Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as serotonin 5-HT4 receptor agonists

A series of N-azabicycloalkyl-1-alkyl-2-oxo-1,2-dihydro-3-quinolinecarboxamides were synthesized and tested for serotonin 5-HT4 receptor-stimulating effects in the regulation of electrically-evoked contraction in guinea pig muscle. Among them, N-azabicycloalkyl-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, 9c, 10c, 11c, 12c) exhibited potent serotonin 5-HT4 receptor-stimulating activity. The most potent compound, N-(endo-8-methyl-8-azabicyclo[3.2.1 oct-3-yl)-1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxamide (8c, ED50 = 36.3 nMi), was seven times as active as cisapride, while 8c had no affinity for 5-HT1A, 5-HT1D, D2, muscarinic M2 or muscarinic M3 receptors even at 10 microM. Compound 8c stimulated digestive tract motility in conscious fed dogs (1.0 mg/kg p.o.).     

Synthesis and pharmacology of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives, a new class of potent serotonin-3 (5-HT3) receptor antagonists.

A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v.     

Synthesis and biological evaluation of 1,2,3,4-tetrahydroisoquinoline derivatives as potent and selective M2 muscarinic receptor antagonists.

A series of 1,2,3,4-tetrahydroisoquinoline derivatives containing the 5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one skeleton were prepared and evaluated for their in vitro binding affinities to muscarinic receptors and for antagonism of bradycardia in vivo. Among them, compound 3f had the highest affinity for M2 muscarinic receptors in the heart (pKi = 9.1) with low affinity for M3 muscarinic receptors in the submandibular gland. A structure-activity relationship (SAR) study suggested that the benzene ring fused piperidine and the alkyl linker chain length are crucially important for increased M2 affinity.     

Synthesis and evaluation of 3-methyl-4-oxo-6-phenyl-4,5,6,7-tetrahydrobenzofuran-2-carboxylic acid ethyl ester derivatives as potent antitumor agents

For the construction of new combinatorial libraries, a lead compound was created by replacing the core structure of a hit compound discovered by screening for cytotoxic agents against a tumorigenic cell line. The newly designed compound maintained biological activity and allowed alternative library construction for antitumor drugs.     

Synthesis and isomeric conversions of several 2-substituted 1,4-dihydro-4-oxo-3-quinolinecarboxylic acid derivatives

Ethyl ester derivatives of 6- and 8-substituted 2-methyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids have been synthesized by treatment of the diethyl ester of acetylmalonic acid with 2- or 4-substituted anilines. Condensation of these newly synthesized quinolinecarboxylic acid derivatives with 4-nitrobenzaldehyde resulted in the formation of 6- and 8-substituted 2-[2-(4-nitrophenyl)-vinyl]-1, 4-dihydro-4-oxo-3-quinolinecarboxylic acids and ethyl esters of 6- and 8-substituted 2-[2-(4-nitrophenyl)vinyl]-4-acetoxy-3-quinolinecarboxylic acids. The tautomeric and conformational transformations of these newly synthesized compounds have also been investigated, using IR, NMR, and UV spectroscopy.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 931–938, July, 1988.     

Synthesis,characterization, and docking studies of novel cyanopyridone analogs with serotonin 5-HT1B receptor agonists

The medications in use for treating migraine are directed either towards inhibiting the characteristic migraine pain or towards preventing it from occurring. In this pursuit, ergotamine and sumatriptan class of 5-HT_1B receptor agonists have been proved to be extremely effective. Further research into this field led us to design cyanopyridone derivatives that were synthesized through cyclization of 2-cyano-N-phenylacetamides with malonitrile and 2,3-dihydrobenzo[b][1,4]dioxine-6-carbaldehyde. The synthesized cyanopyridones analogs, when docked with active site of 5-HT_1B receptor, showed better binding affinity compared to standard antimigraine medications. Additionally, in silico ADME prediction for drug-likeness and pharmacokinetics revealed that all compounds are safer and can be used as antimigraine medicine. The structure of the synthesized compounds has been elucidated on the basis of spectral analysis.     

Studies on chemotherapeutics I. Synthesis of 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acid derivatives

Ethyl 5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylates were synthetized by reacting 1,3,5-triazine with 4-substituted ethyl acetoacetate derivatives in ethanol, in the presence of sodium ethoxide. The l-alkyl-5-substituted-4-oxo-1,4-dihydro-3-pyridinecarboxylic acids required for the antimicrobial studies were prepared by N-alkylation (with triethyl phosphate or alkyl halides) and alkaline hydrolysis of the pyridone esters.     

Synthesis of 2-quinolinecarboxamide derivatives as potential HDAC inhibitors

Inhibition of histone deacetylase activity appears as an original and effective approach for the treatment of cancer. A series of novel quinoline-containing derivatives has been synthesized and found that some of these compounds possess nanomolar histone deacetylase inhibitory activity.     

Synthesis and structure-activity relationships of 4-amino-5-chloro-N-(1,4-dialkylhexahydro-1,4-diazepin-6-yl)-2-methoxybenzamide derivatives,novel and potent serotonin 5-HT3 and dopamine D2 receptors dual antagonist

In search of a dopamine D2 and serotonin 5-HT3 receptors dual antagonist as a potential broad antiemetic agent, a number of benzamides were prepared from 4-amino-5-chloro-2-methoxybenzoic acid derivatives and 6-amino-1,4-dialkylhexahydro-1,4-diazepines and evaluated for their binding affinity for the dopamine D2 and the serotonin 5-HT3 receptors using rat brain synaptic and rat cortical membranes, respectively. From the results of both in vitro receptor binding and in vivo biological assays for the dopamine D2 receptor, 1-ethyl-4-methylhexahydro-1,4-diazepine ring was selected as an optimum amine moiety. Introduction of one methyl group on the nitrogen atom at the 4-position and/or modification of the substituent at the 5-position of the 4-amino-5-chloro-2-methoxybenzoyl moiety caused a marked increase in the dopamine D2 receptor binding affinity along with a potent 5-HT3 receptor binding affinity. Among the compounds, 5-chloro-N-(1-ethyl-4-methylhexahydro-1,4-diazepin-6-yl)-2-methoxy-4-methylaminobenzamide (82), 5-bromo (110), and 5-iodo (112) analogues exhibited a much higher affinity for the dopamine D2 receptor than that of metoclopramide (IC50=17.5-61.0 nM vs. 483 nM). In particular, 82 showed a potent antagonistic activity for both receptors in vivo tests. Optical resolution of the racemate 82 brought about a dramatic change in the pharmacological profile with the (R)-enantiomer exhibiting a strong affinity for both the dopamine D2 and the 5-HT3 receptors, while the corresponding (S)-enantiomer had a potent and selective serotonin 5-HT3 receptor binding affinity.     

Synthesis of GR 125487, a selective 5-HT4 receptor antagonist

The 5-HT₄ receptor (5-HT₄R) agonists are important in treating gastrointestinal motility disorders. Their role is currently being evaluated for the treatment of cognitive and mood disorders. A selective 5-HT₄R antagonist GR 125487 is used in many biological assays to cross confirm the 5-HT₄R agonist’s activity. A practical synthesis of GR 125487 is developed so as to have it in desired quantities. The synthesis consists of seven steps starting from commercially available methyl 5-fluoroindole 3-carboxylate. The GR 125487 thus synthesized was used in blocking the activity of 5-HT₄R agonist compound in animal models of cognition.     

A convenient synthesis of N-aryl-1,2-dihydro-2-oxo-3-pyridinecarbox-amides,N-aryl-N-methyl-1,2-dihydro-2-oxo-3-pyridinecarboxamides and their 1-methyl (O-methyl)-derivatives

A new and versatile method for the preparation of the isonixine analogues, N-aryl-1,2-dihydro-2-oxo-3-pyridinecarboxamides and N-aryl-N-methyl-1,2-dihydro-2-oxo-3-pyridinecarboxamides is described via the selective chlorination of 2-hydroxynicotinic acid. In order to prepare these new compounds, the chemistry of the methyl-blocked forms of each tautomer is discussed.     

Synthesis of novel apio carbocyclic nucleoside analogues as selective a(3) adenosine receptor agonists

On the basis of the biological activity of neplanocin A and apio-dideoxyadenosine (apio-ddA), novel apio-neplanocin A analogues 5a-d, combining the properties of two nucleosides, were stereoselectively synthesized. The apio moiety of the target nucleosides 5a-d was stereoselectively introduced by treating lactol 10 with 37% formaldehyde in the presence of potassium carbonate. The carbasugar moiety of neplanocin A was successively built by exposing diene 12 on a Grubbs catalyst in methylene chloride. The final nucleosides 5a-d were synthesized from the condensation of the glycosyl donor 14 with nucleic bases under the standard Mitsunobu conditions. Similarly, apio-aristeromycin 6 and (N)-apio-methanocarbaadenosine 7 were derived from the common intermediate 13 using catalytic hydrogenation and Simmons-Smith cyclopropanation as key steps. All of the final nucleosides 5a-d, 6, and 7 did not show significant inhibitory activity against S-adenosylhomocysteine hydrolase (SAH) up to 100 muM, maybe due to the absence of the secondary hydroxyl group at the C3'-position, which should be oxidized by cofactor-bound NAD(+). However, apio-neplanocin A (5a) showed potent and highly selective binding affinity (K(i) = 628 +/- 69 nM) at the A(3) adenosine receptor without any binding affinity at the A(1) and A(2A) adenosine receptors. In conclusion, we have first developed novel carbocyclic nucleosides with unnatural apio-carbasugars using stereoselective hydroxymethylation and RCM reaction and also discovered a new template of human A(3) adenosine receptor agonist, which play a great role in developing new A(3) adenosine receptor agonist as well as in identifying the binding site of the receptor.     

1-Oxo-5-hydroxytryptamine: a surprisingly potent agonist of the 5-HT3 (serotonin) receptor

A novel synthetic route to 1-oxo-5-hydroxytryptamine, the benzofuran analogue of serotonin, has been developed. The new synthesis proceeds via the [3+2] cycloaddition of p-benzoquinone and 2,3-dihydrofuran, followed by a Lewis acid-catalyzed isomerization. This molecule proves to be a competent agonist (equipotent to serotonin) of the 5-HT3 receptor, demonstrating that the indolic proton of serotonin is not essential to its activation of the receptor.     

Synthesis of 1,4-dihydro-2-methyl-4-oxo-3-quinolineglyoxylic acid and related compounds

The synthesis of 1,4-dihydro-1-methoxy or ethyl -2-methyl-4-oxo-3-quinolineglyoxylic acid derivatives are described. α-Acetoxy-1,4-dihydro-1-hydroxy-2-methyl-4-oxo-3-quinolineacetic acid esters ( 7a, 7a ), which are key intermediates, were prepared by catalytic hydrogenation of 2-acetoxy-3-acetyl-4-hydroxy-4-(2-nitrophenyl) crotonic acid lactone ( 6 ) in methanol or ethanol.