- Novel halogenated 1,4-dihydropyridines: synthesis, bioassay, microsomal oxidation and structure-activity relationships
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Nine new 1,4-dihydropyridines (DHPs) were synthesized and evaluated for their relaxant ability (rat aorta) and their antihypertensive activity in spontaneously hypertensive rats; their microsomal oxidation rate (MOR) was determined.In terms of relaxant activity, the 4-(3,5-difluorophenyl) analogues were more potent than those with 4-(4-fluorophenyl) but weaker than those with 4-(3-nitrophenyl) substituents, while in terms of antihypertensive activity the 4-(3,5-difluorophenyl) derivatives were more potent than their 4-(3-nitrophenyl) analogues.Their MOR could beexplained the basis of the electron-withdrawing effect of the substituents, and in some cases they permitted a rationalization of discrepancies noted between DHP antihypertensive and relaxant activities.A parabolic relationship was found between the size of the carboxylic ester substituents and their contributions calculated from a Free-Wilson/Fujita-Ban analysis of relaxant activity data. 1,4-dihydropyridine / aorta relaxant activity / antihypertensive activity / microsomal oxidation rate / structure-activity relationship.
- Hernandez-Gallegos, Z.,Lehmann, P. A. F.,Hong, E.,Posadas, F.,Hernandez-Gallegos, E.
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- Based on the three-step synthesis process of preparation of the nitrendipine (by machine translation)
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The invention discloses a method based on three-step preparation of the nitrendipine synthesis process, comprising the following steps: S1 ammoniation reaction: liquid ammonia with methyl acetoacetate reflect the generated β - amino-crotonic acid methyl ester; S2 condensation reaction: will be m formaldehyde and acetyl ethyl acetate in the catalyst piperidine and glacial acetic acid under the action of the condensation reaction to obtain the pure 2 - (3 - nitryl asia phenmethyl) - acetyl ethyl acetate; S3 ring-closure reaction: the β - amino-crotonic acid methyl ester with 2 - (3 - nitryl asia phenmethyl) - acetyl ethyl acetate in the catalyst diisopropyl ethylamine/glacial acetic acid under the action of the Michael reaction, then molecule in cyclization to obtain nitrendipine; S4 refining, the invention - nitrobenzaldehyde between (SM1), acetyl ethyl acetate (SM2) and methyl acetoacetate (SM3) as the starting raw material preparation, heating the ring, three-step reaction qualified products can be obtained nitrendipine, not containing special reaction conditions. (by machine translation)
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Paragraph 0020; 0023; 0031-0032; 0034; 0040; 0046; 0052
(2019/02/04)
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- Design and synthesis of 4-alkyl-2-amino(acetamino)-6-aryl-1,3-thiazine derivatives as influenza neuraminidase inhibitors
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With a convenient and economical method, two series of 1,3-thiazine derivatives 1 and 2 were synthesized, and their neuraminidase (NA) inhibitory activities were evaluated. The pharmacological results showed that most of the compounds have potent NA inhibitory activity. Especially, 1g exhibited the best activity against influenza virus A (H1N1) NA (IC50 = 29.06 μg/mL), and its crystal structure was determined by single-crystal X-ray diffraction. The preliminary biological assay indicated that 1,3-thiazine could be used as a core structure to design novel influenza NA inhibitors. Two series of novel 1,3-thiazine analogs were synthesized and their neuraminidase (NA) inhibitory activities were evaluated. Most of the compounds have potent NA inhibitory activity. Compound 1g exhibited the best activity against influenza virus A (H1N1) NA with an IC50 of 29.06 μg/mL, and its crystal structure was determined by single-crystal X-ray diffraction.
- Li, Wan,Xia, Lin,Hu, Aixi,Liu, Ailin,Peng, Junmei,Tan, Weiqing
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p. 635 - 644
(2013/09/24)
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- A facile synthesis of trisubstituted alkenes from β-diketones and aldehydes with AlCl3 as catalyst
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Preparation of trisubstituted alkenes from low-activity β-diketones and aldehydes with aluminum chloride as catalyst has been studied. The frequently used catalyst AlCl3 is used for the first time to promote this condensation. The procedure is a convenient, low toxicity, and highly efficient method for industrial synthesis of trisubstituted alkenes in high yield. Springer Science+Business Media B.V. 2011.
- Li, Zheng-Nan,Chen, Xiao-Liang,Fu, Yu-Jie,Wang, Wei,Luo, Meng
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experimental part
p. 25 - 35
(2012/05/20)
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- Catalytic effect of nanosized metal oxides on the knoevenagel reaction
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The effect of nanosized metal oxides (Al, Mg, Cu, Ni oxides) on the synthesis of chalcones that are key intermediate in the synthesis of Nitrendipine and Felodipine drugs was examined.
- Titova,Fedorova,Ovchinnikova,Rusinov,Charushin
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experimental part
p. 656 - 660
(2012/08/08)
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- Catalytic effect of nanosized metal oxides on the Hantzsch reaction
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The effect of nanosized copper and aluminum oxides, which have a higher sorption capacity than that of bulk samples, on the Hantzsch reaction was studied. The adsorption of starting benzaldehydes and ethyl acetoacetate on the surface of copper and aluminum nanooxides resulted in the activation of these molecules and accelerated the Hantzsch reaction. In addition, considerable activation of ammonia and intermediates (chalcone and enamine) on the surface of aluminum nanooxide facilitated an increase in the rate and selectivity of the process. The experimental results were used to develop a one-pot method for the preparation of nifedipine and nitrendipine.
- Fedorova,Koryakova,Valova,Ovchinnikova,Titova,Rusinov,Charushin
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experimental part
p. 566 - 572
(2011/01/07)
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- Investigation of the antioxidant properties of some new 4-hydroxycoumarin derivatives
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The aim of this investigation was to measure the activity of four 4-hydroxycoumarin derivatives - three of them were described before and one was newly synthesized. The substances were ethyl 2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxyphenyl)methyl]-3-oxobutanoate (SS-14), 4-[1-(4-hydroxy-2-oxo-2H-chromen-3-yl)-2-(ethoxycarbonyl)-3-oxobutyl]benzoic acid (SS-17), ethyl 2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)(3-nitrophenyl)methyl]-3-oxobutanoate (SS-21) and ethyl 2-[(3,4,5-trimethoxyphenyl)(4-hydroxy-2-oxo-2H-chromen-3-yl)methyl]-3-oxobutanoate (T-2). The synthesis of T-2 consists of two steps. First step was Knoevenagel reaction between 3,4,5-trimethoxybenzaldehyde and ethylacetoacetate. Ethyl 2-(3,4,5-trimethoxy)-phenylmethyleneacetoacetate was the product. Second step was Michael addition reaction between the latter product and 4-hydroxycoumarin. All the compounds were tested in vitro for antioxidant activity in hypochlorous system. The assay was based on the luminol-dependent chemiluminescence of free radicals, which decreased in the presence of 4-hydroxycoumarin derivative. Compound SS-14 (ethyl 2-[(4-hydroxy-2-oxo-2H-chromen-3-yl)(4-hydroxyphenyl)methyl]-3-oxobutanoate) expresses the best scavenger activity at the highest concentration (10-4 mol/L).
- Stanchev,Hadjimitova,Traykov,Boyanov,Manolov
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experimental part
p. 3077 - 3082
(2009/09/27)
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- Synthesis, computational study and cytotoxic activity of new 4-hydroxycoumarin derivatives
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Six new 4-hydroxycoumarin derivatives have been synthesized. They were characterized by UV-vis, IR, 1H NMR, 13C NMR, mass spectral data, elemental analysis, TLC and melting point determination. The new 4-hydroxycoumarin derivatives a
- Stanchev, Stancho,Momekov, Georgi,Jensen, Frank,Manolov, Ilia
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p. 694 - 706
(2008/09/21)
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- Dimethylamine benzoate or p-anisate catalysed process for the preparation of 4-(nitrophenyl)-dihydropyridines
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PCT No. PCT/EP96/01090 Sec. 371 Date Aug. 18, 1997 Sec. 102(e) Date Aug. 18, 1997 PCT Filed Mar. 14, 1996 PCT Pub. No. WO96/29310 PCT Pub. Date Sep. 26, 1996A method for the preparation of 4-(nitrophenyl)-dihydro-pyridines by reacting a benzaldehyde with an acetoacetate and reacting the resulting benzylidene derivative with an enamine derivative. Both reactions are catalyzed by dimethylamine benzoate or p-anisate.
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- Novel 2-amino-1,4-dihydropyridine calcium antagonists. II. Synthesis and antihypertensive effects of 2-amino-1,4-dihydropyridine derivatives having N,N-dialkylaminoalkoxycarbonyl groups at 3- and/or 5-positions
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Novel 2-amino-1,4-dihydropyridine derivatives I, which contain N,N-dialkylaminoalkoxycarbonyl groups at the 3- and/or 5-position, were synthesized and their antihypertensive effects were evaluated in spontaneously hypertensive rats. Remarkably prolonged duration of antihypertensive action was observed when a tertiary amino group was introduced into either the 3- or 5-ester side-chain of the 1,4-dihydropyridine ring. In particular, the compounds containing cyclic amino moieties at the 3-position showed greater potency than those with acyclic amino moieties. Chemical modification studies indicated that the two ester side-chains of 1,4-dihydropyridine at the 3- and 5-position might function in a different manner in relation to the antihypertensive activities. 3-(1-Benzhydrylazetidin-3-yl) 5-isopropyl 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine-dicarboxyl ate, I-43 (CS-905), exhibited potent and long-lasting antihypertensive effects with gradual onset of action, and is a promising candidate as an antihypertensive drug.
- Kobayashi,Inoue,Nishino,Fujihara,Oizumi,Kimura
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p. 797 - 817
(2007/10/02)
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- Synthesis of 1,4-dihydro-2,6-dimethyl-4-(substituted phenyl)-5-N-methylaminocarbonyl-pyridine-3-carboxylate
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Michael addition of β-amino-N-methylcrotonamide to aralkylideneacetoacetic acid ester is followed by ring closer to give novel 4-aryl-1,4-dihydro-2,6-dimethyl-5-N-methylaminocarbonylpyridine-3-carboxylates (5).
- Sainani, J. B.,Shah, A. C.,Arya, V. P.
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p. 573 - 575
(2007/10/03)
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- 1,4-dihydropyridine derivatives
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1,4-Dihydropyridine derivatives of formula: STR1 wherein Ar1 represents an aromatic hydrocarbon group or an aromatic heteromonocyclic or heterobicyclic group containing therein 1 to 3 atoms selected from the group consisting of oxygen, sulfur and nitrogen; R1 represents a hydrocarbon group which may have one or more substituents; A represents (i) a straight chain or branched chain unsaturated hydrocarbon group, (ii) a cyclic unsaturated hydrocarbon group, or (iii) a group selected from the group consisting of --R--O--N=CH--, --R--N=N--, --R--CH=N-- and --R--N=CH--, in which R is an alkylene group having 1 to 6 carbon atoms; B represents an alkylene or alkenylene group having 1 to 3 carbon atoms, which may have a substituent; Ar2 represents an aromatic hydrocarbon group or a heterocyclic group; Ar3 represents a heterocyclic group which may have one or more substituents; and n is 0 or 1, and the corresponding optical active 1,4-dihydropyridine derivatives, having an optically active cite as indicated by *, have both superior vasodilative and platelet aggregation inhibiting activities.
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- Synthesis and antihypertensive activities of new 1,4-dihydropyridine derivatives containing a nitrooxy moiety at the 3-ester position
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The synthesis of a new series of dihydropyridines containing a nitrooxy moiety at the 3-ester position is described. The antihypertensive activity of the compounds was examined and compared with that of nifedipine; some of them were relatively potent. The structure-activity relationship is also discussed.
- Ogawa,Nakato,Tsuchida,Hatayama
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p. 108 - 116
(2007/10/02)
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- Studies on cerebral protective agents. II. Novel 4-arylpyrimidine derivatives with anti-anoxic and anti-lipid peroxidation activities.
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In a search for new cerebral protective agents with anti-anoxic (AA) and anti-lipid peroxidation (ALP) activities, a series of 4-arylpyrimidines, bearing an amino moiety in the C-5 position of the pyrimidine nucleus, was synthesized and tested for AA and
- Kuno,Sugiyama,Katsuta,Sakai,Takasugi
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p. 2423 - 2431
(2007/10/02)
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- Studies on cerebral protective agents. I. Novel 4-arylpyrimidine derivatives with anti-anoxic and anti-lipid peroxidation activities
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Novel 4-arylpyrimidine derivatives were synthesized by the oxidation of 4-aryl-1,4-dihydropyrimidines, and their effects on anti-anoxic (AA) activity in mice and anti-lipid peroxidation (ALP) activity in rat brain mitochondria were investigated. Among these compounds, ethyl 6-methyl-2-phenyl-4-(4-pyridyl)-5-pyrimidinecarboxylate (4b) has AA activity (10mg/kg, i.p.) and ethyl 6-methyl-4-(3-nitrophenyl)-2-phenyl-5-pyrimidinecarboxylate (4f) has ALP activity (73% inhibition at 10-5 g/ml). The latter compound (100mg/kg, i.p.) was also effective on arachidonate-induced cerebral edema in rats with comparable potency to that of vitamin E.
- Kuno,Sugiyama,Katsuta,Kamitani,Takasugi
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p. 1452 - 1461
(2007/10/02)
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- Dimeric 1,4-Dihydropyridines as Calcium Channel Antagonists
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A series of 1,n-alkanediylbis(1,4-dihydropyridines) (n = 2, 4, 6, 8, 10, 12) bridged at C3 of 2,6-dimethyl-3-carboxy-5-carbethoxy-4-(3-nitrophenyl)-1,4-dihydropyridine were synthesized and evaluated in a radioligand binding assay, nitrendipine in intestinal smooth muscle, as C2+ channel ligands.Binding activity was comparable to that of nitrendipine itself but independent of chain length, suggesting the lack of a major binding contribution by the second 1,4-dihydropyridine group.Analogues lacking the second 1,4-dihydropyridine nucleus or possessing an inactive function (4-nitrophenyl) were no less active, confirming that this series of ligands likely does not bridge adjacent 1,4-dihydropyridine receptors of the Ca2+ channel.
- Joslyn, Alan F.,Luchowski, Elizabeth,Triggle, David J.
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p. 1489 - 1492
(2007/10/02)
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- Pharmaceutically useful dihydropyridinyldicarboxylate amides and esters incorporating arylpiperazinylalkyl moities
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A series of 1,4-dihydropyridin-3,5-yl dicarboxylic acid amides and esters incorporating an arylpiperazinylalkyl moiety have been prepared possessing the general formula STR1 wherein R4 is cycloalkyl, aryl or hetaryl, generally with electronwithdrawing substituents; R2 and R6 are lower alkyl, alkanol, alkoxyalkyl, or alkylaminoalkyl; R5 is R2 or arylpiperazinylalkyl; X is 0 or NH; Y is lower alkylene, alkoxyalkylene, alkylaminoalkylene; and Z is phenyl, substituted phenyl, pyridinyl, substituted pyridinyl, or pyrimidinyl. Compounds of this series demonstrate activity as calcium and alphaadrenergic blockers in in vitro testing and antihypertensive, antiischemic, and platelet function inhibiting actions in in vivo screens.
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- SYNTHESIS OF HETEROCYCLIC COMPOUNDS. XXXVI. PREPARATION OF ALKYL SUBSTITUTED PYRANCARBONITRLES.
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The cyclization of the ketonitriles obtained from the reaction of suitably substituted propenones with propanedinitrile leads to alkyl substituted 4H-pyrans.Some of the starting propenones had to be prepared by base promoted opening of an isoxazole ring in the presence of an aldehyde.An exception to the general synthesis is also reported.
- Soto, Jose L.,Seoane, Carlos,Martin, Nazario,Quinteiro, Margarita
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- Dihydropyridyl cyclic imidate esters and their pharmaceutical use
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A series of 1,4-dihydropyrid-5-yl cyclic imidate esters have been prepared possessing the general formula STR1 wherein R and R1 are independently selected from hydrogen, lower alkyl or alkoxyalkyl groups; R2 is lower alkyl, aryl, or
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- Synthesis and comparative pharmacological studies of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylates with non-identical ester functions
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Michael-addition of 3-aminocrotonic acid ester 7 to aralkylidene acetoacetic acid esters 6 is followed by ring closure to give novel 4-aryl-1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylates 8 with non-identical ester functions. In the series of 3-nitrophenyl derivatives (8, Ar=3-nitrophenyl) the pharmacological activities (coronary vasodilation, anti-hypertensive activity) of the asymmetrically substituted derivatives are shown to be superior to those of the corresponding symmetrically substituted derivatives in many cases. One representative of this class 3-ethyl-5-methyl-1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedica rboxylate (nitrendipine, Bay e 5009, No. 3) was selected for further development as an antihypertensive drug.
- Meyer,Bossert,Wehinger,Stoepel,Vater
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p. 407 - 409
(2007/10/02)
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