Synthesis and pharmacological properties of 2-nitro-3-substituted-amino benzo[b]thiophenes and 1-substituted benzothieno[2,3-d]imidazoles

The synthesis of 1-substituted benzothieno[2,3-d]imidazoles and their most suitable synthesis precursor 2-nitro-3-substituted-amino benzo[b]thiophenes is reported. Most of these latter compounds show analgesic and antiinflammatory activities sometimes comparable to those of phenylbutazone with less toxicity and gastric lesivity.     

Neue Synthese 1-unsubstituierter 1H-Pyrazolo [3.4-b] pyridin-5-carbonsäureester

New Synthesis of Unknown 1-Unsubstituted 1H-Pyrazolo [3.4–b] pyridin-5-carboxylates A new synthesis of the unknown 1-unsubstituted 1H-pyrazolo [3.4-b] pyridine-5-carboxylates 6,11, 15 and 16 is described. Two different routes are employed. The one method uses pyridine derivative 1 , the other pyrazoles 7d–f as starting materials. The 1-position of the pyrazoles is protected by an easily cleavable heteroaryl-methyl moiety.     

7-[3-Hydroxy-2-halogenpropyl]-tetrahydropurine

7-[3-Hydroxy-2-halogenopropyl]-tetrahydropurines The addition of HOBr or HOJ to the allylic group (at N-7) of purine derivatives affords primary alcohols. The structure of the side chain is studied by ¹H–NMR-spectra.     

Tetrahydroindol-4-one aus cyclischen β-Dicarbonyl-Verbindungen

Tetrahydro-indole-4-ones from Cyclic β-Dicarbonyl Compounds Cyclic β-diketones and desylaniline are condensed to 1,2,3-triphenyl -4,5,6,7-tetrahydro-indole-4-ones.     

4-Phenylthio-3-pyrrolcarbonsäureester

4-(Phenylthio)-pyrrole-3-carboxylic Acid Esters Dihydro(dimethoxy)methylfurancarboxylic acid esters 4A/B have been applied to the synthesis of the title compounds. With amines as catalysts they react with thiophenols to give the addition products 12a–d , which upon heating with acids eliminate methanol to form the furancarboxylic acid esters 13a–b and 17 , whereas reactions with ammonia or amines lead to the pyrrolecarboxylic acid esters 20a–e . Reactions of 4 with 2-aminothiophenol yield the fused pyrrole and pyrrolidine derivatives 15 and 16 . Compounds 20b and e were transformed to the benzothiopyranopyrrole carboxylic acid esters 23a and b .     

Synthesis of [3α‐3H] 17α‐Hydroxy pregnenolone and [3α‐3H] Pregnenolone

For the first time, [3α‐³H] 17α‐hydroxy pregnenolone (1) was synthesized through a multiple step sequence. The presence of [3β‐³H] isomer in RP‐HPLC purified product was identified by tritium NMR. The [3β‐³H] isomer was then separated from [3α‐³H] 17α‐hydroxy pregnenolone with chiralPAK AD‐H column. [3α‐³H] pregnenolone (2) was synthesized from commercial available 5‐pregnen‐3,20‐dione in one step with an improved procedure.     

Lactone, 16. Mitt.: Synthese von 4,9-Dihydropyrano[3,4-b]indol-1(3H)-onen aus α-Ethoxalyl-δ-valerolacton

Lactones, XVI: Synthesis of 4,9-Dihydropyrano[3,4-b]indol-1(3H)-ones from α-Ethoxalyl-δ-valerolactone Treatment of α-ethoxalyl-δ-valerolactone (1) with diazotized anilines and indolization of the intermediate hydrazones 4 leads to the pyranoindolones 5 . Compared to the recently reported reaction of α-ethoxalyl-γ-butyrolactone with arylhydrazines²⁾, this synthesis is more versatile with regard to variation of substituents at the aromatic ring. Stereochemistry and reactivity of the α-arylhydrazonolactones are discussed.     

4-Hydroxy-2H-[1]benzopyran-2-on als Baustein zur Synthese von Bisbenzopyranopyridinen

4-Hydroxy-2H-[1]benzopyran-2-one as Starting Material for the Synthesis of Bisbenzopyranopyridines A mechanism for the formation of 4 and 6 from 1 via 5a is discussed. Under acid catalysis, 1 and 3 react to yield 6 and 7. In the presence of DBN of 6 is formed from 3 and 8. When the reaction is catalyzed with piperidine, the major product is 9a , whose structure was elucidated by degradation reactions: KOH transforms 9a into the pyridone 10. Hydrazine converts 9a via 11 to the hydrazone 12a , which can be hydrolyzed to the lactone 12b     

Über Dialkyl-[β,β,β-trichlor-bzw. β,β,β-triphenyl-äthyl]-amine. 34. Mitt. über α-halogenierte Amine

Dialkyl-[β,β,β-trichloro- or β,β,β-triphenyl-ethyl]-amines Reactions of α-halo amines 2 with trichloromethyllithium give dialkyl-[β,β,β-triphenyl-ethyl]-amines 1 , with triphenylmethyllithium dialkyl-[β,β,β-triphenyl-ethyl]-amines 3 .     

Zur Keto-Enol-Tautomerie bei heterocyclischen β-Ketocarbonsäureestern 3. Mitt.: Konfiguration und Konformation 2,6-dialkylsubstituierter β-Ketodicarbonsäureester

Keto-Enol-Tautomerism of heterocyclic β-Ketocarboxylic Acid Esters The configuration and conformation of 1-aza-, 1-oxa-, 1-thia- and 1-selena-cyclohexanone dicarboxylic acid esters has been studied by proton resonance spectroscopy. In the keto forms of these compounds, the substituents at C-2, -3, -5 and -6 have the following relative configuration: 2,6-/3,5-cis, 2,3-/5,6-trans. The preferred conformation of these ketones is the chair conformation in which all substituents have equatorial positions.     

Tetrahydroindol-4-one aus Enaminen cyclischer β-Dicarbonylverbindungen

Tetrahydroindole-4-ones from Enamines of β-Dicarbonyl-Compounds Enamines of cyclic β-diketones yield 2,3-disubstituted 4,5,6,7-tetrahydro-indole-4-ones by condensation with α-ketols.     

The Anaesthetic Potency of 3α-Hydroxy-5α-pregnan-20-one and 3α-Hydroxy-5β-pregnan-20-one Determined with an Intravenous EEG-Threshold Method in Male Rats

Abstract: Two progesterone metabolites 3α-hydroxy-5α-pregnan-20-one (5-α) and 3α-hydroxy-5β-pregnan-20-one (5-β) were investigated for anaesthetic potency in male rats with an EEG-threshold method. Dose rate curves were obtained by infusing 5-α and 5β intravenously with different rates until an EEG-criterion (a burst suppression of one sec. or more, the “silent second”) was seen in the EEG. The potency of the investigated drugs has been estimated by comparing threshold doses at optimal infusion rates. 5-α and 5-β were tested on both young (44 to 46 days) and adult (109 to 118 days) rats. The relation between age and the anaesthetic sensitivity of 5-β was tested by weekly threshold determinations. 5-α and 5-β infused separately with different infusion rates gave almost V-shaped dose rate curves. The optimal infusion rate was in all age groups 2 mg/kg/min. In young rats 5-α (6.7 mg/kg) was more potent than 5-β (8.9 mg/kg). In adult rats the sensitivity was increased but the relation in potency between 5-α (5.1 mg/kg) and 5-β (6.6 mg/kg) was unchanged. With 5-β the main change in this age-related increase in anaesthetic sensitivity was seen between 49 and 70 days of age. Both 5-α and 5-β exhibited an excitatory action seen as jerks during induction of the EEG-criterion.     

3-Hydroxy-1,3-oxazinan-4-one und 1,4,2-Dioxazole aus 3-Hydroxycarbohydroxamsäuren und Carbonylverbindungen

3-Hydroxy-1,3-oxazinan-4-ones and 1,4,2-Dioxazoles from 3-Hydroxycarbohydroxamic Acids and Carbonyl Compounds The acid-catalysed cyclization of 3-hydroxycarbohydroxamic acids 4 with benzaldehyde dimethylacetal or paraformaldehyde gives 3-hydroxy-1,3-oxazinan-4-ones 5 and 7 . Depending on the substituents, the reaction of 4 with cyclohexanone produces either 1,3-oxazinan-4-ones of type of 8 or 1,4,2-dioxazole of type 9 .     

Lactone, 11. Mitt. Synthese von 4.9-Dihydropyrano[3.4-b]indol-1(3H)-onen aus α-Ethoxalyl-γ-lactonen

Lactones, XI: Syntheses of 4.9-Dihydropyrano[3.4-b]-indol-1(3H)-ones from α-Ethoxalyl-γ-lactones Cleavage and decarboxylation of the α-ethoxalyl-γ-lactones 1a-d followed by treatment with phenylhy-drazines yield the hydrazones 4a-l , which can be rearranged to the indololactones 5a-m. Starting from the δ-lactones 6 and 10 , the same reactions lead to indoles without lactone ring closure.     

Die Kondensation von γ-und δ-Oxo-carbonsäureester mit 1,2-, 1,3- und 1,4-Alkylendiaminen

Condensation of Esters of γ- and δ-Oxocarboxylic Acids with Alkylene-1,2,1,3- and 1,4-diamines. Esters of γ-and δ-Oxocarboxylic acids condense with alkylene-1,2-, 1,3-, and 1,4-diamines and yield bicyclic lactams (5) . The path of the reaction was studied by spectroscopic methods using ethyl levulinate and N-methyl-propylene-1,2-diamine. The first step is the formation of an “aminalester” by reaction of the CO-group of ethyl levulinate with alkylene diamine, followed by intramolecular ring closure.     

Selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis. 1. [4-[2-[(2-Hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetates.

The ester methyl [4-[2-[(2-hydroxy-3-phenoxypropyl)amino]ethoxy]phenoxy]acetate (8) has been identified as the most interesting member of a series of selective beta 3-adrenergic agonists of brown adipose tissue and thermogenesis in the rat. In vivo it acts mainly via the related acid 10. Potency was generally markedly reduced by placing substituents on the phenyl ring of the phenoxypropanolamine unit of 8; only the 2-fluoro analogue 16 had comparable potency to 8. Other structure-activity relationships are discussed. Further testing of 8 (ICI 198157) has shown that in the rat it stimulates the beta 3-adrenergic receptor in brown adipose tissue at doses lower than those at which it affects beta 1 and beta 2 adrenergic receptors in other tissues. It increases metabolic rate, as judged by an increase in oxygen consumption, and in the genetically obese Zucker rat it causes a reduced rate of weight gain. This class of compound may be useful in the treatment of obesity in man.     

Indoxyl-δ-aminosäuren aus Hydromorphon und Hydrocodon

Indoxyl-δ-Amino Acids from Hydromorphone und Hydrocodone When hydromorphone and hydrocodone are reacted with 2-nitrobenzaldehyde and potassium hydroxide, cleavage of the C-ring occurs to yield the indoxyls 6 .