Synthesis and biological activity of condensed derivatives of thieno[3,2-<Emphasis Type="Italic">d</Emphasis>]thiazolo(thiazino,thiazepino)[3,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidines

Methods for the synthesis of new heterosystems including condensed pyrano[4′,3′:4,5]pyrido[2,3-b]-thieno[3,2-d]thiazolo(thiazino, thiazepino)[3,2-a]pyrimidines, thiazolo(thiazino, thiazepino)[3″,2″:1′,2′]pyrimido[4′,5′:4,5]thieno[2,3-c]isoquinolines, and cyclopenta[4′,3′:4,5]pyrido[2,3-b]thieno[3,2-d]thiazolo(thiazino)[3,2-a]pyrimidines are developed. The synthesis is carried out on the basis of 1-amino-2-ethoxycarbonylpyrano[4,3-d]thieno[2,3-b]pyridines and -thieno[2,3-b]isoquinolines. Antitumor and anticonvulsant properties of the synthesized products have been evaluated. Compounds possessing low toxicity and moderate biological activity are found. Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 43, No. 3, pp. 17–21, March, 2009.     

Thiophen als Strukturelement physiologisch aktiver Substanzen, 2. Mitt. Die Synthese von basisch substituierten 3H-Thieno[2,3-d]-imidazolen

Thiophene as a Structural Element of Physiologically Active Compounds, II: Synthesis of Base-Substituted 3H-Thieno[2,3-d]imidazoles The synthesis of the substituted 3H-thieno[2,3-d]imidazoles 14 and 15 is described. It proceeds by Curtius rearrangement of (acylalkylamino)thiophenecarbonylazides 11 .     

Synthese und Eigenschaften 6-substituierter 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-one

Synthesis and Properties of 6-Substituted 4-Alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones Reactions of the N-alkoxy-2-(2-thienyl)glycolamides 1B with dicyclohexylcarbodiimide yield the 4-alkoxy-5,6-dihydro-4H-thieno[3,2-b]pyrrol-5-ones 2b . Acid catalyzed methanolysis of the tetrahydropyranyl group in 2B, Bk results in the formation of the bicyclic lactams 5 .     

Thiophen als Strukturelement physiologisch aktiver Substanzen, 10. Mitt. Substituierte 3-Alkoxy-4,5,6,7-tetrahydro-8H-thieno[2,3-b]indole

Thiophene as Structural Element of Physiologically Active Compounds, X: Substituted 3-Alkoxy-4,5,6,7-tetrahydro-8H-thieno[2,3-b]indoles The title compounds 1 were synthesized from 9 . Attempts to prepare allyloxy substituted intermediates for the preparation of 1 trough a Fischer′ reaction led to 8 .     

Synthesis and antimicrobial activity of [6′-methyl-4′-methoxy-2-oxo-2H-[1]-benzopyran)-2″,4″-dihydro-[1″, 2″, 4″]-triazol-3″-one and 3″-phenyl-thiazolidin-4″-one-phenoxymethyl derivatives of dipyranoquinoline

A series of bioactive 3H,7H,8H,11H-9-[(5″-(6′-methyl-2-oxo-2H-[1]-4′-benzopyranoxy)-2″,4″-dihydro-[1″,2″,4″]-triazol-3″-one)methyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (4) and 3H,7H,8H,11H-9-[(2′-(3″-phenyl-thiazolidin-4″-one)-phenoxymethyl]-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (7) analogs of 3H,7H,8H,11H-9-bromomethyl-3,8,11-trioxo-dipyrano[2,3-f;2,3-c]quinoline (1) have been synthesized and evaluated for their antibacterial activity against Gram-positive bacteria (S. aureus) and Gram-negative bacteria (S. typhi and E. coli). Pyranoquinolines with triazole and thiazolidine moieties exhibited promising antibacterial activity. The structures of all synthesised compounds were confirmed on the basis of analytical and spectral data.     

Synthese von 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-onen und 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-on

Synthesis of 7,12-Dihydro-indolo[3,2-d][1]benzazepin-6-(5H)-ones and 6,11-Dihydro-thieno-[3′,2′:2,3]azepino[4,5-b]indol-5(4H)-one The title compounds 4 and 6 were prepared by Fischer indole synthesis. 4a is substituted in 10-position by reaction with bromine in glacial acetic acid. A fast ring inversion is observed for the azepine ring in 4 and 6 .     

3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸的合成研究

目的设计并合成3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸。方法以柠檬酸为起始原料,经氧化酯化、Gewald反应、氮取代、环合、水解、脱羧反应制备得到目标化合物。结果合成了目标化合物,并利用质谱和核磁数据确证了结构;HPLC归一化法测得质量分数为96.98%。目标化合物的总收率为2.7%。结论 3,6-双羧甲基-4-氨基-6H-噻吩并[2,3-B]吡咯-2-羧酸的合成为雷奈酸锶中杂质的研究提供了方便。     

Thiophene as a structural element of physiologically active compounds. 16. Thienoisoxazoles by substitution at the oxime nitrogen

Thiophene as a Structural Element of Physiologically Active Compounds, XVI: Thienoisoxazoles by Substitution at the Oxime Nitrogen Thieno[2,3-d]isoxazolacetic acid (5) is synthesized from 7-hydroxy-5H-thieno[3,2-b]pyran-5-one (4) by ring transformation using hydroxylamine-HCl. The sulfonamide 1 is obtained by modification of the side chain. It is the thiophene analogue of the anticonvulsant AD 810 (A) . It shows, however, practically no activity in the antipentetrazol and the electroshock tests.     

Enhancement of hepatocarcinogenesis by combined administration of food-derived heterocyclic amines at low doses in the rat

Effects of simultaneous administration of five or 10 heterocyclic amines (HCAs) at low dose levels on rat liver carcinogenesis were investigated using a medium-term bioassay protocol. Male F344 rats were initially given diethylnitrosamine (DEN, 200 mg/kg, ip) and received HCAs starting 2 wk later for 6 wk. All animals were subjected to two-thirds partial hepatectomy at wk 3 and were killed at wk 8. Five carcinogenic HCAs in the first two experiments: 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 2-aminodipyrido[1,2-a:3′,2′-d]imidazole, 2-amino-3-methylimidazo-[4,5-f]quinoline, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-3,8-dimethylimidazo-[4,5-f]quinoxaline in experiment 1 and 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-6-methyl-dipyrido[1,2-a:3′,2′-d]imidazole,2-amino-3-methyl-9H-pyrido-[2,3-b]indole, 2-amino-9H-pyrido[2,3-b]indole, and 2-amino-l-methyl-6-phenylimidazo[4,5-b]pyridine in experiment 2] were administered together or individually in the diet at levels of 1/1, 1/5 or 1/25 carcinogenic doses, and all 10 chemicals were given at 1/10 or 1/100 levels in experiment 3. Induction of preneoplastic glutathione S-transferase placental form (GST-P) positive foci was increased in some combination groups over the sums of effects for the individual groups at the same doses (apparent synergism). This was most obvious in the group given all 10 chemicals at the 1/10 dose levels. However, it was of interest that the values in the combined groups were generally very close to the averages of five or 10 individual results for the corresponding higher dose groups, indicating isoadditivity of HCA effects. True (strict) synergism, however, was expected for the results of groups including Ph1P and Trp-P-2 in combination, since they are non-hepatocarcinogenic but induce the key metabolic enzyme for HCAs (CYPIA2).     

1,3-Bis(pyridin-2-ylthio)propan-2-one,Bis(thieno[2,3-b]pyridin-2-yl)-ketone und 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-one

1,3-Bis(pyridin-2-ylthio)propan-2-ones, Bis(thieno[2,3-b]pyridin-2-yl)ketones and 5H-Bispyrido[3′,2′:4,5]thieno[2,3-b:2′,3′-e]pyridin-11-ones Reaction of 1a-d with 1,3-dichloroacetone gives the bissulphides 2a-d . Base catalyzed cyclization of 2a-d affords heterocyclically substituted ketones 3a-e . Treatment of 3a and 3b in conc. H₃PO₄ leads to the bispyridothienopyridines 5a and 5b .     

Synthesis and cytotoxic activity of the products of heterocyclization of trifluoromethylcyanovinyl phosphonates

Heterocyclization reactions of trifluoromethylcyanovinyl phosphonates (TFMCPs) with aminopyrazoles, aminopyridines, amidines, and arylhydrazines have been studied. It is shown that TFMCPs can be used as precursors of 4,5-dihydropyrazolo[1,5-a]pyrimidines; 4,7-dihydropyrazolo[3,4-b]pyridines; 2H-pyrido-[1,2-a]pyrimidines; 1,4-dihydropyrimidines; 5-oxo-4,5-dihydro-1H-imidazoles; and 2,3-dihydro-1H-pyrazoles modified by both trifluoromethyl and diethoxyphosphoryl groups. The cytotoxic activity of some of the synthesized compounds and a series of fluorinated heterocycles obtained earlier from vinyl phosphonates has been investigated in vitro at the National Cancer Institute (USA) on a standard panel consisting of 60 human tumor-cell lines.     

Synthese [b]-kondensierter azepindione durch dealkoxycarbonylierung

Synthesis of [b]-Fused Azepinediones by Dealkoxycarbonylation The 2,3,4,5-tetrahydro-1H-1-benzazepinediones 2 and 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine-5,8-dione (11) are obtained by dealkoxycarbonylation in wet dimethylsulfoxide from fused azepinecarboxylic esters 3 and 10, respectively, 3b and 10 are prepared by Dieckmann reaction with KH in DMF/toluene from diesters 6 and 9, respectively.     

„Inverse”︁ Diels-Alder Additionen, 8. Mitt. Azepine als „inverse”︁ Dienophile

“Inverse” Diels-Alder Additions, VIII: Azepines as “Inverse” Dienophiles. We describe “inverse” [4+2]-cycloadditions of various azepines as dienophiles with the s-cis-azine system in 3,6-bis(methoxycarbonyl)tetrazine. The azepines 2, 8 and 15 react with their 4,5-π-bonds. In the case of 2-diethylamino-3H-azepine ( 11 ) twofold cycloaddition was observed.     

Naphtho[2,3-c]pyrane und Benz[g]isochinoline aus 6-Methoxy-2H-pyran-3(6H)-on1)

Naphtho[2,3-c]pyrans and Benz [g]isoquinolines from 6-Methoxy-2H-pyran-3(6H) one Cycloaddition of the dihydromethoxy-3-pyranone 2 with isobenzofuran 1 yields 3 (exo/endo) which can be converted into naphtho[2,3-c]pyran 6 by dehydration, reduction and repeated water elimination. Reaction with ammonium acetate/acetic acid leads to the benzoisoquinoline 7 . Subsequent N-alkylation and hydrogenation result in the formation of the tetrahydro derivative 9 .     

Synthesis of new series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones for their bacterial and cyclin-dependent kinases (CDKs) inhibitory activities

Two series of pyrazolo[4,3-d]pyrimidin-7-ones and pyrido[2,3-d]pyrimidin-4-ones were designed, synthesised, and evaluated for their antibacterial activities and CDKs inhibitory activities. The pyridazine derivative: 6-phenyl-5-phenylhydrazono-2,3,4,5-tetrahydropyridazine-3,4-dione (3a) revealed activity against Staphylococcus aureus as Gram-positive bacteria while compound 2-(2-Ethoxyphenyl-5-Phenylpiperazinosulfonamido)-3H-pyrido[2,3-d]pyrimidin-4-one (13c) was showing moderate antifungal activity against Candida albicans.     

Biological evaluation of novel 1,4-dithiine derivatives as potential antimicrobial agents

The preparation of twelve aminoalkanol derivatives of 2,3-dihydro-5H-[1,4]dithiino[2,3-c]pyrrole-5,7(6H)-dione was described. Newly obtained compounds, as well as their propyl and butyl analogues, were evaluated in vitro against selected viruses. Selected derivatives were tested for their antibacterial and antifungal activity. Compounds 3h, 3j, 4b and 5a–d showed moderate to significant protections against CVB-2, HSV-1 and YFV viruses. The molecular structures of 4a, 5c and 5g were determined by an X-ray analysis.     

Synthese von 5H-Pyrido[2,3-c]-2-benzazepinen

Synthesis of 5H-Pyrido[2,3-c]-2-benzazepines The title compounds can be obtained by two differend ways: Ring closure of 2-benzazepine enaminonitrile 1 and the C₂-building blocks 2, 7 and 8 gives rise to the title compounds 6, 9 and 10 . - The second way starts with Wolff-Kishner-reduction of the 2-amino-3-benzoylpyridines 16a,b to the 2-amino-3-benzylpyridines 18a,b . Benzoylation of 18a,b leads to the dibenzoylated compounds 20 and 21 , respectively, which can be transformed to the monobenzoylated pyridines 22 resp. 23 . Applying the Bischler-Napieralski-reaction on 22a,b and 23a,b leads to the 5H-pyrido[2,3-c]-2-benzazepines 24a,b and 25a,b . By means of ¹H-, ¹³C- and ¹⁵N-NMR-data it is demonstrated that ethyl benzoylcyanacetimidate ( 12a ) exists as benzoylketene-O,N-acetal 12a AE .     

The Biotransformation of 8-Chloro-6-phenyl-4H-s-triazolo[4, 3-a][1,4] benzodiazepine (D-40TA), a New Central Depressant,in Man,Dog and Rat

1. Metabolic studies of 8-chloro-6-phenyl-4H-^s-triazolo [4,3-a] [1,4] benzodiazepine (D—40TA) in man, dog and rat led to identification of the following metabolites: six hydroxylation products; 8-chloro-2,4-dihydro-6-phenyl-1H-s-triazolo[4,3-a] [1,4]benzodiazepin-1-one (I), 8-chloro-6-(4-hydroxyphenyl)-4H-s -triazolo[4,3-a][1,4]benzodiazepine (II), 8-chloro-6- (3-hydroxyphenyl)-4H-s-triazolo[4,3-a] [1,4] benzodiazepine (III), 8-chloro-4-hydroxy-6-phenyl-4H-s- triazolo[4,3-a][1,4]benzodiazepine (IV), 8-chloro-2,4-dihydro-6- (4-hydroxy-phenyl)-1H-s-triazolo[4,3-a] [1,4] benzodiazepin-1-one (V) and 8-chloro-2,4-dihydro-6-(3-hydroxyphenyl)- 1H-s- triazolo[4,3-a][1,4]benzodiazepin-1-one (VI); five ring-opened metabolites; 5-chloro-2-(4H-1,2,4-triazol-4-yl) -benzophenone (VII), 5-chloro-2- (2,3-dihydro-3-oxo- 4H -1,2,4- triazol-4-yl)benzophenone (VIII), 5-chloro-2- (2,3-dihydro-3-oxo-4H - 1,2,4-triazol-4-yl)-2-hydroxybenzophenone (IX), 5-chloro-2- (2,3-dihydro-3-oxo-4H-1,2,4-triazol-4-yl)-4'-hydroxybenzophenone (X) and 5-chloro-2-(3,5-dioxo-2,3,4,5-tetrahydro-1H-1,2,4-triazol-4-yl) benzophenone(XI).

2. In man, metabolites I, IV, VII and VIII are present as the free form in the urine, and I, II, IV and VIII are present as conjugates. In the dog, all the metabolites are present. The rat transforms the compound mainly to metabolites I, II, IV and V. None of the ring-opened metabolites are observed in the rat.     

Beiträge zur Chemie des Pyridazinsystems, 29. Mitt. Synthese von 4-Arylpyrimido[4,5-d]pyridazinen aus (5-Amino-4-pyridazinyl)arylketonen

Pyridazine Chemistry XXIX: Synthesis of Pyrimido[4,5-d]pyridazines from (5-Amino-4-pyridazinyl)arylketones The pyrimido[4,5-d]pyridazin-2(1H)ones 4 and 6 are prepared in high yields from the amino ketones 1 or 5 . Procedures for the synthesis of the 4-arylpyrimido[4,5-d]pyridazines 8a, b, c via the imido esters 7a, b, c are described.     

Beiträge zur Chemie des Pyridazinsystems, 34. Mitt.: Synthese neuer Diaza-Analoga des Acridons,Xanthons und Thioxanthons aus 3,4-disubstituierten Pyridazinen

Pyridazine Chemistry XXXIV^{1, 2)}: Synthesis of Novel Diaza Analogues of Acridone, Xanthone and Thioxanthone from 3,4-Disubstituted Pyridazines. Reactions of 3-chloropyridazine-4-carbonitrile 5 with arylamines, phenol or thiophenol, followed by PPA promoted cyclisation, provide access to the new tricyclic systems pyridazinol 3,4-b|quinolin-5(10H)one,5H-|1|benzopyrano|2,3-c|pyridazin-5-one and 5H-|1|benzothiopyrano|2,3-c|pyridazin-5-one.