Dieter Heber

General Method for the Preparation of Substituted 2-Amino-4H,5H-pyrano[4,3-b]pyran-5-ones and 2-Amino-4H-pyrano[3,2-c]pyridine-5-ones

Pharmaceutical Institute, Christian-Albrechts University of Kiel, Gutenbergstr. 76, D-24118 Kiel,GermanyTel.: (+49-431) 880-1118, Fax: (+49-431) 880-1352, E-mail: dheber@pharmazie.uni-kiel.de*Author to whom correspondence should be addressed.Received: 7 December 1999 / Accepted: 31 December 1999 / Published: 21 January 2000Abstract: Reaction of 4-hydroxy-6-methyl-2-pyrone (1a) as well as 4-hydroxy-6-methyl-2(1H)-pyridones (1b-d) with arylmethylene malononitriles or arylmethylene methyl cyano-acetates (2a-h) leads to the formation of the very stable 5,6-fused bicyclic 2-amino-4H-pyran derivatives 3a-3af.Keywords: pyrano[4,3-b]pyran, pyrano[3,2-c]pyridine, arylmethylene malononitrile, aryl-methylene cyanoacetate, Michael addition.IntroductionWiener et al. first published [1] that 4-hydroxycoumarin cyclized through Michael addition to ben-zylidene malononitrile in pyridine as solvent to give a derivative of 2-aminopyrano[3,2-c]benzopyran(A) (Figure 1). Later, Junek and Aigner [2] found a second case of this heterocyclization via additionof 4-hydroxy-6-methyl-2-pyrone (1a, “triacetic acid lactone”, Scheme 1) to tetracyanoethylene, thuspreparing a substituted 2-amino-4H,5H-pyrano[4,3-b]pyran (B). Many years thereafter, Shaker [3] re-

Synthesis, Pharmacological and Biophysical Characterization, and Membrane-Interaction QSAR Analysis of Cationic Amphiphilic Model Compounds⊥

Cationic amphiphilic drugs have a propensity to interact with biological interphases. This study was designed to gain more insight into the molecular properties of catamphiphilic drugs which govern this type of interaction. A series of phenylpropylamine model compounds were synthesized in which modifications were incorporated at the aromatic part of the molecule. The replacement of (45)Ca(2+) from phosphatidylserine monolayers served to monitor drug binding to the phospholipid. The influence on the phase-transition temperature of liposomes of dipalmitoylphosphatidic acid was measured to assess the perturbing action of the drugs on the structural organization of phospholipid assemblies. The antiarrhythmic activity of the compounds was determined in Langendorff preparations of guinea pig hearts to assess the membrane-stabilizing action. Quantitative structure-activity relationship (QSAR) models for these endpoints were developed using both intra- and intermolecular QSAR descriptors. Intermolecular membrane-interaction descriptors were derived from molecular dynamics simulations of the compounds in a model phospholipid monolayer. QSAR models were derived for all endpoints using partial least-squares regression (PLS) and a genetic algorithm tool, the genetic function approximation (GFA). Membrane-interaction descriptors appear to be of a particular importance in explaining the influence of the compounds on the phase-transition temperature of DPPA liposomes, while the other endpoints can be adequately modeled by intramolecular descriptors. The calcium-displacing activity at phosphatidylserine monolayers is governed by the electrostatic properties of the compounds. Measures of lipophilicity and molecular size are of particular importance for antiarrhythmic activity. Possible improvements to both the molecular modeling and the applied computational protocol of membrane-solute systems are identified and discussed.

Synthesis and evaluation of pyrido[ 1,2-a]pyrimidines as inhibitors of nitric oxide synthases

A series of new 3-aroylpyrido[1,2-a]pyrimidines were synthesized from aryl methyl ketones in a simple two-step procedure and evaluated as nitric oxide synthases (NOS) inhibitors. In order to perform a structure-activity relationship study, different aroyl groups were introduced in 3-position and methyl groups were introduced at different positions of the pyrimidine heterocycle. Compounds with a biphenyloyl, benzyloxybenzoyl or naphthoyl group displayed the highest inhibitory effects which were further increased by introduction of a methyl group in position 8 of the pyrido[1,2-a]pyrimidine moiety. Some of the compounds exhibited promising inhibitory effects with selectivity toward the purified inducible NOS (iNOS) and were also active against iNOS expressed in stimulated RAW 264.7 cells.

Reaktionen von N-alkoxycyclimoniumsalzen—V: Vinyloge phosphorane aus N-methoxypyridiniumsalzen

Zusammenfassung Die cyansubstituierten N-Methoxypyridiniumsalze 1 reagieren mit Aethoxycarbonylmethylen (triphenyl)phosphoran in dipolar aprotischen Losungsmitteln (DMF, HMPT u.a.) unter Spaltung des Pyridinringes zu vinylogen Phosphoranen 6 . Nach den 1 H-NMR-Spektren der ringoffenen Verbindungen besitzen die konjugierten Doppelbindungen all-trans-Konfiguration.

The ability of cationic amphiphilic compounds to depress the transition temperature of dipalmitoylphosphatidic acid liposomes depends on the spatial arrangement of the lipophilic moiety

The hypothesis was tested with the help of model compounds that the ability of cationic amphiphilic drugs to depress the phase-transition temperature Tt of dipalmitoylphosphatidic acid (DPPA) liposomes depends on the spatial arrangement of the lipophilic moiety. The main structure of the compounds with identical cationic side chain was 1-dimethylamino-3-phenylpropane (compound I). A further phenyl ring was introduced either at C3 of the propane chain (compound II) to broaden the lipophilic moiety, or in para-position of the phenyl ring (compound III) to elongate it. As shown by differential scanning calorimetry, the reduction of Tt (control 64 degrees) amounted for compound I to 29 degrees, for compound II to 28 degrees and for compound III to 53 degrees. In order to assess the binding affinity of the compounds to DPPA, their inhibitory effect on 45Ca(2+)-binding to DPPA films was measured. The IC50 values were 2100 microM for compound I, 40 microM for compound II, and 9 microM for compound III. Thus, binding affinity corresponded with the hydrophobicity of the compounds. In contrast, the depressing effect on the transition temperature was only augmented by the additional phenyl ring when substituted in the elongating position.

Synthesis and Reactions of Aroyl Substituted Enone Mannich Salts

The classical Mannich reaction of aromatic methyl ketones with paraformaldehyde and dimethylamine hydrochloride resp. dimethyl(methylene)ammonium chloride has been extended to a few cases of 1-aryl-2-dimethylaminomethyl-prop-2-en-1-ones (ADMP reagents). They have gained remarkable attention in medicinal chemistry, but only more recently their properties as valuable building blocks for ring closure reactions to form either aroyl or dimethylaminomethyl substituted heterocyclic compounds has been evaluated. In this review, a collection of representative examples for their preparation (Scheme 2) and biological effects as well as the synthetic potential for the synthesis of heterocycles (Scheme 3—8) is given. The reaction of 4-hydroxycoumarin delivers with ADMP reagents, via the formation of detectable 3-(2-benzoylallyl)-4-hydroxycoumarins as secondary substitution products, after ring closure 3-benzoyl-3,4-dihy-dro-2H,5H-1-benzopyrano[4,3-b]pyran-5-ones (Scheme 4). The reaction of 4-hydroxy-6-methylpyran-2-one with ADMP reagents is investigated systematically in order to assess its suitability in carbon—carbon bond forming reactions as well as to provide the conditions for subsequent ring closure or intermolecular addition of further nucleophiles to the enone double bond of the intermediate 3-(2-benzoylallyl)-4-hy-droxy-6-methylpyran-2-ones yielding miscellaneous 3-substituted 2-pyrones (Scheme 5 and 8), and their application as building blocks for the combinatorial chemistry. The condensation of ADMP reagents with 2-aminopyridines gives rise to 3-benzoyl-3,4-dihydro-2H-pyrido[1,2-a]pyrimidines (Scheme 6) and the corresponding reaction using amidines affords 5-benzoyl-1,4,5,6-tetrahydropyrimidines (Scheme 7).

Triggering the Directional Selectivity of a Ring‐Closure Reaction Leads to Pyridoazacarbazoles with Anticancer Properties

We herein describe a facile and versatile synthetic route to the tetracyclic system of 6-substituted 5,6-dihydro-11H-pyrido[3,2-i]-1-azacarbazoles with promising anticancer properties. These derivatives are built up by an elegant one-step base-catalyzed synthetic procedure from commercially available building blocks. One additional step provides the corresponding skeleton hitherto unknown in the literature. The possibility to synthesize a large library of compounds with various substitution patterns utilizing this method underlines the importance of this synthetic procedure.

Reaktionen von N-Alkoxycyclimoniumsalzen, VI. Polyene aus N-Methoxypyridiniumsalzen und Carbanionen

Elektronegativ substituierte N-Methoxypyridiniumsalze 1 reagieren mit CH-aciden Verbindungen in dipolar aprotischen Losungsmitteln (Dimethylformamid, Hexamethylphosphorsauretriamid) unter Spaltung des Pyridinringes zu den Polyenen 2-7. Die Umsetzung mit dem ambidenten nucleophilen Reagens β-Aminocrotonitril fuhrt zu 6 b und 8, die in Abhangigkeit vom Reaktionsmedium in unterschiedlichem Mengenverhaltnis anfallen. Nach ihren 1H-NMR-Spektren besitzen die konjugierten Doppelbindungen all-trans-Konfiguration. Die IR- und UV-Spektren werden diskutiert. Reactions of N-Alkoxycyclimonium Salts, VI. - Polyenes from N-Methoxypyridinium Salts and Carbanions In dipolar aprotic solvents (dimethylformamide, hexamethylphosphoric acid triamide), the electronegatively substituted N-methoxypyridinium salts 1 undergo ring cleavage on reaction with CH-acidic compounds to give the polyenes 2-7. The ambident nucleophilic reagent β-aminocrotononitrile reacts with 1 yielding 6b and 8 in varying ratios depending on the solvent used. All-trans-configuration of the conjugated double bonds follows from the IH-NMR spectra. The IR and UV spectra are discussed.

11‐Substituted Benzo[c]phenanthridines: New Structures and Insight into Their Mode of Antiproliferative Action

The synthesis of various new structures of a library of 11‐substituted 6‐amino‐11,12‐dihydrobenzo[c]phenanthridines (BP) and 11‐substituted 6‐aminobenzo[c]phenanthridines (BP‐D) is presented. These structures, further synthetic modifications, and the preparation of follow‐up products which delivered about 40 new derivatives are described. Their potential as antiproliferative drug candidates was investigated by comparison of NCI 60 developmental therapeutics program (DTP) human tumor cell line screening data based on the results of in vitro tumor cell growth inhibition, including about 40 hitherto unpublished compound test results with up to 60 cancer cell lines. NCI‐COMPARE studies helped to suggest the modes of action of the highly active antiproliferative drugs. These findings are supported by in vitro biological investigations showing either inhibition of tubulin polymerization and depolymerization or topoisomerase inhibition. Together with physicochemical parameters of the drug candidates, structure–activity relationships are critically discussed. Tubulin interaction or inhibition of topoisomerase I and IIα/β activity are two rationales that can explain the antiproliferative activity observed in the NCI 60 DTP human tumor cell line screen. However, it can also be reasonably assumed that these compounds address several targets, thus prohibiting the identification of simple structure–activity relationships. The new structures described herein are thought to act as so‐called multitarget drugs, thus being of special interest in the area of multidrug resistance.

1H, 13C and 15N NMR spectral analysis of substituted 1,2,3,4‐tetrahydro‐pyrido[1,2‐a]pyrimidines

The NMR spectroscopic data of a series of thirty‐four 3‐acylpyrido[1,2‐a]pyrimidinium salts are analyzed, which were prepared as either perchlorates or chlorides. Methyl group substituted 3‐aroyltetrahydropyrido[1,2‐a]pyrimidines with the methyl substituent in positions 6, 8 and 9 as well as both in positions 6 and 8 were investigated bearing various aroyl substituents. Unequivocal assignment of all resonances was achieved via two‐dimensional 1H,1H‐COSY measurements, 1H,13C and 1H,15N HSQC as well as HMBC experiments, and important diagnostic CH and NH couplings in the heteroaromatic ring system are evaluated. The influence of the methyl substituents was analyzed on the proton, carbon and nitrogen shifts. A significant effect of the counter ion on some chemical shifts of the nuclei under discussion of the pyridopyrimidines is found, allowing the indirect detection of the anion, which is confirmed by direct measurement of the 35Cl nucleus of the perchlorates. Copyright