Furane und Thiophene aus Etacrynsäure

Furans and Thiophenes from Etacrynic Acid . The 1,4-dicarbonyl- and 1,4,7-tricarbonyl compounds 1 react with polyphosphoric acid (PPA) to yield the furans 3 ; with P₄S₁₀ the thiophenes 4 are obtained. The γ-keto carboxylic acid 2 cyclizes with PPA to form the α,β-unsaturated butyrolactone 6. 2 is reduced by NaBH₄ chemo- and diastereoselectively to give the γ-hydroxy carboxylic acid 5 . The lactone 7 is prepared by dehydration of 5 with PPA. The sulfones 8a,b are obtained from the thiophenes 4a,b by oxidation with magnesium monoperoxyphthalate (MMPP). Under the same conditions the furan 3b is cleaved to yield the enedione 9 , which tautomerizes slowly forming 10 .     

Zur bromometrischen Bestimmung von Secobarbital-Natrium

Bromometric Assay of Secobarbital Sodium Secobarbital sodium ( 1a ) and the 1,3-bis-(4-nitrobenzyl)barbituric acid 2 react with KBrO₃ and KBr in acetic acid/HCl to yield the bromohydrines 3 and the dibromo compounds 5 . Dehydrobromination leads to the pyrano[2,3-d]pyrimidines 7 and 8 , respectively. The α-bromoketones 6 are obtained from 3 by oxidation with CrO₃. 6 cyclizes with thiourea to form the amino-thiazole 9 , while silver benzoate gives the activated ester 10 . In methanol secobarbital (1) reacts with Br₂ to yield the furo[2,3-d]pyrimidine 11 .     

Bicyclische α-Aminosäuren, 3. Mitt. Zur Synthese von 2-(1-Tetralyl)- und 2-[5-(5,6,7,8-Tetrahydro)-chinolyl]-glycin

Bicyclic α-Amino Acids, III: On the Preparation of 2-(1,2,3,4-Tetrahydronaphthalen-1-yl)- and 2-(5,6,7,8-Tetrahydroquinoline-5yl-)glycine Attempted halogenation of 2 does not yield the expected bromo(1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid 4 but the cyclic ketone 3 . The α-ketoesters 5 can be decarbonylated to yield the substituted malonic esters 6 . Compounds 6a and 7a react with isopropyl nitrite to yield the oximinocarboxylic acid 8a which can be hydrogenated at room temperature to yield the title compound 9a . Hydrogenation at 80° C leads to the decalylamino acid 10a . The analogous sequence of reactions ( 6b and 7b→8b→9b ) fails to yield tetrahydroquinolinylglycine 9b .     

Dithio- und Thionester, 60. Mitt.: Addition von Dithiocarbonsäure-dianionen an Aldehyde und Ketone

Dithio and Thiono Esters, LX: Addition of Dithioic Acid Dianions to Aldehydes and Ketones Aliphatic dithiocarboxylic acids such as dithioethanoic acid ( 1a ), dithiopropanoic acid ( 10a ) or 2-methyl-dithiopropanoic acid ( 10e ) react with 2 moles of n-BuLi to form the corresponding dilithium dithioenolates 2a , 11a or 11e . These add to aldehydes and ketones to give the aldol adducts 3a-f and 12a-e . Methylation with methyl iodide leads to the more stable β-hydroxy dithioesters 4 and 13 . The esters 4 have been dehydrated to yield the α,β-unsaturated dithioesters 5 . Addition of the dilithium dithioenolate 2a to methylvinyl ketone, cyclohexenone or cyclopentenone followed by methylation gives rise to the δ,ε-unsaturated dithioesters 6–8 .     

Siliciumhaltige Wirkstoffe, 2. Mitt. Synthese silylierter Bisacodyl-Analoga

Silicon Containing Agents, II: Preparation of Silylated Analogues of Bisacodyl The three isomeric esters of pyridinecarboxylic acid 4 react with 4-(trimethylsilyl)phenyllithium ( 5b ) to the tertiary pyridylmethanols 6 . The alcohols 6a and 6b can be hydrogenolised to the diphenylpyridylmethane derivatives 7a and 7b , while 7c results from reduction of the chloro compound 8 by LiAlH₄.     

3-Hydroxy-2'-methoxy-6-methylflavone: a potent anxiolytic with a unique selectivity profile at GABA(A) receptor subtypes

Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA_A receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA_A receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2′-methoxy-6-methylflavone (3-OH-2′MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1–3γ2L but not α3/5β1–3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC₅₀ values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2′MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4–11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2′MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2′MeO6MF for α4β2/3δ receptors (EC₅₀ values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA_A receptors. 3-OH-2′MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2′MeO6MF (1–100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2′MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA_A receptor subtypes.     

3-Hydroxy-2′-methoxy-6-methylflavone: A potent anxiolytic with a unique selectivity profile at GABAA receptor subtypes

Genetic and pharmacological studies have demonstrated that α2- and α4-containing GABA_A receptors mediate the anxiolytic effects of a number of agents. Flavonoids are a class of ligands that act at GABA_A receptors and possess anxiolytic effects in vivo. Here we demonstrate that the synthetic flavonoid, 3-hydroxy-2′-methoxy-6-methylflavone (3-OH-2′MeO6MF) potentiates GABA-induced currents at recombinant α1/2β2, α1/2/4/6β1–3γ2L but not α3/5β1–3γ2L receptors expressed in Xenopus oocytes. The enhancement was evident at micromolar concentrations (EC₅₀ values between 38 and 106 μM) and occurred in a flumazenil-insensitive manner. 3-OH-2′MeO6MF displayed preference for β2/3- over β1-containing receptors with the highest efficacy observed at α2β2/3γ2L, displaying a 4–11-fold increase in efficacy over α2β1γ2L and α1/4/6-containing subtypes. In contrast, 3-OH-2′MeO6MF acted as a potent bicuculline-sensitive activator, devoid of potentiation effects at extrasynaptic α4β2/3δ receptors expressed in oocytes. The affinity of 3-OH-2′MeO6MF for α4β2/3δ receptors (EC₅₀ values between 1.4 and 2.5 μM) was 10-fold higher than at α4β1δ GABA_A receptors. 3-OH-2′MeO6MF acted as a full agonist at α4β2/3δ (105% of the maximal GABA response) but as a partial agonist at α4β1δ (61% of the maximum GABA response) receptors. In mice, 3-OH-2′MeO6MF (1–100 mg/kg i.p.) induced anxiolytic-like effects in two unconditioned models of anxiety: the elevated plus maze and light/dark paradigms. No sedative or myorelaxant effects were detected using holeboard, actimeter and horizontal wire tests and only weak barbiturate potentiating effects on the loss of righting reflex test. Taken together, these data suggest that 3-OH-2′MeO6MF is an anxiolytic without sedative and myorelaxant effects acting through positive allosteric modulation of the α2β2/3γ2L and direct activation of α4β2/3δ GABA_A receptor subtypes.     

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 .     

The Prejunctional Inhibitory Effect of α-Methylnoradrenaline in the Rat Vas Deferens is Not Mediated via α2-Adrenoceptors

In field-stimulated rat vas deferens, clonidine (10^?9–10^?7 m ) and α-methylnoradrenaline (10^?7–3 times 10^?5 m ) concentration-dependently inhibited twitch response to electrical field stimulation. The inhibitory effects of clonidine and α-methylnoradrenaline were similarly reduced by phenoxybenzamine (10^?6 m ). However, idazoxan (3 times 10^?7 m ) antagonized clonidine but not α-methylnoradrenaline-induced responses. The inhibitory effect of α-methylnoradrenaline was also not antagonized by phentolamine (3 times 10^?7 m ), SK&F 104856 (2-vinyl-7-chloro-3,4,5,6-tetrahydro-4-methylthienol[4,3,2 ef][3]benzazepine) 3 times 10^?6 m ) or yohimbine 3 times 10^?7 m ). These antagonists however, attenuated the twitch-inhibiting effect of clonidine. The -logK_B values were 8·02 ± 0·05, 6·91 ± 0·10, and 7·58 ± 0·07 for phentolamine, SK&F 104856 and yohimbine respectively. In-vivo treatment of rats with N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (6 mg kg^?1), to inactivate prejunctional α₂-adrenoceptors, attenuated clonidine, but not α-methylnoradrenaline-induced responses. It was concluded that adrenoceptors are not involved in the prejunctional inhibitory effects of α-methylnoradrenaline in the rat vas deferens.     

Interaction between clonidine and histamine on the guinea-pig isolated trachea

In experiments on guinea-pig isolated tracheal spirals, clonidine, in concentrations of 10^?6 to 3 times 10^?4 M. had a contracting effect which was strongly inhibited by prazosin but not significantly modified by yohimbine. Moreover, clonidine (3 times 10^?5 to 3 times 10^?4 M) potentiated histamine-induced contractions; this latter effect was inhibited specifically by α₁-adrenoceptor antagonists (e.g. prazosin, AR-C 239) but unmodified by yohimbine, nicardipine or agents acting on the arachidonic acid cascade. It would therefore appear that clonidine in high concentrations contracts the guinea-pig trachea by stimulating α₁-adrenoceptors and that, contrary to what has been reported with other animal species, notably the dog, the guinea-pig trachea is devoid of α₂-adrenoceptors that mediate contractions.     

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.     

Über N-Substitutionsprodukte von 4,4-Dialkyl-homophthalimiden 14. Mitt. über N-α-Halogenalkyl-carbonsäureamide

N-Substitution Products of 4,4-Dialkyl-1,3(2H,4H)-isoquinolinediones. 4,4-Dialkyl-1,3(2H,4H)-isoquinoline-diones ( 1 ) are converted into N-chloromethylderivatives ( 5 ) by halogenating their N-hydroxymethylcompounds ( 2 ). Reactions of 5 with sodium salts of benzenesulfinic-acid, diethylmethylmalonate or α-phenylacetoacetic acid-nitrile lead to 1,3(2H,4H)-isoquinoline-dione-derivatives 6. 7 or 8 . Secondary amines react with N-chloromethyl-compounds 5 under formation of the N-Mannichbasehydrochlorides, which are accessible also by condensation of 4,4-dialkyl-1,3(2H,4H)-isoquinoline-diones ( 1 ) with formaldehyde and the corresponding secondary amine.     

PHARMACOLOGICAL CHARACTERIZATION OF α-ADRENORECEPTOR SUBTYPES IN RAT ISOLATED THORACIC AORTA

• 1 The subtype of α-adrenoreceptor mediating contraction in rat isolated thoracic aorta was classified pharmacologically using preferential agonists and antagonists, and by utilizing mixed agonist and antagonist interactions.
• 2 Noradrenaline was 8 to 10-times more potent at contracting the aorta than phenylephrine and both agonists were about 1000 and 10,000-fold respectively more potent than azepexole (a preferential α2,-agonist).
• 3 Prazosin (a preferential α₁,-antagonist) inhibited the dose-response curves to noradrenaline and phenylephrine 100 and 1000-times respectively more effectively than either phentolamine or rauwolscine (a preferential α₂-antagonist). Furthermore, prazosin (5 times 10^-9M). completely abolished contractions elicited by a single concentration of azepexole (3 times 10^-4M).
• 4 In mixed antagonist studies, rauwolscine (5 times 10^-7M) failed to shift the dose-response curves to nor-adrenaline and phenylephrine obtained in the presence of prazosin (5 times 10^-9M).
• 5 In mixed agonist experiments, azepexole (3 times 10^-4M) acted as a partial antagonist toward phenylephrine-induced contractions.
• 6 The results suggest that the α-adrenoreceptor of the rat thoracic aorta is predominantly, if not exclusively, of the α₁-subtype.

     

Conformational preferences of oligopeptides rich in α-aminoisobutyric acid. III. Design,synthesis and hydrogen bonding in 310-helices

Two sterically constrained peptides {ⁱBoc-Aib-Aib-Aib-DkNap-Leu-Qx-Ala-Aib-Aib-F1, (Dk⁴Qx⁶[7/9]) and ⁱBoc-Aib-Aib-Aib-DkNap-Leu-Aib-Ala-Aib-Aib-Fl, (Dk⁴7/9)} containing α-aminoisobutyric acid (Aib) and Aib-class amino acids in conjunction with selected mono-α-alkyl amino acids were synthesized by an optimized TBTU/HOBt procedure. The use of Aib-class amino acids (e.g. DkNap and Qx), defined and discussed here, gives rise to the same overwhelmingly 3₁₀-helical backbone conformation as that provided by simpler Aib-rich peptides and homopeptides. The synthetic α,α-dialkylamino acids (DkNap, Qx) are aromatic homologues of the known alicyclic variants of Aib, the Ac₅c and Ac₆c amino acids. Two new organic solubilizing groups for peptides, ⁱBoc and 2-methoxyethylamine, are introduced. The ¹H nuclear magnetic resonance analyses of the Dk⁴s/p[7/9] and Dk⁴Qx⁶[7/9] peptides demonstrate the unambiguous 310s/b-helical hydrogen bonding pattern of these peptides, confirming the design objective of these sequence patterns containing greater than 50% Aib and Aib-class composition. © Munksgaard 1994.     

AN IN VITRO STUDY OF INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT VASCULAR α1-ADRENOCEPTORS

1. Isolated perfused male Sprague-Dawley rat tail artery segments were used to investigate interactions between the α-₁-adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the α₁-adrenoceptor agonist. 2. In concentrations of up to 10–⁵ mol/L, enalaprilat had no effect on arterial responses to PE. 3. Doxazosin produced a concentration-dependent competitive α₁-adrenoceptor antagonism, yielding a mean pA₂ value of 8.72. 4. In the continuous presence of 10^?6 mol/L enalaprilat, doxazosin with a pA₂ value of 9.10 was a 2.4-fold more potent α₁-adrenoceptor antagonist than in the absence of enalaprilat. 5. These results are interpreted to indicate that endogenously produced angiotensin II can modulate the activity of α₁-adrenoceptors in vascular smooth muscle.     

A STUDY ON THE POSTJUNCTIONAL EXCITATORY α-ADRENORECEPTOR SUBTYPES IN THE MESENTERIC ARTERIAL BED OF THE RAT

• 1 The nature of the postsynaptic adrenoreceptor subtypes which mediate vasoconstriction in the mesenteric arterial bed of the rat was investigated using mixed and selective α₁, α₂ and β-agonists and antagonists.
• 2 Phenylephrine (PE) an α₁selective agonist and noradrenaline (NA) a mixed α₁and α₂-agonist, produced a rise in perfusion pressure (vasoconstriction). The responses to NA remained stable with time whereas responses to PE considerably increased.
• 3 UK14304 an α₂-selective agonist at low doses (10^?8 ?10^?7 moles), caused small, slow contractions in most preparations. Repeated administration of these doses or slightly higher ones, desensitized the tissue to this compound but not to NA or PE. Finally, UK14304 given simultaneously with NA or PE, at doses higher than 5 × 10^?7 moles, reduced contractions to the latter compounds and this effect was not altered by 10^?7 M rauwolscine, an α₂-selective antagonist.
• 4 Prazosin, an α₁-selective antagonist, as expected, reduced contractions to NA considerably at 10^?10 ?10^?8 M and abolished contractions to UK14304 at 2 × 10^?9 M.
• 5 Rauwolscine, at 10^?8 M, potentiated contractions to NA and at 10^?6 M reduced contractions to both NA and PE (when compared to time controls).
• 6 When propranolol (10^?6 M), a β-antagonist was included in the perfusion fluid, rauwolscine no longer potentiated responses to NA but reduced them at all concentrations. Under the same conditions rauwolscine affected the responses to PE in a similar direction to that observed in the absence of propranolol.
• 7 These results suggest that in the rat mesenteric arterial bed:

• a. rauwolscine exerts an effect additional to α₂-adrenoreceptor antagonism. Modification of this effect by propranolol indicates an interaction between this effect of rauwolscine and the β-adrenoreceptor.
• b. vasoconstriction in the mesenteric arterial bed of the rat is mainly mediated postsynaptically by α₁-adrenoreceptors although the contribution of an α₂-mediated component cannot be excluded.
• c. UK14304 is an α₁-partial agonist as well as an α₂-agonist.

     

Iminiumkohlensäurederivat-Salze, 7. Mitt. Teil I: Elektrophile Reaktionen von 2-Methylthio-5,6-dihydro-4H1,3-thiaziniumiodiden, 2-Methylthio-4,5-dihydrothiazoliumiodiden und 2-Methylthio-5-methylthiazoliumiodiden mit N-Nucleophilen

Iminium Carbonic Acid Derivative Salts VII, Part I: Electrophilic Reactions of 2-Methylthio-5,6-dihydro-4H-1,3-thiazinium Iodides, 2-Methylthio-4,5-dihydrothiazolium Iodides, and 2-Methylthio-5-methylthiazolium Iodides with N-Nucleophiles Cyclic salts of the dithiocarbonic acid diester imidium type ( 3, 5 ) react with NH₂-nucleophiles to the cyclic isothioureas 6 – 8 . Some of these compounds were oxidized to cyclic isothiourea-S,S-dioxides ( 9, 10 ).     

Influence of α‐Adrenoceptor Agonists and Antagonists on Imipramine‐Induced Hypothermia in Mice

Abstract: Effects of adrenoceptor agonists and antagonists on imipramine‐induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10–40 mg kg^?1), α₂‐adrenoceptor agonist clonidine (0.05–0.1 mg kg^?1), α₁‐adrenoceptor agonist phenylephrine (6 mg kg^?1) and α₁‐adrenoceptor antagonist prazosin (1–4 mg kg^?1) but not α₂‐adrenoceptor antagonist yohimbine (1–4 mg kg^?1) induced significant hypothermia. The hypothermic response induced by imipramine (10–30 mg kg^?1) was not altered by clonidine (0.05–0.1 mg kg^?1) or phenylephrine (2–6 mg kg^?1). The response of imipramine (10–30 mg kg^?1) was reduced significantly by yohimbine (2 mg kg^?1) and was potentiated by prazosin (1 mg kg^?1). The hypothermic effect of clonidine (0.1 mg kg^?1) and imipramine (20 mg kg^?1) were also decreased significantly by different doses of yohimbine (1–4 mg kg^?1). The hypothermia induced by different doses of prazosin (1–4 mg kg^?1) was not altered by yohimbine (2 mg kg^?1) or by low dose of imipramine (10 mg kg^?1). It is concluded that α₂‐adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

Synthese und Reaktionsverhalten neuer tri- sowie tetracyclischer Schwefelanaloga des Indols, 2. Mitt

Synthesis and Reactivity of New Tri- and Tetracyclic Sulfur Analogues of Indole, II: The ketone oxime 1 was rearranged to the lactam 2 . Hydrolysis lead to the amino acid 3b and to the salt 3a . With “Meerwein salt” we received the lactimether 4 , with P₄S₁₀ the thiolactam 5 , with methyl iodide the thiolactim ether 6 . Compound 4 reacted with malodinitril to yield the derivative 7 . From 4 and 1-phenyl-3-methyl-5-pyrazolone we received compound 8 . Substituted hydrazides react with 4 to yield compounds 9a–9h . After heating of 9e, 9d, 9f and 9g we isolated 10, 11, 12 and 13 , respectively. Compound 2 reacts with PCI₅ and NaN₃ to yield the tetrazole 14 . Acylation of benzothiophene (15) with the ester chloride 16 leads to a mixture of the esters 17 and 18 from which we received the acids 19 and 20 . Cyclisation leads to the ketones 21 and 22 . The tropone derivative 28 was synthesized from thiophenol 23 via compound 25 , acid 26 and ketone 27 .     

Darstellung disubstituierter 4-Oxo-4H-pyrazol-1,2-bis-oxide

Preparation of Disubstituted 4-Oxo-4H-pyrazole-1,2-bis-oxides The α,β-unsaturated aromatic oximes 1 , 3 , 4 , 6 , 7 , 9 react with nitric acid/sodium nitrite or nitrogen tetroxide to 4-oxo-4H-pyrazole-1,2-bis-oxides 2 , 5 , 8 , 10 , the structures of which are elucidated by synthesis and spectroscopy. In acetic acid, mixtures of 4-oxo-4H-pyrazole-1,2-bisoxides and 4-hydroximino-4H-pyrazole 1,2-bis-oxides from the oximes 1 , 3a – d , 6a are obtained, which are separated by thin layer chromatography.