- Nimodipine impurity IV reference substance as well as preparation method and application thereof
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The invention discloses a nimodipine impurity IV reference substance and a preparation method thereof. The method includes the steps that diketene, ethyl alcohol and triethylamine are taken and addedinto a container to be heated and cooled, reaction liquid is washed with water, washing liquid is discarded, anhydrous sodium sulfate is added and placed overnight, filtrate is obtained after filtration, ammonia gas is introduced into the filtrate until the filtrate is saturated, and the nimodipine impurity IV reference substance is obtained; and after the reaction is finished, m-nitrobenzaldehyde, methoxyethyl acetoacetate and ethanol are added, heating refulx is performed, the mixture is cooled and filtered, the solvent is removed through volatilization in a water bath to obtain a yellow viscous liquid, and recrystallization is carried out to obtain a yellow acicular crystal, namely the nimodipine impurity IV reference substance. The invention also discloses an application of the nimodipine impurity IV reference substance in nimodipine tablet consistency evaluation. According to the preparation method, the impurity IV can be prepared in a general analysis laboratory, special preparation equipment is not needed, the operation is simple, the purity of the obtained impurity reference substance can reach 98.4%, the purity requirement of the reference substance is met, and the preparation method can be used for consistency evaluation of the variety.
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Page/Page column 0051; 0053-0054
(2020/11/22)
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- Unsymmetric dihydropyridines bearing 2-pyridyl methyl carboxylate as modulators of P-glycoprotein; Synthesis and biological evaluation in resistant and non-resistant cancer cells
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Multi-drug resistance (MDR) in cancer cells is often associated with overexpression of P-glycoprotein (P-gp or ABCB1 or MDR1); therefore, modulators of this transporter might be helpful in overcoming MDR. In this study, 16 novel unsymmetrical dihydropyridine (DHP) derivatives bearing 2-pyridyl methyl carboxylate at C3 and a nitroimidazole or nitrophenyl ring at C4 positions of the DHP ring were synthesized. Their cytotoxicity was tested against four human cancer cells by MTT assay. The reversal capacity of MDR was examined in P-gp overexpressing cells (MES-SA/DX5) by measuring the alteration of doxorubicin's IC50 and performing flow cytometric determination of intracellular rhodamine 123 accumulation. The calcium channel blocking (CCB) activity, as a side effect of DHPs, was tested on the ileum of a guinea pig. Molecular docking was performed to explain the binding mode of compounds. Two derivatives, 4a and 4c, containing 4-nitrophenyl at C4 and possessing methyl (4a) and iso-propyl (4c) carboxylates at the C5 position of DHP core demonstrated superior cytotoxic and MDR reversal activities and lower CCB effect. Docking analysis confirmed the importance of the 4-nitrophenyl ring for P-gp inhibitory activity. Some of the synthesized DHP derivatives with considerable MDR reversal capacity could be promising compounds for further discovery of useful agents for management of drug resistant cancer.
- Nejati, Maryam,Sadeghpour, Hossein,Ranjbar, Sara,Javidnia, Katayoun,Edraki, Najmeh,Saso, Luciano,Firuzi, Omidreza,Miri, Ramin
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p. 603 - 614
(2019/08/06)
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- Synthesis method of isopropyl 3-aminocrotonate
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Isopropyl 3-aminocrotonate is an important chemical intermediate and has excellent industrial production value; however, methods in the prior art have problems of incomplete raw material conversion, difficulty of raw material removal, low product content and low yield; the method in the invention includes steps of with isopropyl acetoacetate and ammonium salt as raw materials, mixing the raw materials and performing a heating reaction, and when the isopropyl acetoacetate is reacted completely, separating the product to prepare the isopropyl 3-aminocrotonate. The method has simple operation, more completely converts the raw materials, and is high in product purity.
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Paragraph 0022; 0024; 0026; 0028; 0030-0032; 0034; 0036
(2018/06/26)
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- Compound and its as L-type calcium channel blocker or/and application of acetylcholine esterase inhibitors
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Disclosed in this invention are compounds and the uses as L-type calcium channel blocker and/or acetylcholinesterase inhibitor thereof. The uses of said compounds in the manufactures of a medicament for the treatment of cardiovascular diseases, apoplexy or senile dementia are also disclosed in the present invention.
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Paragraph 0153; 0154
(2016/10/07)
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- Preparation method of azelnidipine
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The invention relates to a preparation method of azelnidipine, which comprises the following steps: carrying out Knoevenagel reaction on cyanoacetic acid and m-nitrobenzaldehyde used as starting materials to generate a compound 1; hydrolyzing cyano group of the compound 1 to generate a compound 2; carrying out esterification on the compound 2 and 1-diphenylmethyl-3-azetidin-ol under the action of DCC (N,N'-dicyclohexylcarbodiimide) to generate a compound 3; carrying out Hantzsch cyclization on the compound 3 and isopropyl 3-aminocrotonate under alkaline conditions to generate an azelnidipine crude product; and refining the crude product to obtain the azelnidipine fine product. The method is simple to operate and suitable for industrial production; and the reaction product is easy to separate.
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Paragraph 0016
(2017/03/08)
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- Cytotoxic and multidrug resistance reversal activities of novel 1,4-dihydropyridines against human cancer cells
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Multidrug resistance (MDR) caused by P-glycoprotein (P-gp, ABCB1, MDR-1) transporter over-expression in cancer cells substantially limits the effectiveness of chemotherapy. 1,4-Dihydropyridines (DHPs) derivatives possess several pharmacological activities. In this study, 18 novel asymmetrical DHPs bearing 3-pyridyl methyl carboxylate and alkyl carboxylate moieties at C3 and C5 positions, respectively, as well as nitrophenyl or hetero aromatic rings at C4 were synthesized and tested for MDR reversal with the aim of establishing a structure-activity relationship (SAR) for these agents. Effect of these compounds on P-gp mediated MDR was assessed in P-gp over-expressing MES-SA/DX5 doxorubicin resistant cells by flow cytometric detection of rhodamine 123 efflux. MDR reversal was further examined as the alteration of doxorubicin's IC50 in MES-SA/DX5 cells in the presence of DHPs by MTT assay and was compared to nonresistant MES-SA cells. Direct anticancer effect was examined against 4 human cancer cells including HL-60, K562, MCF-7 and LS180. Calcium channel blocking (CCB) activity was also measured as a potential side effect. Most DHPs, particularly compounds bearing 3-nitrophenyl (A2B2 and A3B2) and 4-nitrophenyl (A3B1 and A4B1) moieties at C4 significantly inhibited rhodamine 123 efflux at 5-25 μM, showing that the mechanism of MDR reversal by these agents is P-gp transporter modulation. Same derivatives were also able to selectively lower the resistance of MES-SA/DX5 to doxorubicin. A2B2 bearing ethyl carboxylate at C5 had also high direct antitumoral effect (IC50 range: 3.77-15.60 μM). Our findings suggest that SAR studies of DHPs may lead to the discovery of novel MDR reversal agents.
- Shekari, Farnaz,Sadeghpour, Hossein,Javidnia, Katayoun,Saso, Luciano,Nazari, Farhad,Firuzi, Omidreza,Miri, Ramin
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p. 233 - 244
(2015/04/16)
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- Reversal of multidrug resistance in cancer cells by novel asymmetrical 1,4-dihydropyridines
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Multidrug resistance (MDR) is an important obstacle that limits the efficacy of chemotherapy in many types of cancer. In this study, 14 novel asymmetrical DHPs possessing pyridyl alkyl carboxylate substitutions at C 3 and alkyl carboxylate groups at C5 in addition to a nitroimidazole or nitrophenyl moiety at C4 position were synthesized. Calcium channel blocking (CCB) activity was measured in guinea pig ileal longitudinal smooth muscle. Cytotoxicity was tested on 4 human cancer cell lines, while MDR reversal capacity was examined on P-glycoprotein overexpressing doxorubicin resistant MES-SA-DX5 and compared with non-resistant MES-SA cells. Compounds showed different CCB (IC50: 29.3 nM-4.75 μM) and cytotoxic activities (IC50: 6.4 to more than 100 μM). Several compounds having nitrophenyl moiety at C4, could significantly reverse resistance to doxorubicin at 0.5 and 1 μM. The most active ones were 7e and 7g containing ethyl carboxylate and isopropyl carboxylate at C 5, respectively. CCB activity, which is considered an undesirable effect for these agents, of 7e and 7g were 33 and 20 times lower than nifedipine, respectively. In conclusion, the newly synthesized asymmetrical DHP compounds showed promising MDR reversal and antitumoral activities with low CCB effects and could be of therapeutic value in drug resistant cancer.
- Firuzi, Omidreza,Javidnia, Katayoun,Mansourabadi, Elham,Saso, Luciano,Mehdipour, Ahmad Reza,Miri, Ramin
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p. 1392 - 1402
(2013/12/04)
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- Synthesis of β-amino acid derivatives via copper-catalyzed asymmetric 1,4-reduction of β-(acylamino)acrylates
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A new set of reaction conditions has been established to facilitate the copper-catalyzed enantioselective 1,4-reduction of β-(acylamino)acrylates toward a selection of β-alkyl-β-amino acid derivatives in high yields and with uniformly high ee values (up to 99%) irrespective of the use of (E)- or (Z)-substrates.
- Wu, Yan,Qi, Shan-Bin,Wu, Fei-Fei,Zhang, Xi-Chang,Li, Min,Wu, Jing,Chan, Albert S. C.
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supporting information; experimental part
p. 1754 - 1757
(2011/05/12)
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- Synthesis and biological evaluation of some new 1,4-dihydropyridines containing different ester substitute and diethyl carbamoyl group as anti-tubercular agents
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Tuberculosis is a leading infectious cause of death worldwide. Because of the concern of the resistance to most of the commonly used drugs displayed by the considered mycobacteria, most efforts have been done to introduce new anti-tubercular agents. Recent studies showed that 1,4-dihydropyridine-3,5-dicarbamoyl derivatives with lipophilic groups have significant anti-tubercular activity. In this study, we synthesized new derivatives of 1,4-dihydropyridines in which different alkyl and aryl esters and diethyl carbamoyl are substituted in C-3 and C-5 of the DHP ring. In addition nitroimidazole ring is substitutes at C-4 position. These asymmetric analogues were synthesized by a modified Hantzsh reaction using procedure reported by Meyer. The in vitro anti-tubercular activity of compounds against Mycobacterium tuberculosis was evaluated. The results indicate that the compounds containing aromatic esters are more potent than alkyl ones. The most potent aromatic compound (R = 3-phenylpropyl) exhibits comparable anti-tubercular activity (MIC = 1 μmol/ml) with reference compound isoniazide (INH) (MIC = 1 μmol/ml). Conformational analysis, SAR studies of these compounds showed that increasing in lipophilicity and rotable bonds of these compounds resulted in increasing anti-tubercular activity.
- Khoshneviszadeh, Mehdi,Edraki, Najmeh,Javidnia, Katayoun,Alborzi, Abdolvahab,Pourabbas, Bahman,Mardaneh, Jalal,Miri, Ramin
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experimental part
p. 1579 - 1586
(2009/07/11)
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- An efficient, metal-free, room temperature aromatization of Hantzsch-1,4-dihydropyridines with urea-hydrogen peroxide adduct, catalyzed by molecular iodine
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A mild, highly efficient and metal-free synthetic method for aromatization of 1,4-dihydropyridines employing urea-hydrogen peroxide adduct as oxidant catalyzed by 20 mol % of molecular iodine was developed. The reaction was carried out in ethyl acetate at room temperature and the products were isolated in high to excellent yields. A plausible free-radical mechanism is proposed based on results obtained with derivatives having alkyl and aryl substituents in the 1,4-dihydropyridine ring.
- Filipan-Litvi?, Mirela,Litvi?, Mladen,Vinkovi?, Vladimir
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p. 5649 - 5656
(2008/09/21)
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- Iridium-catalyzed hydrogenation of β-dehydroamino acid derivatives using monodentate phosphoramidites
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The iridium-catalyzed asymmetric hydrogenation of 13 different β-dehydroamino acid derivatives to give optically active β-amino acid esters has been examined. Readily accessible monodentate octahydrobinaphthol- based phosphoramidites were used as chiral ligands. Good to excellent enantioselectivities and yields were obtained for the E isomers, whereas poorer catalyst performance was found for the Z isomers. Importantly, to obtain high enantioselectivity, substitution at the 3,3′-positions of the ligands was necessary. Enantioselectivities of up to 94% ee were achieved under optimized conditions. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Enthaler, Stephan,Erre, Giulia,Junge, Kathrin,Schroeder, Kristin,Addis, Daniele,Michalik, Dirk,Hapke, Marko,Redkin, Dmitry,Beller, Matthias
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experimental part
p. 3352 - 3362
(2009/04/07)
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- Development of practical rhodium phosphine catalysts for the hydrogenation of β-dehydroamino acid derivatives
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The rhodium-catalyzed asymmetric hydrogenation of various β-dehydroamino acid derivatives to give optically active β-amino acids has been examined. Chiral monodentate 4,5-dihydro-3H-dinaphthophosphepines, which are easily tuned and accessible in a multi-10-g scale, have been used as ligands. The enantioselectivity is largely dependent on the nature of the substituent at the phosphorous atom and on the structure of the substrate. Applying optimized conditions up to 94% ee was achieved.
- Enthaler, Stephan,Erre, Giulia,Junge, Kathrin,Holz, Jens,Boerner, Armin,Alberico, Elisabetta,Nieddu, Ilenia,Gladiali, Serafino,Beller, Matthias
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p. 568 - 577
(2012/12/31)
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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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