避孕新药双烯孕腈的临床前研究进展

双烯孕腈(Dienogestril)又名STS 557,化学名:17β-羟基-17α氰甲基-4,9(10)-雌甾二烯-3-酮。结构如下:     

3,5-甾二烯化合物的合成及抗早孕活性

以18-甲基-17β-羟基-17α-乙炔基-雌甾-4-烯-3-酮(18-甲基炔诺酮),17β-羟基-17α-乙缺基-雌甾-4-烯-3-酮(炔诺酮),17β-羟基-17α-乙炔基-雄甾-4-烯-3-酮(妊娠素)和17a-羟基孕甾-4-烯-3,20二酮(17α-羟基黄体酮)为原料,经NaBH,还原、脱水、双键转位和酯化等反应合成一系列3,5-甾二烯化合物,用¹HNMR和MS证明了它们的结构。动物筛选结果表明,17β-丙酰氧基-17α-乙炔基-雌甾-3,5-二烯(IV_b2有明显的抗早孕活性。中断早期妊娠的作用似与其雌激素活性有关。     

Natazia

Natazia是由拜耳公司生产的一种新上市的口服避孕药，于2010年6月6日通过FDA审批。Natazia的主要成分是地诺孕素(dienogest)和戊酸雌二醇酯(estradiol valerate)。 戊酸雌二醇酯的中文化学名：雌甾-1,3,5(10)-三烯-3,17β-二醇- 17-戊酸酯；英文化学名：Estra-1,3,5(10)-triene-3,17-diol(17β)-,17-pentanoate；分子式：C23H32O3 ；相对分子质量：356.5；CAS登记号：979-32-8。地诺孕素的中文化学名： (17α)-17β-羟基-3-氧代-19去甲基孕甾-4,9-二烯-21-腈；英文化学名： (17α)-17β-Hydroxy-3-oxo-19-norpregna-4,9-diene-21-nitrile；分子式：C20H25NO2；相对分子质量：311.42 ；CAS登记号：65928-58-7。     

硬棘软珊瑚醋酸乙酯部位的化学成分研究

目的研究硬棘软珊瑚醋酸乙酯部位的化学成分。方法采用正、反相硅胶柱色谱以及半制备高效液相色谱进行分离,并根据理化性质和波谱数据鉴定化合物的结构。结果分离得到11个化合物,其中3个环丁烯内酯类化合物,分别鉴定为(S)-13-(2-羟基-3,4-二甲基-5-氧代-2,5-二氢呋喃-2-基)十三烷酸(1)、(S)-11-(2-羟基-3,4-二甲基-5-氧代-2,5-二氢呋喃-2-基)十一烷酸(2)、羟基二氢博伏内酯(3);1个嘌呤类化合物,鉴定为1,3-二甲基黄嘌呤(4);7个甾体类化合物,分别鉴定为孕甾-20-烯-3-酮(5)、孕甾-1,4,20-三烯-3-酮(6)、3β-羟基-孕甾-20-烯(7)、3β-羟基-孕甾-5,20-二烯(8)、20-羟基-孕甾-1,4-二烯-3-酮(9)、20-羟基-孕甾-1-烯-3-酮(10)、17β-羟基-雄甾-1-烯-3-酮(11)。结论环丁烯内酯类化合物是首次从该属软珊瑚中分离得到,其中化合物1和2为新化合物,而硬棘软珊瑚醋酸乙酯部位的化学成分主要为甾体类化合物。     

孕二烯酮有关物质的合成

目的为更好地对孕二烯酮原料药质量进行控制,合成孕二烯酮原料药中的2种有关物质。方法以13β-乙基-15α-羟基雌甾-4-烯-3,17-二酮为起始原料,经过3位羰基缩酮化保护、17位乙炔化和水解脱保护基共3步反应,得到有关物质13β-乙基-15α,17β-二羟基-18,19-双去甲基-17α-孕甾-4-烯-20-炔-3-酮,收率为12.1%;该有关物质经乙酰化得到另一种有关物质13β-乙基-17β-羟基-15α-乙酰氧基-18,19-双去甲基-17α-孕甾-4-烯-20-炔-3-酮,收率为72.9%。结果与结论合成了孕二烯酮原料药中的2种有关物质,并经1H-NMR、13C-NMR和MS谱确证结构,2种有关物质的纯度经HPLC检测均在98%以上,可以作为孕二烯酮原料药质量控制的对照品。     

13α-去氢表雄酮的皮质甾类侧链及其13β-差向异构体的合成

17-酮基甾体化合物在催化量乙二胺的存在下与硝基甲烷反应得到相应硝基烯衍生物。本文以13β醋酸去氢表雄酮为原料经三步反应转变成13α-去氢表雄酮(3)。化合物(3)经缩合,乙酰化,还原等反应合成了3β,21-二乙酰氧基-13α-孕甾-5,16-二烯-20-酮(8)。同时还合成了这些化合物13β-差向异构体,以比较反应性及波谱差异。并发现乙二胺用量的改变会得到一个副产物,其结构为13α-去氢表雄酮肟(9)。     

5α-△~(9(11))-16β-甲基-3β,17α,21-三羟基-孕甾烯-3β,21-双醋酸酯-20酮和5α,17α-甲基-17β-羟基-雄甾-3酮的微生物转化

用诺卡氏菌与节杆菌混合菌种转化从蕃麻皂素制得的中间体5α-△~((?)(11))-16β-甲基-3β,17α,21三羟基孕甾烯-3β,21-双醋酸酯-20酮(Ⅰ)得50％的16β-甲基-△~(1,4,9(11))-孕甾三烯-20酮(Ⅱ)和少量的16β-甲基-9,11α环氧-△~1,4孕甾二烯-20酮(Ⅲ)。另外,又用同样的混合菌种转化从剑麻皂素制得的中间体5α,17α甲基-17β羟基-雄甾-3酮(Ⅳ)得50％17α甲基-17β羟基-△~(1,4)-雄甾二烯-3酮(Ⅴ)。如改变培养基则得3,17β-羟基-17α-甲基-9酮基-9,10开环-1,3,5(10)雄甾三烯化合物。     

7α-甲基双烯孕腈的合成

甾体事后避孕药是一直受到人们重视的一个研究领域,已发现了一些很有希望的化合物,如RU-486(1),RMI-12936(2),STS-557(3)等。其中17α-氰甲基-17β-羟基-4,9(10)-雌甾二烯-3-酮(双烯孕腈,Dienogestril,STS-557),系1979年由Ponsold等报道的     

地诺孕素药学特性及其临床应用前景

<正> 孕激素是一类重要的化学药物,临床应用广泛且具不可替代性(表1)。孕激素依来源与结构大体分为三类,即:17α—羟基黄体酮及其它们的合成衍生物和19—失碳孕激素,其中后者因发现了普美孕酮(promegestone)、诺美孕醇(nomegestrol)、曲美孕酮(trimegestone)等所谓“混合孕激素”,现似已有再次形成一孕激素研究与开发“热”的趋势。所谓“混合孕激素”是指这些孕激素同时具有天然和合成孕激素的药理学优点,它已随着其第一个药物地诺孕素(dienogestril,17α—氰甲基—17β—羟基—4,9—雌甾二烯—3—酮。图1)的上市而正式走上了临床。本文介绍地诺孕素的药学特性及其临床应用潜力。     

卤倍他索丙酸酯相关杂质的合成

目的为加强对皮质类激素卤倍他索丙酸酯原料药的质量控制,首次合成了卤倍他索丙酸酯的3个杂质。方法以卤倍他索丙酸酯及二氟拉松为起始原料,经过水解反应制得21-氯代-6α,9-二氟-11β,17-二羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮(杂质Ⅰ);以二氟拉松为起始原料,经过磺化反应、氯代反应及酯化反应得到21-氯代-6α,9-二氟-17-羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮-11-丙酸酯(杂质Ⅱ);以二氟拉松为起始原料,通过酯化反应生成6α,9-二氟-11β-羟基-16β-甲基孕甾-1,4-二烯-3,20-二酮-17-丙酸酯-21-乙酸酯(杂质Ⅲ)。结果与结论合成的3种杂质的结构经~1H-NMR、HPLC-MS确证与美国药典中杂质结构一致,可以作为卤倍他索丙酸酯原料药质量控制的杂质对照品。     

Angiotensin-converting enzyme inhibitors: perhydro-1,4-thiazepin-5-one derivatives

alpha-[6-[[(S)-1-(Ethoxycarbonyl)-3-phenylpropyl]amino]-5-oxoperhydro -1,4-thiazepin-4-yl]acetic acids (monoester monoacids) and their dicarboxylic acids having the hydrophobic substituents at the 2- or 3-position of the thiazepinone ring were prepared and assayed for angiotensin-converting enzyme (ACE) inhibitory activity. The dicarboxylic acids having the pseudoequatorial amino groups at the 6-position and the pseudoequatorial hydrophobic substituents at the 2- or 3-position of the chair conformation of the thiazepinone ring had potent in vitro inhibitory activity. The monoester monoacids having the hydrophobic substituents at the 2-position suppressed pressor response to angiotensin I for a longer duration than those having the substituents at the 3-position when administered orally. The structure-activity relationship was studied by conformational energy calculations of the thiazepinone ring.     

Leukotriene B4 receptor antagonists: the LY255283 series of hydroxyacetophenones.

A series of hydroxyacetophenones was prepared for evaluation as leukotriene B4 (LTB4) receptor antagonists, culminating in 1-[5-ethyl-2-hydroxy-4-[[6-methyl-6-(1H-tetrazol-5- yl)heptyl]oxy]phenyl]ethanone (compound 35, LY255283). Using an assay for inhibition of specific [3H]LTB4 binding to human PMN, we found that substitution of a nonpolar substituent in the 5-position was required for activity. Best activity was realized with hydrogen in the 3-position, hydroxyl in the 2-position, short chain alkyl ketone in the 1-position, and a six- or eight-carbon chain linking the oxygen in the 4-position with an unsaturated terminal function. Compound 35, having an IC50 of 87 nM in the binding assay, was chosen for further preclinical evaluation.     

Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists

As a potent, specific antagonist for the brain cannabinoid receptor (CB1), the biarylpyrazole N-(piperidin-1-yl)-5-(4-chlorophenyl)-1-(2, 4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide (SR141716A; 1) was the lead compound for initiating studies designed to examine the structure-activity relationships of related compounds and to search for more selective and potent cannabimimetic ligands. A series of pyrazole derivatives was designed and synthesized to aid in the characterization of the cannabinoid receptor binding sites and also to serve as potentially useful pharmacological probes. Therapeutically, such compounds may have the ability to antagonize harmful side effects of cannabinoids and cannabimimetic agents. Structural requirements for potent and selective brain cannabinoid CB1 receptor antagonistic activity included (a) a para-substituted phenyl ring at the 5-position, (b) a carboxamido group at the 3-position, and (c) a 2,4-dichlorophenyl substituent at the 1-position of the pyrazole ring. The most potent compound of this series contained a p-iodophenyl group at the 5-position, a piperidinyl carboxamide at the 3-position, and a 2,4-dichlorophenyl group at the 1-position of the pyrazole ring. The iodinated nature of this compound offers additional utility as a gamma-enriching SPECT (single photon emission computed tomography) ligand that may be useful in characterizing brain CB1 receptor binding in vivo.     

Structure-activity studies of analogs of β, γ-methylene-ATP at P2X-purinoceptors in the rabbit ear central artery

Structure-activity studies using naphthylmethyl analogs of β, γ-methylene-ATP were conducted at the P_2X-purinoceptor that mediates contraction of the rabbit ear central artery by ATP, α, β-m-ATP. On the adenine base, substitution at the C²-position (WRC-0440) increased the agonist potency 2-fold and substitution at the C⁸-position (WRC-0431) did not change agonist potency, and both compounds had the same maximal response as β, γ-m-ATP, whereas substitution at the N⁶-position (WRC-0416) abolished activity. On the D-ribose sugar, substitution on the 2′-hydroxyl generated a partial agonist (WRC-0479), which had a maximal effect of only 39% of that of β-γ-m-ATP. Attempts to substitute the 3′-hydroxyls by naphthylmethyl failed, but substitution by p-methoxybenzyl (WRC-0617) did not change potency or the maximal response. Cyclic substitution of both the 2′- and 3′-hydroxyls by naphthylmethylidine (WRC-0498) had no effect on the agonist potency or the maximal response relative to β-γ-m-ATP. On the β, γ-methylenetriphosphonate chain, substitution on the methylene linkage by naphthylmethyl (WRC-0433) had no effect on agonist potency, but the maximal response increased to 122% that of β-γ-ATP. However, the contractile response to WRC-0433 was not desensitized by α, β-γ-ATP (contractile responses to all other agonists were abolished by α-β-γ-ATP pretreatment), but was blocked by the α₁ antagonist prazosin (10^?6 M). WRC-0433 appears to act at a prejunctional site that mediates ATP-induced release of norepinephrine. Purine nucleotides with substituents at the 2′-position of the ribose sugar could provide a lead to the generation of P_2X-purinoceptor antagonists. © 1995 Wiley-Liss, Inc.     

Synthesis and structure-activity relationships of new arylfluoronaphthyridine antibacterial agents

Novel arylfluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acids have been prepared and their antibacterial activity evaluated. These derivatives are characterized by having a fluorine atom at the 6-position, substituted amino groups at the 7-position, and substituted phenyl groups at the 1-position. The in vitro antibacterial potency is greatest when the 1-substituent is either p-fluorophenyl or o,p-difluorophenyl and the 7-substituent is a 3-amino-1-pyrrolidinyl group. 1-(2,4-Difluorophenyl)-6-fluoro-7-(3-amino-1-pyrrolidinyl)-1,4-dihydro- 4-oxo-1,8-naphthyridine-3-carboxylic acid (38) was found to possess excellent in vitro potency and in vivo efficacy.     

Identification of the human P450 enzymes involved in the in vitro metabolism of the synthetic steroidal hormones Org 4060 and Org 30659

1. The type of human P450 enzymes involved in the in vitro metabolism of Org 4060 and Org 30659, two synthetic steroidal hormones currently under clinical development by NV Organon for use in oral contraceptive and hormone replacement therapy, was investigated. 2. Both steroids were mainly hydroxylated at the 6 β -position in incubations with human liver microsomes. 3. The results from experiments with supersomes, correlation studies as well as inhibition studies with ketoconazole, a selective inhibitor of CYP3A, strongly suggest that the CYP3A family plays a significant role in the 6 β -hydroxylation of both steroids. 4. Measurements of kinetic parameters of P450 enzymes that could metabolize both steroids, combined with the fact that CYP3A4 is known to be the most abundant P450 enzyme in the human liver, indicate that CYP3A4 will be of major importance for the in vivo human metabolism of Org 4060 and Org 30659.     

Synthesis of indolizine derivatives with selective antibacterial activity against Mycobacterium tuberculosis.

1-substituted indolizines with activity against Mycobacterium tuberculosis have been synthesized. The most active compounds carry an hydroxyphenylmethyl- or hydroxyalkyl substituent in the indolizine 1-position. The alkyl chain should be moderately long (C-5 or C-6). Aryl groups in the 2- and 3-position of the indolizine are also required. Removal of the 3-substituent resulted in significant loss of activity. A nitrile substituent in the 7-position is beneficial for both chemical stability and bioactivity. The compounds studied display a narrow antibacterial spectrum and appear to be quite selective antimycobacterial compounds. Moderate activity against certain pathogenic protozoa was also observed.     

5,6-二芳基-2,3-二氢-1-吡咯里嗪酮类化合物抗炎作用的三维构效关系研究

目的研究5,6-二芳基-2,3-二氢-1-吡咯里嗪酮类化合物抗炎作用的三维构效关系,为进一步设计新结构类型化合物提供理论依据。方法和结果用计算机辅助药物设计专家系统(Apex-3D)软件模拟并构建药效基团模型和三维构效关系(3D-QSAR)方程。结论化合物的抗炎活性与分子总疏水性、空间体积和吡里酮环1位基团和两个次级作用部位的性质有关;增加吡里酮环1位基团π电子密度,降低分子总疏水性,及减弱6位苯环对位取代,都将有利于化合物的抗炎作用。     

Effects of inducers and/or inhibitors on metabolism of lysergic acid diethylamide in rat liver microsomes

1. When lysergic acid diethylamide (LSD) was incubated with liver microsomes obtained from untreated rats, SKF 525-A inhibited most potently the hydroxylation at the 13-position, moderately inhibited N-demethylation at the 6-position, and least affected the metabolism of the side-chain at the 8-position. Furthermore, an atmosphere of 80% CO and 20%O₂ (v/v) caused max. inhibition in N-demethylation, moderate inhibition in 13-hydroxylation, and the minimum in metabolism of the side-chain at the 8-position. These data suggested that the metabolism of LSD is catalysed by three separate enzyme systems.

2. The formation of 13-hydroxy-lysergic acid diethylamide (13-hydroxy-LSD) in liver microsomes obtained from 3-methylcholanthrene-treated rats was not inhibited by CO, although the hydroxylation required NADPH and oxygen.

3. The results of experiments using various inhibitors suggest that the 13-hydroxylation in liver microsomes from 3-methylcholanthrene-treated rats is catalysed by an enzyme system involving an unusual type of cytochrome P-448.     

1,8-Naphthyridine-derivatives from dehydrogenative cyclization (author's transl)]

1,8-Naphthyridine-Derivatives from Dehydrogenative Cyclization . The mercuric EDTA dehydrogenation of 3-(3-aminopropyl)-substituted 1-methylpiperidines yields products with substitution in the 2- and 6-position of the piperidine ring. The reaction in 6-position gives exclusively 6-piperidones, while attack of the 2-position yields octahydro-1,8-naphthyridines, which are partially hydrolysed to 2-piperidones. With 1,7,7-trimethyl-decahydro-1,8-naphthyridine an aminal could be isolated as an intermediate in a double dehydrogenation for the first time.