙酯(Ⅱ)缩合,生成相应的N,N-双-(β-氯乙基)-N′,N″-二-(乙氧羰甲基)磷三酰胺衍生物(Ⅲ);与当量的丝氨酸乙酯(Ⅹ)缩合时生成环状衍生物,2-双-(β-氯乙基)氨基-4-乙氧羟基-四氢-1,2,3-氧膦氮茂,2-氧化物(Ⅺ)。这类化合物经动物实验有显著的抗肿瘤活性。     

关于抗肿瘤药物的研究 Ⅰ.207种合成化合物对动物移植性肿瘤的影响

本文报告几年来从合成化合物中筛选抗肿瘤药的结果,在207种合成化合物中,有效药物主要都是氮芥衍生物,计有N-甲酰溶肉瘤素(M₂),N-乙酰溶肉瘤素(M₃),N-甲酰溶肉瘤素酰苯丙氨酸乙酯(M₄),邻苯二甲谷氨酰溶肉瘤秦(M₅)及α-硝基-β-双(2-氯乙基)氨基己酸乙酯(M₉),α-硝基-β-双(2-氯乙基)氨基-β-(p-二甲苯基氨基)丙酸乙酯(M₁₀)。在其他类型化合物中,只丙烷异硫脲酒石酸锑对吉田腹水肉瘤有一定疗效。有效化合物中以N-甲酰溶肉瘤素(M₂),N-乙酰溶肉瘤素(M₃),N-甲酰溶肉瘤素酰苯丙氨酸乙酯(M₄)及邻苯二甲谷氨酰溶肉瘤素(M5)的疗效比较突出。已经在临床前药理研究的基础上,将N-甲酰溶肉瘤素及N-甲酰溶肉瘤素酰苯丙氨酸乙酯推荐给临床试用。     

(±)-13β,17α-二乙基-17β-羟基甾烷骈[3,2-C]吡唑及[2,3-C]呋咱的合成

以(±)-13β,17α-二乙基-17β-羟基-5α-甾烷-3-酮(Ⅱ)为原料,经甲酰化、缩合反应合成了(±)-13β,17α,-二乙基-17β-羟基-5α-甾烷骈[3,2-C]吡唑(Ⅴ);又将甲酰化反应所得羟次甲基化合物(Ⅳ)依次转变成单肟(Ⅵ)、双肟(Ⅶ)、再坏合成(±)-13β,17α-二乙基-5α-甾烷骈[2,3-C]呋咱(Ⅷ)。采用类似的反应,从(Ⅱ)及(Ⅳ)的5β-异构体(Ⅲ)和(Ⅸ)分别合成了(±)-13β,17α-二乙基-17β-羟基-5β-甾烷骈[3,2-C]吡唑(Ⅹ)与(±)-13β,17α-二乙基-17β-羟基-5β-甾烷骈[2,3-C)呋咱(ⅩⅢ)。     

氚标记强效镇痛剂N-[1-(β-羟基-β-苯乙基)-3-甲基-4-哌啶基]-N-丙酰苯胺的制备以及与阿片受体的结合试验

本文报道以N-[1-(对-溴苯甲酰甲基)-3-甲基-4-哌啶基]-N-丙酰苯胺(Ⅲ)为前体,以PdO/BaSO₄作催化剂,用氚气进行卤—氚置换,氚化还原羰基的反应。反应产物经硅胶纸层析纯化后,用甲基橙比色法定量测定,得到N-{1-[β-羟基-β-氚-β-(对-氚苯基)乙基]-3-甲基-4-哌啶基}-N-丙酰苯胺(Ⅳ,[³H]F-7302),其比放射性为59 Ci/mM,放化纯度为98%。[³H]F-7302与小鼠脑内阿片受体的特异性结合在浓度为4.5×10^-9M时达到饱和,解离常数Kd=1.25×10^-9M,最大结合量B_max=93.08×10¹²M/g蛋白,其特异性结合与非特异性结合比值达10～15。     

国产乙酰普马嗪的药理作用研究——加强作用及对交感神经末梢介质释放的影响

(1)采用热水刺激小白鼠尾巴法試驗鎮痛作用,乙酰普馬嗪0.5毫克/公斤可使“疼痛”反应出現时間延迟,較盐酸嗎啡(2毫克/公斤)为弱;二者均以半量合并应用,鎮痛作用强度虽未見加强,但鎮痛时間則延长。(2)脑室內注射乙鮂振R嗪,可立即引起小白鼠安靜,并使其体溫明显下降;皮下注射同剂量时,安靜及降溫作用均不显著,但可明显加强安替比林及水合氯醛的降溫作用。(3)乙酰普馬嗪局部滴药及皮下注射均可产生角膜麻醉,并可加强普魯卡因的表面麻醉作用,尤以皮下注射法为强。(4)乙酰普馬嗪2.5微克/公斤即可減弱腎上腺素的升压作用;5微克/公斤时,使后者作用翻轉,并使电刺激交感神經节前纤維及注射腎上腺素所引起的瞬膜收縮反应減弱。(5)在离体兔神經——迴腸标本,电刺激交感神經节后纤維引起腸张力下降,运动減弱,乙酰普馬嗪及氯丙嗪均可加强此交感反应。     

The action of CNS drugs on an isolated sympathetic nerve preparation of rabbit.

The effect of some centrally active drugs on the transmission of nerve impulses through the isolated cervical sympathetic nerve and superior cervical ganglion of the rabbit has been studied by recording both preganglionic and ganglionic responses to single square wave stimuli. Chlorpromazine, trifluoperazine and haloperidol have a greater axonal depressant action than the known local anaesthetics procaine and xylocaine. Chlordiazepoxide and diazepam are similar in local anaesthetic potency to procaine while meprobamate and sodium pentobarbitone possess only slight axonal depressant properties. Meprobamate, sodium pentobarbitone and possibly diazepam have ganglion blocking properties while procaine, chlorpromazine, trifluoperazine, haloperidol and chlordiazepoxide reduce the ganglion potential by virtue of their preganglionic action.     

强效镇痛剂研究 Ⅲ.3,5-桥丙烷基哌啶类衍生物的合成

本文根据3,5-桥丙烷哌啶类(Ⅰ)及芬太尼类镇痛剂化学结构与药理作用的特点,合成了3-甲基-3,5-桥丙烷基哌啶类衍生物(Ⅳ)及一类新的合并两者结构后的合成镇痛剂N-[1-(β-芳乙基)-3-甲基(或氢)-3,5-桥丙烷基哌啶基]-N-丙酰芳胺(Ⅲ)。药理初筛表明,所有这些化合物的镇痛强度大多均与吗啡同一水平。     

Quinidine inhibits the 7-hydroxylation of chlorpromazine in extensive metabolisers of debrisoquine

Quinidine is a potent inhibitor of CYP2D6 (debrisoquine 4-hydroxylase). Its effect on the disposition of chlorpromazine was investigated in ten healthy volunteers using a randomised crossover design with two phases. A single oral dose of chlorpromazine hydrochloride (100 mg) was given with and without prior administration of quinidine bisulphate (250 mg). Chlorpromazine and seven of its metabolites were quantified in the 0- to 12-h urine while plasma concentrations of chlorpromazine and 7-hydroxychlorpromazine were measured over 48?h. All volunteers were phenotyped as extensive metabolisers with respect to CYP2D6 using the methoxyphenamine/O-desmethylmethoxyphenamine metabolic ratio. Quinidine significantly decreased the urinary excretion of 7-hydroxylchlorpromazine 2.2-fold. Moreover the urinary excretion of this metabolite correlated inversely (r _s?=??0.80) with the metabolic ratio. The urinary recoveries of chlorpromazine, chlorpromazine N-oxide, 7-hydroxy-N-desmethylchlorpromazine, N-desmethylchlorpromazine sulphoxide and the total of all eight analytes were unaltered by quinidine. However, quinidine administration caused significant increases in the urinary excretions of chlorpromazine sulphoxide, N-desmethylchlorpromazine and N, N-didesmethylchlorpromazine sulphoxide, which indicated that compensatory increase in these metabolic routes of chlorpromazine might have been responsible for the lack of change observed in the urinary recovery of the parent drug. Quinidine administration produced modest decreases (1.2- to 1.3-fold) in the mean peak plasma concentrations and mean areas under the plasma concentration-time curves of 7-hydroxychlorpromazine and increases (1.3- to 1.4-fold) in these parameters for the parent drug chlorpromazine, but none of these changes reached statistical significance. Based on ANOVA the sample sizes required to detect these differences as significant (α?=?0.5) with a probability of 0.8 were determined to vary between 15 and 42. These data suggest that CYP2D6 is involved in the metabolism of chlorpromazine to 7-hydroxychlorpromazine. However, genetic polymorphism in this metabolic process did not play a dominant role in accounting for the extremely large interindividual variations in plasma concentrations encountered with this drug.     

Pharmacochemistry of Novel Aminoketone Phthalimide, Δ4-Tetrahydrophthalimide,and Arylsuccinimide Derivatives with Local Anaesthetic Activity

A number of aminoketones with prospective local anaesthetic activity were prepared. The structure of the synthesized compounds was confirmed by spectroscopic and elemental analyses. The physicochemical parameters (pka and logP) were also investigated. The local anaesthetic activity was determined in vitro on sciatic frog's nerve by the compound action potential technique: the phthalimide derivatives possess considerable local anaesthetic activity equal to that of lidocaine and higher than that of procaine.     

Influence of cationic amphiphilic drugs on the characteristics of ouabain-binding to cardiac Na+/K+-ATPase

The influence of 12 cationic amphiphilic compounds on the equilibrium and kinetic characteristics of the binding of tritium-labelled ouabain to the lipoprotein Na⁺/K⁺-ATPase present in a crude membrane suspension of guinea pig myocardium was investigated. The drugs, e.g. local anaesthetic, antiarrhythmic and psychotropic agents, inhibited specific binding of ouabain in a concentration-dependent manner by reducing its affinity without affecting the number of binding sites. In the presence of chlorpromazine, propranolol and dibucaine, the decreased affinity of ouabain was due to both a diminished association rate and an increased dissociation rate, while in the presence of the weakly potent procaine only the association rate of ouabain was found to be reduced. The different potency of the catamphiphilic drugs was well correlated to the degree of their hydrophobicity. Evidence is presented that the protonized form of the drugs is the effective one. Concerning the mode of action, the catamphiphilic drugs are proposed to interact with the phospholipid part of the lipoprotein Na⁺/K⁺-ATPase, thereby indirectly altering the conformation of the embedded protein moiety and thus reducing the proper fit between ouabain and its receptor.     

强效镇痛剂研究——Ⅰ.芬太尼类衍生物的合成及其镇痛作用

本文报道了芬太尼类衍生物的化学结构与镇痛活性之间的关系。分别改变了芬太尼中的哌啶环1位氮原子的取代基,N-酰芳胺基及哌啶环等部分结构。药理试验结果表明,大部分化合物均具有吗啡样镇痛活性,其镇痛强度分别为吗啡的2～150倍左右。     

Local anesthetics. 99. Synthesis and local anesthetic actions of alkoxyphenylcarbamates]

Within the framework of studying the influence of alterations of the connecting chain in the group of local anaesthetics a series of 24 compounds of 1-propoxymethyl-2-(1-pyrrolidinyl), 2-(1-piperidino)-, and 2-(1-perhydroazepinyl)-ethyl esters of o- and m-alkoxyphenylcarbamic acid were prepared. Studied compounds show a high index of relative local anaesthetic activity as compared to the standards cocaine and procaine, at a relatively low acute toxicity.     

COMPARISON OF THE EFFECTS OF (—)-ISOPRENALINE, ORCIPRENALINE TERBUTALINE, AND ME506 ON HEART RATE, SOLEUS MUSCLE CONTRACTILITY AND PULMONARY RESISTANCE OF ANAESTHETIZED CATS

1. Three resorcinol derivatives with N-isopropyl (orciprenaline), N-t-butyl (terbutaline) and N-p-hydroxypheny-t-butyl (Me506) amine substituents have been compared with (—)-isoprenaline for their ability to produce β-receptor mediated reductions in serotonin-induced increases in pulmonary resistance, decreases in soleus muscle contractility and increases in heart rate in anaesthetized cats. 2. For all parameters studied the four compounds produced similar maximal responses and dose-response curves were close to parallel. From the graphs doses of the compounds producing 50% of the maximal response (ED50) were interpolated, and from these dose-ratios with respect to (—)-isoprenaline [drug ED₅₀: (—)-isoprenaline ED₅₀] were calculated on a molar basis. 3. Increasing the size of the amine substituent from N-isopropyl to N-t-butyl led to an increase in β-receptor stimulant activity in bronchial and skeletal muscle, but not in the heart. The change from N-t-butyl to N-p-hydroxyphenyl-t-butyl did not further affect stimulant activity in any of the parameters studied. 4. Calculation of selectivity ratios [molar dose-ratio (heart): molar dose-ratio (pulmonary resistance)] showed that orciprenaline was non-selective, and that terbutaline and Me506 showed a similar degree of selectivity for β₂- as opposed to β₁-receptor mediated actions.