Untersuchungen an 1,3-Thiazinen, 20. Mitt. Transacylierende N-Acyltetrahydro-1,3-thiazin-2-thione

On 1,3-Thiazines, XX: Transacylating N-Acyltetrahydro-1,3-thiazine-2-thiones The synthesis of novel N-acyltetrahydro-1,3-thiazine-2-thiones 3 with transacylating activity towards nucleophilic compounds is described.     

2-cyano-1,3-dicarbonyl compounds with antiallergic activity.

A number of 2-cyanoindan-1,3-diones and 3-cyano-4-hydroxycoumarins have been prepared and assessed for potential antiallergy activity as measured by their ability to inhibit passive cutaneous anaphylaxis in the rat, mediated by rat serum containing antigen specific IgE. The structural requirements for activity were similar not only for both series of compounds but also for the analogous 2-nitroindan-1,3-diones and 4-hydroxy-3-nitrocoumarins previously reported. The most active compounds were 2-cyano-5,6-diethylindan-1,3-dione (4e) and 3-cyano-6,7-diethyl-4-hydroxycoumarin (11h).     

2-β-(N-arylpiperazino) ethyl indandiones-1,3 and indandiols-1,3

Conclusion By the action of N-arylpiperazines on the tosylates of 2--hydroxyethyl-2-phenyl and 2-methylsubstituted indandiones-1,3 one obtains 2--(N-arylpiperazino) ethyl derivatives of 2-substituted indandiones-1,3 which are reduced by sodium borane to the corresponding indandiol-1,3 derivatives. The arylpiperazino derivatives of 2-substituted indandiones-1,3 and indandiols-1,3 have neurotropic properties. A certain association between structure, toxicity, and pharmacological action of these compounds was noted.Translated from Khimiko-Farmatsevticheskii Zhurnal, No. 10, pp. 25–29, October, 1968.     

Eine bequeme Synthese von 2-Aryl-2-vinyl-[1,3]-dioxolanen und -dioxanen

A Convenient Synthesis of 2-Aryl-2-vinyl-[1,3]-dioxolanes and -dioxanes Cyclocondensation of γ-aryl-γ-oxosulfones 1 with 1,2- or 1,3-dioles 2 and 3 leads to 2-aryl-2-sulfonylethyl-[1,3]-dioxolanes 4 , and -dioxanes 5 , respectively. In the presence of potassium tert-butoxid 4 and 5 eliminate sulfinic acid yielding the title compounds 6 and 7 .     

Untersuchungen an 1,3-Thiazinen, 15. Mitt. Neue Synthese für N-substituierte Tetrahydro-1,3-thiazin-2-thione

1,3-Thiazines, XV: New Synthetic Route to N-Substituted Tetrahydro-1,3-thiazine-2-thiones. A new synthetic route to N-substituted tetrahydro-1,3-thiazine-2-thiones 5 giving good yields for N-aryl compounds is reported. It consists of carbon disulfide cleavage of N,N'-disubstituted 2-iminotetrahydro-1,3-thiazines 3 which leads to 5 and the isothiocyanates 6 .     

Inhibition of prostaglandin biosynthesis by 2-aryl-1,3-indandiones

The effect of several 2-aryl-1,3-indandiones on the biosynthesis of prostaglandin E₂ from arachidonic acid by bovine seminal vesicle microsomes was examined. 2-Phenyl-1,3-indandione appeared to be a weak inhibitor but by introducing electron-withdrawing substituents into the phenyl ring and augmenting lipophilicity, very active compounds were obtained. Activity, however, disappeared entirely on substitution in the ortho position. Inhibition was not related to the presence of an acidic group and was irreversible in some cases. The inhibition of prostaglandin biosynthesis by 2-aryl-1,3-indandiones showed no clear relationship with anti-inflammatory action.     

Synthesis and antibacterial evaluation of 4-substituted-2-phenyl-1-p-tolyl-4-thiomethyl-1,3-diazabuta-1,3-dienes: a novel class of antibacterial agents

A series of novel-2-phenyl-1-p-tolyl-4-thiomethyl-1,3-diazabuta-1,3-dienes compounds (5a-5e) possessing morpholino, diethyl amino, pyrrolidino, piperidino and 2-aminopyridino groups respectively at C-4 were prepared by reaction of alpha-aryliminobenzyl isothiocyanates with secondary amines and S-alklyation of the resultant thioureas with aqueous potassium hydroxide. The isothiocyanates were obtained from easily available starting materials. These 1,3-diazabuta-1,3-dienes were obtained in pure form after recrystallization and their structures were established by analytical and spectral data. The synthesized compounds were screened for their antibacterial activity and some of them were found to exhibit significant antibacterial activity.     

Untersuchungen an 1,3-Thiazinen, 11. Mitt. 3-Acyl-4-oxo-2-thioxo-tetrahydro-1,3-thiazine,neuartige cyclische N,N-Bis-acyl-dithiourethane

1,3-Thiazines, XI: 3-Acyl-4-oxo-2-thioxotetrahydro-1,3-thiazines, a new Type of Cyclic N,N-Bisacyldithiourethanes The 4-oxo-2-thioxotetrahydro-1,3-thiazines 1 and 2 were reacted with acid chlorides in the presence of triethylamine yielding the 3-acyl derivatives 3 and 4 . These compounds were shown by hydrolysis, alcoholysis and aminolysis to be acylating agents.     

Muscarinic subtype affinity and functional activity profile of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine and 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine derivatives

Starting from two previously studied muscarinic full agonists, characterized by a 1,3-dioxolane ((+)-1) and a 1,3-oxathiolane ((+)-2) cycle, two new series of muscarinic ligands were designed, obtained by the steric complication of the parent compounds produced by freezing the aminoalkyl chain into a pyrrolidine ring. Both tertiary amines and the corresponding iodomethyl derivatives were synthesised and studied, and several compounds of the series which behaved as muscarinic agonists have been selected, on the basis of preliminary binding experiments on rat cortex homogenates, for the present work. Results are presented obtained from testing the affinity of the selected compounds against cloned human muscarinic receptors expressed in CHO cells, in order to evaluate subtype selectivity. Their functional activity on classical models of M1-M4 receptors, in guinea pig and rabbit tissues is also reported. With respect to parent compounds, the new molecules present some selectivity toward hm2 receptors; fair M2 selectivity is also evident in functional studies, where these compounds behave as partial agonists. Among the other compounds of the series (2S, 4'R, 2'S)-1,1-dimethyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidinium iodide (-)-3 and (2R, 5'S, 2'S)-1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine (+)-5 present a promising pharmacological profile. Compound (-)-3 shows modest hm2 selectivity in binding experiments but a clearcut M2 selectivity in functional tests, where it behaves as a weak antagonist on M1 and M4 subtypes, as a weak full agonist on the M3 subtype and as a potent partial agonist on M2 subtype. Tertiary amine (+)-5 presents a quite similar profile but appears more interesting since, lacking a permanent charge on the nitrogen atom, it may represent an interesting tool to study CNS muscarinic receptors. Our results confirm that sterical complication of parent compounds (+)-1 and (+)-2 produces more selective muscarinic agonists.     

Synthesis and Antifungal Activity of 1,3-bis-1,2,3-Triazol-1-yl-Propan-2-ol Based Compounds

Pharmaceutical Chemistry Journal - A small series of 4′-substituted 1,3-bis-1,2,3-triazol-1-yl-propan-2-ol compounds was prepared via CuAAC click reaction of 1,3-diazido-2-propanol and...     

Physiological activity of polymethylene and polyoxyethylene bis-(2-amino-1,3-diazepiniuim) iodides

A study was made of physiological activity of a series of new bisquaternary compounds in which the role of cation heads is played by the residues of 2-amino-1,3-diazepinium. Studies performed on a frog neuromuscular preparation showed that the compounds under test effectively block the responses of the postsynaptic membrane to acetylchinoline. The derivatives of diazepinium have pronounced hypotensive and ganglion-blocking properties. Octamethylene-bis-(2-amino-1,3-diazepinium) iodide that appeared to be the most effective of the compounds under test compares very favourably with benzohexonium. It was found to be 1.5 times more powerful as regards the ganglion-blocking and hypotensive activity.     

Toxicology,occurrence and risk characterisation of the chloropropanols in food: 2-Monochloro-1,3-propanediol, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol

Great attention has been paid to chloropropanols like 3-monochloro-1,2-propanediol and the related substance glycidol due to their presence in food and concerns about their toxic potential as carcinogens. The other chloropropanols 2-monochloro-1,3-propanediol, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol have been found in certain foods, but occurrence data are generally limited for these compounds. 1,3-dichloro-2-propanol has the most toxicological relevance showing clear carcinogenic effects in rats possibly via a genotoxic mechanism. The dietary exposure to 1,3-dichloro-2-propanol is quite low. Calculated “Margins of Exposure” values are above 10,000. It is concluded that the 1,3-dichloro-2-propanol exposure is of low concern for human health. The toxicology of 2,3-dichloro-1-propanol has not been adequately investigated. Its toxicological potential regarding hepatotoxic effects seems to be lower than that of 1,3-dichloro-2-propanol. Limited data show that 2,3-dichloro-1-propanol occurs only in trace amounts in food, indicating that exposure to 2,3-dichloro-1-propanol seems to be also of low concern for human health. The dietary 2-monochloro-1,3-propanediol burden appears to be lower than that of 3-monochloro-1,2-propanediol. An adequate risk assessment for 2-monochloro-1,3-propanediol cannot be performed due to limited data on the toxicology and occurrence in food. This article reviews the relevant information about the toxicology, occurrence and dietary exposure to the chloropropanols 2-monochloro-1,3-propanediol, 1,3-dichloro-2-propanol and 2,3-dichloro-1-propanol.     

1,3-thiazines, X: Attempted synthesis of fungitoxic hydrophilic 2-thioxotetrahydro-1,3-thiazin-4-ones (author's transl)

1,3-Thiazines, X: Attempted Synthesis of Fungitoxic Hydrophilic 2-Thioxotetrahydro-1,3-thiazin-4-ones Attempts to synthesize the title compounds by three different methods were not succesful. Instead, the rhodanine-5-acetic acid esters 5 were obtained in good yields from the reaction of dithiocarbamates and maleic esters. They were converted to the acids 6 . In some cases, 5 and 6 were effective against Candida albicans.     

Anellierte Chromone aus heterocyclischen 1,3-Dicarbonylverbindungen

Anellated Chromones from Heterocyclic 1,3-Dicarbonyl Compounds The heterocyclic 1,3-dicarbonyl compounds 2b, 2d, 6c and 9b cyclize with polyphosphoric acid (PPA), forming the chromones 3a, 3b, 7 and 10 . The dicarbonyl compounds 2,6,9 and 11 are completely enolised; direction of enolisation and hydrogen bonding are discussed. The dibenzoylmethane derivative 5c represents a chelated diketone. Structures are elucidated by spectroscopic methods.     

1,3-Diacylaminopropan-2-ols and Corresponding 2-Acyl Derivatives as Drug Carriers: Unexpected Pharmacological Properties

Abstract— The design of lipid vectors (pseudotriglycerides, PTGs), achieved by the amide isosteric substitution of the ester moieties of 1,3-diacylglycerols, is based on the structural similarity with natural triglycerides facilitating the passage of pharmacological agents across biological membranes. 2-S-Acetylthiorphan (hemiacetorphan) pseudotriglycerides, Z-glycine pseudotriglycerides and 1,3-diacylaminopropan-2-ols vector molecules differing by the nature of the acid side-chain are examined in acute toxicity, radioligand binding and guinea-pig ileum experiments. These evaluations have led us to distinguish two types of compounds. Linear derivatives, palmitoyl and decanoyl, are devoid of toxicity and intrinsic activity. Cyclic derivatives, which contain in the acyl chain a phenyl, cyclohexyl, cyclopentyl or adamantoyl ring, present additional properties. Cyclic derivatives of hemiacetorphan are lethal after intravenous administration. The mortality is governed by the 2-hemiacetorphan moiety in the cyclic vector molecules. Hemiacetorphan alone is also lethal. Cyclic vector molecules and related compounds inhibit the contractile response of the guinea-pig ileum induced by electrical stimulation, histamine or acetylcholine (noncompetitive antagonism) whereas linear entities and parent compounds are not active. In particular, the 2-hemiacetorphan 1,3-diadamantoylamide PTG presents pD'2 values 7·87 ± 0·29 (vs histamine) and 7·97 ± 0·12 (vs acetylcholine).     

Synthesis and Antimuscarinic Activity of Derivatives of 2-Substituted-1,3-Dioxolanes

Geometric cis, trans isomers, derivatives of 2-substituted-1,3-dioxolanes and 2-substituted-1,3-dioxanes were designed and studied as antimuscarinic agents. The synthesized compounds were evaluated as perchlorides and methiodides by functional tests with rabit vas deferens (putatvie M₁), guinea-pig heart (M₂) and guinea-pig ileum (M₃). The effect of the replacement of a trimethylammonium group with a dimethylsulfonium in the two rings was also evalutated. Pharmacological results indicate that the 1,3-dioxane nucleus shows the highest stereoselective values on the studied receptors.     

Hypocholesterolemic activity of 1,3-bis(substituted phenoxy)-2-propanones.

A series of 1,3-bis(substituted phenoxy)-2-propanones was found to be active hypocholesterolemic agents at 10 mg/kg/day. The p-chloro- and p-methyl-substituted phenoxy compounds possess the highest activity. These compounds did not possess the estrogenic and antifertility activities of the related previously reported derivatives of the bis(beta-phenylethyl) ketone series. The 1,3-bis(p-methylphenoxy)-2-propanone (7) also lowered serum triglycerides and glycerol which appeared to be due to increased levels of serum lipase and reduced activity of liver lipase. There was reduced incorporation of free fatty acids into complex lipids by the liver. Cholesterol was excreted faster in the treated animals.     

Design and synthesis of new 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones as selective cyclooxygenase (COX-2) inhibitors

A new series of 2-aryl, 3-benzyl-(1,3-oxazolidine or 1,3-thiazolidine)-4-ones, possessing a methylsulfonyl pharmacophore, were synthesized to evaluate their biological activities as selective cyclooxygenase-2 (COX-2) inhibitors. In vitro COX-1 and COX-2 isozyme inhibition studies were performed to acquire structure-activity relationship data with respect to the point that molecular modeling studies showed that designed compounds bind in the primary binding site such that the C-2 para-SO₂Me substituent inserts into the 2° pocket present in COX-2 enzyme. COX-1 and COX-2 inhibition studies showed that all compounds were selective inhibitors of the COX-2 isozyme with IC₅₀ values in the highly potent 0.21 to 0.34 μM range, and COX-2 selectivity indexes in the 222.3 to >476 range. 3-Benzyl-2-(4-methylsulfonylphenyl)-1,3-oxazolidine-4(5H)-one was identified as the most potent (IC₅₀ = 0.21 μM) and selective (S.I. > 476) COX-2 inhibitor among the synthesized compounds. It also was a more selective COX-2 inhibitor than the parent reference compound celecoxib (S.I. > 403).     

2-Methylen-1,3-indandione: Azaaromatische Anticoagulantien ohne Enolisierungsmöglichkeiten

2-Methylene-1,3-indanediones: Azaaromatic Anticoagulants Without Enolizable Carbonyl Functions The anticoagulant activities of five 2-methylene- and two 2-oxaspiro-indanediones show that the enolizability of the carbonyl functions is no structural essential in anticoagulants. The spiro compounds exhibit prolonged activities.     

Synthesen in 2-Stellung substituierter 1,3-Indolizidione

Synthesis of Substituted 1,3-Indolizidiones 1,3-Indolizidiones substituted in 2-position can be synthesized by Dieckmann reaction. This is shown with 2-carbethoxyindolizidione-1,3 ( 4 ), 2-methylencarbethoxyindolizidione-1,3 ( 7 ), 2-methylindolizidione ( 9 ) and 2-ethylindolizidione-1,3 ( 14 ).