- 1, 4-dihydro-1, 6-naphthyridine derivative, pharmaceutical composition of 1, 4-dihydro-1, 6-naphthyridine derivative, and application thereof
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The invention relates to a 1, 4-dihydro-1, 6-naphthyridine derivative, a pharmaceutical compositio of the 1, 4-dihydro-1, 6-naphthyridine derivative, and application of the 1, 4-dihydro-1, 6-naphthyridine derivative and the pharmaceutical composition of the 1, 4-dihydro-1, 6-naphthyridine derivative to treatment and prevention of cardiovascular, metabolic and kidney related diseases, and belongs to the field of medicine.
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Paragraph 0058-0060
(2021/08/07)
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- Phenyl substituted dihydropyridine compound and uses thereof
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The present invention relates to a phenyl substituted dihydropyridine compound and uses thereof, further to a pharmaceutical composition containing the compound. According to the present invention, the compound or the pharmaceutical composition can be used as mineralocorticoid receptor antagonists.
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Paragraph 0177; 0179-0181
(2019/05/16)
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- Barnidipine hydrochloride compound and preparation method thereof
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The invention discloses a barnidipine hydrochloride compound and a preparation method thereof. The preparation method comprises the following steps: (1) using 3-hydroxypropionitrile to react with diketene, to obtain an intermediate 1; (2) enabling the intermediate 1 to react with m-nitrobenzaldehyde and Beta-amino methyl crotonate, to obtain an intermediate 2; (3) enabling the intermediate 2 to behydrolyzed by strong base, to obtain an intermediate 3; (4) enabling the intermediate 3 to be resolved by chiral organic base, to obtain an intermediate 4; (5) enabling the intermediate 4 to react with thionyl chloride, (S)-1-benzyl-3-pyrrolidinol, and HCI ethanol solution, to obtain a crude product of barnidipine hydrochloride; and (6) performing ethyl alcohol pulping and refining, and ethyl alcohol recrystallization on the crude product of the barnidipine hydrochloride, to obtain the barnidipine hydrochloride.
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Paragraph 0042; 0043; 0044; 0056; 0057; 0058
(2019/01/16)
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- 3 - (2 - Nitrile ethyl) -5 - methyl - 2, 6 - dimethyl -4 - (3 - nitrophenyl) - 1, 4 - dihydropyridine - 3, 5 - dicarboxylic ester
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The invention relates to a preparation method of a barnidipine intermediate 3-(2-nitrile-ethyl)-5-methyl-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. The preparation method is characterized by enabling 3-hydroxylpropionitrile and methyl acetoacetate to be subjected to ester exchange under the catalysis of N-bromosuccinimide (NBS), then, ammoniating with a mixture of ammonium acetate and ammonia water, and then, carrying out catalytic reaction by an organic acid, thereby obtaining a final product. The preparation method provided by the invention is used for overcoming the defects of the existing preparation methods that the yield is relatively low and the like, and is applicable to industrial production.
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Paragraph 0018; 0027-0032
(2018/11/03)
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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 0414-0415
(2016/10/07)
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- Novel synthesis method of clevidipine butyrate important intermediate
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The invention discloses a preparation method of a clevidipine butyrate important intermediate. The preparation method comprises the steps that 3-Hydroxypropionitrile and diketene are condensed to obtain ethyl 2-cyanoacetoacetate (intermediate I); ethyl 2-cyanoacetoacetate, 2,3-dichlorobenzaldehyde and methyl 3-aminocrotonate are mixed, Hantzsch reaction is performed to obtain 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine phthalate methyl ester-(2-cyano ethyl)-ester (intermediate II); the 4-(2,3-dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine phthalate methyl ester-(2-cyano ethyl)-ester is hydrolyzed to obtain 4-(2,3- dichlorophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine mono-Methyl phthalate, namely the clevidipine butyrate important intermediate. The intermediate involved in the synthesis process is not needed to be chromatographic separation and purification, the materials for synthesis are cheap and easy to obtain, the reaction speed is high, the conditions are mild, operation is simple and convenient, the process reliability is good, the yield is high, the purity of the obtained clevidipine butyrate important intermediate is above 99%, and the preparation method is suitable for mass production.
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Paragraph 0019
(2016/10/07)
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- Process for synthesis of hydrochloric acid ramiah of lercanidipine (by machine translation)
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The invention discloses a process for synthesizing hydrochloric acid ramiah of lercanidipine, its synthesis process comprises the following steps : (1) 3 -? Hydroxy-propionitrile (I) and (II) reaction of ketene dimer, to obtain compound (VI) ; (2) compound (III) with (VI) reaction between formaldehyde nitrobenzene, to obtain compound (VII) ; (3) compound (VII) with β-amino-crotonic acid ethyl ester (IV) reaction, to obtain compound (VIII) ; (4) by strong alkali hydrolysis of compound (VIII), to obtain compound (IX) ; (5) compound (IX) using chiral organic alkali splitting, to obtain compound (X) ;? (6) compound (X) with benzyl quick (V) reaction, to obtain compound (XI) ; (7) a solution of compound (XI) by adding hydrogen chloride, hydrochloric acid ramiah horizontal (XII) can be obtained. Synthetic process of this invention has the following several advantages : (1) mild reaction conditions, each step the product is easy to separate, purification, controllable quality ; (2) higher yield for each step, the used original helping material is easy to obtain, the total cost is low ; (3) do not need to be too column, is suitable for industrial production. (by machine translation)
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Paragraph 0010
(2016/12/01)
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- Structure-activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels
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Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure-activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.
- Yamamoto, Takashi,Niwa, Seiji,Ohno, Seiji,Onishi, Tomoyuki,Matsueda, Hiroyuki,Koganei, Hajime,Uneyama, Hisayuki,Fujita, Shin-Ichi,Takeda, Tomoko,Kito, Morikazu,Ono, Yukitsugu,Saitou, Yuki,Takahara, Akira,Iwata, Seinosuke,Shoji, Masataka
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p. 798 - 802
(2007/10/03)
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- Synthesis and structural study of new highly lipophilic 1,4-dihydropyridines
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A new series of 1,4-dihydropyridines (1,4-DHPs) endowed with ester groups bearing long and functionalised alkoxy chains at the C3 and C5 positions of the nitrogen ring have been prepared from the corresponding β-keto esters which were in turn prepared by a lipase catalysed transesterification reaction. The structural study has been carried out by X-ray crystallography and theoretical calculations at the semiempirical (AM1), ab initio (HF/6-31G*) and B3LYP/6-31G* levels and reveals that the long alkyl chains do not have any influence on the required geometry of the 1,4-DHPs for biological activity. However, these chains have a strong impact on the lipophilicity and, therefore, they could be used to gain a better control of the duration of the pharmacological action. The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2005.
- Suarez, Margarita,De Armas, Merly,Ramirez, Oney,Alvarez, Amaury,Martinez-Alvarez, Roberto,Molero, Dolores,Seoane, Carlos,Liz, Ramon,De Armas, Hector Novoa,Blaton, Norbert M.,Peeters, Oswald M.,Martin, Nazario
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p. 1567 - 1576
(2007/10/03)
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- Investigations of the reaction mechanism concerning the formation of a 9-hydroxy-β-carboline-4-carboxylic acid from the nifedipine analogous biscyanoethyl ester
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The 3-tert-butyl-5-methyl-1,4-dihydropyridine(DHP)-dicarboxylate 5 reacts with trifluoroacetic acid (TFA) by elimination of the tert-butylester group yielding the 1,4-DHP 6. Irradiation of 6 by UV-A-light affords the corresponding pyridine 7 and the cyclic hydroxamic acid 10. The 2-cyanoethyl-1,4-DHP-carboxylate 13, obtained from the 3-tert-butyl-5-(2-cyano-ethyl)-1,4-DHP-dicarboxylate 12 by treating with TFA, reacts with sodium hydroxide solution to give the title compound 3.
- Gorlitzer,Baltrusch
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p. 747 - 750
(2007/10/03)
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- Synthesis of two optically active calcium channel antagonists labelled with carbon-11 for in vivo cardiac PET imaging
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(±)-S11568 (1, 3-ethyl-5-methyl-(±)-2-[(2-(2-aminoethoxy)ethoxy)methyl]-4-(2,3 -dichlorophenyl)-6-methyl-1,4-dihydropyridine-3,5- dicarboxylate), has an in vitro profile of high potency and of high selectivity for the low-voltage dependent L-type calcium channel. In in vitro binding studies, it displaced specifically bound (-)-[3H]PN 200-110 (isradipine (2), the reference molecule for in vitro studies) from cardiac and vascular smooth muscle preparations with potencies of 5.6 and 51 nM, respectively. It also appears as a pure pharmacological antagonist acting at a single channel L-type and free of any interaction at the benzothiazepine binding site such as amlodipine (3). Both enantiomers of S11568 have in vitro activities, the dextro isomer S12967 ((±)-1) being 6 to 18-fold less potent than the levo one S12968 ((-)-1). Two couples of optically active labelling precursors of S11568, ((-)-10/(+)-10 and (-)-14/(+)-14) have been synthesized using a modified Hantzsch's dihydropyridine synthesis. In both cases, the enantiomers were separated by preparative chiral HPLC. They both have been independently labelled with carbon-11, using [11C]diazomethane or [11C]iodomethane to give multimilliCurie quantities of (-)-1 (S12968) and (+)-1 (S12967) with high specific activities (500-1000 mCi/μmol, 18.5-37.0 GBq/μmol). Both enantiomers appear suitable for PET experiments: their myocardial concentration increases after a bolus injection to reach a maximum in 2 min and then remains on a plateau with a slight downslope while the blood concentration falls rapidly. Myocardial uptake was threefold higher than lung uptake, leading to a good contrast on PET images. The present preliminary biological results obtained in Beagle dogs showed that both enantiomers have similar myocardisk kinetics and in vivo affinity for the left ventricular myocardium.
- Dolle, Frederic,Hinnen, Francoise,Valette, Heric,Fuseau, Chantal,Duval, Raphael,Peglion, Jean-Louis,Crouzel, Christian
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p. 749 - 764
(2007/10/03)
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- Process for preparing 1,4 dihydropyridine compounds
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A 1,4-dihydropyridine derivative represented by formula (I): STR1 wherein X represents an alkyl group, or a group of STR2 in which R1, R2, and R3 may be the same or different and each represent a hydrogen atom, a halogen atom, a nitro group, a nitrile group, or a trifluoromethyl group; R4 represents a substituted or unsubstituted acyloxymethyl group, an alkoxycarbonyloxymethyl group, a (2-oxo-1,3-dioxolen-4 -yl)methyl group, a (5-substituted-2-oxo-1,3-dioxolen-4 -yl)methyl group, or an acyl group; R5 represents a lower alkyl group or a substituted alkyl group; and R6 represents a hydrogen atom, a lower alkoxymethyl group, or a lower acyloxymethyl group, is disclosed. The compound is stereospecifically hydrolyzed by the action of an enzyme to provide an optically active 1,4-dihydro -3-pyridinemonocarboxylic acid which is useful as an intermediate of pharmaceuticals in good optical purity and yield.
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- Derivatives of 1,4-dihydropyridine, their preparation procedure and therapeutic compositions containing them
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The invention relates to compounds having the formula: STR1 in which Ar represents a group selected from 2-nitrophenyl, 3-nitrophenyl, 2-chlorophenyl, 2,6-dichlorophenyl, 2-trifluoromethylphenyl and 3-trifluoromethylphenyl; R1 represents a C1 -C4 alkyl group or a group having the formula: STR2 A represents a group selected from groups having the formulae: STR3 and R2 represents a group selected from 2,4,6-trimethoxyphenyl, 2-thienyl and phenyl, and their addition salts with pharmaceutically acceptable acids. These compounds are calcium inhibitors with therapeutic applications.
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- Calcium channel blocking and positive inotropic activities of ethyl 5-cyano-1,4-dihydro-6-methyl-2-[(phenylsulfonyl)methyl]-4-aryl-3-pyrid ine-carboxylate and analogues. Synthesis and structure-activity relationships
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The synthesis and pharmacological evaluation of a series of 2-[(arylsulfonyl)methyl]-4-aryl-5-cyano-1,4-dihydropyridine-3-carboxyl ic acid esters and analogues are described. These compounds possess a unique profile namely, calcium channel blocking and positive inotropic activities in vitro. Compound 54 was selected as the best compound in the series and was studied in detail. The synthesis and biological profiles of enantiomers of 54 are also reported. The data indicate that although the calcium channel blocking property of 54 is stereospecific the positive inotropic activity is not. Examples of 3- and 6-cyano and other closely related 1,4-dihydropyridine derivatives are described and evaluated for comparison and were found to be devoid of dual activities mentioned above.
- Sircar,Gregor,Anderson,Haleen,Shih,Weishaar,Steffen,Pugsley,Taylor
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p. 2248 - 2260
(2007/10/02)
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- Antihypertensive dihydropyridine derivatives
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Compound of formula 1 are calcium entry antagonists useful for treating hypertension, congestive heart failure, angina, and vasospastic disorders: STR1 wherein n is an integer from 1 to 4; R1 and R2 are lower alkyl; R3 is lower alkyl or alkoxyalkyl; A is alkylene of two to eight carbon atoms; X1 and X2 are each independently --NO2, --CF3, CH3 O--, --CN, --H, lower alkyl or halo; Y is --O--, --S--, --S(O)--, or --S(O)2 --; and R is H, lower alkyl, cycloalkyl, alkoxyalkyl, cycloalkyloxy-alkyl, alkoxycycloalkyl, acyl, or saturated or unsaturated 5- or 6-membered heterocyclyl optionally substituted with lower alkyl or alkoxy, wherein the heteroatom is one oxygen atom.
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