21-氯代达哪唑及其C_6-脱氢物的合成

达哪唑(danazol)国产品名炔睾醇(Ⅲa),是治疗子宫内膜异位症的药物,并具有多方面的生理活性,既能抑制垂体前叶腺素的合成与释放,也是3β-羟基甾体脱氢酶(3βHSD)的抑制剂,国外曾作为女用口服避孕药或与睾丸素酯合用作男性抗生育剂,近年来还作为女用事后避孕药。为了寻找新的抗生育调节剂以适应计划生育工作的需要,我们对达哪唑进行结构改造研究,合成了它的21-氯化物(Ⅳa)及其C_6-脱氢物(Ⅳb)。其合成路线如下:     

达哪唑衍生物的合成

Synthesis of danazol analogues involved transformation of 3-ketosteroids (Ⅰa～c) into 2-hydroxymethylene steroids (Ⅱa～c) and subsequent cyclization to steroidal (2, 3 d) isoxazoles (Ⅲa～c), Further treatment with sodium methoxide gave the corresponding steroidal-3-oxo-2α-carbonitriles (Ⅳa～c). The binding ability of (Ⅲa～c) and (Ⅳa～c) to progesterone receptor were examined and (Ⅲc) was found to be two times as active as danazol.     

达哪唑衍生物的合成

黄体酮是维持正常妊娠所必需的孕激素,一些能抑制黄体酮生物合成或与黄体酮受体有很强结合力的化合物都有可能终止早期妊娠与导致流产。已知甾体[2,3 d]异恶唑类如达哪唑(danazol),azastene和甾体-2α-氰基-3-酮类如cyanoketone,trilostane(4),epos-     

磺胺甲(口恶)唑中间体3-氨甲酰-5-甲基异(口恶)唑的含量测定

提出的磺胺甲(口恶)唑中间体3-氨甲酰-5-甲基异(口恶)唑的容量滴定法扣除了其中共存干扰物的影响,分析结果可靠,方法简便。     

11-酮基-△~9-炔诺酮的合成

在甾体分子的9-位、11-位引入二个双键往往可以增强或改变其生理活性,例如18-甲基三烯炔诺酮与三烯炔诺酮均有比母体18-甲基炔诺酮与炔诺酮更强的抗生育活性。将11-位双键改为11-位酮基,即在11-位引入氧原子,则有抗着床与降胆固醇作用,11-酮基-△~9-炔诺酮(9)100ν对大鼠有抗着床作用,法国Roussel-Uclaf公司进行了全合成,并作简单报道。我们采用炔诺酮中间体,19-羟基-△~4-雄甾烯-3,17-二酮(1)为原料,用半合成路线仅8步反应合成了化合物(9)。     

2-〔4(s)-4-酚胺基-3-氧代-2-异噁唑烷基〕-5-氧代-2-四氢呋喃甲酸钠类化合物的合成

以L-丝氨酸和α-酮戊二酸为原料,采用三条合成路线,经6～8步反应,合成8个目标化合物。其部份中间体的结构经IR,PMR,MS及元素分析证实。产物的结构也经IR及PMR证实。体外抑菌试验表明,TM7和TM8显示较强的广谱抑菌活性,TM6则具有中等强度。TM2和TM3对金葡菌也有一定活性。     

7α,17α-二甲基-17β-羟基雄甾-4-烯-3酮的若干A环骈杂环衍生物的合成

将7α-甲基引进甲基睾丸素后,经甲酰化反应制得2-羟次甲基衍生物(Ⅳ),再先后转变为单肟(Ⅴ)、双肟(Ⅵ),环合得70,17α-二甲基-17β-羟基-雄甾-4-烯骈[2,3-c]呋咱(Ⅶ)。也可使(Ⅳ)与水合肼或盐酸羟胺作用,分别制得相应的雄甾-4-烯骈[3,2-c]吡唑(Ⅷ)及雄甾2,4-二烯骈[2,3-d]异(口恶)唑(Ⅸ)。在酸性反应条件下合成(Ⅸ)时,还分离出它的重排脱水产物7α,17α,17β-三甲基雄甾-2,4,13-三烯骈[2,3-d]异(口恶)唑(Ⅹ)。     

11-酮基-△9-炔诺酮的合成

We have introduced a carbonyl group at the 11-position and a double bond at the 9-position of norethisterone in order to increase its antifertility potency. The starting material for the preparation of 11-keto-Δ⁹-noret-histerone(9) was 19-hydroxy-Δ⁴-androstene-3,17-dione(1), which was converted to the title compound by partial synthesis through the sequence of reactions:(1)→(9).11-Keto-Δ⁹-norethisterone was found to possess very potent antifertility effect by preliminary screening tests.     

17β-羟基-4ɑ,5ɑ-环氧雄甾烷并[2,3-d]异噁唑的合成工艺改进

17β-羟基雄甾-4-烯-3-酮与甲酸乙酯在甲醇钠条件下经缩合生成17β-羟基-2-羟亚甲基雄甾-4-烯-3-酮,与盐酸羟胺环合形成17β-羟基-4-烯-雄甾烷并[2,3-d]异噁唑,最后经m-CPBA环氧化制得曲洛司坦关键中间体17β-羟基-4ɑ,5ɑ-环氧雄甾烷并[2,3-d]异噁唑,总收率为70%,纯度为99.1%。     

血吸虫病化学治疗的研究——ⅩⅪⅤ.5-[2-(5-硝基呋喃基-2)-1-取代乙烯基]-1,3,4-噁二唑酮及其1,3,4-噁二唑衍生物的合成

本文报道硝基呋喃乙烯基-1,3,4-噁二唑及其酮类衍生物44个的合成。关键中间体α-取代β-(5-硝基呋喃基-2)丙烯酰彤魄仿照文献已知方法制备的,然后分别与光气或溴化腈作用生成相应的1,3,4-噁二唑衍生物Ⅰ,Ⅱ。经感染日本血吸虫病小白鼠的预防和治疗试验,发现化合物Ⅰ₁具有显著的抗血吸虫作用,并试用于家犬的血吸虫病,证明有一定的疗效。但效果不及呋喃丙胺,故未作临床观察。     

6-连氮和6α-甲氧基-6β-取代腙青霉素的合成及抗菌活性

本文报道新颖的6-连氮和6α-甲氧基-6β-取代腙青霉素的合成及引入6α-甲氧基的新方法。这类化合物对一些阴性菌和阳性菌有中等活力,且引入6α-甲氧基之后对细菌的抑制作用增强。     

Synthesis and ring transformation of pyrrolo[2,3-d][1,3]oxazine to pyrrolo[2,3-d]pyrimidines

A convenient route is reported for the synthesis of fused pyrrolo [2, 3-d] [1, 3]-oxazine and pyrrolo [2, 3-d]-pyrimidine derivatives from 2-amino-1-benzyl-3-t-butoxycarbonyl-4, 5-dimethylpyrrole.     

国产醋酸甲地孕酮的质量研究:6-羟基-6-甲基-17α-乙酰氧基黄体酮差向异构体的分离与鉴定

用柱层析及薄层层析对国产醋酸甲地孕酮的杂质进行了分析,共分离出7个杂质点:Ⅰ₁,Ⅰ₂,Ⅰ₃,Ⅰ₄,Ⅰ₅,Ⅰ₆,Ⅰ₇,并对其中Ⅰ₃和Ⅰ₄进行分离纯制及光谱分析,确定其结构为6β-羟基-6α-甲基-17α-乙酰氧基黄体酮及其差向异构体6α-羟基-6β-甲基-17α-乙酰氧基黄体酮。本文报道了薄层层析条件(硅胶GF₂₅₄,展开剂:醋酸乙酯-甲苯=7:3)以及光谱鉴别的依据。     

Synthesis and biological activity of conformationally controlled 2-PAM derivatives

A series of conformationally controlled 2-PAM derivatives were prepared from 2-acetylpyridine and 2,3-pyrido[b]cycloalkenones in two steps and their reactivities towards parathion poisoned AChE were evaluated. The most planar 2,3-pyrido[b]cyclohexanone oxime methiodide showed an activity comparable to 2-PAM implying E-syn is that the most active conformation of 2-PAM in the biological system.     

Synthesis and antiviral properties of carbocyclic 3′-oxa-2′,3′-dideoxyguanosine and its 7-deazaguanosine analogue

To evaluate analogues of the antiviral agent (R)-9-(3,4-dihydroxybutyl)guanine in which the side-chain C-3 hydroxyl oxygen is part of a five-membered ring, carbocyclic 3′-oxa-2′,3′-dideoxyguanosine (4) and carbocyclic 3′-oxa-2′,3′-dideoxy-7-deazaguanosine (5) have been synthesized in 17 and 14 steps, respectively, from

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. Compounds 4 and 5 and their 6-chloro precursors were evaluated against a wide variety of DNA and RNA viruses. Only 4 showed any marginal activity and this was limited to HSV-1 and HSV-2. Even though 4 was less potent towards these latter two viruses than acyclovir, its mechanism and target of action is proposed to resemble that of acyclovir. The only toxicity observed for these compounds was observed in the cell growth assay with human embryonic lung cells.     

抗孕激素活性甾族化合物:7α-和7β-甲基-A-环失碳双炔雄甾醇的合成

本文报道利用睾丸酮为原料,经脱氢和二甲基铜锂试剂甲基化,制备7-甲基睾丸酮。采用结晶法分离7α-和7β-异构体后,分别进行锂氨还原、氧化、环合及炔锂炔化等反应,合成7α-和7β-甲基-A-环失碳-2α,17α-双乙炔基-5α-雄甾-2β,17β-二醇(Ⅱa,和Ⅱb),经初步药理试验表明,Ⅱa对大鼠具有较强的抗孕激素活性,口服剂量在2.5 mg/kg时,能明显抑制假孕大鼠蜕膜瘤的生长。抗早孕最低口服有效剂量为3.5 mg/kg/4 d,Ⅱb则较弱。     

Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists

This paper describes the synthesis and the antiplatelet properties of new heterotricyclic N-acylhydrazone derivatives (7a–e), structurally analogous to known hetrazepinic PAF antagonists, exploring molecular hybridization as a tool for molecular designing. The synthetic route employed to access compounds (7a–e) used, as starting material, the previously described methyl 3-hydroxy-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2,3-d]pyridine-2-carboxylate derivative. The results from inhibitory effects of these novel acylhydrazone derivatives (7a–e) upon PAF-induced platelet aggregation, indicated that all compounds present a significant antithrombotic profile.     

7α和7β-甲基-10β,17β-二乙酰氧基-4-雌甾烯-3-酮的合成

由于7α-甲基或10β-乙酰氧基4(5)烯-3-酮雌(雄)甾化合物具有显著的抗着床或抗蜕膜活性,我们合成了既具有7α-甲基或7β-甲基又具有10β-乙酰氧基的两个新甾族化合物(1_a)和(1_b)。经药理试验表明(1_a)和(1_b)对孕鼠均有抗早孕作用。