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 .     

Synthesis of [15N4] purine labeled cytokinin glycosides derived from zeatins and topolins with 9‐β‐d, 7‐β‐d‐glucopyranosyl,or 9‐β‐d‐ribofuranosyl group

Synthesis of [¹⁵N₄] purine labeled cytokinine glycosides derived from zeatins and topolins containing a 9‐β‐d , 7‐β‐d ‐glucopyranosyl, or 9‐β‐d ‐ribofuranosyl group is described. These N⁶‐substituted adenine derivatives are intended as internal analytic standards for phytohormone analysis. All labeled compounds were prepared from 6‐chloro[¹⁵N₄]purine ( 1 ). The equilibrium reaction of 1 with acetobromo‐α‐d ‐glucose gave isomeric 7‐β‐d ( 3 ) and 9‐β‐d ( 4 ) chloro glucosyl precursors, which were treated with the corresponding amines to get desired labeled cytokinin 7‐β‐d ( 6 ) and 9‐β‐d ( 5 ) glucopyranosides. Cytokinins containing 9‐β‐d ‐ribofuranosyl group ( 8 ) were obtained by direct enzymatic transglycosylation reaction of cytokinins ( 7 ) prepared from 6‐chloro[¹⁵N₄] purine ( 1 ).     

Addition von β-Dicarbonylverbindungen an 2-Acetyl-p-benzochinon, 3. Mitt.1): Untersuchung der Umsetzung mit α-Hydroxymethylencycloalkanonen

Addition of β-Dicarbonyl Compounds to 2-Acetyl-p-benzoquinone, III¹⁾: The reaction of α-hydroxymethylenecyclopentanone 2 with acetylquinone 1 yields the spiro-compound 3 . α-Hydroxymethylenecyclohexanone 7 gives the dibenzopyran 8 and the spiro-compound 9 as by-product. Compounds 3, 8 , and 9 are labile, rearrangement to 6 and 11 is examined by NMR spectroscopy. Acetylation of 6 and 11 yields 5 and 12 . With hydrochloric acid the spiro-compounds 6, 11 are rearranged to 16 and 17 , respectively.     

Potentielle Antineoplastica, 2. Mitt. Synthese diarylsubstituierter 2- und 3-Hexene

Synthesis of Diaryl-2- and ?3-Hexenes Dehydration of 5 yields the 2-hexene derivative 7 as the main product and the isomeric trans-stilbene 6 in small amounts. 6 and 7 are converted to the mustard derivatives 9 and 11 via 8 and 10 , respectively. Compounds 5 – 11 , the by-product 12 and some intermediates, which occur in the synthesis of 5 , were investigated by UV, IR, ¹H-NMR and (partially) mass spectroscopy.     

Intramolekulare Aromatenalkylierungen, 25.Mitt. Zur Synthese von Hexahydro-7H-naphtho[1,8-fg]chinolinen und -isochinolinen

Intramolecular Alkylations of Aromatic Compounds, XXV: On the Synthesis of Hexahydro-7H-naphtho[1,8-fg]quinolines and -isoquinolines The carbinol 7 prepared from 5 and 6 is oxidised to yield the ketone 9 , while 16 and 21 are obtained immediately from 14 by Grignard reaction. The ketones 9 , 16 , and 21 are reduced to give the methylene compounds 10 , 17 , and 22 . The hydrogenolysis of 7 or its methyl ether 8 fails to give 10 . Treatment of 10 , 17 , and 22 with methyliodide furnishes the methoiodides 11 , 18 , and 23 , followed by NaBH₄ reduction to yield the tetrahydropyridines 12 , 19 , and 24 . Only 24 undergoes cyclisation to form 26 regioselectively.     

A Novel Metabolite,an Oxepin Formed from Cannabidiol with Guinea-pig Hepatic Microsomes

The metabolic formation of an oxepin derivative, 3-pentyl-6, 7, 7a, 8, 9, 11a-hexahydro-1, 7-dihydroxy-7, 10-dimethyldibenzo-[b,d]-oxepin, from cannabidiol was studied in-vitro using guinea-pig hepatic microsomes. The hepatic microsomes catalysed the formation of the metabolite from cannabidiol and 8S, 9-epoxycannabidiol in the presence of an NADPH-generating system and 3, 3, 3-trichloropropene-1, 2-oxide. 8S, 9-Epoxycannabidiol was thought to be an intermediate in the formation of the metabolite, which was identified by gas chromatography-mass spectrometry. The metabolite synthesized from 8S, 9-epoxycannabidiol diacetate exhibited catalepsy, hypothermia and pentobarbitone-induced sleep prolongation in mice, although the pharmacological effect was less potent than that of Δ⁹-tetrahydrocannabinol.     

Untersuchungen an 1,3-Dicarbonylverbindungen, 15. Mitt. 4,5-Dihydro-5-alkyl-4-oxo-pyrano[3,2-b]indole

1,3-Dicarbonyl Compounds, XV: 4,5-Dihydro-5-alkyl-4-oxopyrano[3,2-b]indoles N-Alkylanthranilic acids react with chloroacetone/K₂CO₃ to form the 1-alkyl-2-acetyl-3-hydroxy-indoles 3 . The 1,3-dicarbonyl compounds 3 condense with dialkyl oxalates to yield the 1,3,5,6-tetra-carbonyl compounds 5 , which cyclize on heating with alcohols, saturated with HCl, to form the alkyl 4-pyrone-2-carboxylates 6 . The acids 8 , obtained from 6 , possess antiallergic activity. Decarboxylation of 8 affords the pyrono[3,2-b]indoles 9 . Condensation of 5 with triethyl orthoformate/acetic anhydride yield the alkyl 4-pyrone-3-ketocarboxylates 7 . Compounds 6 and 9 are converted to the thiocarbonyl compounds 11 and 12 . The amide 10 is obtained from 6c by reaction with ammonia.     

Intramolekulare Aromatenalkylierungen, 17. Mitt. Synthese von trans-3,10b-Dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)isochinolin

Intramolecular Alkylations of Aromatic Compounds, XVII¹⁾: — Synthesis of trans-3,10b-Dimethyl-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)isoquinoline From the cyanhydrine 5b , easily obtained from 4 and trimethylsilyl cyanide, the lactone 6 is prepared, hydrogenation of which gives a mixture of the lactam 7a and the lactone 8 . Compound 7a is reduced to the secondary base 9 , which by treatment with acid is dehydrated to 10 and rearranges to give the isomer 11 , too. Attempted cyclization of the aminoalcohol 12 fails to give 9 or 10 . Rather, the furan 13 is isolated as the final product. N-methylation 10 → 14 and subsequent hydrogenation furnish the 4:1 trans/cis-mixture 2a, b , from which the title compound is separated by column chromatography. From 11 the stereomers 18a, b can be prepared analogously.     

Substituierte 5-Deazaflavine, 4. Mitt. Synthese Donator-substituierter 5-Deazaalloxazine

Substituted 5-Deazaflavins, IV¹: Synthesis of Donor Substituted 5-Deazaalloxazines Treatment of the donor-substituted 6-anilinouracils 6 with Vilsmeier reagent results in three reactions depending on substitution: a) Donors in m-position cause regiospecific cyclisations yielding the 8-substituted 5-deazaalloxazines 8 . b) Donors in p-position yield the 5-formylanilinouracils 11 . c) With the strong m-dimethylamino donor additional formylation and in situ cyclisation to the 6-dimethylamino-9-formyl-5-deazaalloxazines 9 competes with the formation of 8 . These reactions are explained by postulating the vinylogous amidine 7 as intermediate.     

Darstellung von α-Amidoalkylsulfonen

Synthesis of (α-Amidoalkyl)sulfones The title compounds 3, 5, 7, 9 , and 11 are formed from aliphatic sulfinic acids 1 by reaction with aldehydes 2 and amides, by condensation with amidales 4 or amide Mannich bases 6 and 8 , and by reaction with N-(α-halogenoalkyl)amides 10 .     

Pethidin-Analoga mit eingeschränkter Konformation, 2. Mitt.: Stereoselektive Synthese von trans-4-Methyl-10b-carbethoxy-1,2,3,4,4a,5,6,10b-octahydrobenzo(f)chinolin

Pethidine Analogs with Restricted Conformation, II¹⁾: Stereoselective Synthesis of trans-4-Methyl-10b-ethoxycarbonyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinoline Compound 6 , readily available from 4 , reacts with benzylamine to give trans- 9 . The reaction is thermodynamically controled. N-methylation of trans- 9 yields 11 . This can be alkylated by allyl bromide with inversion at C-1 to yield 12 . Subsequent hydroboration and iodation furnish the heterocycle trans- 14 which is catalytically debenzylated to yield the title compound 2a . The configuration of 2 is nmr-spectroscopically assigned with the aid of trans-methoiodide 15a , trans- 1 , and trans- 16 . Compound 12 is converted to the carbinol 13 by hydroboration. Halogenation of 13 causes cyclisation to 14 which, when prepared by this route, fails to undergo hydrogenolysis to 2a . The hydroxy esters 4 , accessible from 3 , can be alkylated to 7 which in turn is oxidized to 8 . Halogen nitrogen exchange or reductive amination fail to yield 2a . Compound 3 resists cyanoethylation, whereas under identical conditions 5 is transformed into 6 by elimination.     

Low concentrations of UD-CG 212 enhance myocyte contractility by an increase in calcium responsiveness in the presence of inorganic phosphate

Recent data show that UD-CG 212 in nanomolar concentrations increases myofibrillar Ca⁺⁺ responsiveness of chemically skinned cardiac preparations in the presence of elevated inorganic phosphate. We studied the effects of UD-CG 212 on cell shortening of intact myocytes and in addition measured the intracellular calcium transients with the aid of INDO-1 fluorescence in the presence of 5 mM inorganic phosphate.The validity of our experimental system was first tested with the calcium channel opener Bay k 8644. Bay k 8644 at 10^–8 M did not significantly influence myocyte shortening ( + 13.9 ± 4.6%, n = 9) but at 10^–7 M and 10^–6 M significantly increased contraction by 40.1 +- 13.6%and52.5 ± 17.0% respectively. Bay k 8644 at 10^–8 M increased the INDO-1 fluorescence ratio by 17.3 ± 4.7% (P < 0.01; n = 9), and at 10^–7 M by 21.5 + 4.3% (P < 0.01; n = 9), whereas 10^–6 M Bay k 8644 had no significant effect on peak INDO-1 ratio. However, 10^–7and 10^–6 M Bay k 8644 accelerated and broadened the calcium transients.Cell shortening of guinea pig ventricular myocytes electrically stimulated at 1 Hz was significantly increased by UD-CG 212 (10^–9-10^–7 M) and isoprena line(3 × 10^–8 M). An increase of 37.0 ± 14.0% (P < 0.05; n = 9) was observed at 10^–9 M UD-CG 212, 90.5±18.2% (P<0.05; n=9) at 10^–8 M UD-CG 212, 164.0 ± 34.9% (P < 0.05; n = 9) at 10^–7 M UD-CG 212, and 258.2 ± 67.4% (P < 0.05; n = 9) at 3 × 10-8 M isoprenaline. Peak INDO-1 fluorescence ratios were not significantly (P > 0.05) influenced after addition of 10^–9 M and 10^–8 M UD-CG 212, but significantly increased by 19.4 ± 4.9%(P < 0.05; n = 9) at 10^–7 MUD-CG 212 and by 81.1 ± 11.1% (P < 0.05; n = 9) at 3 x 10^–8 M isoprenaline.In conclusion, UD-CG 212 (10^–9 - 10^–7 M) Concentration-dependently increased myocyte shortening in the presence of 5 mM inorganic phosphate. Low concentrations of 10^–9 and 10^–8 M UD-CG 212 increased myocyte contractility without altering the peak INDO-1 fluorescence ratio whereas 10^–7 M UD-CG 212 and 3 × 10^–8 M isoprenaline increased cell shortening as well as peak INDO-1 fluorescence ratio. These data suggest that low concentrations of UD-CG 212 increase myocyte contractility by enhancing myofibrillar calcium responsiveness whereas higher concentrations elevate intracellular calcium probably via increased intracellular CAMP brought about by phosphodiesterase inhibition.     

Conformational analyses by 1H NMR and computer simulations of cyclic hexapeptides related to somatostatin containing acidic and basic peptoid residues

We report the conformational analysis by ¹H NMR in DMSO and computer simulations involving distance geometry and molecular dynamics simulations at 300K of peptoid analogs of the cyclic hexapeptide c-[Phe¹¹-Pro⁶-Phe⁷-D-Trp⁸-Lys⁹-Thr¹⁰]. The analogs c-[Phe¹¹-Nasp⁶-Phe⁷-D-Trp⁸-Lys⁹-Thr¹⁰] ( 1 ), c-[Phe¹¹-Ndab⁶-Phe⁷-D-Trp⁸-Lys⁹-Thr¹⁰] ( 2 ) and c-[Phe¹¹-Nlys⁶-Phe⁷-D-Trp⁸-Lys⁹-Thr¹⁰] ( 3 ) where Nasp denotes N-(2-carboxyethyl) glycine, Ndab N-(2-aminoethyl) glycine and Nlys N-(4-aminobutyl) glycine are subject to conformational studies. The results of free and restrained molecular dynamics simulations at 300K are reported and give insight into the conformational behaviour of these analogs. The compounds show two sets of nuclear magnetic resonance signals corresponding to the cis and trans orientations of the peptide bond between residues 11 and 6. The backbone conformation of the cis isomers that we believe are the bioactive isomers of the three compounds are very similar to each other while there are larger variations amongst the trans isomers. The binding data to the isolated receptors show that the introduction of the Nlys residue in analog 3 leads to an enhancement of binding potency to the hsst5 receptor compared with analog 2 while maintaining identical binding potency to the hsst2 receptor. The Nasp⁶ analog 1 binds weakly to the hsst2 and is essentially inactive towards the other receptors. Comparison of the conformations and binding activities of these three analogs indicates that the Nlys residue extends sufficiently far to allow binding to a negatively charged binding domain on the hsst5 receptor. According to this model, the Ndab analog 2 cannot extend far enough to allow for binding to the receptor pocket. The loss of activity observed for the Nasp⁶ compound 1 indicates that the presence of a negatively charged residue in position 6 is unfavorable for binding to the hsst receptors.     

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.     

Untersuchungen zur 6-Hydroxyindol-Bildung bei der Nenitzescu-Reaktion, 3. Mitt.1): Synthese und oxidative Cyclisierung von 3-(4-Hydroxyphenyl)-4-amino-3-penten-2-onen

Investigations on the Formation of 6-Hydroxyindole in the Nenitzescu Reaction, III: 3-Phenyl-4-amino-3-penten-2-ones 8a-g are synthesized from phenylacetone 5 and the 1,3-diketones 6a,b . Oxidative cyclisation of 8b to 9a,b is performed with Pb(OAc)₄. This proves that cyclization of quinol-intermediate 3 within the Nenitzescu reaction can yield 4 . Formation of an intramolecular CT-complex leading to 4 from 3 and to 9a,b from 7 is discussed.     

Comparative conformational analysis and in vitro pharmacological evaluation of three cyclic hexapeptide NK-2 antagonists

The conformational analysis of three cyclic hexapeptides is presented. Cyclo-(-Gln⁶-Trp⁷-Phe⁸-Gly⁹-Leu¹⁰-d -Met¹¹-) (1) and cyclo-(-Gln⁶-Trp⁷-Phe⁸-Gly⁹-Leu¹⁰-Met¹¹-) (2) are NK-2 antagonists in the hamster trachea assay, whereas cyclo-(-Gln⁶-Trp⁷-Phe⁸-(R)-Gly⁹-[ANC-2]Leu¹⁰-Met¹¹-) (3), where Gly⁹[ANC-2]Leu¹⁰ represents (2S)-2-((3R)-3-amino-2-oxo-1-pyrrolidinyl)-4-methylpentanoyl, is inactive as agonist and antagonist in this assay. In DMSO, the NMR results cannot be interpreted as being consistent with a single conformation. However, the combined interpretation of results from NMR spectroscopy, restrained molecular dynamics simulations with application of proton–proton distance information from ROESY spectra, and pharmacological results leads to a reduced number of conformational domains for each peptide, which can be compared with each other and may be classified as responsible for their biological activity. Trying to match the conformational domains approximately with regular β- and γ-turns, we find a γⁿ-turn at the position of the methionine occuring in all peptides. For the active peptides 1 and 2 we arrive at an inverse γⁱ-turn at Phe⁸, and βI′- or βII-turns with Gly⁹ and Leu¹⁰ at the corner positions, these β-turns having a similar topology with respect to the linking peptide unit. Other conformational domains common to only 1 and 2 support their classification as responsible for the biological activity.     

Pharmacology and Toxicology of Major Constituents of Marijuana—On the Metabolic Activation of Cannabinoids and Its Mechanism

Many oxidative metabolites of tetrahydrocannabinols (THCs), active components of Cannabis sativa L. (Cannabinaceae), were pharmacologically potent, and 11‐hydroxy‐THCs, 11‐oxo‐Δ⁸‐THC, 7‐oxo‐Δ⁸‐THC, 8β,9β‐epoxyhexahydrocannabinol (EHHC), 9α,10α‐EHHC and 3'‐hydroxy‐Δ⁹‐THC were more active than THC in pharmacological effects such as catalepsy, hypothermia and barbiturate synergism in mice, indicating that these metabolites are active metabolites of THCs. Cannabidiol (CBD), another major component, was biotransfomred to two novel metabolites, 6‐hydroxymethyl‐Δ⁹‐THC and 3‐pentyl‐6, 7, 7a, 8, 9, 11a‐hexahydro‐1, 7‐dihydroxy‐7,10‐dimethyldibenzo[b,d]oxepin (PHDO) through 8R,9‐epoxy‐CBD and 8S, 9‐epoxy‐CBD as intermediates, respectively, identified by us. Both metabolites have some pharmacological effects comparable to Δ⁹‐THC. Cannabinol (CBN), the other major component, was mainly metabolized to 11‐hydroxy‐CBN by hepatic microsomes of animals including humans. The pharmacological effects of the metabolite were higher than those of CBN demonstrating that 11‐hydroxylation of CBN is an activation pathway of the cannabinoid as is the case in THCs. Tolerance developed to catalepsy, hypothermia and pentobarbital‐induced sleep prolonging effects of Δ⁸‐THC and its active metabolite, 11‐hydroxy‐Δ⁸‐THC. Reciprocal cross‐tolerance also developed to pharmacological effects and the magnitude of tolerance development produced by the metabolite was significantly higher than that by Δ⁸‐THC indicating that 11‐hydroxy‐Δ⁸‐THC has important role not only in the pharmacological effects but also its tolerance development of Δ⁸‐THC. THCs and their metabolites competed with the specific binding of CP‐55,940, an agonist of cannabinoid receptor, to synaptic membrane from bovine cerebral cortex. The Ki value of THCs and their metabolites were closely parallel to their pharmacological effects in mice. A novel cytochrome P450 (cyp2c29) was purified and identified for the first time by us as a major enzyme responsible for the metabolic activation of Δ⁸‐THC at the 11‐position in the mouse liver. cDNA of cyp2c29 was cloned from a mouse cDNA library and its sequence was determined. All of major P450s involving the metabolic activation of Δ⁸‐THC at the 11‐position are belonging to CYP2C subfamily in mammalian liver.     

前列腺素的研究Ⅰ 消旋前列腺素F_(2α)及其ω-乙基同系物的合成

本文对Corey合成光学活性PGF_2α路线进行简化,合成了dl-PGF_2α及dl-ω-乙基PGF_2α,用Arbuzov反应合成2-氧庚烷磷酸二乙酯(7A)及2-氧壬烷磷酸二乙酯(7B)。用Moffatt氧化(DMSO,DGC,无水磷酸)将氢解物(5)氧化为醛(6),用过量二异丁基铝氢于-78°还原3′-醇(9Aα及9Bα),可将其γ-内酯还原为γ-内半缩醛,同时除去5-联苯甲酰基,生成中间体(10Aα)及(10Bα),再与溴化5-三苯鏻戊酸之Wittig试剂缩合得到dl-PGF_2α(11A)及dl-ω-乙基PGF_2α(11B).     

Efficient Syntheses of ω-Chloro-, ω-Imido- and ω-Aminoalkyl-1,2,4-triazoles from N-Acyl-formamidinium Salts or N-Acylformamides and Hydrazines

ω-Halo and ω-amidoalkylcyanides 1 are transformed to ω-functionalized N-acylformamidinium salts 4 or formamide 6a by HCI catalyzed addition of chloromethylene iminium salts, derived from formamides 2 and POCI₃. Advantageously, β-halo-propionyl-formamidinium salts 4 can also be obtained from acrylonitrile. Regiospecific and chemoselective cyclization of N-acyl-formamidinium salts 4 or formamide 6a to ω-functionalized 5-alkyl-1,2,4-triazoles 9 is possible by reaction with hydrazines 5 , via intermediate N-acyl-amidrazones 8 or azines 7 which must be isolated and cyclized separately in a number of cases. 5-Phthalimidoalkyl-1,2,4-triazoles 9 are cleaved to 5-(aminoalkyl)-1,2,4-triazoles 10 .     

Thion- und Dithioester, 52. Mitt.: Zur Reaktion von Dithionmalonestern mit N,N-Dimethylformamidacetalen

Thiono and Dithio Esters, LII¹⁾: Reaction of Dithiono Malonates with N,N-Dimethylformamide Acetals The reaction of the dithiono malonates 1 with the formamide acetals 2 leads to the 2-dialkylaminomethylene dithionomalonates 4 and the thiono acrylates 6 . The condensation of 4 with hydrazines gives rise to the pyrazoles 7 and 8 , with hydroxylamine sulfonic acid to the isothiazoles 10 , and with amidines to the pyrimidines 11 - 13 .