Über das Polymorphie-Verhalten von 7-(β-Hydroxypropyl)- und 7-(β,γ-Dihydroxypropyl)-theophyllin

On the Polymorphism of 7-(β-Hydroxypropyl)-and 7-(β,γ-Dihydroxypropyl)-theophylline The polymorphism of 7-(β-hydroxypropyl)- and 7-(β,γ-dihydroxypropyl)-theophylline was studied with differential scanning calorimetry and thermomicroscopy. Crystallization in vitreous supercooled melts yields polymorphic modifications. Their formation and transformation with time was studied.     

Darstellung und Dehydratisierung von 2-(α-Alkyl)- oder (α-Aryl)-substituierten Hydroxymethyl-5-methoxy-1,3-benzoxathiol-3,3-dioxiden

Synthesis and Water Elimination of 2-(α-Alkyl-) or (α-Aryl)-Substituted Hydroxymethyl-5-methoxy-1,3-benzoxathiol-3,3-dioxides The reaction of α,α-disilylated sulfones 1 with acetaldehyde in the presence of TBAF yields the aldols 2 and 3 together with small amounts of the dialdols 4 and the olefins 5/6 . From aromatic aldehydes the formation of olefins 9 is preferred. A reaction pathway is proposed. Acetylation of the unsilylated derivative 7 yields the 2-acetyl derivatives 12 which may be reduced by selectride. Depending on the conditions the formation either of 2 or of 3 is preferred. Water elimination from 2 and 3 with thionylchloride in pyridine stereoselectivly produces the olefines 5 or 6 , respectively. Intermediates are the halogen compounds 14 which are formed by inversion.     

Einige N-funktionelle Derivate von N-(α-Tosylaminoacyl)-β-alaninen

Syntheses of dipeptidenitriles 1a-e starting from α-tosylaminoacidchlorides and β-aminopropionitrile and their conversion to the esters of dipeptide-imide acids 2a-d , esters of dipeptide acids 5a-d , to amides of dipeptide acids 6a-d and amidines of dipeptide acids 4a-e are described. Condensations of amidines of tosyldipeptide acids 3a, c with ethyl acetoacetate yield pyrimidines 7a, c .     

Darstellung von γ- und δ-Laktoncarbonsäuren aus DL-3-(1′-Methoxymethylpropyl)-glutarsäure

Ether cleavage of DL -3-(1′-methyoxymethylpropyl)-glutaric acid with the protonic acid HBr leads to 4-carboxymethyl-5-methyl-5-ethyl-furanone-(2);ether cleavage with the Lewis acid BBr₃ to carboxymethyl-5-ethyl-pyranone-(2).     

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.     

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 .     

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

Bicyclic α-Amino Acids, II. On the Preparation of 3-(1-Tetralyl)-and 3-[5-(5,6,7,8-Tetrahydro)quinolyl]alanine Carbonyl olefination of the tetralones 4 does not yield the expected compounds 6 but the isomeric acetic acid derivatives 7 with endocyclic double bond, from which the ketoesters 10 can be prepared via intermediates 8 and 9 . Saponification of 9 and 10 fails to yield the α-ketoacids 11 and 12 .     

Lactone, 3. Mitt.1) Zur Synthese von α-Aminoalkyl-γ-lactonen

Lactones, III: Synthesis of α-Aminoalkyl-β-lactones Alkylation of α-acetyl-β-lactones with α-aminoethyl and -propyl chlorides, followed by in situ cleavage of the acetyl group with an excess of ethanolate is a general synthetic route to α-aminoethyl- and α-aminopropyl-β-lactones. The yields are limited by side reactions.     

Improved synthesis and resolution of β-(3-pyridyl)-DL-α-alanine

β-Benzamido-α-(3-pyridyl)-DL-α-alanine hydrochloride was synthesized from 3-pyridinecarboxyaldehyde via the azlactone which was hydrolyzed to the acrylic acid before hydrogenation. The methyl ester was effectively resolved with subtilisin. The optical purity of the D-isomer was established, since the D-isomer was used in synthesis of antagonists of the luteinizing hormone releasing hormone.     

Bicyclische α-Aminosäuren, 4. Mitt.1) Synthese von 3-(1-Tetralyl)- und 3-[5-(5,6,7,8-Tetrahydro)-chinolyl]-alanin

Bicyclic α-Amino Acids, IV: Synthesis of 3-(L1,2,3,4-Tetrahydro-l-naphthalenyl)- and 3-(5,6,7,8-Tetrahydro-5-quinolinyl)alanine The title compounds 1a , b are prepared by Strecker synthesis with the aldehydes 7a , b which are available from 2a , b . The structures of 1a , b and the configurations of the isomeric nitriles 3a , b / 4a , b were elucidated by ¹H- and ¹³C-NMR spectroscopy.     

1H-n.m.r. study of the folding of ribonuclease 12-(β-(3-pyridyl)-l-Ala) S-peptide (1–14)

The ¹H-n.m.r. spectra (360 MHz) of 12-(β-(3-pyridyl)-l -Ala) ribonuclease S-peptide (1–14), a tetradecapeptide incorporating (β-3-pyridyl-l -Ala) instead of His at position 12, have been assigned. The shift vs. temperature dependence has been analyzed at three different pD's in terms of a two-state helix (3–13) ± coil equilibrium, and the corresponding values for the thermodynamic quantities ΔH° and ΔS° determined. Helix populations at 0°C have been measured as a function of pD, showing their dependence on two apparent pK_a's at ? 3.3 and 5.5, with a maximum at pD ? 4.2. All the obtained results show that the new peptide has very similar folding properties to those shown by S-peptide and particularly to those of C-peptide. The 3–13 helix formed is stabilized by two interactions: a salt-bridge Glu 2^-. Arg 10+ and a partial stacking between the aromatic rings of residues Phe 8 and His 12. Calculations involving ring current shifts and potential energies validate the possible existence of this latter interaction, which must present a local geometry defined by χ₁X⁸ 180°, χ₂X⁸ 100°, χ₁¹² – 60 and χ₂¹² 80.     

Association of β-agonists with corresponding β2- and β1-adrenergic pentapeptide sequences

Synthesized β₁- and β₂-pentapeptide sequences corresponding to published adrenoceptor transmembrane activation site subtypes were investigated in vitro for selectivity in association for drug ligands of known selectivity. Both nuclear magnetic resonance spectroscopy and molecular mechanics demonstrated that structural differences among the corresponding pentapeptide activation-site sequences can explain agonist selectivity. Results suggest the agonists bind across the activation site loop on the second transmembrane α-helix by dipole/dipole interactions between a ligand and the peptide. Since electrostatic interactions within the membrane may determine the rate of intercellular ion flux, agonist association across the activation site sequence could thereby decrease electrostatic resistance to positive ion flux into the cell. Interactions between the peptides and the ligands may provide insight into the structures and mechanisms involved in association of ligands for the identical sequences on the β-adrenoreceptors.     

Dimerisierung von α-Piperidinoacetonitril durch t-Butylmagnesiumchlorid IV. Mitt. über Umsetzungen von α-Aminonitrilen

Dimerisation of α-Piperidinoacetonitrile with t-Butylmagnesium chloride Under the influence of t-butylmagnesium chloride α-piperidinoacetonitrile dimerises to 3-amino-2,4-dipiperidinocrotononitrile. The mechanism of the dimerisation has been established.     

Synthesis of α-, β- and cyclic spaglumic acids

A short, one-pot synthesis of α- and β-spaglumic acids (N-acetyl-L-aspartyl-L-glutamic acids, NAAGA) has been developed based on ultrasound-promoted acetylation of aspartic acid, followed by dehydration, condensation with glutamic acid dibenzyl ester and hydrogenolysis. The α- and β-peptides were separated by anion-exchange chromatography. The α-peptide shows a remarkable tendency to cyclize during methylation with diazomethane and yields cyclic N-acetylaspartylglutamic acid dimethyl ester, which could be hydrolysed to the hitherto unreported diketopiperazine dicarboxylic acid, cyclic spaglumic acid (cyclic NAAGA).     

β1- and β2-Adrenoceptor Affinity and Stimulatory Effects of (S)-Pindolol and Iodinated (S)-Pindolol

Abstract: The β₁- and β₂-adrenoceptor affinity and stimulatory effects of iodinated (S)-pindolol (IPIN) and (S)-pindolol were investigated in vitro using β-adrenoceptor binding technique and isolated right atrium (rate increase, β₁) and uterus (relaxation, β₂) of the rat. IPIN had a higher affinity towards β-adrenoceptors compared to (S)-pindolol, with some β₂-adrenoceptor selectivity. In the rat uterus, IPIN produced only marginal stimulatory effects, while (S)-pindolol caused a concentration-dependent relaxation with a maximal effect that was 55% of that generated by isoprenaline. In the right atrium IPIN caused an increase in the atrial rate similar to that caused by (S)-pindolol. The concentration of IPIN required in the right atrium for a half-maximal response (pD₂ = 7.81) was markedly greater than that required for occupation of half the β-adrenoceptor population (pK_B = 9.81). The β₁-selective blocker metoprolol antagonized the effect of (S)-pindolol and IPIN on the atrial rate but a greater concentration of metoprolol (5 × 10^?6 M compared with 5 × 10^?7 M) was required to antagonize the effect of IPIN significantly. It is concluded that iodination of (S)-pindolol increased its affinity and decreased its efficacy towards β-adrenoceptors.