The synthesis of valperinol and various 3-aminomethyl derivatives of 2,9-dioxatricyclo[4,3,1,0(3,7)]decane from didrovaltrate

3-Aminomethyl derivatives of 2,9-dioxatricyclo [4,3,1,0(3,7)]decane, can be synthesized via an amination, starting from (1R, 3S, 4S, 6R, 7S, 8R, 10R)-3-iodomethyl-4-acetoxy-8-methoxy-10-methyl-2, 9-dioxatricyclo [4,3,1,0(3,7)]decane or (1R, 3S, 4S, 6R, 7S, 8R)-3-iodomethyl-4-acetoxy-8-methoxy-10-methylen-2,9- dioxatricyclo [4,3,1,0(3,7)]decane, which can be prepared from didrovaltrate.     

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidine derivatives as diuretics

New 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidines 1 and 6,10-dihydro-5H-pyrido[3',2':5,6]pyrimido[2,1-c] [1,2,4]triazines 4 with 5-one, 5-thione or 5-hydrazono substituents and in some cases 1,2,3,4 or 8,9 hydrogenated are synthetized. The diuretic, natriuretic and kaliuretic activities of these compounds in Wistar rats at a dose of 24 mg/kg were estimated. A series of 24 possible derivatives of 1 and 4 possessing diuretic and saliuretic activities are investigated for structure-activity relationships in light of Fujita-Ban model. The Fujita-Ban group contributions have been calculated for different structural variations on the parent ring 1a. It is observed that the hydrogenation of pyridine, [1,3]thiazole or [1,2,4]triazine rings on 1 or 4 decrease the diuretic and saliuretic activities.     

Synthesis and pharmacological evaluation of aromatic dihydroxylated spiro[indan-1,3'-pyrrolidine] and spiro[indan-2,2'-pyrrolidine] derivatives

Aromatic hydroxylated derivatives of the spiro[indan-1,3'-pyrrolidine] and spiro[indan-2,2'-pyrrolidine] ring systems have been synthesized and evaluated for dopaminergic agonist and antagonist activities. None of these conformationally restricted catecholamines possessed any dopaminergic activity, but 5,6-dihydroxy spiro[indan-1,3'-pyrrolidine] hydrobromide exhibited weak dopamine antagonist properties.     

[1]Benzothieno[3,2-b]thiochromone und Thiochromono[3,2-b]indole

[1]Benzothieno[3,2-b]thiochromones and Thiochromono[3,2-b]indoles The 2-(3-benzo[b]thienyl)- and 2-(3-indolyl)-benzothioic acids 2 cyclize with polyphosphoric acid (PPA) to yield the title compounds 3 , which are characterized by their sulfones and thiones.     

Thiazolo[3,2-a]pyrimidine derivatives as calcium antagonists.

Some new thiazolo[3,2-a]pyrimidine derivatives were prepared refluxing 2-thioxo-1,2,3,4-tetrahydropyrimidine derivatives with phenacyl bromide in glacial acetic acid. Calcium antagonistic activities of these compounds were evaluated in K(+)-depolarized rat aorta, using nifedipine as reference compound.     

Investigations on the synthesis and properties of new derivatives of pyrido[3,2-e]-1,3-thiazino[3,2-a]-s-triazine

It has been found that the condensation of esters of 3H-2-imino-7-methyl-4-oxopyrido[3,2-e]-1,3-thiazine-5- and -6-carboxylic acids (I, II) with formaldehyde and primary amines affords the corresponding derivatives of a new heterocyclic system pyrido[3,2-e]-1,3-thiazino [3,2-a]-s-triazine (IX-XXIV).     

吲哚并[3,2-c]喹啉衍生物的微波辅助合成

目的合成吲哚并[3,2-c]喹啉衍生物并优化其工艺。方法微波辅助Michael加成、环合、Fischer吲哚合成。结果合成了6个吲哚并[3,2-c]喹啉衍生物。结论微波能缩短反应时间,提高Michael加成和Fischer吲哚合成反应的收率。     

Synthesis of new [1,3,4]thiadiazolo[3,2-a]thieno[2,3-d]pyrimidinone derivatives with antiinflammatory activity

New thiadiazolothienopyrimidinones were synthesized in continuation of efforts to prepare thienopyrimidine derivatives with analgesic and antiinflammatory activities. In this study, the effect of various substituents in the thiophene ring on the pharmacological activity of the compounds was investigated.     

Substituierte 3,7-Diaza-bicyclo-[3,3,1]-nonanole-(9)

Substituted 3,7-Diaza-bicyclo-[3,3,1]-nonane-9-ols Substituted 3,7-diaza-bicyclo-[3,3,1]-nonane-9-ols are prepared by reduction of the corresponding ketones with sodium borohydride. The stereoselectivity of this reduction is very high. In one example, the configuration at C-9 was elucidated by NOE measurements in the spectrum of a methoiodide.     

Thiophene bioisosteres of spirocyclic sigma receptor ligands. 1. N-substituted spiro[piperidine-4,4'-thieno[3,2-c]pyrans

Herein, the synthesis and pharmacological evaluation of thiophene bioisosteres of the highly potent spirocyclic benzopyran 1 are detailed. The synthesis of 1-benzyl-6'-methoxy-6',7'-dihydrospiro[piperidine-4,4'-thieno[3.2- c]pyran] (2a) was performed starting with 3-bromothiophene (3). After introduction of the acetaldehyde substructure (7), halogen metal exchange, addition of 1-benzylpiperidin-4-one, and cyclization led to the spirocyclic thienopyran 2a. The removal of the benzyl group afforded the secondary amine 2f, which was substituted with various residues. With respect to sigma 1 affinity the N-benzyl derivative 2a, the N-cyclohexylmethyl derivative 2d, and the N-p-fluorobenzyl derivative 2i represent the most potent compounds of this series binding with K i values of 0.32, 0.29, and 0.62 nM, respectively. Electronic properties of the substituents have only little impact on sigma 1 affinity. The most potent sigma 1 ligands display high selectivity against sigma 2, 5-HT 1A, 5-HT 6, 5-HT 7, alpha 1A, alpha 2, and NMDA receptors. The activity of 2a in the mouse capsaicin assay seems to indicate sigma 1 antagonistic activity.     

Synthesis and analgesic activity of some spiro[dibenz[b,f]oxepin-10,4'-piperidine] derivatives.

A series of 10,11-dihydro-11-oxospiro[dibenz[b,f]oxepin-10,4'-piperdine] derivatives (II) was synthesized and evaluated for analgesic activity in the phenylquinone writhing assay (PQW) and the tail-flick test in mice. Preliminary structure-activity correlations indicate that optimum activity is associated with a short-chain (R less than or equal to C2) N substituent and a nuclear fluorine function, as exemplified by 9b. This compound, when administered orally, was equipotent to morphine in protecting against mouse writhing. The observation that the PQW activity of 9b remained relatively unchanged after naloxone challenge seems to favor a nonnarcotic profile.     

Synthesis and antitumor properties of new spiro(benzo[h]quinazoline-7,1′-cyclohexane) derivatives

4-Amino-3-cyano-1,2-dihydrospiro(naphathaline-2,1′-cyclohexane) (aminonitrile) was converted by interaction with p-tolyl acid chloranhydride into 4-(4-methylbenzoyl)amino-3-cyano-1,2-dihydrospiro(naphthaline-2,1′-cyclohexane) (II), which was subjected to cyclization to form 2-(p-tolyl)-4-oxo-3,4,5,6-tetrahydrospiro(benzo[h]quinazoline-5,1′-cyclohexane) (III). This aminonitrile was converted, using a known method, to 4-ethoxymethyleneimino-3-cyano-1,2-dihydrospiro(naphthaline-2,1′-cyclohexane) (IV). Compound IV was condensed with hydrazides of aromatic, alkylaromatic, and alkoxyaromatic acids in dimethylformamide, producing 5-substituted 7,8-dihydrospiro(benzo[h]triazolo[2,3-c]quinazolines) (Va-v) at high yield. The antitumor properties of the resulting compounds were studied using two models of grafted mouse tumors-Ehrlich ascites carcinoma (EAC) and sarcoma 180. Anumber of the newly synthesized compounds had, along with moderate acute toxicity, marked antitumor activity in experimental conditions. __________ Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 42, No. 2, pp. 6–9, February, 2008.     

5H-呋喃并[3,2-g]色烯类化合物的合成及其抗肿瘤活性

目的 设计合成5H-呋喃并[3,2-g]色烯类化合物,并测定其体外抗肿瘤活性。方法 以2’,4’-二羟基苯乙酮为原料,经缩合、催化氢化和 Fries 重排等反应合成目标化合物。采用人骨肉瘤细胞U2OS-EGFP-4A12G对目标化合物的体外抗肿瘤活性进行初步评价。结果与结论 合成了10个未见文献报道的5H-呋喃并[3,2-g]色烯类化合物,其结构经红外光谱、质谱、核磁共振氢谱确证。化合物7a、7e 和 7h 对人骨肉瘤细胞 U2OS-EGFP-4A12G 的抑制活性较强,其IC₅₀值分别为16.53、7.74、13.27 μmol·L^-1。5H-呋喃并[3,2-g]色烯类化合物是一类具有新型骨架结构的抗肿瘤化合物,值得进一步研究。     

Synthesis and fungistatic activity of 3-(2-dialkylaminoethylthio)thieno [2,3-c] and [3,2-d] isothiazole derivatives

A series of 5-acyl-4-amino-3-(2-dialkylaminoethyl)thieno-[2,3-c] and [3,2-d]isothiazole derivatives was synthesized. The compounds were evaluated for antifungal activity.     

NMR-Spektren substituierter 3,7-Diaza-bicyclo-[3,3,1]-nonanone-(9)

NMR Spectra of Substituted 3,7-Diaza-bicyclo-[3,3,1]-nonane-9-ones 3,7-Diaza-bicyclo-[3,3,1]-nonane-9-ones with alkoxycarbonyl substituents at C-1 and C-5 and with pyridyl-(2), pyridyl-(3) or pyridyl-(4) groups at C-2 and C-4 are synthesized and studied by ¹H-NMR spectra. In several examples it could be shown that vicinal NH and CH protons are coupled.     

Synthesis and biological evaluation of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine)

The synthesis of 6-amino-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (3,7-dideazaguanine, 2) has been accomplished from 3-(ethoxycarbonyl)pyrrole-2-acetonitrile. In contrast to 3-deazaguanine, compound 2 did not show any antitumor, antiviral, or antibacterial properties. Furthermore, it was not a substrate for hypoxanthine-guanine phosphoribosyltransferase or purine nucleoside phosphorylase.     

Synthesis and 5-HT2A antagonist activity of derivatives of the novel heterocycles indolo[3,2-d]pyrrolo[3,2-g]azecine and benzo[d]pyrrolo[3,2-g]azecine compared to the benz[d]indolo[2,3-g]azecine derivative LE 300

An indolo[3,2-d]pyrrolo[3,2-g]azecine and a benzo[d]pyrrolo[3,2-g]azecine analogue of the potent dopamine receptor antagonist LE 300 (7-methyl-6,7,8,9,14,15-hexahydro-5H-benz[d]indolo[2,3-g]azecine) have been prepared in multi-step reactions via C-N bond cleavage of corresponding quaternary N-methylquinolizinium iodides. LE 300, the target compounds and two precursor quinolizines have been tested in vitro for antagonist activity at 5-HT2A receptors (rat tail artery) and H1 receptors (guinea-pig ileum), respectively. LE 300 and compound 19 (3,6-dimethyl-4,5,6,7,8,13-hexahydro-3H-benzo[d]pyrrolo[3,2-g]azecine) competitively inhibited 5-HT-induced contractions with similar nanomolar potency (pA2 = 8.32 and 8.01, respectively) but were less active than the reference antagonist ketanserin (pA2 = 9.55). Compound 19 displayed moderate H1-antihistaminic activity in the guinea-pig ileum assay (pA2 = 7.37).