pyrimidinones and piperidine

The de novo synthesis of piperidine nucleosides from our homologating agent 5,6-dihydro-1,4-dithiin is herein reported. The structure and conformation of nucleosides were conceived to faithfully resemble the well-known nucleoside drugs Immucillins H and A in their bioactive conformation. NMR analysis of the synthesized compounds confirmed that they adopt an iminosugar conformation bearing the nucleobases and the hydroxyl groups in the appropriate orientation.

Topics: Adenine; Adenosine; Magnetic Resonance Spectroscopy; Molecular Conformation; Nucleosides; Piperidines; Purine Nucleosides; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

Dihydropyrimidinone derivatives containing piperidine moiety were synthesised in a good yield. All the compounds were confirmed by elemental analysis and spectral data. Anti-ulcer activity of novel dihydropyrimidinone-piperidine hybrids (1-18) was evaluated. Among them, four compounds (3, 8, 11 and 15) were found to be most active in 80% ethanol-induced ulcer experimental animal model. All the potent compounds were further evaluated for anti-ulcer activity by different in vivo anti-ulcer models to study the effect of compounds on anti-secretory and cytoprotective activities. All the active compounds inhibited the formation of gastric ulcers and increased the formation of gastric mucin secretion. Compound 15 was found to be the most potent compound of the series as anti-ulcer agent. Additional experimental studies on lead compound 15 will result in a new class of orally active molecule for anti-ulcer activity.

Topics: Animals; Anti-Ulcer Agents; Crystallography, X-Ray; Disease Models, Animal; Dose-Response Relationship, Drug; Ethanol; Models, Molecular; Molecular Structure; Piperidines; Pyrimidinones; Rats; Rats, Wistar; Stomach Ulcer; Structure-Activity Relationship

The title compound, piperidinium 6-amino-3-methyl-5-nitroso-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ide 6-amino-3-methyl-5-nitrosopyrimidine-2,4(1H,3H)-dione, C(5)H(12)N(+).C(5)H(5)N(4)O(3)(-).C(5)H(6)N(4)O(3), (I), crystallizes with Z' = 2 in the space group P1. There is an intramolecular N-H...O hydrogen bond in each pyrimidine unit and within the selected asymmetric unit the six independent components are linked by 11 hydrogen bonds, seven of the N-H...O type and four of the N-H...N type. These six-component aggregates are linked into sheets by five further hydrogen bonds, three of the N-H...O type and one each of the N-H...N and C-H...O types.

Topics: Crystallography, X-Ray; Hydrogen Bonding; Molecular Structure; Piperidines; Pyrimidinones

All the nine 1,3-dialkylated-pyrimidin-2,4-diones investigated are active against all the 59 human tumor cell lines. Compounds 2, 3, 4, and 6 show significant anti-cancer activities at some specific cell lines while compounds 7 and 9 exhibit anti-cancer activities against more number of cell lines. The structure-activity relationship studies indicate that the presence of piperidine/pyrrolidine at the end of C-6 chain, benzoyl group at C-5, and benzyl groups at N-1, N-3 of the pyrimidine ring increases the anti-cancer activities of these molecules.

Topics: Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Humans; Neoplasms; Piperidines; Propanolamines; Pyrimidines; Pyrimidinones; Pyrrolidines; Structure-Activity Relationship

We have previously described compound 1a as a high-affinity subtype selective alpha(1a) antagonist. In vitro and in vivo evaluation of compound 1a showed its major metabolite to be a mu-opioid agonist, 4-methoxycarbonyl-4-phenylpiperidine (3). Several dihydropyrimidinone analogues were synthesized with the goal of either minimizing the formation of 3 by modification of the linker or finding alternative piperidine moieties which when cleaved as a consequence of metabolism would not give rise to mu-opioid activity. Modification of the linker gave several compounds with good alpha(1a) binding affinity (K(i) = < 1 nM) and selectivity (>300-fold over alpha(1b) and alpha(1d)). In vitro analysis in the microsomal assay revealed these modifications did not significantly affect N-dealkylation and the formation of the piperidine 3. The second approach, however, yielded several piperidine replacements for 3, which did not show significant mu-opioid activity. Several of these compounds maintained good affinity at the alpha(1a) adrenoceptor and selectivity over alpha(1b) and alpha(1d). For example, the piperidine fragments of (+)-73 and (+)-83, viz. 4-cyano-4-phenylpiperidine and 4-methyl-4-phenylpiperidine, were essentially inactive at the mu-opioid receptor (IC(50) > 30 microM vs 3 microM for 3). Compounds (+)-73 and (+)-83 were subjected to detailed in vitro and in vivo characterization. Both these compounds, in addition to their excellent selectivity (>880-fold) over alpha(1b) and alpha(1d), also showed good selectivity over several other recombinant human G-protein coupled receptors. Compounds (+)-73 and (+)-83 showed good functional potency in isolated human prostate tissues, with K(b)s comparable to their in vitro alpha(1a) binding data. In addition, compound (+)-73 also exhibited good uroselectivity (DBP K(b)/IUP K(b) > 20-fold) in the in vivo experiments in dogs, similar to 1a.

Topics: Adrenergic alpha-1 Receptor Antagonists; Adrenergic alpha-Antagonists; Animals; Biological Availability; Blood Pressure; Dogs; Drug Design; Drug Evaluation, Preclinical; GTP-Binding Proteins; Half-Life; Humans; In Vitro Techniques; Male; Microsomes; Piperidines; Prostate; Pyrimidinones; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Receptors, Opioid, mu; Recombinant Proteins; Stereoisomerism; Structure-Activity Relationship; Urethra

An optimized automated PNA synthesis protocol is reported. Under optimal conditions the product yield of a test 17-mer PNA is approximately 90%. The average coupling yield is 99.4%. The synthesis strategy is Boc/Z and the deprotected amine is neutralized in situ. The monomers are added in molar excess to HATU and pre-activated for 60 s before delivery to the resin. The concentration of the activated monomers is 0.08 M during the couplings. Heteroselective solvation provides the highest coupling yields. Acetic anhydride is used as capping reagent followed by a piperidine wash. The protocol has been developed in a 5 mumol scale but is easily scaled up to 10-50 mumol scale syntheses on the automated synthesizer (ABI 433A).

Topics: Biopolymers; Chromatography, High Pressure Liquid; Glycine; Nucleic Acids; Peptides; Piperidines; Purines; Pyrimidinones; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization