5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮的合成

丙酰肼与三光气缩合环化得到5-乙基-1,3,4-噁二唑-2(3H)-酮,继与2-苯氧乙胺反应后在碱性条件下环合得到抗抑郁药奈法唑酮中间体5-乙基-2,4-二氢-4-(2-苯氧乙基)-3H-1,2,4-三唑-3-酮,总收率66.3%.     

盐酸尼非卡兰的合成

以3-苯基丙酸为原料，经硝化、N-酰化和还原反应合成中间体N-(2-羟乙基)-N-[3-(4-硝基苯基)丙基]胺（Ⅰ），Ⅰ与1，3-二甲基-6-[[2-(p-甲苯磺酰)氧基]乙基]氨基-2，4(1H，3H)-嘧啶二酮（Ⅱ）缩合、成盐得盐酸尼非卡兰。     

盐酸尼非卡兰的合成

以1，3－二甲基脲为原料，经环合、氯化、胺解和磺酸酯化反应合成中间体6－[[2－（p－甲苯磺酰基氧基）乙基]氨基]－1，3－二甲基－2，4（1H，3H）－嘧啶二酮，再与中间体2－[3-(4-硝苯基）再基氨基]乙醇缩合、成盐得盐酸尼非卡兰，总收率26．6％。     

单胺氧化酶抑制剂的合成 Ⅰ.若干含氮、氧、硫的双酰肼的制备

本文报导36个碳链上杂有醚键、硫醚键、胺键的双酰肼类化合物的合成.其合成法系由氧杂、硫杂、氮杂的二元酸二乙酯或4-苯基-1-哌嗪乙酸乙酯与水合肼缩合,生成相应酰肼,后者先与带有不同取代烃基的醛或酮缩合,再用钾硼氢还原制成;肼上带有苄基及苯乙基取代的酰肼系由相应酯与苄肼或苯乙肼直接缩合制得.经体内及体外单胺氧化酶抑制试验后找出了一个毒性很低,治疗指数较高的药物4-硫杂庚二酰(2-异丙基)肼(简称硫双肼),已推荐临床试用。     

依托度酸的合成工艺优化

本研究改进了依托度酸(1)的合成工艺.以邻乙基溴苯(3)为起始原料,经水合肼肼解后成盐精制制得邻乙基苯肼盐酸盐(4),4在碱性条件下游离后经Amberlyst 15树脂催化与2,3-二氢呋喃(5)反应生成7-乙基色醇(2),2不经分离与3-氧代戊酸甲酯(6)缩合环化得依托度酸甲酯(7),最后水解制得目标产品1,纯度99...     

盐酸昂丹司琼有关物质B的合成

为了盐酸昂丹司琼的质控,合成了欧洲药典7.0中规定的有关物质B[6,6′-亚甲基双[9-甲基-3-[(2-甲基-1H-咪唑-1-基)甲基]-1,2,3,9-四氢-4H-咔唑-4-酮]]:用4,4′-二氨基二苯甲烷经重氮化及还原得到4,4′-二肼基二苯甲烷二盐酸盐,与1,3-环己二酮缩合后进行Fischer环合生成6,6′-亚甲基双(1,2,3,9-四氢4H-咔唑-4-酮),再经甲基化、与多聚甲醛进行羟醛缩合反应,最后与2-甲基咪唑进行Michael加成制得.     

1β-甲基碳青霉烯双环母核的合成

邻羟基苯甲酰胺和环己酮经酰化、与(3R,4R)-4-乙酰氧基-3-[(1R)-1-(叔丁基二甲硅氧基)乙基]氮杂环丁烷-2-酮(4)缩合、水解得(3S,4S)-4-[(1R)-1-羧乙基]-3-[(1R)-1-(叔丁基二甲硅氧基)乙基]氮杂环丁烷-2-酮(6).6再经缩合、脱保护、环合、烯醇化及酯化得1β-甲基碳青霉烯双环母核,总收率约29%(以邻羟基苯甲酰胺计).     

盐酸阿洛司琼的合成工艺改进

据文献报道，以3-甲氧甲酰基-2，4-二氧哌啶钠盐（2）为原料，采用两条不同的合成路线，成功地制备了盐酸阿洛司琼（alosetron，1）。路线一以化合物2与1-甲基-1-苯肼硫酸盐缩合得到5，6-二氢-4-(2-甲基-2-苯肼)-2(1H)-吡啶酮（3），再经环合、对接制得盐酸阿洛司琼，总收率为10%。路线二以化合物2经脱竣制得2，4-哌啶二酮（5），与1-甲基-1-苯肼缩合制得3，再经环合、对接制得盐酸阿洛司琼，总收率为23.7%。经IR、UV、^1H-NMR、^13C-NMR及MS测试确证目标化合物结构。     

盐酸氮Zhuo斯汀的合成

以N－甲基哌啶－4－酮为原料，经扩环，酰肼化，缩合等反应合成了抗变态反应药物盐酸氮Zhuo斯汀，反应总收率48．6％。     

盐酸米那普仑右旋异构体的合成

苯乙腈和(R)-2-氯甲基环氧乙烷在甲苯中,加NaNH2和相转移催化剂氯化苄基三乙基铵反应得到(1S,2R)-1-苯基-3-氧杂二环[3.1.0]己烷-2-酮,不需分离,直接经Gabrial反应、酰氯化、酰胺化和肼解,最后成盐得到盐酸米那普仑,总收率1 3.6%.     

CYP2D6-mediated catalysis of tamoxifen aromatic hydroxylation with an NIH shift: similar hydroxylation mechanism in chicken,rat and human liver microsomes

1. 4-Tritiated-tamoxifen (4-[(3)H]-tamoxifen) and 4-deuterated-tamoxifen (4-[(2)H]-tamoxifen) were synthesized to examine tamoxifen metabolism by human P450 (CYP) forms and also for the possibility of determining tamoxifen-4-hydroxylation in humans in vivo. 2. Liver microsomes from several species and cDNA-expressed human P450s were incubated with 4-[(3)H]-tamoxifen and the reaction monitored by assaying 4-hydroxytamoxifen (4-OH-tam) and (3)H(2)O formed. However, tamoxifen-4-hydroxylation did not generate stoichiometric amounts of (3)H(2)O and the expected unlabelled 4-OH-tam but instead yielded radiolabelled 4-OH-tam, apparently from [(3)H]-migration to the ortho-position, referred to as the NIH shift. 3. CYP2D6 was the prime catalyst of tam-4-hydroxylation, whereas CYP2B6, 2C9 and 2C19 yielded only low levels of 4-OH-tam; nevertheless, in all cases the 4-OH-tam was radioactive, apparently resulting from reactions involving an NIH shift. 4. Chicken liver microsomal preparation, being catalytically the most active in tamoxifen-4-hydroxylation, was incubated with deuterated tamoxifen (4-[(2)H]-tamoxifen) in order to determine whether an NIH shift occurs. Ion-trap mass-spectrometry of the HPLC-purified 4-OH-tam, from that incubation, indicated about 60% of [(2)H]-retention in 4-OH-tam, signifying an NIH shift. These findings indicate that the aromatic hydroxylation of tamoxifen does not entail hydroxyl insertion with an Sn2-displacement of hydrogen or a hydrogen isotope ((2)H or (3)H), but apparently involves epoxidation followed by migration of the (3)H, (2)H or (1)H to the ortho-position, and dissociation of the (1)H in preference to (3)H or (2)H, i.e. retention of the hydrogen isotope appears to be related to the bond strengths: C-(3)H>C-(2)H>C-(1)H.     

A cytoplasm-sensitive peptide vector cross-linked with dynein light chain association sequence (DLCAS) enhances gene expression

We previously engineered a novel, non-viral, multifunctional gene vector (STR-CH(2)R(4)H(2)C) containing stearoyl (STR) and a block peptide consisting of Cys (C), His (H), and Arg (R). STR-CH(2)R(4)H(2)C forms a nano-complex with pDNA and is stabilized by electronic interactions and disulfide cross linkages. In blood, pDNA, a cytosol-sensitive gene vector, is released from the complex into the cytosol. The current study aimed to make STR-CH(2)R(4)H(2)C capable of active nuclear localization. The dynein light chain association sequence (DLCAS) was disulfide cross-linked to STR-CH(2)R(4)H(2)C/pDNA through disulfide linkages, and the gene expression ability of this DLCAS cross-linked gene vector was evaluated. We examined the gene transfection efficiency of S-180 cells transfected with the STR-CH(2)R(4)H(2)C/DLCAS/pDNA complex. STR-CH(2)R(4)H(2)C/DLCAS/pDNA showed significantly higher and faster gene expression compared with STR-CH(2)R(4)H(2)C/pDNA. We also evaluated the cellular uptake ability of STR-CH(2)R(4)H(2)C/DLCAS/Cy5-labeled pDNA complex. STR-CH(2)R(4)H(2)C/DLCAS/pDNA showed significantly lower cellular uptake compared with STR-CH(2)R(4)H(2)C/pDNA. This result indicates that high gene expression of STR-CH(2)R(4)H(2)C/DLCAS/pDNA does not facilitate its cellular uptake. In addition, the gene expression of DLCAS/STR-CH(2)R(4)H(2)C/pDNA in S-180 cells pretreated with the tubulin polymerization inhibitor, nocodazole (NCZ), was significantly lower than that in the absence of NCZ. These results indicate that the high transfection efficiency of DLCAS/STR-CH(2)R(4)H(2)C/pDNA is dependent on intra-cellular transport utilizing the microtubule motor protein, dynein. Taken together, our results suggest that DLCAS-modified STR-CH(2)R(4)H(2)C may be a promising gene delivery system.     

Some pyridazinone and phthalazinone derivatives and their vasodilator activities

In this study, 6-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 4-[(4-arylidene-2-phenyl-5-oxoimidazolin-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesized by reacting 6-(4-aminophenyl)-4,5-dihydro-3(2H)-pyridazinone or 4-(4-aminophenyl)-1(2H)-phthalazinone compound with different 4-arylidene-2-phenyl-5(4H)-oxazolone derivatives. The vasodilator activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed appreciable activity.     

Synthesis, anti-inflammatory and analgesic evaluation of thioxoquinazolinone derivatives

A series of 3-substituted-2-thioxoquinazolin-4(3H)-one derivatives have been synthesized and their structures have been elucidated on the basis of IR, (1)H-NMR, elemental analysis and mass spectroscopic studies. Anti-inflammatory and analgesic activity of the synthesized compounds was evaluated by Carrageenan induced rat paw edema method and Eddy's hot plate method respectively. Among the synthesized compounds N-(4-hydroxyphenyl)-N-(4-oxo-3-phenyl-2-thioxo-3,4-dihydroquinazolin-1(2H)methyl)acetamide (PTQ01) showed excellent anti-inflammatory activity. N-(4-ethoxyphenyl)-N-(3-(naphthalen-2yl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)acetamide (NTQ02), N-(4-Hydroxyphenyl)-N-((3-naphthalen-2-yl)-4-oxo-2-thioxo-3,4-dihydorquinazolin-1(2H)-ylmethyl)acetamide (NTQ01), N-((3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)-N-(4-hydroxyphenyl)acetamide (ETQ01) N-(3-(4-ethoxyphenyl)-4-oxo-2thioxo-3,4-dihydroquinazolin-1(2H)-ylmethyl)-N-(4-hydroxyphenyl)acetamide (ETQ04), N-(4-ethoxyphenyl)-N-((4-oxo-3-phenyl-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (PTQ02) and N-(4-ethoxyphenyl)-N-(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydoquinazolin-1(2H)-yl)methyl)acetamide (ETQ02) at a dose of 20 mg/kg exhibited significant anti-inflammatory activity compared to that of standard drug diclofenac sodium. The compound 2-(2,3-dimethylphenyl)(3-(4-ethoxyphenyl)-4-oxo-2-thioxo-3,4-dihydroquinazolin-1-2H)-1ylmethylamino)benzoic acid PTQ03 and sodium 2-(2-((2,6-dichlrophenyl)(3-(4-oxo-2-thioxo-3,4-dihydroquinazolin-1(2H)-yl)methyl)amino)phenylacetate (PTQ04) showed moderate anti-inflammatory activity. The compounds PTQ01, PTQ02, PTQ04, ETQ01 and ETQ02 showed significant analgesic activity compared with that of standard drug pentazocin.     

Synthesis of 3-aryl-2-substituted-4(3H)-quinazolines as potential antimicrobial agents

Three new series of 4(3H)-quinazolinone derivatives were synthesized, namely: [3-Aryl-4(3H)-quinazolinon-2-yl]-methylenehydrazino-(N- substituted)-thiocarbamides, 3-Aryl-2-(3-substituted-4-phenyl-2,3-dihydrothiazol-2-ylidenehy drazonomethyl)-4 (3H)-quinazolinones and 3-Aryl-2-(3-substituted-4-oxothiazolidin-2-ylidenehydrazonometh yl)-4(3H)-quinazolinones. The antimicrobial activities of the synthesized compounds were also studied.     

Non-steroidal antiinflammatory agents. Synthesis of novel 2-pyrazolyl-4(3H)-quinazolinones

Four novel series of pyrazolyl-4(3H)-quinazolinones have been prepared through the reaction of 3-aryl-2-hydrazino-4(3H)-quinazolinones with antipyrylazo-derivatives of ethyl acetoacetate, acetylacetone or diethyl malonate. These series of compounds are 3-aryl-2-[1-ethoxycarbonyl-1-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H - pyrazol-4-yl)hydrazono-2-propylidene]hydrazino-4(3H)-quinazo linones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3-methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]-4(3H)-quinaz olinones; 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)azo -3,5- dimethyl-1H-pyrazol-1-yl]-4(3H)-quinazolinones and 3-aryl-2-[4-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl) hydrazono-3,5-dioxo-pyrazolidin-2-yl]-4(3H)-quinazolinones. The antiinflammatory activity of some representatives of the prepared compounds was studied.     

Über N-Substitutionsprodukte von 4,4-Dialkyl-homophthalimiden 14. Mitt. über N-α-Halogenalkyl-carbonsäureamide

N-Substitution Products of 4,4-Dialkyl-1,3(2H,4H)-isoquinolinediones. 4,4-Dialkyl-1,3(2H,4H)-isoquinoline-diones ( 1 ) are converted into N-chloromethylderivatives ( 5 ) by halogenating their N-hydroxymethylcompounds ( 2 ). Reactions of 5 with sodium salts of benzenesulfinic-acid, diethylmethylmalonate or α-phenylacetoacetic acid-nitrile lead to 1,3(2H,4H)-isoquinoline-dione-derivatives 6. 7 or 8 . Secondary amines react with N-chloromethyl-compounds 5 under formation of the N-Mannichbasehydrochlorides, which are accessible also by condensation of 4,4-dialkyl-1,3(2H,4H)-isoquinoline-diones ( 1 ) with formaldehyde and the corresponding secondary amine.     

Synthesis of (aminoalkylamine)-N-aminoalkyl)azanonaborane(11) derivatives for boron neutron capture therapy

New boron-containing polyamine have been synthesized: (aminoalkylamine)-N-(aminoalkyl)azanonaborane(11) derivatives [H(2)N(CH(2))(n)H(2)NB(8)H(11)NH(CH(2))(n)NH(2)], where n = 4-6 and 12, and [H(2)N(CH(2))(3)H(2)NB(8)H(11)NH(CH(2))(4)NH(2)]. (4-Aminobutylamine)-N-(4-aminobutyl)azanonaborane and (3-aminopropylamine)-N-(4-aminobutyl)azanonaborane were less toxic in vitro (LD(50) of approximately 700 and approximately 1100 microM, respectively) than spermine, while (4-aminobutylamine)-N-isopropylazanonaborane with its hydrophobic isopropyl group and those with n = 5, 6, and 12 were already toxic under similar conditions (LD(50) < 500 microM). These compounds may be useful as delivery agents for boron neutron capture therapy.     

Urinary excretion of c-hydroxy derivatives of methaqualone in man.

1. Six monohydroxy metabolites of methaqualone have been identified by g.l.c.-mass spectrometry in the urine of healthy human subjects who received therapeutic doses (250 mg) of the drug (Melsed) daily for ten day. 2. The three major metabolites were 2-methyl-3-(2'-hydroxymethylphenyl)-4(3H)-quinazolinone, 2-methyl-3-(2'-methyl-3'-hydroxyphenyl)-4(3H)-quinazolinone and 2-methyl-3-(2'-methyl-4'-hydroxyphenyl)-4(3H)-quinazolinone. Three minor metabolites in descending order of importance were 2-hydroxymethyl-3-o-tolyl-4(3H)-quinazolinone, 2-methyl-6-hydroxy-3-o-tolyl-4(3H)-quinazolinone and 2-methyl-8-hydroxy-3-o-tolyl-4(3H)-quinazolinone. 3. The 8-hydroxy metabolite is identified as a urinary metabolite or methaqualone in humans for the first time.