Synthese von 2-Äthyl-3-oxo-3H-naphtho-(1.8-bc)thiophen - ein zu Phenalenon iso-π-elektronisches Thia-pseudophenalenon

Synthesis of 2-Ethyl-3H-naphtho[1.8-bc]thiophen-3-one — a Thiapseudophenalen-3-one which is Iso-π-electronic with Phenalenone 2-Ethylbenzo[b]thiophene (1) reacts with cinnamic chloride in the presence of SnCl₄ to yield 3-(2-ethylthionaphthyl) styryl ketone (2) which in turn reacts with 2,4-dinitrophenylhydrazine or p-methylbenzenesulfonohydrazide to give the substituted hydrazones 3a and 3b ; the Thiapseudophenalen-3-one is obtained from the α,β-unsaturated ketone 2 with aluminium chloride by elimination of benzene.     

Heterocyclische 12-π- und 14-π-Molekülsysteme, 44. Mitt. Zum Reaktionsverhalten tetracyclischer Pseudohydroxyphenalenone

Heterocyclic Systems with 12 or 14 π Electrons, XLIV: Chemical Reactivity of Tetracyclic Hydroxypseudo-phenalenones 1,2-Dihydro-7-hydroxy-5H-cyclopenta[cd] phenalen-5-one (1) reacts with nitric acid in acetic acid to yield the hydroxy(nitro)pseudophenalenone 3 . With chlorine in acetic acid the dichloro derivative 4 , with bromine compound 5 , and with phenyldiazoniumsulfate the azodye 6 are formed. Compound 1 also reacts with 1,2-dibromoethane in the presence of potassium carbonate to yield the spiro compound 7 . The condensation of 1 with benzaldehyde in the presence of pyridine yields 8 . In an analogous way 5H-7-hydroxycyclopenta[cd]phenalene-5-one (2) was chlorinated to yield the dichloro derivative 9 . Compound 2 reacts with bromine at position 6 to yield compound 10 .     

Heterocyclische 12-π- und 14-π-Molekülsysteme, 35. Mitt. Synthesen und chemisches Reaktionsverhalten von Azapseudo-phenalenonen,ihrer Kationen und eines Aza-penta-pseudophena-fulvalens

Heterocyclic 12-π- and 14-π-Systems, XXXV: Syntheses and Reactivities of Azapseudophenalenones, Their Cations and of an Azapentapseudo-phenafulvalene The reaction of 1-phenyl-2-methyl-4,5-dihydro-6H-pyrrolo[3.2.1-i, j]quinolin-6-one (3) with triphenylmethyltetrafluoroborate yields the azapseudophenalenone 4 , which reacts easily with trifluoroacetic acid under protonation to yield the azapseudophenalenium salt 5 . The azapseudophenalenethione 7 is obtained by the reaction of 4 with P₄S₁₀, the (methylmercapto)azapseudophenalenium salt 8 by reaction of 7 with CH₃J and the iminoazapseudophenalenone derivatives 9a, 9b by reaction of 8 with N-nucleophiles. The compounds 4, 7, 8 react under different conditions with tetrachlorocyclopentadiene to yield the azapentapseudophenafulvalene 10 .     

Heterocyclische 12-π- und 14-π-Molekülsysteme, 40. Mitt. Synthesen und Chemie neuer Indolsysteme – Möglichkeiten und Grenzen, 2. Mitt.

Heterocyclic Systems with 12 and 14 π-Electrons, XL: Syntheses and Reactions of New Indoles, II Heating of 1-benzoylamino-5-benzoyloxynaphthalene (3) in polyphosphoric acid at 75 to 80°C yields a mixture of compounds 4, 5 , and 6 . Starting from 4 and 5 we obtained the azapseudophenalen-5-one (2b) . This compound reacts with C-nucleophiles to yield the azapseudophenafulvalenes 7a–7d as mixtures of E/Z-isomers, the azapseudophenafulvalene 8 , the 1-methyl-2-phenyl-5-ethoxyazapseudophenalenium salt (9) . By thionation of 2b we prepared the azapseudophenalene-5-thione 10 . Alkylation of 10 leads to the 1-methyl-2-phenyl-5-(methylmercapto)azapseudophenalenium salt (11) . Compounds 2b and 10 react with trimethylsilyl trifluoromethanesulfonate to yield the pseudophenalenium salts 13a and 13b .     

Synthese und Eigenschaften des 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]chinazolin-2-carbonitrils

Synthesis and Properties of 3-Hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile Anthranilic acid reacts with 2-chloro-5-cyano-4-hydroxypyrid-6-one (3) in glacial acetic acid to yield 3-hydroxy-1,10-dioxo-5,10-dihydro-1H-pyrido[2,1-b]quinazoline-2-carbonitrile (4) . When the reaction is carried out in DMF under Ullmann conditions, 2-(dimethylamino)-5-cyano-4-hydroxypyrid-6-one (5) forms as a by-product. The methylation of 3 with diazomethane affords 2-chloro-5-cyano-2-methoxy-N-methylpyrid-6-one (9) and 2-chloro-5-cynao-4,6-dimethoxypyridine (10) . Under similar conditions compound 4 undergoes an esterifying ring cleavage to furnish methyl 2-(5-cyano-4,6-dimethoxypyrid-2-ylamino)benzoate (7) .     

Synthesis of [1,2,4]triazolo[3′,4′: 3,4] [1,2,4]triazino[5,6-b]indole derivatives and 3-substituted 5-ethyl-H-1,2,4-triazino[5,6-b] Indole

5-Ethyl-3-hydrazino-5H-1,2,4-triazino|5,6-b|indole ( 2 ) reacts with aromatic aldehydes in anhydrous ethanol to yield substituted arylidene-(5-ethyl-5H-1,2,4-triazino|5,6-b|indol-3-yl)hydrazones 3 . Treatment of 3 with excess SOCl₂ gave 10-ethyl-1-aryl-10H-| 1,2,4]triazolo|3′,4′:3,4| 1,2,4|triazino|5,6-b|indoles 4 , while the reaction of 2 with CS₂ in methanolic KOH afforded 10-ethyl-2,10-dihydro-1 H-| 1,2,4|triazolo|3′,4′3,4‖ 1,2,4|triazino|5,6-b|indol-1-thione ( 5 ). Fusion of 1 with aromatic amines leads to 3-(arylamino)-5-ethyl-5H-1,2,4-triazino|5,6-b|indoles 6 , whereas the reaction of 1 with alkyl or aralkyl halides in anhydrous acetone and in the presence of anhydrous K₂CO₃ results in the alkylation of the thiol group to give the alkylthio or aralkylthio derivatives 7.     

Umsetzung von 1,2-Dihydro-3-indazolon mit ω-Dialkylaminoalkylhalogeniden und α,ω-Dihalogenalkanen

Reaction of 1,2-Dihydro-3-indazolone with ω-Dialkylaminoalkyl Halides and α, ω-Dihalogenalkanes The reaction of the potassium salt of 1,2-dihydro-3-indazolone with ω-dialkylaminoalkyl halides in anhydrous dioxane leads to basic lactim ethers, which are analgesics. On the other hand two basic compounds are formed, when α, ω-dihalogenopropanes participiate. Compound 1 was identified as 3,4-dihydro-2H-[1,3]oxazino[2, 3-b]indazole and compound 2 as 2,3-dihydro-lH-pyrazolo[1,2-a]indazol-9-one. Compound 2 is reduced by LiAlH₄, to 2,3-dihydro-lH, 9H-pyrazolo[1, 2-a]indazole ( 5 ).     

Untersuchungen an 1,3-Dicarbonyl-Verbindungen, 20. Mitt. 3-Acyl-4,5-dihydro-5-methyl-4-oxo-pyrano[3,2-b]indole

1,3-Dicarbonyl Compounds, XX: 3-Acyl-4,5-dihydro-5-methylpyrano[3,2-b]indol-4-ones On treatment with POCl₃/DMF the BF₂ chelate 2 , obtained from the 1,3-dicarbonyl compound 1 , yields the fused 3-formyl-4-pyrone 3 . The carbinol 6 , the carboxylic acid 7 and the tetrazole 9 can be prepared from 3 .     

10-Carbethoxymethyl-3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole and Derivatives at its 10-Position

Reaction of 3-phenyl-10H-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole ( 4 ) with ethyl chloroacetate gave 10-carbethoxymethyl-3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indole ( 3 ). Condensation of 3 with hydrazine hydrate gave (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)acetylhydrazine ( 5 ). Reactions of 5 with a number of aromatic aldehydes, acetophenone, cyclohexanone and D-galactose gave the corresponding hydrazones 6 - 12 . Condensation of 5 with acetylacetone gave the pyrazole 15 . Cyclization of 5 with CS₂ gave (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)(2-thiol-1,3,4-oxadiazol-5-yl)methane ( 16 ). Reaction of 16 with ethyl chloroacetate gave the carbethoxy alkylated derivative (3-phenyl-1,2,4-triazolo[4′,3′:2,3][1,2,4]triazino[5,6-b]indol-10-yl)[2-(thiocarbethoxymethyl)1,3,4-oxadiazol-5-yl]methane ( 17 ).     

Synthesis of Some New Derivatives of Thiazolo[4,3-b]- and Thiazolo[2,3-b] quinazolone

The new 5H-thiazolo[4,3-b]quinazoline-3,5(1H)-diones 3, 4a–c, 5a–c and 5H-thiazolo[2,3-b]quinazoline-3,5(2H)-diones 9a–c, 11a–c were prepared by reaction of anthranilic acid with the 2-thiazolidinone-4-thione derivatives 1b, 6a–c, 7a–c and the 5-substituted 2-(alkylmercapto)-2-thiazolin-4-ones 8a-c, 10a-c , respectively.     

Reaktionen von 2-Amino-imidazo[2,1-b]-1,3,4-thiadiazolen mit Dicarbonsäureestern in Polyphosphorsäure (PPA)

Reactions of 2-Aminoimidazo[2,1-b]-1,3,4-thiazoles with Ethyl Dicarboxylates in Polyphosphoric Acid (PPA) The 2-amino-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 1d,e cyclise on heating in polyphosphoric acid (PPA) with ethyl malonate or ethyl diethylmalonate to yield the 2-aryl-6,8-dioxodihydro-6H-imidazo[2,1-b]-1,3,4-thiadiazolo[3,2-a] pyrimidines 3d,e or the 7,7-diethyl compounds 4d,e . Compounds 1a – f cyclise in PPA with ethyl succinate or ethyl phthalate to yield the 6-aryl-2-succinimido- or 6-aryl-2-phthalimido-imidazo[2,1-b]-1,3,4-thiadiazoles 5a, b, d-f and 6a – f . Compounds 1d,e were condensed with ethyl oxalate to yield the 2-(ethoxycarbonyl-formylamino)-6-arylimidazo[2,1-b]-1,3,4-thiadiazoles 7d,e. Ethyl levulinate with 1d,e in PPA probably forms 6-aryl-2-(2-methyl-5-oxo-Δ³-pyrrolino)imidazo [2,1-b]-1,3,4-thiadiazoles.     

Indoles,III Lactamisation of 4.9-Dihydropyrano [3.4-b]indol-1(3H)-ones. - A New Synthetic Route to the β-Carboline Ring System

Reaction of the pyrano[3.4-b]indolones 1a-d with aniline, benzylamine, phenylethylamine and propylamine at 200–210 °C yields the 2.3.4.9-tetrahydro-1H-pyrido[3.4-b]indol-1-ones 5a-j , which can be converted to the 2.3.4.9-tetrahydro-1H-pyrido[3.4-b]indoles 6a-j by reduction with LiAlH₄. After treatment with methylamine and 2 only the amides 3 and 4 could be isolated. Unsubstituted tetrahydro-β-carboline 7 is available by regioselective debenzylation of 6c .     

Reaktionen mit 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridin-8-oxid

Reactions with 4-Hydroxy-5-oximino-7-methyl-5H-pyrano[2,3-b]pyridine 8-Oxide The pyrano[2,3-b]pyridine 1a with a vinylogous hydroxamic acid structure reacts with dimethyl sulphate, acetic anhydride or nitric acid to give the monomethyl ether 2 , the diacetyl compound 3 or the mono- and dinitro derivatives 5 and 6 . Reduction reactions leading to 4-hydroxy-5-oximinopyrano[2,3-b]pyridine 4 or the 4-hydroxy-2-pyridone derivative 8 are also described.     

Anellierte 2-Tetrazolyl-4-pyrone

Fused 2-Tetrazolyl-4-pyrones The synthesis of the 2-(1H-tetrazol-5-yl)-4-oxo-4H-[1]benzofuro[3,2-b]pyrane, -4-oxo-4H–[1]benzothieno[3,2-b]pyrane and -4,5-dihydro-5-alkyl-4-oxopyrano[3,2-b]indoles is described.     

Regiospezifische Synthese von 2-Phenyl-pyrano[3,4-b]pyranonen (Oxaflavon-Derivaten) mit Tetrahydro-3-pyranon

Regiospecific Synthesis of 2-Phenylpyrano[3,4-b]pyranones (Oxaflavone Derivatives) with Tetrahydro-3-pyranone Under controlled conditions tetrahydro-3-pyranone ( 5 ) reacts with trimethylchlorosilane regiospecifically to yield the enolether 6 . Cleveage with methyllithium and reaction with cinnamoyl chloride furnishes the 4-cinnamoylpyranone 8 . Proton catalysed cyclisation and dehydrogenation with DDQ afford the pyrano[3,4-b]pyranones 9 and 10 .     

Anellierte Thiopyrone, 3. Mitt. Sulfone aus Thiopyrano[3,2-b]indol-4(5H)-on- und Thiopyrano[2,3-b]indol-4(9H)-on-2-carbonsäuremethylestern

Fused Thiopyrones, III: Sulfones from Methyl 4,5-Dihydro-4-oxothiopyrano[3,2-b]indole-2-carboxylate and Methyl 4,9-Dihydro-4-oxothiopyrano[2,3-b]indole-2-carboxylate On treatment with m-chloroperbenzoic acid (mCPBA) the thiopyrones 1 and 4 are oxidized to the sulfones 2 and 5 , which add ethanol to yield the thiopyranosulfones 3 and 6 as mixtures of diastereomers. In one case a 3-hydroxy compound ( 7 ) could be isolated.     

Novel Antiinflammatory Analgesics: 3-(2-/4-Pyridylethyl)-Benzoxazolinone and Oxazolo[4,5-β]pyridin-2-one Derivatives

Twenty-two new 3-[2-(2-and/or 4-pyridyl)ethyl]benzoxazolinone and oxazolo[4,5-b]pyridin-2-one derivatives have been synthesized by reacting 2-and/or 4-vinylpyridine and appropriate benzoxazolinones and oxazolo[4,5-b]pyridine-2-one. Their chemical structures have been proven by IR, ¹H-NMR, ¹³C-NMR, mass spectroscopy, and elemental analysis. The analgesic activities of these compounds were investigated by a modified Koster′s Test. Test results revealed that, at 100 mg/kg dose level, most of the compounds showed significant analgesic activities when compared to aspirin. Therefore the compounds were screened for their antiinflammatory activities using the carrageenan hind paw edema test. Compounds 1, 7, 10, 11, 12, 13, 15, 18, 20, 21 were found more active than indomethacine. In gastric ulceration studies gastrointestinal bleeding was not observed at 100 mg/kg dose level in compounds 1 and 2 .     

Reaktionen an Heterocyclen mit 2-Acyl-2-propenon-Teilstruktur, 3. Mitt. Pyrido[3,2-c]cumarine aus 3-substituierten 1-Benzopyranen und Enaminen

Reactions with Heterocycles Containing a 2-Acyl-2-propenone Structure, III: Pyrido[3,2-c] coumarins from 3-Substituted 1-Benzopyrans and Enamines 4-Oxo-4H-chromene-3-carbaldehydes 1 react with enamines 2 and 3 to form 5-hydroxy-5H-[1]benzopyrano[4,3-b] pyridines 4 and 5 . Oxidation of the products leads to pyrido[3,2-c]coumarines 6 and 7 which are also obtained directly from the 4-oxo-4H-chromene-3-carboxylic acid 8 and from the carboxylic acid ester 9 . From the chromanone Mannich base 14 the pyridocoumarine 6a can be obtained by C-alkylation of the enamine 2 , cyclisation, and oxidation with chromium(VI) oxide.     

Spectroscopic analysis of [Trp3]-β-casomorphin analogs Comparative structure conformation-activity studies

A series of [3-tryptophan]-β-casomorphin-5([Trp³]-β-CM-5) analogs were investigated by circular dichroism (CD) and fluorescence spectroscopy to explore their structure-conformation properties in solution. In addition, the comparative opioid activities of these compounds were evaluated using the in vitro guinea pig ileum (GPI) and mouse vas deferens (MVD) assays. Specifically, the pentapeptide sequence of [Trp³]-β-CM-5, H-Tyr-Pro-Trp-Pro-Gly-OH (I) was modified at Pro-2 and Pro-4 by d -Pro substitutions to provide two diastereometric analogs, [Trp³-d -Pro-4]-β-CM-5 (II) and [d -Pro^2,4,Trp³]-β-CM-5 (III). In the GPI and MVD assays, β-CM-5 effected IC₅₀ values of 1.3 μm and 8.9 μm , respectively, which confirmed its known μ/δ-selectivity on these two peripheral opioid receptor subtypes. The potencies of compounds I, II, and III were 0.2, 2.0, and < 0.005 relative to β-CM-5 on the GPI assay. Compounds I and II exhibited pronounced μ/δ-selectivities (> 18.9- and 12.4-fold respectively), whereas compound III was essentially inactive in both the GPI and MVD assays. CD studies of β-CM-5 and its [Trp³]-β-CM-5 analogs showed striking differences in their near-UV and far-UV spectra in aqueous or organic solvents. In the far UV CD spectra, weak (20%) α-helicity (maximum at 193 nm and minima at 208 and 222 nm) for β-CM-5 was obtained in trifluoroethanol (TFE); however, none of the [Trp³]-β-CM-5 analogs showed such CD bands. Of potential relevance to γ-turn or C₇ secondary structure was the observation of a strong negative band at 245 nm for compounds II and III which was not solvent-dependent in H₂O or TFE, whereas compound I showed this CD band exclusively in TFE. In the near-UV CD at 275 nm (Trp electronic transition), the relative order of intensities of this band were determined for the [Trp³]-β-CM-5 compounds to be II > I > III, which was identical to their relative biological potencies in both the GPI and MVD assays. Fluorescence energy transfer (FET) experiments of compounds I-III provided the intramolecular distances (r) between their Tyr (donor) to Trp (acceptor) side-chains, by the Förster method, and were as follows: [Trp³]-β-CM-5, r = 10.6Å; [Trp³, d -Pro⁴]-β-CM-5, r = 9.6Å; and [d -Pro^2,4,Trp³]-β-CM-5, r = 11.0Å. A rank order correlation existed between the Tyr-Trp intramolecular distances and biological activity with shorter distance corresponding to higher biological potency. Furthermore, based on the fluorescence lifetime data analysis (Globals software) of the [Trp³]-β-CM-5 analogs, which were best fitted to a double exponential decay model, the relative ranking of long (> 1.5 ns) lifetime fractions of these three compounds was II > I > III. In summary, detailed spectroscopic analysis of three [Trp³]-β-CM-5 diastereomeric analogs by CD and FET have provided intriguing data indicating a possible structure conformation-activity relationship among these μ/δ-selective opioid-mimetic compounds.     

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 .