Synthesis and biological activity of functionalized indole-2-carboxylates, triazino- and pyridazino-indoles.

Condensation of aryl hydrazines with ethyl pyruvate gave the respective hydrazones 4-6; Fischer indolization led to substituted-1H-indole-2-carboxylic acid ethyl esters 7-9. The Mannich reaction of these compounds with formaldehyde and morpholine yielded ethyl 3-(morpholinomethyl)-substituted-1H-indole-2-carboxylates 10-12. The 5,7-dichloro-1H-indole-2-carbohydrazide 13 was cyclized with methyl orthoformate in DMF to give 6,8-dichloro[1,2,4]triazino[4,5-a]indol-1(2H)-one 14. Vilsmeier-Haack formylation of 7-9 gave ethyl 3-formyl-substituted-1H-indole-2-carboxylates 15-17 whose 2,2'-((5-chloro-2-(ethoxycarbonyl)-1H-indol-3-yl)methylene)bis-(sulfanediyl) diacetic acid 18 was prepared. The reaction of 15 and 16 with substituted anilines by conventional and microwave methods gave ethyl 3-(N-aryliminomethyl)-5-halo-1H-indole-2-carboxylates 19-29. In a cyclocondensation reaction of 19-25 with thiolactic acid or thioglycolic acid substituted indolylthiazolidinones 30-33 were prepared. Reaction of hydrazine hydrate with 15-17 did not give the respective hydrazones but directly led to the cyclized products substituted-3H-pyridazino[4,5-b]indol-4(5H)-ones 34-36, while a reaction with 2,4-dichlorophenylhydrazine yielded the uncyclized hydrazones. The chlorination of 35 and 36 with POCl3 gave pyridazino[4,5-b]indoles 39 and 40, respectively; reaction of the latter compounds with morpholine gave 4-(substituted-5H-pyridazino[4,5-b]indol-4-yl)morpholine 41 and 42. Mannich reaction of 34 with formaldehyde and N-ethylpiperazine gave 8-chloro-3-((4-ethylpiperazin-1-yl)methyl)-3H-pyridazino[4,5-b]indol-4(5H)-one 43. The microwave assistance of selected reactions has a profound effect on the reaction speed. The structures of the new compounds were confirmed by both analytical and spectral data. Some compounds were subjected to investigations concerning their antimicrobial, tranquilizing, and anticonvulsant activities.

Angelicins, angular analogs of psoralens: chemistry, photochemical, photobiological and phototherapeutic properties.

Angelicin and some of its derivatives are naturally occuring compounds which show interesting photobiological properties. In this review various aspects of angelicin and its derivatives have been reported. The natural occurrence and the chemical synthesis both of naturally occurring and synthetic angelicins have been reviewed. Photochemical and photophysical properties of angelicins have been considered with particular reference to the capacity to generate active forms of oxygen, photoreactions with nucleic acids, proteins and unsaturated fatty acids. Photobiological effects have been considered: skin phototoxicity, antiproliferative effects, genotoxicity, ability to induce hemolysis in erythrocytes, inactivation of prokaryotic and eukaryotic microorganism and of viruses. The ability of some angelicins to induce photocarcinogenesis has been reviewed as well as in the activity as photochemotherapeutic agents.

Structure-activity relationship of miltirone, an active central benzodiazepine receptor ligand isolated from Salvia miltiorrhiza Bunge (Danshen).

Twenty one o-quinonoid-type compounds and one coumarin-type compound related to miltirone (1) have been synthesized with the aim to identify the key structural elements involved in miltirone's interaction with the central benzodiazepine receptor. On the basis of their inhibition of [3H]flunitrazepam binding to bovine cerebral cortex membranes, it is apparent that ring A of miltirone is essential for affinity. Although increasing the size of ring A from six-membered to seven- and eight-membered is well-tolerated, the introduction of polar hydroxyl groups greatly reduces binding affinity. The presence of 1,1-dimethyl groups on ring A is, however, not essential. On the other hand, the isopropyl group on ring C appears to be critical for binding as its removal decreases affinity by more than 30-fold. It can, however, be replaced with a methyl group with minimal reduction in affinity. Finally, linking ring A and B with a -CH2CH2- bridge results in analogue 89, which is 6 times more potent than miltirone at the central benzodiazepine receptor (IC50 = 0.05 microM).

Studies on annelated 1,4-benzothiazines and 1,5-benzothiazepines. III--Synthesis and CNS activity of some 1-substituted derivatives of the novel heterocyclic system 4,5-dihydro-s-triazolo [3,4-d]-1,5-benzothiazepine.

A series of new 4,5-dihydro-s-triazolo [3,4-d]-1,5-benzothiazepines has been prepared. All the described compounds are representative of a novel ring system. Some of these compounds were tested for their CNS activity and effects comparable with the ones of diazepam were observed.

The absolute configuration of SU 23397: a novel neuroleptic agent.

The absolute configuration of a novel chiral neuroleptic agent SU 23397 (I) was determined by ORD comparison of (+)-5-methoxy dihydro coumarilic acid (VIII), a synthetic precursor of SU 23397 (I), with (+)-dihydro coumarilic acid, whose absolute configuration is known. This assignment was confirmed by oxidative degradation of (+)-5-methoxy dihydro coumarilic acid VIII to D-(+)-malic acid.

Analgesic and tranquilizing activity of 5,8-disubstituted 1-tetralone Mannich bases.

5,8-Disubstituted 1-tetralone Mannich bases represent semirigid variants of classical (i.e., chlorpromazine) neuroleptic agents. 8-Chloro-5-methoxy-2-morpholinomethyl-1-tetralone exhibits neuroleptic potency in the thiothixene range in animal models. Of greater potential interest, however, is the analgesic potency of the 8-chloro-5-methoxy-2-pyrrolidinomethyl analogue which was in the morphine range. This compound did not induce tolerance nor was its activity reversed by naloxone. Structure-activity relationships of the series are discussed.

Synthesis of certain benzo- and pyridodiazepines likely to possess tranquilizing effect.

The synthesis of certain 1.5-benzodiazepinediones, some of their oxygen-free analogues and a number of the 7-nitro derivatives is described. Condensation of 3.4-diaminopyridine with diethylmalonate instead of affording the expected pyridodiazepine, yielded an imidazopyridine, the structure of which was inferred from spectral data Nevertheless, the pyridodiazepine was obtained by condensing the diamino-heterocycle with malonyl dichloride.

[Chemical and pharmacological research on pyran derivatives. VI. 2-Dialkylamino-4-oxo-4H-naphto/1,2-b/pyrans and derivatives]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota VI-2-dialchilammino-4-oxo-4H-nafto [1,2-b] pirani e derivati

The 2-dialkylamino-4-oxo-4H-naphtho [1,2-b]pyrans are obtained by the reaction of N,N-dialkylethoxycarbonylacetamides with alpha-naphthol and with substituted alpha-naphthols. The products on treatment with formaldehyde and morpholine or piperidine or N-methylpiperazine are transformed into the 2-dialkylamino-3-dialkylaminomethyl-4-oxo-4H-naphtho [1,2-b]pyrans. Pharmacological investigation has shown that 2-dimethylamino (K 12164), 2-(N-ethyl, N-methyl)amino- (K 12087) and 2-diethylamino-4-oxox-4H-naphtho [1,2-b]pyran (K 12165) show clear neurotropic activity of the neuroleptic type whereas compounds of the isomeric series, 1H-naphtho-[2,1-b]pyrans, studied previously (1), show anticonvulsive and sedative activity. This difference in pharmacological activity has prompted a more complete comparative examination of the activity of the two series of compounds. Study of antagonism to the effects of reserpine by both 4H-naphtho [1,2-b]pyrans and 1H-naphtho [2,1-b]pyrans has shown that in the latter series the 1-oxo-3-dimethylamino- (K 8291), the 1-oxo-3-(N-ethyl, N-methyl)amino- (K 8409) and the 1-oxo-3-diethylamino-1H-naphtho [2,1-b]-pyran (K 8292) have marked neurotropic activity of the antidepressive type.

[Research on substances with psychotropic activity. IV. Synthesis of 2,3-diphenyl-4-methyl-4H-1,4-benzothiazin-1,1-dioxide by thermal cyclization of N-(2-desylsolfonylphenyl) glycine]. / Ricerche su sostanze ad attività psicotropa. Nota IV -Sintesi del 2,3-difenil-4-metil-4H-1,4-benzotiazin-1,1-diossido per ciclizzazione termica della N-(2-desilsolfonilfenil)glicina

Treatment of the ethyl ester of N-benzoyl-N-(2-benzylsolfonylphenyl)glycine with potassium in benzene gave, by rearrangement, N-(2-desylsolfonylphenyl)glycine, which via thermal intramolecular cyclization and simultaneous decarboxylation gave 2,3-diphenyl-4-methyl-4H-1,4-benzothiazin-1,1-dioxide. The structure of the latter compound was confirmed chemically by oxidising the known 2,3-diphenyl-4-methyl-4H-1,4-benzothiazine with hydrogen peroxide in formic acid and by I;R. and N.M,R; spectral data.

Derivatives of 3, 3-spirobi-5-methyltetrahydrofuranone-2 as potential neurotropic agents. Part I.

Starting from 3,3'-spirobi-5-bromomethyltetrahydrofuranone-2 (2) the amino derivatives 3a--g were obtained. The pharmacological examination showed that the new compounds are deprived of the hypnotic activity characteristic for 3,3'-spirobi-5-methyltetrahydrofuranone-2 (2) and behaved in most tests as tranquillizers.