Modified Hantzsch Reaction Research Articles

ChemInform Abstract: Synthesis and Calcium Channel Antagonist Activity of New Symmetrical and Asymmetrical 4‐[2‐Chloro‐2‐(4‐chloro‐6‐methyl‐2‐oxo‐2H‐pyran‐3‐yl)vinyl]‐substituted 1,4‐Dihydropyridines.

AbstractA variety of new symmetrically and unsymmetrically substituted title dihydropyridines (V) and (IV), resp., are synthesized via modified Hantzsch reactions and evaluated for their calcium channel blocking activity.

Synthesis and Calcium Channel Blocking Activity of 1, 4-Dihydropyridine Derivatives Containing Ester Substitute and Phenyl Carbamoyl Group

Problem statement: Several studies on the synthesis of new nifedipine analogs have been carried out, but the literature reveled that no study on the synthesis and calcium channel blocking activity of the substituted ester with an amide (5-phenylcarbamoyl) moiety has been reported. Approach: Six new derivatives of m-nifedipine have been successfully synthesized by substituting an ester moiety with an amide (5-phenylcarbamoyl) moiety, using a modified Hantzsch reactions and tested for their pharmacological activities. The nifedipine analogs 1-6 were characterized and confirmed using elemental analysis, Infrared spectroscopy (IR), Nuclear Magnetic Resonance (1H NMR) and Mass spectroscopy. The purity of the compounds was ascertained by melting point and TLC. The in vitro calcium channel blocking activities were evaluated using the high K+ concentration of Porcine Coronary Artery Smooth Muscles (PCASM) assay. Results: The compounds (1-2) failed to exhibit any blocking activity (IC50 = 10−7 to 10−5 M range), while the compounds 3-6 relaxed precontracted porcine coronary artery smooth muscles with pEC50 values ranging between 4.37±0.10 (compound 3) and 6.46±0.07 (compound 5), indicating that compounds 3-6 exhibit comparable potencies in blocking calcium channels to reference drug varapamil (6.97±0.15) and m-nifedipine (6.48±0.05). Conclusion: The results of this study showed that some of the developed new compounds possess maximal calcium channel blocking effects comparable to m-nifedipine. The developed compounds in the present study will predicatively show an increased metabolic stability and consequently longer duration of actions compared to m-nifedipine and could be, therefore, suitable candidates for further optimization to be evaluated as a new class of antihypertensive drugs.

Synthesis and calcium channel antagonist activity of new symmetrical and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines

New symmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-di-hydropyridines were synthesized in moderate to good yields via the modified Hantzsch reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of an excess amount of NH4OAc. Also, the reaction of β-dicarbonyl compounds with (Z)-3-chloro-3-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)acrolein in the presence of enamino esters and ketones was performed, and asymmetrical 4-[2-chloro-2-(4-chloro-6-methyl-2-oxo-2H-pyran-3-yl)vinyl]-substituted 1,4-dihydropyridines were obtained in moderate to good yields at room temperature. The calcium channel blocking activity of these compounds was assessed. They demonstrated moderate to weak effects, although one compound had a comparable effect (IC50 =1.40×10−7 M) with respect to the reference drug Nifedipine.

ChemInform Abstract: A Facile Four Component One‐Pot Synthesis of Polyhydroquinoline Derivatives Catalyzed by Ionic Liquid via Modified Hantzsch Reaction.

AbstractThe ionic liquid 1‐vinyl‐3‐ethylimidazolium iodide is applied as catalyst to a modified Hantzsch reaction.

Synthesis of New 1,4-Dihydropyridine Derivatives Containing Thiazolyl Substituents

A series of 4-[2-methyl (or aryl) thiazole-4-yl]-2,6-dimethyl-3,5-diacetyl (or dibenzoyl) 1,4-dihydropyridines were synthesized using a modified Hantzsch reaction involving the condensation of the corresponding aldehyde with acetyl acetone or benzoyl acetone. The preparation of the corresponding aldehydes (2-methylthiazole-4-carboxaldehyde and some 2-arylthiazole-4-carboxaldehydes) was achieved by a simplified protocol of the published synthesis.

Synthesis of Chiral Ethyl 5-(Acetoxyimino)-2,7,7-trimethyl-4-(1-naphthyl)-5,6,7,8-tetrahydroquinoline-3-carboxylate via Lipase-Catalyzed Hydrolysis

Novel racemic polyhydroquinoline derivatives were synthesized by a one-pot approach via a modified Hantzsch reaction and then by aromatization. The optical resolution was carried out by using lipase l-2 in MTBE containing one equivalent of butanol. This method allows the preparation of (+)-7 (>99% ee) and (-)-8 (99% ee) in 50% yield, respectively. The E value is up to 1175.

Synthesis, QSAR and Calcium Channel Modulator Activity of New Hexahydroquinoline Derivatives Containing Nitroimidazole

The discovery that 1,4-dihydropyridine class of calcium channel antagonists inhibit Ca2+ influx represented a major therapeutic advance in the treatment of cardiovascular disease. In contrast to the effects of known calcium channel blockers of the Nifedipine-type, the so-called calcium channel agonists, such as Bay K8644 and CGP 28392, increase calcium influx by binding at the same receptor regions. Our goal was to discover a dual cardioselective Ca2+-channel agonist/vascular selective smooth muscle Ca2+ channel antagonist third-generation 1,4-dihydropyridine drug which would have a suitable therapeutic profile for treating congestive heart failure (CHF) patients. A series of unsymmetrical alkyl, cycloalkyl and aryl ester analogues of 2-methyl-4-(1-methyl)-5-nitro-2-imidazolyl-5-oxo-1,4,5,6,7, 8-hexahydroquinolin-3-arboxylate were synthesized using modified Hantzsch reaction. All compounds show calcium antagonist activity on guinea-pig ileum longitudinal smooth muscle and some of them show agonist effect activity on guinea-pig auricle. Effect of structural parameters on the Ca2+ channel agonist/antagonist was evaluated by quantitative structure-activity relationship analysis. These compounds could be considered as a synthon for developing a suitable drug for treating CHF patients.

Hantzsch 1,4-dihydropyridines containing a diazen-1-ium-1,2-diolate nitric oxide donor moiety to study calcium channel antagonist structure–activity relationships and nitric oxide release

A group of racemic 3-isopropyl 5-[(2-piperazin-1-yl)ethyl] 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 12a– c), 3-isopropyl 5-{2-[4-nitrosopiperazinyl]ethyl} 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 14a– c) and 3-isopropyl 5-{2-[( O 2-acetoxymethyldiazen-1-ium-1,2-diolate)( N, N-dialkylamino or 4-piperazin-1-yl)]ethyl} 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates ( 22– 30) were prepared using modified Hantzsch reactions. This group of compounds ( 12a– c, 14a– c, and 22– 30) exhibited less potent calcium channel antagonist activity (IC 50 = 0.11 to 3.35 μM range) than the reference drug nifedipine (IC 50 = 0.01 μM). The point of attachment of the isomeric C-4 substituent was a determinant of calcium channel antagonist activity providing the potency profile 2-pyridyl ⩾ 3-pyridyl ⩾ 4-pyridyl. The N-nitrosopiperazinyl compounds ( 14a– c) did not release nitric oxide. The prodrugs 22– 30 that have a C-5 2-[( O 2-acetoxymethyldiazen-1-ium-1,2-diolate)( N, N-dialkylamino or 4-piperazin-1-yl)]ethyl ester substituent, upon incubation with guinea pig serum, undergo consecutive cleavage of the O 2-acetoxymethyl moiety to give a nitric oxide donor diazenium-1-ium-1,2-diolate species that subsequently releases nitric oxide. The extent of nitric oxide released from the diazen-1-ium-1,2-diolate group is dependent upon the nature of the amino functionality attached directly to the diazen-1-ium N-1 position where the nitric oxide release profile is 1,4-piperazinyl > N-Et > N-( n-Bu) ≫ N-Me upon exposure to guinea pig serum esterase(s). The results from this study suggest this class of hybrid calcium channel antagonist/nitric oxide donor prodrugs should release the vasodilator nitric oxide in vivo, preferentially in the vascular endothelium, to enhance the smooth muscle calcium channel antagonist effect to produce a combined synergistic antihypertensive effect.

Synthesis of Dialkyl 1,4‐Dihydro‐2,6‐dimethylpyridine‐3,5‐dicarboxylates and Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates Possessing a C‐4 2,4‐Dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl (Uracil) Substituent to Determine Calcium Channel Modulation Structure—Activity Relationships.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis of dialkyl 1,4‐dihydro‐2,6‐dimethylpyridine‐3,5‐dicarboxylates and alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates possessing a c‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl (uracil) substituent to determine calcium channel modulation structure‐activity relationships

AbstractThe Hantzsch condensation of 5‐formyluracil (1) with methyl, isopropyl or isobutyl acetoacetate (2a‐c) in the presence of ammonium hydroxide afforded the respective dialkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(2,4‐dloxo‐1,2,3,4,‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3a‐c). A group of alkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylates (6a‐c) were also prepared using a modified Hantzsch reaction that involved the condensation of 5‐formyluracil with nitroacetone and either methyl, isopropyl or isobutyl 3‐aminocrotonate (5a‐c). A C‐4 2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl substituent is not a suitable bioisostere for the traditional C‐4 aryl or heteroaryl substituents present in 1,4‐dihydropyridine calcium channel modulators since diisopropyl 1,4‐dihydro‐2,6‐dimemyl‐4‐(2,4‐dioxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐3,5‐dicarboxylate (3b) and isobutyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2,4‐dloxo‐1,2,3,4‐tetrahydropyrimidin‐5‐yl)pyridine‐5‐carboxylate (6c) did not exhibit any in vitro calcium channel antagonist activity using a guinea pig smooth muscle calcium channel antagonist assay, or a guinea pig left atrium calcium channel agonist (positive inotropic) assay.

Syntheses, calcium channel modulation effects, and nitric oxide release studies of O2‐alkyl‐1‐(pyrrolidin‐1‐yl) diazen‐1‐ium‐1,2‐diolate 4‐aryl(heteroaryl)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxylates

AbstractA group of racemic 4‐aryl(heteroary)‐1,4‐dihydro‐2,6‐dimethyl‐3‐nitropyridine‐5‐carboxy‐lates possessing a potential nitric oxide donor C‐5 O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester [alkyl=(CH2)n, n=1–4] substituent were synthesized using a modified Hantzsch reaction. Compounds having a C‐4 2‐trifluoromethylphenyl (16), 2‐pyridyl (17), or benzofurazan‐4‐yl (20) substituent generally exhibited more potent smooth‐muscle calcium channel antagonist activity (IC50 values in the 0.55 to 38.6 μM range) than related analogs having a C‐4 3‐pyridyl (18), or 4‐pyridyl (19) substituent with IC50 values > 29.91 μM, relative to the reference drug nifedipine (IC50=0.0143 μM). The point of attachment of C‐4 isomeric pyridyl substituents was a determinant of antagonist activity where the relative potency profile was 2‐pyridyl > 3‐pyridyl and 4‐pyridyl. Subgroups of compounds 16a–d, 17a–d, and 20a–d having alkyl spacer groups of variable chain length [–CO2(CH2)nO–, n=1–4] exhibited small differences in calcium channel antagonist potency. Replacement of the ester “methyl” moiety of Bay K 8644 by an O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate group provided the Bay K 8644 group of analogs 16a‐d that retained the desired cardiac positive inotropic effect. The most potent compound in this group, O2‐ethyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(2‐trifluoromethylphenyl)pyridine‐5‐carboxylate (16b, EC50=0.096 μM) is about eightfold more potent positive inotrope (cardiac calcium channel agonist) than the reference compound Bay K 8644 (EC50=0.77 μM). A similar replacement of the ester “isopropyl” group in the C‐4 benzofurazan‐4‐yl group of compounds by an O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester substituent provided compounds 20 (n=1 and 4) that were approximately equipotent cardiac positive inotropes with the parent reference compound PN 202‐791 (3, EC50=9.40 μM). The O2‐alkyl‐1‐(pyrrolidin‐1‐yl)diazen‐1‐ium‐1,2‐diolate ester moiety present in 1,4‐dihydropyridine calcium channel modulating compounds 16–20 is not a suitable •NO donor moiety because the percent nitric oxide released upon in vitro incubation with either l‐cysteine, rat serum, or pig liver esterase was less than 1%. Drug Dev. Res. 60:204–216, 2003. © 2003 Wiley‐Liss, Inc.

Synthesis and Calcium Channel Antagonist Activities of 3‐Nitrooxyalkyl, 5‐Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐ (1‐methyl‐5‐nitro‐2‐imidazolyl)‐3,5‐pyridinedicarboxylates.

AbstractFor Abstract see ChemInform Abstract in Full Text.

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

AbstractA group of racemic 1,4‐dihydro‐2,6‐dimethyl‐5‐nitro‐3‐pyridinecarboxylates possessing either a C‐4 2‐trifluoromethylphenyl (22–24), benzofurazan‐4‐yl (42–44), 2‐pyridyl (45–47), 3‐pyridyl (48–50), or 4‐pyridyl (51–53), substituent in conjunction with a nitric oxide donor C‐3 ester [3‐(benzenesulfonyl)furoxan‐4‐yloxy]alkyl substituent were synthesized using modified Hantzsch reactions. Compounds 45–53 having a C‐4 2‐, 3‐, or 4‐pyridyl substituent exhibited more potent in vitro calcium channel antagonist activity (IC50's in the 0.46 to 5.23 μM range) on guinea pig ileum longitudinal smooth muscle (GPILSM) than related analogs having a C‐4 2‐trilfuoromethylphenyl (22–24) or benzofurazan‐4‐yl (42, 44) substituent (IC50 ≥ 29.91 mM). The point of attachment of the pyridyl ring (2‐, 3‐, or 4‐), and the length of the C‐3 ester alkyl spacer [‐CH2(CH2)n, n=1–3], were not determinants of smooth muscle calcium channel antagonist activity. Replacement of the C‐3 ester methyl substituent of Bay K 8644, or the ester isopropyl substituent of the 4‐(pyridyl) isomers 4a‐c by a [3‐(benzensulfonyl)furoxan‐4‐yloxy]alkyl moiety retained the desired calcium channel agonist (positive inotropic) effect on guinea pig left atrium (GPLA). Compounds having C‐4 3‐pyridyl (48–50), or 4‐pyridyl (51–53), substituents were the most potent cardiac positive inotropes (EC50's in the 3.02 to 19.74 μM range) relative to the reference drug Bay K 8644 IC50=0.77 μM). The % nitric oxide released in vitro in the presence of L‐cysteine for this group of compounds was higher (36–74% range) than for the reference drug glycerol trinitrate (20%). A quantitative structure‐activity analysis showed an inverse correlation between a molecular weight (MW) descriptor and % nitric oxide released. Model hybrid (calcium channel modulation, nitric oxide donor) compounds that show dual cardioselective agonist (positive inotropic)/smooth muscle selective antagonist activities constitute a novel type of 1,4‐dihydropyridine calcium channel modulator that provides a potential drug design concept targeted toward the treatment of congestive heart failure, and is a useful probe to study the structure‐function relationship of calcium channels. Drug. Dev. Res. 56:1–16, 2002. © 2002 Wiley‐Liss, Inc.

Synthesis and calcium channel antagonist activities of 3-nitrooxyalkyl, 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates

A group of racemic 3-[(2-nitrooxyethyl), (3-nitrooxypropyl), (4-nitrooxybutyl) or (1,3-dinitrooxy-2-propyl)], 5-methyl (ethyl or propyl) 1,4-dihydro-2,6-dimethyl-4-(1-methyl-5-nitro-2-imidazolyl)-3,5-pyridinedicarboxylates ( 18– 29) were synthesized using modified Hantzsch reaction that involved the condensation of 2-nitrooxyethyl ( 8), 3-nitrooxypropyl ( 9), 4-nitrooxybutyl ( 10) or 1,3-dinitrooxy-2-propyl ( 13) acetoacetate with methyl ( 14), ethyl ( 15) or isopropyl ( 16) 3-aminocrotonate and 1-methyl-5-nitroimidazole-2-carboxaldehyde ( 17). In vitro calcium channel antagonist activities were determined using a guinea pig ileum longitudinal smooth muscle assay. Compounds 18– 29 exhibited superior, or equipotent, calcium antagonist activity (IC 50=10 −11–10 −13 M range) relative to the reference drug nifedipine (IC 50=1.07±0.12×10 −11 M), which could serve as potential probes to investigate the in vivo release of nitric oxide which induces vascular muscle relaxation.

Design and syntheses of 4-[3-(1-methoxycarbonyl-1,6-dihydropyridyl)]- and 4-[3-(1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl)]- derivatives of alkyl 1,4-dihydro-2,6-dimethyl-3-nitro-5-pyridine-carboxylates with calcium channel modulating activities

A group of 4-(3-(1-methoxycarbonyl-1,6-dihydropyridyl))- derivatives of alkyl 1,4-dihydro-2,6- dimethyl-3-nitro-5-pyridinecarboxylates 8a-e were synthesized by the regioselective reduction of the corresponding 4-(3-pyridyl)- analogs in the presence of methyl chloroformate using Li(t- BuO)3AlH. Alternatively, a related group of 4-(3-(1-methoxycarbonyl-4-substituted-1,4- dihydropyridyl))- compounds 14-18 were prepared using a modified Hantzsch reaction involving the condensation of 1-methoxycarbonyl-4-substituted-1,4-dihydropyridyl-3-carboxaldehydes 11a-c with an alkyl 3-aminocrotonate 12 and nitroacetone 13. In contrast to the 4-(3-pyridyl)- compound 2b, which exhibits an undesirable calcium channel agonist smooth muscle

Total synthesis of dendroamide A, a novel cyclic peptide that reverses multiple drug resistance.

Dendroamide A (1) was isolated from a blue-green alga on the basis of its ability to reverse drug resistance in tumor cells that overexpress either of the transport proteins, P-glycoprotein or MRP1. Because of this activity, methods for the synthesis of analogues of this oxazole- and thiazole-containing cyclic peptide have been developed, and the total synthesis of 1 has been completed. Highlights of the synthetic strategy are as follows: (1) a dicyclohexylcarbodiimide coupling of D-Ala and L-Thr, followed by reaction with Burgess reagent and DBU-assisted oxidation to form D-Ala-oxazole; (2) formation of D-Val-thiazole and D-Ala-thiazole via modified Hantzsch reactions; and (3) use of molecular modeling to select the preferred precursor for the final cyclization of the peptide analogue. Synthetic 1 demonstrated spectral properties identical to those of the natural product and reversed P-glycoprotein-mediated drug resistance more effectively than MRP1-mediated resistance. Certain of the synthetic precursors had biological activity, indicating that cell permeability and peptide cyclization are necessary for optimal activity. Thus, the structure and the biological activities of the natural product are confirmed, and methods for the synthesis of analogues for further structure-activity explorations are defined.

Synthesis and calcium channel modulating effects of modified Hantzsch nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates

AbstractA group of racemic nitrooxyalkyl 1,4‐dihydro‐2,6‐dimethyl‐3‐nitro‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐pyridinecarboxylates 8a–o were synthesized using modified Hantzsch reactions. In vitro calcium channel antagonist activities, determined using a guinea pig ileum longitudinal smooth muscle (GPILSM) assay, showed that compounds 8a–o exhibited weaker calcium antagonist activity (10–5 to 10–7 M range) than the reference drug nifedipine (IC50 = 1.43 × 10–8 M). Compounds 8 possessing a C‐4 R1 = 2‐pyridyl substituent were always more potent than the approximately equiactive analogs having an R1 = 3‐pyridyl, 4‐pyridyl or 2‐CF3‐C6H4‐substituent, within each subgroup of nitrooxyalkyl compounds [R2 = – (CH2)nONO2 (n = 2, 3, 4) or –CH(CH2ONO2)2]. Although the length of the R2 = –(CH2)nONO2 substituent (n = 2–4) was not a determinant of smooth muscle calcium antagonist activity when the C‐4 R1‐substituent was 2‐pyridyl, when R1 was a 3‐pyridyl, 4‐pyridyl, or 2‐CF3‐C6H4‐substituent, the relative potency order with respect to the R2 = –(CH2)nONO2 substituent was n = 3 and 4 > n = 2. Replacement of the isopropyl substituent of the ester moiety of the calcium antagonist (±)‐2‐pyridyl 3a by a –(CH2)nONO2 (n = 2–4) moiety increased calcium antagonist activity on GPILSM by 8‐fold. In contrast, replacement of the isopropyl substituent of the ester moiety of the calcium agonists (±)‐3‐pyridyl 3b, (±)‐4‐pyridyl 3c or the methyl substituent of the ester moiety of Bay K8644 by a R2 nitrooxyalkyl substituent resulted in abolition of their calcium agonist effects on GPILSM that is replaced by a smooth muscle calcium antagonist effect. These calcium antagonist data support the concept that incorporation of a nitrooxyalkyl ester substituent constitutes a valuable drug design strategy to enhance Hantzsch 1,4‐dihydropyridine calcium antagonist and/or abolish calcium agonist effects on smooth muscle. Replacement of the isopropyl (8b–c), or the methyl (8d) group by a –CH2CH2ONO2 moiety resulted in retention of the cardiac positive inotropic effect where the relative potency order with respect to the C‐4 substituent was 2‐CF3‐C6H6‐ (8d) > 3‐pyridyl (8b) ≈ 4‐pyridyl (8c). Model hybrid (calcium channel modulation, ·NO release) compounds, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4‐dihydropyridine CC modulator that offers a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:225–232, 2000. © 2001 Wiley‐Liss, Inc.

Hantzsch 1,4-dihydropyridines containing a nitrooxyalkyl ester moiety to study calcium channel antagonist structure-activity relationships and nitric oxide release

A group of 3-nitrooxyalkyl 5-alkyl 1,4-dihydro-2,6-dimethyl-4-(pyridyl)-3,5-pyridinedicarboxylates were prepared using a modified Hantzsch reaction that involved the condensation of a nitrooxyalkyl acetoacetate with an alkyl 3-aminocrotonate and a pyridinecarboxaldehyde. 1H NMR nuclear Overhauser enhancement (nOe) studies for 3-(3-nitrooxypropyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2-pyridyl)-3,5-pyridinedicarboxylate (17) indicates a predominant rotamer exists in solution where the pyridyl nitrogen atom is orientated above the 1,4-DHP ring system, and the pyridyl nitrogen atom is antiperiplanar to the 1,4-DHP ring H-4 proton. Variable temperature 1H NMR studies (–30 to +60°C) showed the 1,4-DHP NH proton in 17 is H-bonded in CHCl3 solution. This interaction is believed to be due to intermolecular H-bonding between the pyridyl nitrogen free electron pair and the 1,4-DHP NH proton. In vitro calcium channel antagonist (CCA) activities were determined using a muscarinic-receptor-mediated Ca+2-dependent contraction of guinea pig ileal longitudinal smooth muscle assay. This class of compounds exhibited lower CCA activity (IC50 = 5.3 × 10–6 to 3.5 × 10–8 M range) than the reference drug nifedipine (IC50 = 1.4 × 10–8 M). For compounds having C-3 –CH2CH2ONO2 and C-4 pyridyl substituents, the C-5 alkyl was a determinant of CCA (i-Pr > the approximately equipotent i-Bu, t-Bu, and Et analogs). The point of attachment of the isomeric C-4 pyridyl substituent was a determinant of CCA when C-3 –CH2CH2ONO2 and C-5 i-Pr substituents were present providing the potency profile 2-pyridyl ≥ 3-pyridyl > 4-pyridyl. CCA with respect to the C-3 nitrooxyalkyl substituent was inversely dependent on the length of the alkyl spacer. The percent nitric oxide (·NO) released in vitro by this group of compounds (range of 0.03–0.43%/ONO2 group), quantified as nitrite by reaction with the Griess reagent, was lower than that for the reference drug glycerol trinitrate (3.81%/ONO2 group). Nitric oxide release studies showed that the %·NO released was dependent on the number of ONO2 groups/molecule. A QSAR study for this group of compounds showed a correlation between the specific polarizability descriptor (SpPol) and %·NO release. Drug Dev. Res. 51:233–243, 2000. © 2001 Wiley-Liss, Inc.

Synthesis and calcium channel modulation effects of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylates possessingortho-,meta-, andpara-CH2S(O)nMe and -S(O)nMe (n = 0-2) phenyl substituents

A group of isopropyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-phenylpyridine-5-carboxylates (13–15) possessing ortho-, meta-, and para-CH2S(O)nMe and –S(O)nMe (n = 0–2) phenyl substituents were synthesized using a modified Hantzsch reaction. Calcium channel (CC) modulating activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) in vitro assays. This class of –CH2S(O)nMe and –S(O)nMe (n = 0–2) compounds (13–15a–f) exhibited weaker CC antagonist activity on GPILSM (IC50 = > 1.1 × 10–5 to 4.1 × 10–6 M range) than the reference drug nifedipine (IC50 = 1.4 × 10–8 M). The oxidation state of the sulfur atom was a determinant of smooth muscle CC antagonist activity where the relative activity profile was generally thio (13, -CH2SMe, -SMe) and sulfonyl (15, -CH2SO2Me, -SO2Me) > sulfinyl (14, -CH2SOMe, -SOMe). The point of attachment of the phenyl substituent was a determinant of activity for the –CH2SMe (13a–c), -CH2SOMe (14a–c) and SOMe (14d–f) isomers where the relative potency order was meta and para > ortho. Compounds in this group (13–15), unlike Bay K 8644 (EC50 = 2.3 × 10–7 M on GPILSM), did not exhibit an agonist effect on GPILSM. The meta-CH2SMe (13b), ortho-CH2SMe (13c), meta-SMe (13e), and ortho-CH2SO2Me (15c) C-4 phenyl derivatives exhibited respectable in vitro cardiac positive inotropic activities (EC50 = 1.00 × 10–6 to 7.57 × 10–6 M range) relative to the reference drug Bay K 8644 (EC50 = 7.70 × 10–7 M) in the GPLA assay. In contrast to Bay K 8644, which acts as an undesirable calcium channel agonist on smooth muscle (GPILSM), compounds 13b (IC50 = 4.11 × 10–6 M), 13c (IC50 = 2.29 × 10–5 M), 13e (IC50 = > 1.20 × 10–5 M) and 15c (IC50 = 6.22 × 10–6 M) exhibited a desirable simultaneous calcium channel antagonist effect on smooth muscle at a similar (13b, 15c), or lower (13c, 13e), concentration relative to its cardiac agonist EC50 value. Model compounds such as 13b, 13c, 13e, and 15c, that exhibit dual cardioselective agonist / smooth muscle selective antagonist activities, represent a novel type of 1,4-dihydropyridine CC modulators that offer a potential approach to drug discovery targeted toward the treatment of congestive heart failure and for use as probes to study the structure–function relationship of calcium channels. Drug Dev. Res. 51:177–186, 2000. © 2001 Wiley-Liss, Inc.

Synthesis of valproate, valerate, and 1-methyl-1, 4-dihydropyridyl-3-carbonyloxy ester derivatives of Hantzsch 1,4-dihydropyridines as potential prodrugs and their evaluation as calcium channel antagonist and anticonvulsant agents

A group of 3-(hydroxyalkyl) 5-alkyl 1,4-dihydro-2,6-dimethyl-4-aryl-3,5-pyridinedicarboxylates (11–15) were prepared using a modified Hantzsch reaction, which were then elaborated to valproate (16–18), valerate (19, 20), and 1-methyl-1,4-dihydropyridyl-3-carbonyloxy (25, 26) derivatives. Alternatively, the valproate derivative 3-(2-n-propylpentanoyloxymethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (34) was prepared by the reaction of isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (30) with chloromethyl valproate (33). This class of lipophilic compounds possess partition coefficients (Kp) in the 149–452 range, relative to the reference drug nimodipine (Kp = 187). All compounds exhibited potent calcium channel antagonist (CCA) activity (IC50 = 10–7 to 10–10 M range), relative to the reference drug nimodipine (IC50 = 1.49 × 10–8 M). CCA structure–activity relationships showed the parent C-3 2-hydroxyethyl compounds were more potent than their valproate derivatives, but less active than their valerate derivatives. Compounds having a 1-methyl-1,4-dihydropyridyl-3-carbonyloxy chemical delivery system (CDS) were approximately equiactive to the parent C-3 2-hydroxyethyl compounds. Anticonvulsant activity was determined in the maximal electroshock (MES) and subcutaneous metrazol (scMet) screens. 3-(2-Hydroxyethyl) 5-isopropyl 1,4-dihydro-2,6-dimethyl-4-(2,3-dichlorophenyl)-3,5-pyridinedicarboxylate (12) provided modest protection in the MES and scMet screens. In the C-3 valproate [CO2(CH2)nO2CCH(n-Pr)2] group of compounds, those possessing an ethylene spacer (n = 2) provided protection in the MES screen, whereas those having a propylene spacer (n = 3) or methylene spacer (n = 1) were inactive. Related C-3 valerate esters [CO2(CH2)2O2C-n-Bu] also provided protection in the MES screen, whereas those having a 1-methyl-1,4-dihydropyridyl-3-carbonyloxy CDS moiety were inactive. Drug Dev. Res. 48:26–37, 1999. © 1999 Wiley-Liss, Inc.