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At least 109 records · Page 6Linked to original sources
PubMed1999

Axially chiral 1,7-naphthyridine-6-carboxamide derivatives as orally active tachykinin NK(1) receptor antagonists: synthesis, antagonistic activity, and effects on bladder functions.

Cyclic analogues of N-[3,5-bis(trifluoromethyl)benzyl]-7,8-dihydro-N, 7-dimethyl-5-(4-methylphenyl)-8-oxo-1,7-naphthyridine-6-carboxamide (1) having a 6-9-membered ring (6-9) were synthesized and evaluated for NK(1) antagonistic activities. The 8-membered ring compound with a beta-methyl group at the C((9))-position, (aR,9R)-7-[3, 5-bis(trifluoromethyl)benzyl]-8,9,10, 11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g] [1, 7]naphthyridine-6,13-dione [(aR,9R)-8b], was atropodiastereoselectively synthesized by cyclization of a chiral intermediate, 10g. On the other hand, the 7-membered ring compound with a beta-methyl group at the C((9))-position [(9S)-7b] was obtained as an equilibrium mixture of atropisomers with a ratio of ca. 3:2 in solution at room temperature (measured by NMR in CDCl(3)). Compounds (9S)-7b and (aR,9R)-8b exhibited excellent antagonistic activities both in vitro [IC(50) (inhibition of [(125)I]BH-SP binding in human IM-9 cells) = 0.28 and 0.45 nM, respectively] and in vivo (iv and po). Significantly, the in vitro activity of (aR, 9R)-8b was ca. 750-fold higher than that of its enantiomer (aS, 9S)-8b, ca. 40-fold higher than its atropisomer (aS,9R)-8b, and ca. 20-fold higher than its diastereomer (aR,9S)-8b. The structure-activity relationships in this series, along with the X-ray analysis of (aR,9R)-8b, indicated that the stereochemistry around the -C((6))(=O)-N((7))-CH(2)Ar moiety is important for NK(1) receptor recognition. The NK(1) antagonists showed effects on bladder functions in guinea pigs upon intravenous injection: i.e., the antagonists increased the shutdown time of distension-induced rhythmic bladder contractions and the bladder volume threshold, and the effects on the shutdown time were found to correlate well with the NK(1) antagonistic activities. Compound (aR,9R)-8b has been identified as a potential clinical candidate for the treatment of bladder function disorders.

Animals↗
PubMed2000

Palladium-catalyzed cross-coupling reactions for the synthesis of 6, 8-disubstituted 1,7-naphthyridines: a novel class of potent and selective phosphodiesterase type 4D inhibitors.

Recently, four subtypes of the human phosphodiesterase type 4 (PDE4A-D) enzyme have been described. So far, only very few PDE4 subtype-selective inhibitors are known. Herein, we describe the synthesis of 6,8-disubstituted 1,7-naphthyridines and their characterization as potent and selective inhibitors of PDE4D which suppress the oxidative burst in human eosinophils with IC(50) values as low as 0.7 nM. SAR development and the extended use of palladium-catalyzed cross-coupling reactions led to compound 11 which inhibited human PDE4D with an IC(50) value of 1 nM. Thus, compound 11 was 55, 175, and 1000 times more potent in inhibiting PDE4D over PDE4B, PDE4A, and PDE4C. In a Brown Norway rat model of allergic asthma, compound 11 when given by the oral route (1 mg/kg) reduced by more than 50% the influx of eosinophils, T-cells, and neutrophils into bronchoalveolar lavage fluid (BALF) samples obtained from antigen-challenged animals. Thus, PDE4D-selective inhibitors of the 1,7-naphthyridine class have the potential as an oral therapy for treating asthma.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed2004

Intramolecular inverse-electron-demand Diels-Alder reactions of imidazoles with 1,2,4-triazines: a new route to 1,2,3,4-tetrahydro-1,5-naphthyridines and related heterocycles.

The intramolecular inverse-electron-demand Diels-Alder reaction between imidazoles and 1,2,4-triazines linked by a trimethylene tether from the imidazole N1 position to the triazine C3 proceed in excellent yields to produce 1,2,3,4-tetrahydro-1,5-naphthyridines. The reaction proceeds by a cycloaddition with subsequent loss of nitrogen, followed by a presumed stepwise loss of a nitrile. The analogous intramolecular cycloadditions employing a tetramethylene tether also proceeded to give 2,3,4,5-tetrahydro-1H-pyrido[3,2-b]azepines in acceptable yields. The reaction to produce the tetrahydro-1,5-naphthyridines can also be promoted with microwave irradiation.

Cyclization↗
PubMed2004

Methods for the synthesis of 5,6,7,8-tetrahydro-1,8-naphthyridine fragments for alphaVbeta3 integrin antagonists.

The preparation of 3-(5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl)propan-1-amine 2a and 3-[(7R)-7-methyl-5,6,7,8-tetrahydro-1,8-naphthyridin-2-yl]propan-1-amine 2b, key intermediates in the synthesis of alpha(V)beta(3) antagonists, is described. The syntheses rely on the efficient double Sonogashira reactions of 2,5-dibromopyridine 3 with acetylenic alcohols 4a/4b and protected propargylamines 10a-e followed by Chichibabin cyclizations of 3,3'-pyridine-2,5-diyldipropan-1-amines 9a/9b.

Integrin alphaVbeta3↗
PubMed2005

Synthesis of a soluble ureido-naphthyridine oligomer that self-associates via eight contiguous hydrogen bonds.

[structure; see text] An iterative synthetic route to organic-soluble ureido-naphthyridine oligomers has been developed. Use of this protocol allowed synthesis of a short ureido-naphthyridine oligomer, which presents a self-complementary DDAADDAA hydrogen bonding array (D = hydrogen bond donor, A = hydrogen bond acceptor). Strong self-association via eight hydrogen bonds was observed in organic solution.

Hydrogen Bonding↗
PubMed1987

Antimalarial activity of Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol against Plasmodium falciparum in vitro.

Mono- and di-Mannich bases derived from 4-(7'-bromo-1',5'-naphthyridin-4'-ylamino)phenol and 4-(7'-trifluoromethylquinolin-4'-ylamino)phenol were assayed for antimalarial activity (using an in vitro radioisotopic technique) against two isolates of Plasmodium falciparum. Many from these two series of compounds had an IC50 value (concentration of compound causing 50% inhibition of 3H-hypoxanthine incorporation) comparable to or better than those of mefloquine and amodiaquine, for both a chloroquine-sensitive isolate (FCQ-27) and the chloroquine-resistant isolate (K1). At least one compound, 2,6-bis (piperidin-1''-ylmethyl)-4-(7'-trifluoromethylquinolin -4'-ylamino)phenol (TN112), showed significant superior activity to the three antimalarials chloroquine, mefloquine and amodiaquine against both isolates. (Statistically superior activity compared to these three antimalarials was found for TN112, except that against the K1 isolate its activity was just outside the range of significance relative to mefloquine.) Some of the 7-bromo-1,5-naphthyridine Mannich bases were appreciably less toxic in mice than amodiaquine.

Amines↗
PubMed2004

Properties and application of oligodeoxynucleotides containing the naphthyridine:imidazopyridopyrimidine base pairs with the ability to form four hydrogen bonds.

As our continuing study to develop base pairing motifs which stabilize and regulate DNA structure, we designed novel 1,8-naphthyridine C-nucleosides possessing Na-O(N) and Na-N(O) bases. These C-nucleosides formed two sets of naphthyridine:imidazopyridopyrimidine base pairing motifs (Na-O(N):Im-N(O) and Na-N(O):Im-O(N)) with four hydrogen bonds, and duplexes containing the pairs were markedly thermally stabilized independent of the manner in which the new pairs are incorporated.

Base Pairing↗
PubMed2005

NMR structural analysis of the G.G mismatch DNA complexed with naphthyridine-dimer.

Naphthyridine-dimer (ND) specifically recognizes G.G mismatch DNA (Figure 1). However, its detailed recognition mechanism is not clear. Here a DNA oligomer d(CTAACGGAATG)/d(CATTCGGTTAA) complexed with ND was studied by NMR. The stoichiometry of DNA to ND was determined to be 1:2 at NMR concentration (2.5 mM). Proton resonances were completely assigned including H5' and H5'' using 1H-1H and 1H-13C 2D spectra of the complex. These spectra showed that four naphthyridine rings are staked in the helix and form hydrogen bonds with the four G residues in CGG/CGG region. These results indicate ND can specifically recognize the CGG/CGG sequence.

Base Pair Mismatch↗
PubMed1996

The novel use of Rh(I) complexes with naphthyridine ligands and poly(oxyethylene) as antitumorals.

Rh(I) complexes adsorbed on polymers, as a way to improve their transport and solubility properties, were studied as antitumor agents. The binding constants of the complexes to the polymer were evaluated in order to determine the conditions for maximum association to the vehicle. The toxicity of the pure complexes and those bound were determined in vivo using female mice. [Rh(NBD)(2,4N)]CIO4, complex A; where NBD = norbornadiene, (2,4N) = 3,3'-dimethylene-2,2'-di-1,8-naphthyridine, was investigated on primary solid tumors and ascitic tumors. [Rh(NBD)(3,4N)]CIO4, complex B; where (3,4N) = 3,3'-trimethylene-2,2'-di-1,8-naphthyridine, was investigated on ascitic tumors. These Rh(I) complexes appear to be promising drugs because of their solubility in aqueous polymer, which make them easier to handle in comparison with the neutral species. These complexes show a similarity to cisplatin by reducing tumor growth and by increasing the survival life span of mice. Poly (oxyethylene) was used to solubilize these poorly water-soluble compounds and to stabilize the compounds in the solution before injection. These studies suggest that both complexes, A and B, are good candidates for tumor control growth and increase the survival time.

Animals↗
PubMed2001

5-amino-4-(4-diethylaminophenyl)-2-(4-hydroxyphenyl)-7-(pyrrolidin-1-yl)-1,6-naphthyridine-8-carbonitrile.

In the title compound, C29H30N6O, the naphthyridine moiety is planar with a dihedral angle between the fused rings of 1.9 (1) degrees. The phenol ring is nearly coplanar, while the diethylaminophenyl substituent is orthogonal to the central naphthyridine ring and the pyrrolidine ring makes an angle of 11.2 (1) degrees with it. The O atom of the hydroxy substituent is coplanar with the phenyl ring to which it is attached. The molecular structure is stabilized by a C-H...N-type intramolecular hydrogen bond and the packing is stabilized by intermolecular C-H...pi, O-H...N and N-H...O hydrogen bonds.

Crystallography, X-Ray↗
PubMed2000

Antiviral properties of a series of 1,6-naphthyridine and 7, 8-dihydroisoquinoline derivatives exhibiting potent activity against human cytomegalovirus.

A series of 1,6-naphthyridine (L. Chan, H. Jin, T. Stefanac, J. F. Lavallee, G. Falardeau, W. Wang, J. Bedard, S. May, and L. Yuen, J. Med. Chem. 42:3023-3025, 1999) and isoquinoline (L. Chan, H. Jin, T. Stefanac, W. Wang, J. F. Lavallee, J. Bedard, and S. May, Bioorg. Med. Chem. Lett. 9:2583-2586, 1999) analogues exhibiting a high level of anti-human cytomegalovirus (HCMV) activity were investigated in a series of studies aimed at better understanding the mechanism of action of some representatives of this class of compounds. In vitro antiviral profiling revealed that these compounds were active against a narrow spectrum of viruses, essentially the human herpesviruses and type 2 rhinovirus. In HCMV assays, a 39- to 223-fold lower 50% inhibitory concentration was obtained for compound A1 than for ganciclovir against strains AD 169 and Towne. In addition, ganciclovir, foscarnet, cidofovir, and BDCRB (2-bromo-5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole)-resistant HCMV strains remained susceptible to 1,6-naphthyridines and 7, 8-dihydroisoquinolines tested in this study, supporting the view that a novel mechanism of action could be involved. Drug combination studies showed a small but significant synergistic antiviral effect between compound B2 and ganciclovir. Cytotoxicity profiling of representative compounds under various cell growth conditions indicated a generally similar cytotoxic effect, relative to ganciclovir, in log-phase growing cells. However, in stationary cells, a relatively higher level of toxicity was observed than that for control compound. Effect of time of drug addition showed that the anti-HCMV activity of compound A1, ganciclovir, and cidofovir was lost at approximately the same time (72 h postinfection), indicating that the compound was affecting events at the early and late stage of virus replication. This interpretation is also supported by reduction of de novo synthesis of pp65 tegument protein and lack of any effect of the compound on viral adsorption. A reduction of the HCMV enhancer-promoter-directed luciferase expression was also observed in a stably transfected cell line when compound A1 was present at relatively high concentrations.

Antiviral Agents↗
PubMed2006

Ratiometric fluorescence detection of pyrimidine/purine transversion by using a 2-amino-1,8-naphthyridine derivative.

A new class of abasic site-binding fluorescence ligands, Naph-NBD in which 7-nitrobenzo-2-oxa-1,3-diazole (NBD) is connected to 2-amino-7-methyl-1,8-naphthyridine (Naph) by a propylene linker, is presented for the ratiometric assay for SNPs typing. In solutions buffered to pH 7.0 (I = 0.11 M, at 5 degrees C), Naph-NBD is found to selectively recognize pyrimidine bases over purine bases opposite the abasic site in DNA duplexes (K11/M(-1): T, 8.1 x 10(6); C, 2.5 x 10(6): G, 0.33 x 10(6); A, 0.27 x 10(6)). The binding of Naph-NBD is accompanied by significant quenching of the fluorescence from the naphthyridine moiety (lambda max, 409 nm), while the emission from the NBD (lamda max, 544 nm) is relatively unaffected. Such a fluorescence response of Naph-NBD allows the emission ratio detection of pyrimidine/purine transversion.

Base Pairing↗
PubMed1976

[Synthesis and biological activity of 1,2,3-triazol-1,8-naphthyridines].

The reaction of 2-methyl-5-azido-1,8-naphthyridine with active methylene compounds was investigated. Several naphthyridines which possess the 1,2,3-triazole ring as a substituent were obtained. Among these compounds (IV o) showed an analgesic activity twice that of phenylbutazone.

Analgesics↗
PubMed1989

[Synthesis of 7-(1,7-disubstituted-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxamido) -cephalosporins].

A series of new 7-(1, 7-disubstituted-1, 4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxamido)-cephalosporins has been prepared by acylation of the 7-amino group of 7-ADCA, 7-ACA, 7-ACT and 7-ACD with 1, 7-disubstituted-1, 4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. Mixed carboxylic-carbonic anhydride method was adopted in the reactions. Isolation and purification were fulfilled with Sephadex LH-20 column chromatography and centrifugal-TLC technique. Twenty four new cephalosporin derivatives were synthesized. Their structures have been confirmed by elemental analysis, IR and 1HNMR. In preliminary In vitro antibacterial sensitivity tests, most of these new derivatives were found to show good sensitivity to Gram-positive bacteria. Bacteriostasis were also observed for some Gram-negative bacteria.

Cephalosporins↗
PubMed1976

1,8-naphthyridine derivatives: synthesis and pharmacological evaluation of beta-receptor blocking activity.

The synthesis of a number of 1-alkyl-7-(2-hydroxy-3-alkylaminopropoxy)-1,8-naphthyridin-2-ones is described. The compounds studied were prepared by reaction of 1-alkyl-7-hydroxy-1,8-naphthyridin-2-ones with epichlorohydrin. The substituted epoxy intermediates obtained were allowed to react with amines and gave the desired products. All the compunds prepared were devoid of beta-blocking activity.

Adrenergic beta-Antagonists↗
PubMed1978

Synthesis of some 11H-indolo[3,2-c][1,8]naphthyridines.

The preparation of some 11H-indolo[3,2-c] [1,8]naphthyridines (V), having oxygen functions at positions 3 or 3 and 10 or 3 and 8, as in steroidal active compounds, is described. Compounds (V) were obtained using the Fisher indole synthesis. The preparation of the parent nucleus: 11H-indolo [3,2-c] [1,8]naphthyridines (V n) is also described. Some compounds were subjected to pharmacological screening, but none was found to be significantly active.

Animals↗
PubMed1994

Synthesis and benzodiazepine receptor activity of some 4,5-dihydro-1H-pyrazolo[4,3-c][1,8]naphthyridine derivatives.

The preparation of 5-substituted 1-aryl-4,5-dihydro-1H-pyrazolo[4,3- c][1,8] naphthyridines by reaction of 5-substituted 3-hydroxymethylene-2,3-dihydro-1,8-naphthyridin-4(1H)-ones with various phenylhydrazines is described. The benzodiazepine binding activity of these compounds was evaluated in vitro. Only the 5-methyl substituted derivatives showed affinity for the benzodiazepine receptor, with K1 values ranging from 2.9 to 0.195 microM for the para-phenyl substituted compounds. A hypothesis of interaction of these ligands with the receptor site is reported.

Animals↗