Synthesis and Gastrointestinal Prokinetic Activity of Novel Benzamide Derivatives with Amphoteric Side Chains.

Abstract

Metoclopramide (1a), possessing a dopamine D 2 receptor antagonist and weak serotonin 5-HT 4 receptor agonist activities, 1a) is used clinically as a gastrointestinal prokinetic and an antiemetic agent. 1b) However, its clinical application is limited due to its side effects, such as extrapyramidal syndrome, parkinsonism and elevated serum prolactin levels, caused by blockage of the dopamine D 2 receptor.We previously reported that the introduction of a methylenephenoxy group between the benzamide moiety and the terminal aminoalkyl groups of 1a led to the discovery of itopride (2), with an appropriate dopamine D 2 receptor antagonist activity and a distinctive acetylcholine esterase inhibitory activity.2) On the other hand, we suggested that amphoteric-ionization would be a useful approach to discovering a new drug, and actually succeeded in finding selective histamine H 1 antagonists by applying this method to classical antihistaminics.3) We initially applied the amphoteric-ionization to 1a in order to find a new type of gastrointestinal prokinetic agent. Although we preliminarily synthesized an amphoteric-ionized compound (3) by the introduction of an alkanecarboxylic acid moiety onto the terminal nitrogen atom of 1a, it had no significant gastrointestinal prokinetic activity. Cisapride (1b), 4) which has a conformationally restricted amino moiety in comparison with 1a, has been found to show more potent gastrointestinal prokinetic activity than 1a. We therefore expected that some kind of conformational restriction of 3 would lead to an increased gastrointestinal prokinetic activity, and designed a series of [[(4-amino-5-chloro-2-methoxybenzoyl)amino]cycloamino]alkanecarboxylic acid derivatives (4).In this paper, we describe the synthesis and gastrointestinal prokinetic activity of a series of [[(4-amino-5-chloro-2-methoxybenzoyl)amino]cycloamino]alkanecarboxylic acids (4). We also discuss conformational effects on gastrointestinal prokinetic activity and the evaluation of ester prodrugs of 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetic acid (19), which exhibited the most excellent gastrointestinal prokinetic activity.Chemistry New amphoteric compounds (19-24, 32a-c, 38, 43d-f) and prodrugs (44-60) of compound 19 were synthesized as shown in Charts 2-6.As shown in Chart 2, benzamides (19-24) with 1- 19-24, 32a-c, 43d-f

Synthesis of New 1H‐Indazoles through Diels–Alder Transformations of 4‐Styrylpyrazoles under Microwave Irradiation Conditions

“…The structure 18d is supported by the presence in the 1 H NMR spectrum of two singlets at δ = 3.85 ppm and 4.10 ppm, due to the resonance of the methoxy groups (CO 2 CH 3 ) of the dienophile, the absence of the singlet characteristic of the acetyl group resonance and the presence of a singlet due to the resonance of H-3ЈЈЈ. We also observed some typical signals of compound 18d in the 13 C NMR spectrum, such as i) the signals due to the resonance of the methoxy groups of DMAD at δ = 52.4 and 53.9 ppm, ii) the signals due to the resonance of vinylic carbons at δ = 105.9 ppm (C-3ЈЈЈ) and δ = 141.8 ppm (C-2ЈЈЈ), and iii) the signals due to the resonances of the DMAD carbonyl groups at δ = 162.7 and 165.0 ppm.…”

“…NMR spectra were recorded on a Bruker Avance 300 spectrometer (300. 1 H assignments were made by use of 2D gCOSY spectra, whereas unequivocal 13 C assignments were made 1H-Indazoles by Diels-Alder Reactions with the aid of 2D gHSQC (or HETCOR) and gHMBC experiments (delays for one-bond and long-range J C/H couplings were optimised for 145 and 7 Hz, respectively). Mass spectra (EI, 70 eV) were measured on VG Autospec Q and M mass spectrometers, whereas mass spectra (ESI + ) were measured on a Micromass Q-TOF-2 TH spectrometer [dilution of 1 µL of the sample chloroform solution (≈ 10 -5 ) in 200 µL of 0.1 % trifluoroacetic acid/methanol solution; nitrogen was used as nebulizer gas and argon as collision gas; the needle voltage was set at 3000 V, with the ion source set at 80°C and desolvation temperature at 150°C; cone voltage was 35 V].…”

“…Also characteristic of these compounds are the signals observed in the 13 C NMR spectra corresponding to the resonance of two CO 2 CH 3 groups (at δ = 20.8-21.1 and 21.4-21.6 ppm and also at δ = 168.9-169.1 and 169.2-169.4 ppm).…”

“…[1][2][3][4][5][6] Many synthetic indazoles, however, are known and recognized by their pharmaceutical activity, which has inspired the development of a number of new syntheses for the indazole ring system. [7][8][9][10] Certain indazoles act as dopamine D2 receptor antagonists, [11][12][13] antipyretic and anti-inflammatory agents (bendazac and benzidamine), [14] analgesics [15,16] or anti-HIV protease [17,18] and Rho kinase inhibitors [19,20] and are used in the treatment of diabetes [7,21,22] and obesity. [23] Other derivatives exhibit antitumour (combretastatin), [24][25][26][27][28] CNS (granisetron), [8] bronchodilatory, vasodilatory or neuroprotectant activities.…”

Synthesis and pharmacological properties of novel hydrophilic 5-HT4 receptor antagonists

“…30 This reduced bioavailability is most likely caused by a lack of lipophilicity. The corresponding ester prodrugs to the amphoteric compounds were therefore prepared and since these compounds are expected to have some biological activity the receptor binding and AC activity were determined.…”