抗血吸虫病药物的研究 取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类的合成

应用Elslager等法合成了35个取代(4-氨基-1-萘偶氮)苯和取代[4-(二乙氨基乙基氨基)-1-萘偶氮]苯类,同时又合成了5-(4-氨基-1-萘偶氮)尿嘧啶和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶。经动物筛选证明,有13个化合物对日本血吸虫病有预防和治疗作用,其中以2-氯-4-硝基[4-(二乙氨基乙基氨基)-1-萘偶氮]苯(化合物26)和5-[4-(二乙氨基乙基氨基)-1-萘偶氮]尿嘧啶(I_b)的治疗作用最显著,灭虫率达70％左右。     

抗疟新药的研究——苯骈[b]1,5-萘啶衍生物的合成

作者等用2-取代基-7,10-二氯苯骈[b]1,5-萘啶分别与取代氨基烃基胺和取代胺在苯酚中作用,合成了2-取代基-7-氯-10-(取代氨基烃基氨基)苯骈[b]1,5-萘啶(Ⅱ_1～10,表1)和相应的10-(取代氨基)-苯骈[b]1,5-萘啶(Ⅱ_11～14,表1);将2-取代基-7,10-二氯苯骈[b]1,5-萘啶与取代苯酚的钾盐作用,又合成了相应的10-(取代苯氧基)苯骈[b]1,5-萘啶(Ⅲ,表2)。在具有取代氨基烃基胺侧链的化合物中,以Ⅱ_2,6,10对血液转种的Plasmodium berghei和子孢子诱发感染的P.yoelii两种鼠疟原虫的作用最显著;具有N-甲基-N′-氨基哌嗪侧链的Ⅱ₁₁,经后一种鼠疟试验,也呈现了优于伯喹的显著的疗效;化合物Ⅲ_1,3,4,7,8仅对后一种模型呈现较弱的作用。     

疟疾防治药物的研究——Ⅰ.2,4-二氨基-5-取代氨基嘧啶和2,4-二氨基-6-甲基-5-取代氨基嘧啶衍生物的合成及其抗疟作用

本文报道2,4-二氨基-5-取代氨基嘧啶和2,4-二氨基-6-甲基-5-取代氨基嘧啶衍生物的合成及其抗疟活性的研究。这类化合物的合成是分别以2,4,5-三氨基嘧啶或2,4,5-三氨基-6-甲基嘧啶与相应的取代的苯甲醛缩合成席夫氏碱,然后经还原,亚硝化或甲酰化制得。经鼠疟原虫-斯氏按蚊系统的病因性预防初筛,发现有12个化合物有效,其中2,4-二氨基5-[(3′,4′-二氯代苯亚甲基)-氨基]嘧啶(化合物V₃)和2,4-二氨基-5-[(4′-溴代苄基)-N-亚硝基-氨基]嘧啶(化合物Ⅶ₄)效果最好,口服10 mg/kg共三天,可使小白鼠得到保护,血中未查见原虫。     

N-(1-乙氧羰基-3-苯氨甲酰基丙基)甘氨酰甘氨酸衍生物的合成

报道4个N-(1-[1-乙氧羰基-3-(对甲)苯氨甲酰基]丙基甘氨酰｝-N-取代甘氨酸(XI_1～4)和5个1-[1-乙(或甲)氧羰基-3-(对甲)苯氨甲酰基]丙基-4-取代-1,4-哌嗪-2,5-二酮(XII_1～5)共9个估计有血管紧张素转化酶抑制活性化合物的合成和鉴定。所有这些化合物及9个相应的酯(X_1～9)均未见文献报道。药理初试结果,化合物XII₂,XII₅,XI₄和XII₁均有较强降压活性。     

1-烷基-5-氨基-6-苯乙基尿嘧啶的合成

研究1-烷基-5-氨基-6-苯乙基尿嘧啶（1a，1b）方便、高产率的合成方法，此类化合物有可能作为非核苷类HIV-1RT抑制剂。以6-甲基尿嘧啶（2）为起始物，经硝化、烷基化、苄基化及一锅反应脱苄基及还原反应等合成目标化合物，并用NMR、MS、IR、Anal鉴定化合物结构。探索出了一种合成1-烷基-5氨基-6-苯乙基尿嘧啶类化合物的方便方法。首次于用3或4步反应、高产率合成了1-烷基-5-氨基-6-苯乙基尿嘧啶（1a，1b）并发现化合物1a有中度抗HIV-1RT的活性（IC50=29μM）。     

2-[5-取代苯并咪(噻)唑-2-硫基]-1-(4-取代苯基)乙酮缩氨基胍的合成及NHE1抑制活性

目的设计合成缩氨基胍类化合物并研究其NHE1抑制活性。方法以4-取代苯乙酮(1)为原料,经溴代得α-溴代物(2),再与2-巯基-5-取代苯并咪(噻)唑(3)反应得到2-(5-取代苯并咪(噻)唑-2-硫基)-1-(4-取代苯基)乙酮(4),最后与氨基胍缩合得到目标化合物;以血小板肿胀模型进行初步的体外NHE1抑制活性筛选。结果与结论合成了12个新化合物,其结构经IR、1H-NMR及MS确证。初步的药理试验表明,12个目标化合物均有一定的NHE1抑制活性,其中化合物5b和5h的活性明显优于阳性对照药卡立泊来德。     

肿瘤的化学治疗Ⅲ. 几种尿嘧啶和6-甲基尿嘧啶的5-取代基衍生物

1.合成了四个5-对-取代基苯偶氮尿嘧啶(Ⅴ)和六个5-对-取代基苯偶氮-6-甲基尿嘧啶.上述十个化合物口服对小白鼠艾氏腹水瘤无显著抑制作用.2.又合成了四个5-取代基尿嘧啶(Ⅶ)和八个5-取代基-6-甲基尿嘧啶(Ⅷ),此十二个化合物口服或腹腔注射对肉瘤180无明显抑制作用.     

N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类的合成及抗真菌活性

根据氮唑类和烯丙胺类抗真菌化合物的构效关系、作用机理。设计合成了30个N-(6,6-二甲基-2-庚烯-4-炔基)-N-甲基-α-取代-1-(4-取代)萘甲胺类化合物。初步体外抑菌试验结果表明,大多数目标化合物对八种试验菌株都有不同程度的抗真菌活性。化合物Ⅰ_1a的真菌活性大致与克霉唑相当,对白念珠菌的活性明显高于naftifine和terbinafine,但对其它七种菌株的活性均不及naftifine和terbinafine;化合物Ⅲ_1a对八种试验菌株的活性均与terbinafine相当。     

抗疟药的研究——Ⅲ.2-(取代苯乙烯基)-4-氨基吡啶类的合成

本文报道2-(取代苯乙烯基)-4-(4′-二乙氨基-1′-甲基丁基氨基)-吡啶类的合成。动物筛选的初步结果表明:口服给药6.25mg/kg,化合物Ⅲ₂、Ⅲ₄和Ⅲ₇能完全抑制感染伯氏鼠疟原虫氯喹敏感株(Plalmodium berghei)小白鼠的原虫血症;皮下给药1.8mg/kg,化合物Ⅲ,即能达到完全抑制。     

N~1-(4-取代氨基-6-三氟甲基-2-嘧啶基)-N~3-(卤苯基)胍的合成及其抗丝虫作用

报道了N~1-[4＇-[3-(二烷胺基)甲基和3, 5-双[(二烷胺基)甲基]-4-羟基苯胺基]-6-三氟甲基-2-嘧啶基]-N~3-(4-卤苯基)胍的合成。合成了24个化合物,经药理初筛表明,该类型化合物对感染沙鼠的棉鼠丝虫微丝蚴或成虫有一定的杀灭作用。     

Synthesis and antimicrobial activity of some 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted piperazin-1-yl)acetamido]-2-(p-substituted phenyl)benzoxazoles

In this study, a series of twelve novel 5-[2-(morpholin-4-yl)acetamido] and/or 5-[2-(4-substituted pip-erazine-1-yl)acetamido]-2-(p-substituted phenyl]benzoxazole derivatives have been synthesized and their structures were confirmed by IR, (1)H NMR, and mass spectral data. These compounds were prepared by reacting 5-(2-chloroacetamido)-2-(4-p-substituted-phenyl)benzoxazoles, which were obtained by using 5-amino-2-[p-substituted-phenyl]benzoxazoles with chloroacetyl chloride, in the presence of morpholine or 1-substituted piperazines. All synthesized compounds 3-14 were tested by using the method of twofold serial dilution technique for in vitro activities against certain strains of Gram-positive, Gram-negative bacteria as well as the yeasts Candida albicans, Candida krusei, and Candida glabrata in comparison with standard drugs. Microbiological results showed that the newly synthesized compounds possessed a broad spectrum of activity, showing MIC values of 3.12-50 mug/mL against the Candida species.     

Synthesis of deuterium-labeled CCR2 antagonist JNJ-26131300, [4-(1H-indol- 3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid

Synthesis of multiple deuterium-labeled CCR2 antagonist JNJ-26131300, that is, [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid, is described. First, condensation of indole-D₇ with 4-piperidone produced 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole-D₅, which subsequently underwent catalytic hydrogenation to give 3-piperidin-4-yl-1H-indole-D₅. Next, bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid was prepared through multiple steps from 3-(3,4,5-trifluoro-phenyl)-acrylic acid and bromo-piperidin-4-yl-acetic acid ethyl ester. Nucleophilic coupling of 3-piperidin-4-yl-1H-indole-D₅ with bromo-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid afforded the desired compound [4-(1H-indol-3-yl)-piperidin-1-yl]-{1-[3-(3,4,5-trifluoro-phenyl)-acryloyl]-piperidin-4-yl}-acetic acid-D₅.     

A Search for New 5-HT1A/5-HT2A Receptor Ligands. In Vitro and in vivo Studies of 1-[ω-(4-Aryl-1-piperazinyl)alkyl]indolin-2(1H)-ones

A series of 1-[ω-(4-aryl-1-piperazinyl)alkyl]indolin-2(1H)-one derivatives 2–14 was synthesized in order to obtain ligands with a dual 5-HT_1A/5-HT_2A activity. The majority of those compounds ( 2–5, 7, 10–13 ) exhibited a high 5-HT_1A (K_i = 2 – 44 nM) and/or 5-HT_2A affinity (K_i = 51 and 39 for 5 and 7 , respectively). Induction of lower lip retraction (LLR) and behavioral syndrome and inhibition of these efects evoked by 8-hydroxy-2-(di-n-propyl-amino)tetralin (8-OH-DPAT) were used for determination the agonistic and antagonistic activity, respectively, at 5-HT_1A receptors. The 5-HT_2A antagonistic activity was assessed by the blocking effect on the head twitches induced by (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in mice. Two of the tested compounds, 1-{3-[4-(3-chlorophenyl)-1-piperazinyl]propyl}-6-fluoroindolin-2(1H)-one ( 5 ) and 1-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}indolin-2(1H)-one ( 7 ), demonstrated a high 5-HT_1A/5-HT_2A affinity and an in vivo antagonistic activity towards both receptor subtypes.     

Studies on condensed-heterocyclic azolium cephalosporins. III. Synthesis and antibacterial activity of 7 beta-[2-(2-amino-5-substituted-thiazol-4-yl)-2 (Z)-alkoxyiminoacetamido]-3-(condensed-heterocyclic azolium)methyl-3-cephem-4- carboxylates.

As a part of our research on the synthesis of cephalosporins bearing condensed-heterocyclic azolium groups at the 3 position in the cephalosporin nucleus, we describe herein the synthesis of 7 beta-[2-(2-amino-5-halogeno-, methylthio-, methylsulfinyl-, methylsulfonyl- and sulfothiazol-4-yl)-2(Z)-alkoxyiminoacetamido] cephalosporins and their antibacterial activity. Among the compounds prepared, 7 beta-[2-(2-amino-5-chlorothiazol-4-yl)-2(Z)- methoxyiminoacetamido]-3-(imidazo[1,5-a]-pyridinium-1-yl)methyl-3-cephem -4-carboxylate (14) showed good antibacterial activity against both Staphylococcus aureus including methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa, whereas the antibacterial activity against other Gram-negative bacteria was a slightly lower than that of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoxyiminoacetamido]-3-(im ida zo [1,2-a]pyridinium (I-1) and imidazo[1,5-a]pyridinium (I-4)-1-yl)methyl-3-cephem-4-carboxylates.     

Synthesis and Pharmacological Evaluation of N-Phenyl-N′-[1-[3-(1-aryl-4-piperazinyl)propan-2-ol]]ureas

N-Phenyl-N’-[1-[3-(1-aryl-4-piperazinyl)propan-2-ol]]ureas ( 3 ) were synthesized from the 3-phenylcarbamoyl-5-[(1-aryl-4-piperazinyl)methyl]-2-iminooxazolidines ( 1 ) via the corresponding 2-oxazolidinones ( 2 ). The prepared compounds were screened for their antiallergic and analgesic activities.     

Mixed Dopaminergic/Serotonergic Properties of Several 2-Substituted 4-[2-(5-Benzimidazole)ethyl]-1-arylpiperazines

A series of substituted 4-[2-(5-benzimidazole)ethyl]-arylpiperazines was synthesized by introducing different substituents into position 2 of benzimidazole ring of 4-[2-(N,N-di-n-propyl-amino)ethyl]-1,2-diaminobenzenes. They were evaluated for in vitro binding affinity at the D₁ and D₂ dopamine and 5-HT_1A serotonin receptors using synaptosomal membranes of the bovine caudate nuclei and hippocampi, respectively. Tritiated SCH 23390 (D₁ receptor-selective), spiperone (D₂ receptor selective) and 8-OH-DPAT (5-HAT_1A receptor selective) were employed as the radioligands. Only compound 6 expressed a moderate binding affinity at the dopamine D₁ receptor, while the remaining ligands were inefficient or weak competitors of [³H]SCH 23390. Compound 12 was an absolutely inactive competitor of all three radioligands. Also, compound 7 was an inefficient displacer of [³H]-8-OH-DPAT. Compound 19 with a K_i value of 3.5 nM was the most potent competitor of [³H]spiperone and compound 13 (K_i = 3.3 nM) was the most efficient in displacing [³H]-8-OH-DPAT from the 5-HAT_1A serotonin receptor. Ligands 5, 6, 8–11 , and 13–20 expressed mixed dopaminergic/serotonergic activity in nanomolar range of concentrations with varying affinity ratios which strongly depended on the properties of the substituents introduced into position 2 of benzimidazole ring of the parent compounds.     

Synthesis and anti-HIV evaluation of the novel 2-(m-chlorobenzyl)-4-substituted-7-methyl-1, 1, 3-trioxo-pyrazolo[4, 5-e] [1, 2, 4]thiadiazines

A novel series of 2-(m-Chlorobenzyl)-4-substituted-1, 1, 3-trioxo-2H,4H-pyrazolo[4, 5-e][1, 2, 4] thiadiazines (7a-k) were synthesized, and evaluated for their anti-HIV replication in MT-4 cell cultures. Compound (7a) showed activity against HIV-1-induced cytopathicity, with an EC₅₀ value of 45.6 μM, but none of the compounds exhibited inhibitory activity against HIV-2.     

Synthesis of 2-[2-(1-Imidazolyl)ethyl]-4-phenylcycloalka[g]phthalazin-1(2H)-ones as Thromboxane A2 Synthase Inhibitors

A series of 2-[2-(1-imidazolyl)ethyl]-4-phenylcycloalka[g]phthal-azin-1(2H)-ones ( 3a—d ) with variable cycloalkene ring size was prepared and tested in vitro for thromboxane A₂ synthase inhibitory activity.     

Synthesis and antimycobacterial activity of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1<Emphasis Type="Italic">H</Emphasis>-3-pyrazolyl]-2-methylphenol derivatives

In the present investigation, 4-hydroxy-3-methylacetophenone, on condensation with appropriate aldehydes in methanolic potassium hydroxide solution, yielded the corresponding chalcones (C_I-XI). These corresponding chalcones were reacted with phenyl hydrazide in glacial acetic acid, which led to the formation of novel 4-[5-(substituted phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol derivatives. All newly synthesized compounds were evaluated for their antimycobacterial activities against isoniazid-resistant Mycobacterium tuberculosis using agar dilution. 4-[5-(4-Fluoro phenyl)-1-phenyl-4,5-dihydro-1H-3-pyrazolyl]-2-methylphenol showed good antimycobacterial activity, with a minimum inhibitory concentration of 0.62 μg/ml.     

Syntheses and antifungal activities of 1-[4-phenyl-2-(phenylthio or acyloxy)-n-butyl]-1H-imidazole derivatives]

The title compounds (4b, d-f, h-j) were prepared from 1-[4-(p-substituted phenyl)-2-chloro-n-butyl]-1H-imidazoles and the corresponding thiophenols or mercaptopyridines. Acyloxy compounds (5a-e) were prepared from alcohol (2b) and the corresponding acyl chlorides. In the antifungal activity test, p-tolyl compounds (4e, f) showed as good activity as butoconazole (4c).