Synthese von 2,2a,3,4-Tetrahydro[1,2-d]benz[b]-1,4-oxazin-2,4-dionen, 2. Mitt.

Synthesis of 2,2a,3,4,-Tetrahydro[1,2d]benz[b]-1,4-oxazine-2,4-diones, II The diasteromeric 3-amino-β-lactams 7 and 8 were obtained from the azides 5 and 6 and the phthalimido derivatives 9 and 12 . Compound 9 was synthesized directly from 2 by means of phthalimidoacetyl chloride/triethylamine, whereas 12 is accessible from 11 only by the Mitsunobu reaction. Acylation of 7 or 8 (to 13 or 14 ) is followed by hydrolysis of the ester function (to 15 or 16 ) and debenzylation to yield 17 or 18 which are lactonized to 19 or 20 by the action of DCC.     

Fused 1,2,6-Thiadiazines Tetrahydrobenzo[b]thieno[2,3-c] [1,2,6]thiadiazine 2,2-Dioxides

Suitably substituted derivatives of tetrahydrobenzo[b]thiophene were treated with sulfamoyl chlorides to give sulfamoyl esters and nitriles. Ring closure of these compounds, under various conditions, afforded tetrahydrobenzo[b]thieno[2,3-c][1,2,6]thiadiazine 2,2-dioxides. Their herbicidal activities were tested.     

Synthese von 2,2a,3,4-Tetrahydro-azeto[1,2-d]benz[b]-1,4-oxazin-2,4-dionen

Synthesis of 2,2a,3,4-Tetrahydroazeto[1,2-d]benzo[b]-1,4-oxazine-2,4-diones The 1-(2-hydroxyaryl)-4-oxoazetidine-2-carboxylic acids 7c, 7d and 10 react with dicyclohexylcarbodiimide to give the title compounds 11, 12 and 13 . Compound 13 can also be obtained by nitration of 12 . The starting materials 7c , 7d and 10 are synthesized from the l-aryl-4-oxoazetidine-2,2-dicarboxylates 4a and 4b , which are available from 1 by a method analogous to that described by Sheehan²⁾ or via 8 and 9 .     

Synthesis and hormonal activity of [Tyr 22] glucagon and [desHis 1, Tyr 22] glucagon

[Tyr²²] glucagon and [desHis¹, Tyr²²] glucagon were synthesized by an improved solid phase procedure on a Pam-resin. The course of the synthesis was monitored by quantitative ninhydrin analysis and preview sequencing. Following cleavage by the low/high HF method the peptides were purified by ion exchange chromatography and reverse phase HPLC. The overall yield of homogeneous isolated peptide from the first amino acid was 41%. Circular dichroism measurements on dilute solutions in mixed aqueous organic solvents at pH 2, 6.9 and 9.2 showed increased β-sheet structure relative to glucagon. [Tyr²²]glucagon was a full agonist with 20–30% activity in the rabbit blood glucose assay and 10% activity in the rat liver membrane adenyl cyclase assay. [desHis¹, Tyr²²] glucagon had only a trace of activity in the adenyl cyclase assay (>0.002%) but bound to membranes in a competitive [¹²⁵I] glucagon assay 1.0% as well as glucagon. The analog completely inhibited formation of cAMP by natural glucagon, with 50% inhibition at a ratio of 83:1 and pA₂ = 6.7. The data are discussed in terms of models of glucagon structure in dilute solution.     

Anellierte Thiopyrone, 4. Mitt.1): Indeno[1,2-b]-, Indolo[3,2,-b]-, [1]Benzofuro[3,2-b]- und [1]Benzothieno[3,2-b]thiopyrone

Fused Thiopyrones, IV: Indeno[1,2-b]-, Indolo[3,2-b]-, [1]Benzofuro[3,2-b]-, and [1]Benzothieno[3,2-b]thiopyrones The thiopyrones 2 are obtained from the corresponding thiopyranones 1 by dehydration with tritylperchlorate or SeO₂. Treatment of the benzofurane 2d with m-chloroperbenzoic acid (mCPBA) yields the thiopyrone-S, S-dioxide 3d. Starting from the benzothienothiopyrone 2e only one product, the thiophene-sulfone 3e , can be isolated.     

Synthesis and fungicidal activity of substituted tetrahydro-[3, 4-c]- and benzo[h]tetrahydropyrido[3,4-c]coumarins

Translated from Khimiko-farmatsevticheskii Zhurnal, Vol. 24, No. 2, pp. 140–143, February, 1990.     

Synthesis of new derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol with potential antimicrobial activity

A series of 13 new ether-linked derivatives of 2,2-dimethyl-2,3-dihydro-7-benzo[b]furanol have been designed and synthesized. Ten of them were evaluated for their potential antimicrobial activity against some Gram-positive and Gram-Negative bacteria and fungi of the Candida species.     

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.     

Design,synthesis and antitumor activity of C3/C3 bis-fluoroquonolones cross-linked with [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazole

To contribute to the development of an efficient method for the conversion of antibacterial fluoroquinolones to antitumor fluoroquinolones, a series of C3/C3 bis-fluoroquinolone fused heterocycles cross-linked with a [1,2,4]-triazolo[3,4-b] [1,3,4]-thiadiazole core as a common bioisostere of two carboxylic acid groups was designed and synthesized as their hydrochloride salts. Structures were characterized by elemental analysis and spectral data and their in vitro antitumor activity against L1210, CHO and HL60 cell lines was screened by determination of their IC₅₀ values in the methylthiazole trazolium (MTT) assay. Two compounds were highly potent against the HL60 cell line and represent promising lead compounds for future development.     

Synthesis and biological activity of cocaine analogues. 2. 6H-[2]Benzopyrano[4,3-c]pyridin-6-ones.

1,2,3,4-Tetrahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (20) and cis- and trans-1,2,3,4,4a,10b-hexahydro-2-methyl-6H-[2]benzopyrano[4,3-c]pyridin-6-one (3a and 3b) were synthesized. The design of 3b was based on the proposal that the active conformation of cocaine is one in which the phenyl and amino groups are arranged in a manner that will superimpose upon a beta-phenethylamine in a trans-staggered conformation. The compounds were compared with cocaine and tropacocaine for their ability to inhibit uptake of [3H]norepinephrine by rat brain synaptosomal preparations. The test compounds (IC50 = 3.2 X 10(-4) M, 20; 6.5 X 10(-4) M, 3a; and 3.2 X 10(-4) M, 3b; respectively) were considerably weaker than cocaine (IC50 = 5.8 X 10(-7) M) and tropacocaine (IC50 = 5.6 X 10(-6) M). Compound 3b showed selectivity at 1 X 10(-5) M for inhibiting the uptake of norepinephrine (36%). It inhibited dopamine (3%) and serotonin (0%) uptake to a much lesser extent, if at all, at this concentration.     

2,2'-Phthaloyl-,2,2'-isophthaloyl-, and 2,2'-terephthaloylbis[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts): synthesis, partition coefficients, toxicity and effect on ganglionic transmission

2,2'-Phthaloyl-, 2,2'-isophthaloyl, and 2,2'-terephthaloyl-boff++[1,1,1-trimethylhydrazinium] dihydroxide, bis(inner salts) 7, 8, and 9 and their hydrazide and hydrazinium diiodide precursors were synthesized and tested for toxicity and their ability to block sympathetic ganglionic transmission. Only the 2,2'-phthaloyl and isophthaloylhydrazinium diiodides 4 and 5 produced weak inhibition of nerve transmission (35% at 2.15 X 10(-3) M). The inner salts were appreciably less toxic than the hydrazinium diiodides in brine shrimp testing. The log P (log10, chloroform pH 7 buffer system) values of all compounds were determined and those of the inner salts and hydrazinium diiodides were in the range of -3.03 to -3.60.     

Synthesis and biological activity of pyrimido[2,1-b][1,3]thiazine, [1,3]thiazino[3,2-a]purine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives and thiazole analogues.

Some series of thiazolo[3,2-a]pyrimidine, pyrimido[2,1-b] [1,3]thiazine, thiazolo[3,2-a]purine, [1,3]thiazino[3,2-a]purine, thiazolo[3,2-a][1,2,3]triazolo[4,5-d]pyrimidine and [1,2,3]triazolo[4,5-d][1,3]thiazino[3,2-a]pyrimidine derivatives, variously functionalized, were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely: E. coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, S. faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, C. tropicalis, Aspergillus sp., and for antiviral activity on Herpes simplex virus Type 1, Vesicular stomatitis virus and Coxsackievirus B5. The compounds proved to be devoid of activity against viruses and gram-negative bacteria, while some of them exhibited modest activity against gram-positive bacterial strains.     

Synthesis and biological activity of new heterocyclic structures: [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c] [1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo [4', 5': 4,5] pyrimido[6,1-b][1,3]thiazine.

Some derivatives of thiazolo[3,2-c]pyrimidine, pyrimido[6,1-b][1,3]thiazine, thiazolo[2,3-i]purine, [1,3]thiazino[2,3-i]purine, thiazolo[3,2-c][1,2,3]triazolo[4,5-e]pyrimidine and [1,2,3]triazolo[4',5':4,5]pyrimido[6,1-b][1,3]thiazine were prepared. The compounds were tested for antimicrobial and antimycotic activity on a number of strains, namely, Escherichia coli, Proteus vulgaris, P. mirabilis, Pseudomonas aeruginosa, Salmonella sp., Staphylococcus aureus, Streptococcus faecalis, Bacillus subtilis, Sarcina lutea, Candida albicans, Aspergillus sp., and for antiviral activity on Herpes simplex virus, Type 1 (HSV-1), Vesicular stomatitis virus (VSV) and Coxsackievirus B5 (CoxB5). The compounds proved to be devoid of activity against viruses, mycetes and gram-negative bacteria, while some of them exhibited a modest activity against gram-positive bacterial strains.     

Synthesis, antimalarial activity, and molecular modeling of new pyrrolo[1,2-a]quinoxalines, bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines

Three pyrrolo[1,2-a]quinoxalines, 15 bispyrrolo[1,2-a]quinoxalines, bispyrido[3,2-e]pyrrolo[1,2-a]pyrazines, and bispyrrolo[1,2-a]thieno[3,2-e]pyrazines were synthesized from various substituted nitroanilines or nitropyridines and tested for their in vitro activity upon the erythrocytic development of Plasmodium falciparum strains with different chloroquine-resistance status. Bispyrrolo[1,2-a]quinoxalines showed superior antimalarial activity with respect to monopyrrolo[1,2-a]quinoxalines. The best activity was observed with bispyrrolo[1,2-a]quinoxalines linked by a bis(3-aminopropyl)piperazine. Moreover, it was observed that the presence of a methoxy group on the pyrrolo[1,2-a]quinoxaline nucleus increased the pharmacological activity. Drug effects upon beta-hematin formation were assayed and showed similar or higher inhibitory activities than CQ. A possible mechanism of interaction implicating binding of pyrroloquinoxalines to beta-hematin was supported by molecular modeling.     

Induction of anti-Escherichia coli activity in mice by phenothiazines, benzo[a]phenothiazines and benz[c]acridines.

The abilities of 14 phenothiazines, 8 benzo[a]phenothiazines and 12 benz[c]acridines to induce anti-Escherichia coli activity in mice were compared. Pretreatment with several benzo[a]phenothiazines or benz[c]acridines protected mice from lethal infection of Escherichia coli in a dose-dependent manner, whereas most of the phenothiazines induced much weaker anti-Escherichia coli activity. However, direct contact of Escherichia coli with these compounds or their administration just after bacterial inoculation were ineffective. These data suggest the immunopotentiation activity of benzo[a]phenothiazines and benz[c]acridines.     

Dehydro-enkephalins. III. Synthesis and biological activity of [ΔAla2, Leu5]-enkephalin

[ΔAla², Leu⁵]-enkephalin has been prepared and shown to be more active than the parent saturated enkephalin in a binding assay using rat brain membranes and [³H] dihydromorphine as a tracer. In a comparison of potencies against [³H] dihydromorphine and [³H]-[d -Ala², d -Leu⁵]-enkephalin as tracers, [ΔAla², Leu⁵]-enkephalin showed preference for μ opiate receptors, possibly due to the hydrophobicity of the ΔAla² residue. A synthetic tetrapeptide enkephalin [ΔAla²]-desLeu⁵-enkephalin had weak activity and high selectivity for the μ receptors. O-Acylation of a serine residue in the peptide was achieved by coupling between the peptide and a carboxylic acid using DCC and a catalytic amount of 4-dimethylaminopyridine.