Syntheses, Calcium Channel Antagonist and Anticonvulsant Activities of Substituted 1,4‐Dihydro‐3,5‐pyridinedicarboxylates Containing Various 3‐Alkyl Ester Substituents

Abstract

A group of 3-alkyl 5-isopropyl 4-aryl-1,4-dihydro-2,6-dimethyl- 3,5-pyridinedicarboxylates 10-20 containing an amine, quaternary ammonium, aryl (heteroaryl)alkenyl, 4-(4-fluorophenyl)- piperazin-1-yl or methoxy moiety in the C-3 alkyl ester R-substituent in combination with a C-4 phenyl ring bearing a 2,3-Cl2, 3-NO2, 3-NMe2, 4-NMe2 or 3,4,5-(OMe)3 X-substituent were prepared using the Hantzsch 1,4-dihydropyridine reaction. In vitro calcium channel antagonist activity (CCA) was determined using a guinea pig ileum longitudinal smooth muscle assay. In the C-4 3-nitrophenyl series of compounds, the C-3 ester R-substituent was a determinant of CCA activity where the relative potency order was -CH2CH2CH=C-(2-methylphenyl)2 > or = -CH2CH2NMe2.HCI> -CH2CH2CH=C-(3-methyl-2-thienyl)2 > -CH2CH2+NMe3I -. The position and nature of the C-4 phenyl X-substituent, were also determinants of CCA activity where the relative activity order was 3-NMe2 > 4-NMe2 > 3,4.5-(OMe)3. Anticonvulsant activities were determined in mice using the subcutaneous metrazol (scMet) and maximal electroshock (MES) screens. The compounds investigated were generally not effective for protecting against scMet induced seizures, except for 10 (X = 2,3-Cl2, R = 2-[4-(4- fluorophenyl)piperazin-l-yl]ethyl] and 14a (X = 3-NMe2.HCl, R = CH2CH2OMe), which exhibited modest activity. Compound 11a (X = 3-NO2, R = -CH2CH2NMe2.HCl) was the most effective agent in the MES screen. All of the compounds investigated, except for 11b (X = 3-NO2, R = -CH2CH2+NMe3 I-, Kp = 0.15), are lipophilic with n-octanol/aqueous phosphate buffer (pH = 7.4) partition coefficients (Kp) in the 121-424 range relative to the reference drug nimodipine (Kp = 187). The structure-activity relationships acquired reinforce the concept that calcium is only one of several factors that are involved in seizure generation.

Synthesis, Calcium Channel Antagonist Activity, and Anticonvulsant Activity of 3-Ethyl 5-Methyl 1,4-Dihydro-2-[(2-hydroxyethoxy)methyl]-6-methyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate Coupled to a 1-Methyl-1,4-dihydropyridyl-3-carbonyl Chemical Delivery System

“…n-Octanol-phosphate buffer Kp values were determined using a modified procedure based on the Fujita method [16] as described previously [17] .…”

Fused 1,4-Dihydropyridines as Potential Calcium Modulatory Compounds

“…DHPs have many biological features included vasodilator, antihypertensive, bronchodilator, antiatherosclerotic, anticonvulsant, hepatoprotective, antitumor, antimutagenic, geroprotective, antidiabetic, antioxidant, antiradical and controlling cellular proliferation [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24]. Although DHP's have been developed as cardiovascular agents some of them have been used for other medical applications.…”

Syntheses, calcium channel agonist‐antagonist modulation effects, and nitric oxide release studies of [3‐(Benzenesulfonyl)furoxan‐4‐yloxy]alkyl 1,4‐Dihydro‐2,6‐dimethyl‐5‐nitro‐4‐(2‐trifluoromethylphenyl, benzofurazan‐4‐yl, 2‐, 3‐, or 4‐pyridyl)‐3‐pyridinecarboxylates

“…Silica gel column chromatography was performed using Silicycle silica gel (70-230 mesh). Glycerol trinitrate [Marken et al, 1977], 3,4-bis(benzenesulfonyl)furoxan (7) [Kelly et al, 1977], 4-bromo-1-butanol (10) [Nguyen et al, 2000], nitroacetone (17) [Hurd and Nilson, 1955], 2-cyanoethyl 3-aminocrotonate (19) [Ogawa et al, 1993], benzofurazan-4-carboxaldehyde (25) [Heitzmann, 1987], 2-amino-1-nitroprop-1-ene (26) [Miri et al, 2000], and 2-cyanoethyl acetoacetate (27) [Yiu and Knaus, 1997] were prepared according to procedures reported in the literature. All other reagents were purchased from Aldrich Chemical (Milawukee, WI).…”

“…The 3-(benzenesulfonyl)-4-(2-, 3-, or 4-bromoalkoxy)furoxans (11-13), required for subsequent coupling to the acids 21, 29, 39-41, were prepared in 78-99% yield by reaction of 3,4-bis(benzensulfonyl)furoxan (7) with the bromoalkanols (8-10, Br(CH 2 )nOH, n ¼ 2-4) in the presence of aqueous NaOH in THF as illustrated in Figure 2. It was anticipated that the 2-cyanoethyl esters (20,28,(36)(37)(38) would undergo a facile b-elimination reaction upon treatment with diazabicyclo[5.4.0]undec-7-ene (DBU) to afford the required acids (21,29,(39)(40)(41) [Yiu and Knaus, 1997].…”