Synthesis and antiulcer activity of novel 5-(2-ethenyl substituted)-3(2H)-furanones.

In order to investigate new antiulcer agents, spizofurone 1 (AG-629) was fragmented and reassembled to generate 5-phenyl-2,2-dimethyl-3(2H)-furanone (bullatenone, 2). Because of the antiulcer activity of 2,5-phenyl-substituted 2,2-dimethyl-3(2H)-furanones (3-6) were made and shown to have poor activity. Insertion of an ethenyl link between the furanone and phenyl rings gave 5-(2-phenylethenyl)-2,2-dimethyl-3(2H)- furanone (7). This compound had better activity than 2. Compounds 8-41 were synthesized to evaluate the SAR in 5-(2-ethenyl substituted)-3(2H)-furanones. Electron-withdrawing substituents on the aromatic ring (8, 10, 19, and 20) gave 2-3-fold higher activity. Further increases in the activity were found when the phenyl ring was replaced by heterocyclic nuclei. Compounds that contained a thiophene (29), pyridine (24-26), or quinoline ring (32) had the best activity. Replacement of the methyl group on the furanone ring with a phenyl (34) or p-fluorophenyl (40) substituent in the 2-pyridine series gave compounds with activity that ranked with the best obtained in this study. The best compounds from the above SAR studies were evaluated in the ethanol-necrosis model for duration of cytoprotection action. Compounds 19, 24, and 29, which had the best duration of action, were tested with AG-629 in the acidified aspirin and indomethacin-induced lesion models. Only compound 24 had equivalent activity with AG-629 in both models.     

Synthesis and pharmacologic activity of 3-quinolizidine-1'-yl-5-R-indoles

By acid action on the mixture of homolupinal diethylacetal and arylhydrazines several 3-quinolizidin-1'-yl-5-R-indoles (III a - III e) were prepared. The homolupinal diethylacetal, whose hydrolysis gives rise to the unknown aldehyde, was obtained through the action of lupinylmagnesium chloride on diethylphenylorthoformate. Compounds (III) were subjected to wide pharmacological screening; all of them exhibited calcium blocking, negative cardioinotropic and diuretic activities, while single compounds showed antiinflammatory (III d), anticonvulsant and hypoglycemic (III e) activities.     

Derivatives of 1H-tetrahydrobenzodiazepine-1,5

Synthesis of acyl derivatives of 2-aminomethylene-4-phenyl-1H-tetrahydrobenzodiazepine-1,5: compounds 5, 7 and 8, of a Schiff base 6 acids 9 and 10, and esters of aryl- or alkyl-1H-tetrahydro-1,5-benzodiazepine-2-carboxylic acids 11-14 is described. Compounds 9-13 showed potent antagonism towards pentetrazol, and compound 13 also potentiated the action of DOPA and had antiserotonin properties.     

Synthesis and Action on the Central Nervous System of 3-Substituted 2-Phenyl-2,3-dihydro-4H-1,3,2-benzoxazaphosphorin-4-one 2-Oxide and 2-Sulfide Derivatives

The synthesis of 3-substituted 2-phenyl-2,3-dihydro-4H-1,3,2-benzoxazaphosphorin-4-one 2-sulfide derivatives is described. The action of a series 2-oxide ( 1–6 ) and 2-sulfide ( 7–12 ) derivatives on the central nervous system has been evaluated. Compounds 1–4, 6, 7–10 exhibit neuroleptic activity. Derivatives of sulfide series act as antiserotoninergic drugs.     

Synthesis and pharmacological evaluation of a series of new 3-methyl-1,4-disubstituted-piperidine analgesics

The synthesis and intravenous analgesic activity of a series of 3-methyl-4-(N-phenyl amido)piperidines, entries 34-79, is described. The methoxyacetamide pharmacophore produced a series of compounds with optimal analgesic potency and short duration of action. cis-42 was 13,036 times more potent than morphine and 29 times more potent than fentanyl; however, the corresponding diastereomer 43 was only 2778 and 6 times more potent, respectively. Compounds 40, 43, 47, and 57 are extremely short acting; all had durations of action of about 2 min, which was about 1/5 of that of fentanyl in the mouse hot-plate test at a dose equivalent to 2 times the ED50 analgesic dose. Among the many compounds that displayed exceptional analgesic activity, duration of action was one of the main factors for choosing a candidate for further pharmacological investigation. At present, cis-1-[2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl]-3-meth yl-4- [N-in equilibrium 2-fluorophenyl)methoxyacetamido]piperidine hydrochloride (40) (Anaquest, A-3331.HCl, Brifentanil) is in clinical evaluation. Opiate analgesics that possess short duration of action are excellent candidates for short surgical procedures in an outpatient setting where a rapid recovery is required.     

Design, synthesis, and pharmacological evaluation of ultrashort- to long-acting opioid analgetics

In an effort to discover a potent ultrashort-acting mu opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent mu opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[(1-oxopropyl)phenylamino]-1-piperidinepropanoi c acid alkyl esters, were evaluated in vitro in the guinea pig ileum for mu opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent mu agonists in vitro, but depending upon the alkyl ester substitution the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The SAR with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.     

Antiviral agents. 6. Variation of substituents in the series of N'-substituted N-(adamantyl-(1))-thioureas]

Variation of Substituents in the Series of N′-Substituted N-[Adamantyl-(1)]-thioureas . N-[Adamantyl-(1)]-thioureas 3 arise from the interaction of 1-amino-adamantane ( 1 ) with isothiocyanates 2 . Compounds 3a, b, c , and d exhibit marked antiviral activity. Thiosemicarbazone ( 6 ) formation occurs upon the action of aldehydes, like anisaldehyde ( 5 ), on 4-[adamantyl-(1)]-thiosemicarbazide ( 4 ).     

Synthesis and biological activity of pyrazo-[3,4-b]-pyridine derivatives. Part I

3 (3'-Morpholino-2'-hydroxypropoxy)--7--9 as well as 3 (3'-morpholino-2'-hydroxypropyloamino) 14 -- 16 derivatives of 1-methyl and 1-phenyl pyrazo-[3,4-b]-pyridines were prepared and screened for expected circulatory activity. Compounds 7, 11--14, 20 mg/kg, produced hypotension in cats; Compounds 7 and 14, 50--80 mg/kg, had antiarrhytmic action in BaCl2 -- induced arrhytmic in the rabbit.     

Design, synthesis and biological evaluation of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives as potential antidepressants with a dual mode of action: serotonin reuptake inhibition and 5-HT1A receptor antagonism

It has been suggested that the combination of a selective serotonin reuptake inhibitor (SSRI) and a 5-HT1A receptor antagonist may facilitate the onset of the SSRIs antidepressant action. Accordingly, we describe the synthesis of a series of new 3-[(4-aryl)piperazin-1-yl]-1-arylpropane derivatives with structural modifications performed in Ar1, Ar2 and Z (Z is different functional groups) to obtain the sought dual activity. Compounds were evaluated for in vitro affinity at 5-HT1A receptors and 5-HT transporter. The antidepressant-like activity of derivatives with the higher affinity was assessed initially using the forced swimming test (FST). Compound 1-(2,4-dimethylphenyl)-3-[(2-methoxyphenyl)piperazin-1-il]-1-propa none (III.1.a) showed the best antidepressant-like activity which was further confirmed in the learned helplessness test.     

Synthesis and pharmacological properties of 2,4-disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives. Part II.

2,4-Disubstituted 5-amino-6-pyrimidinecarboxylic acid derivatives 5-20 were synthesized and evaluated for their pharmacological activity. Compounds 11-14, 17-19 showed antiaggressive effect, compounds 5, 8, 9, 11, 12 and 19 displayed antiserotonin activity while compound 14 exerted antireserpine action.     

Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids

A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.     

Synthesis and properties of 4-substituted-1-piperazinyl-propyl derivatives of 1-phenyl-7-methylpyrimido-[4,5-d]pyrimidin-4-one.

In reactions of 1-phenyl-7-methyl-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimido[ 4,5-d]pyrimidin e (1) with 1-(3-chloropropyl)-4-methyl(phenyl, 3-chlorophenyl, 2-pyrimidynyl, 2-thiazolyl)piperazines (5), mixtures of isomeric N- and S-substituted derivatives of compound 1 (3 and 4) were obtained. Isomers were separated by fractional crystallization. The structure of novel compounds 3 and 4 was confirmed by elemental and spectral analyses. In pharmacological screening compounds 3b and 4b displayed rather strong analgesic action, inhibited amphetamine hyperactivity and abolished apomorphine stereotypy. Compounds 3e,3d and 4e attenuated m-chlorophenylpiperazine-induced hypothermia.     

Synthesis of novel benzimidazole derivatives: as potent analgesic agent

1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols have been synthesized using o-phenylinediamine and naphthaldehyde in the presence of sodium hydride and THF. 1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols were evaluated for the analgesic activity by tail flick method in rats. Synthesized1-(1-alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols in doses of 50 mg/kg increased the pain threshold significantly after 0, 30, 60, 90, and 120 min of administration in the tail flick model. Compounds B₃a, B₂b, and B₁b showed time-dependent action in all the experimental models. The present study indicates that Compounds B₃a, B₂b, and B₁b show analgesic properties.     

肿瘤化学治疗的研究——Ⅱ.斑蝥素衍生物和类似物的合成

前文报道合成了一些斑蝥素衍生物,其中羟基斑蝥胺已推荐临床试用。作者进一步改变斑蝥素结构合成了五个类型81个化合物,希望从中找到毒性低、疗效高的新抗肿瘤药,并观察化学结构与抗肿瘤活性的关系。动物筛选结果表明,该类亚胺化合物的毒性均低,除短链斑蝥亚胺化合物(66)有活性外,其余化合物均无显著抗肿瘤活性。     

Synthesis and pharmacological properties of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid

Synthesis of N,N-dialkyl(dialkenyl)amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5-9) and their 1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl] derivatives (10-14) is described. Compounds 10-14 were tested for analgesic and sedative activities as well as for mu-opioid receptors binding affinities. All the amides, being the object of investigation, displayed an interesting analgesic action, which in case of the compounds 10-12 and 14 was superior to that of acetylsalicylic acid in two different tests. Furthermore all the amides (10-14) significantly suppressed the spontaneous locomotor activity, prolonged barbiturate sleep in mice and showed a weak affinity to mu-opioid receptors.     

Synthesis and biological action of some pyrido-[1,3]-diazepine and pyrido-[2, 3-d]-pyrimidine derivatives

The following compounds were synthesized and tested for their action on the circulatory system and smooth muscle preparations: 3H,4,9-dihydropyrido-[2,3-e] [1,3]-diazepino-4,9-dione 1a, 3,4-dihydropyrido-[2,3-d]-pyrimidinone-4 2a and their derivatives: N-methylmorpholine 1b and 2b, N-methylopiperidine 1c and 2c, N-beta-hydroxy-gamma-morpholinopropyl 1d and 2d, and N-beta-diethylaminoethyl 1e and 2e. Compounds 1b-e and 2c showed weak hypotensive action in rats when given in a dose of 50 mg/kg, compounds 2d and 2e: 30 mg/kg and up.     

Ganglionic action of some newly synthesized glutarimide compounds

20 newly synthesized glutarimide compounds and their organic bases were investigated for their action on the autonomic ganglion in cats. Compounds 1 to 7 having piperidine moiety showed mainly ganglionic stimulant activity as evidenced by rise in blood pressure, contraction of nictitating membrane and rise in urinary bladder pressure of cats, which was completely blocked by C6 and partly by atropine. Compound 8 and 9 having diethylamine moiety showed initial stimulation--followed by blockade of the autonomic ganglia. Compounds 10 to 13 having morpholine moiety showed stimulation of both sympathetic and parasympathetic autonomic nervous system. The responses were due to effect partly on ganglia and partly on the receptors. Compounds 14 to 20, which have alkyl substitution chain at position 4 of beta-carbon atom, showed depressor action. The ganglionic activity of the glutarimide compounds in various groups was found to be in inverse ratio to the length of the alkyl side chain at position 4 of the beta-carbon atom.     

Antifungal, antimitotic and anti-HIV-1 agents from the roots of Wikstroemia indica

With guidance of Pyricularia oryzae bioassay, daphnoretin (1), (+)-nortrachelogenin (2), genkwanol A (3), wikstrol A (4), wikstrol B (5) and daphnodorin B (6) were isolated from the roots of Wikstroemia indica. Compounds 1-6 induced morphological deformation of P. oryzae mycelia with MMDC values of 68.4 +/- 1.3, 31.3 +/- 1.8, 45.8 +/- 0.5, 70.1 +/- 2.4, 52.3 +/- 0.9 and 73.7 +/- 1.6 microM, respectively. Compounds 3-6 showed moderate activity against microtubule polymerization with IC50 values of 112 +/- 4, 131 +/- 3, 184 +/- 6 and 142 +/- 2 microM in vitro, respectively. Compounds 2, 3, 5 and 6 were moderately active against HIV-1 in vitro. The findings of bioactivity of 1-6 support the antifungus, antimitosis and anti-HIV-1 uses for W. indica roots.     

Correlation of antifungal activity with fungal phospholipase inhibition using a series of bisquaternary ammonium salts

A series of bisquaternary ammonium salts with a 12-carbon spacer between the positive charges were synthesized, and their antifungal activity has been investigated. Compounds with butyl, pentyl, and isopentyl headgroups were the most potent antifungal agents with MICs in the range of 2.2-5.5 microM against both Cryptococcus neoformans and Candida albicans. The antifungal activity of these compounds correlated with their inhibition of cryptococcal phospholipase B1 (PLB1), a newly identified virulence factor. This indicates that the mode of action of these compounds may be inhibition of the fungal PLB1 enzyme, further validating this enzyme as a target for the development of novel antifungal therapies.     

Cytotoxicities of xanthones and cinnamate esters from Hypericum hookerianum

5-Hydroxy-2-methoxyxanthone (1), 2-hydroxy-3-methoxyxanthone (2), trans-kielcorin (3), 4-hydroxy-3-methoxyphenyl ferulate (4) and 3beta-O-caffeoylbetulinic acid (5) were isolated from Hypericum hookerianum. Compounds 1-5 were tested against the growth of three human tumor cell lines, MCF-7, NCI-H460 and SF-268. Compounds 4 and 5 exhibited significant inhibitory activity effects against all three; GI50 values for 4 were 15.1 +/- 1.6, 18.7 +/- 2.3 and 15.9 +/- 2.7 and for 5 12.2 +/- 2.4, 19.6 +/- 2.3 and 24.3 +/- 2.5. Compound 3 was less active with GI50 values of 55.1 +/- 2.3, 49.7 +/- 3.0 and 40.5 +/- 1.5, while 1 and 2 exhibited only weak effects. Compounds 4 and 5 were moderately effective in influencing the mitogenic response to human lymphocytes to hemoagglutinin, with IC values of 26.1 +/- 3.6 and 40.8 +/- 4.9, respectively.