- Facile synthesis of 1,4-dihydropyridine monocarboxylic acids and unsymmetric dicarboxylates via quaternary ammonium salts of 2-aminoethyl 1,4-dihydropyridine-3,5-dicarboxylates
-
Useful 1,4-dihydropyridine unsymmetric dicarboxylates [nitrendipine (1), nicardipine (2)] and monocarboxylic acid 4 were prepared from unsymmetric 2-aminoethyl methyl 1,4-dihydropyridine-3,5-dicarboxylates 2 and 3 via their corresponding quaternary ammonium salts 5-9.
- Kinugawa, Masahiko,Ogasa, Takehiro
-
-
Read Online
- METHODS FOR TREATING CHRONIC FATIGUE SYNDROME AND MYALGIC ENCEPHALOMYELITIS
-
In one aspect the invention relates to a method of treatment selected from the group consisting of: (a) treating a symptom such as pain in a subject identified or diagnosed as having Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS); (b) treating a symptom such as pain in a subject having dysfunctional TRPM3 ion channel activity; (c) restoring NK cell function in a subject having dysfunctional TRPM3 ion channel activity; and (d) restoring calcium homeostasis in a subject having dysfunctional TRPM3 ion channel activity. The method comprises the step of administering to the subject a therapeutically effective amount of at least one therapeutic compound selected from the group consisting of: (i) an opioid receptor antagonist; (ii) an opioid antagonist; and (iii) a therapeutic compound that restores TRPM3 ion channel activity. In some embodiments the therapeutic compound is naltrexone hydrochloride.
- -
-
-
- Preparation method of nitrendipine
-
The invention belongs to the technical field of medicines, and particularly relates to a preparation method of nitrendipine, which comprises the following steps: adding (E)-2-(3-nitrobenzylidene)-3-oxobutyrate and methyl 3-aminocrotonate into a first solvent, and carrying out a reflux reaction at a first temperature to obtain a first reaction solution; adding acetic anhydride into the first reaction solution at a second temperature to react to obtain a second reaction solution; carrying out a stirring reaction on the second reaction solution at a third temperature, and filtering to obtain a crude product of nitrendipine; and recrystallizing the crude product of nitrendipine to obtain nitrendipine. The invention provides a preparation method of nitrendipine, and aims to effectively controldimethyl ester impurities and diethyl ester impurities, improve the yield and shorten the reaction time so as to improve the productivity.
- -
-
Paragraph 0051-0071
(2020/05/14)
-
- Based on the three-step synthesis process of preparation of the nitrendipine (by machine translation)
-
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)
- -
-
-
- Preparation method of nitrendipine
-
The invention belongs to the field of drug synthesis, and particularly relates to a preparation method of nitrendipine. The preparation method is characterized by including following steps: (1), allowing 3-nitrobenzylidene ethyl acetoacetate intermediate and 3-aminomethyl crotonate according to a molar ratio of 1:1-1.1 to react at 70-75 DEG C in advance; (2), adding concentrated hydrochloric acidinto a reaction system of the step (1), and allowing reaction at 70-75 DEG C after adding is completed, wherein adding amount of the concentrated hydrochloric acid is 10-15% of molar weight of the 3-nitrobenzylidene ethyl acetoacetate intermediate; (3), cooling to 15-20 DEG C after reaction in the step (2) is completed, continuing reaction, and performing solid-liquid separation and recrystallization to obtain nitrendipine. Through process control, content of ester exchange impurities can be lowered effectively, and product yield can be increased.
- -
-
Paragraph 0042-0058
(2019/05/22)
-
- Synthesis, docking simulation, biological evaluations and 3D-QSAR study of 1,4-dihydropyridines as calcium channel blockers
-
Resurgence to target L-type voltage-dependent calcium channels has been applied by the synthesis of two series of nifedipine analogues where the ortho- or a meta-nitrophenyl ring is retained. A pre-synthetic molecular docking study with a receptor model followed by molecular alignment has been performed on 47 compounds to predict the most active member. The IC50 values revealed that some of the compounds are similar to or more active than nifedipine. Substitution of groups at the 3- and 5-positions of the dihydropyridine (DHP) ring gave 3k, which is more active than nifedipine. Our valid three-dimensional quantitative structure–activity relationship (3D-QSAR) model prefigures the influence of lipophilicity, bulkiness and chelating effects of the C3 and C5 substituents. Bulky groups interfere with ring-to-ring hydrophobic interaction with tyrosine (Tyr)4311 and limit the efficiency of increasing the length of the hydrocarbon chain of esters at the 3- and 5-positions of the DHP ring as an approach to increasing the activity. The presence of a chelating substituent on the phenyl ring at the 4-position of the DHP ring ensures strong binding to the receptor and hence stabilization of the closed-channel conformation. The validation of 3D-QSAR model indicated its proficiency in predicting activity of newly compounds belonging to the same chemical class.
- El-Moselhy, Tarek Fathy,Sidhom, Peter Ayoub,Esmat, Eman Ahmed,El-Mahdy, Nageh Ahmed
-
p. 893 - 903
(2018/10/31)
-
- An efficient and recyclable 3D printed α-Al2O3 catalyst for the multicomponent assembly of bioactive heterocycles
-
A catalytic methodology is reported that enables the efficient, operationally simple and environmentally friendly synthesis of diverse 1,4-dihydropyridines and 3,4-dihydropyrimidin-2(1H)-ones, including some relevant drugs and pharmacologically active derivatives. This strategy is based on the use of a 3D printed Al2O3 woodpile material that was sintered to generate a rigid structure with controlled porosity and noteworthy catalytic performance. The 3D printed Al2O3 catalyst exhibits remarkable efficacy as a Lewis acid in Biginelli and Hantzsch reactions and it can be recovered and reused ten times without any decrease in the activity. Remarkable E factors, excellent recyclability and scalability, broad substrate scope, short reaction times, excellent yields, solvent-free conditions and easy isolation procedures are key features of this methodology.
- Azuaje, Jhonny,Tubío, Carmen R.,Escalante, Luz,Gómez, Mónica,Guitián, Francisco,Coelho, Alberto,Caama?o, Olga,Gil, Alvaro,Sotelo, Eddy
-
p. 203 - 210
(2016/12/09)
-
- First Report About the Use of Micellar Keggin Heteropolyacids as Catalysts in the Green Multicomponent Synthesis of Nifedipine Derivatives
-
Abstract: Micellar Keggin heteropolyacid catalysts were prepared using hexadecyltrimethylammonium bromide (cetyltrimethylammonium bromide—CTAB), 1-hexadecyl-pyridinium chloride, and Keggin heteropolyacids H3PMo12O40 and H4PMo11VO40 as precursors. Four catalysts were prepared (PMo12C16, PMo11VC16, PMo12C16Py, and PMo11VC16Py) and characterized by 31P NMR, FT-IR, XRD, SEM analysis and textural properties (SBET). The acidic characteristics of the catalysts were determined by potentiometric titration with n-butylamine. A series of bioactive 1,4-dihydropyridine derivatives such as nifedipine and nemadipine B were synthesized using these new materials, in a one-pot procedure in ethanol. This methodology requires a reaction time of 8?h, and a temperature of 78?°C to obtain good to excellent yields of 1,4-dihydropyridine derivatives. The micellar Keggin catalysts are insoluble in polar media, which allows easy removal of the reaction products without affecting their catalytic activity. The leaching test showed that they have an excellent stability and can be used five times as heterogeneous catalysts without appreciable loss of the catalytic activity. Using the same material, unsymmetrical 1,4-dihydropyridines such as nitrendipine can be obtained through a sequence of steps in very good yield (78?%). Graphical Abstract: [Figure not available: see fulltext.]
- Palermo, Valeria,Sathicq, ángel G.,Constantieux, Thierry,Rodríguez, Jean,Vázquez, Patricia G.,Romanelli, Gustavo P.
-
p. 1634 - 1647
(2016/08/30)
-
- Synthesis and antihypertensive activity evaluation in spontaneously hypertensive rats of nitrendipine analogues
-
The antihypertensive activity of nitrendipine analogues can be improved by properly lengthening its alkyl chain in 3- or 5-position. Nitrendipine and its seven analogues were synthesized, and their antihypertensive activities in spontaneously hypertensive rats (SHR) were evaluated by ig administration. It was found that 5-n-heptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4- dihydropyridine- 3,5-dicarboxylate [(±)-5] exhibited the strongest antihypertensive effect amongst eight compounds. (?)-5-nheptyl 3-methyl 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine- 3,5-dicarboxylate [(+)-5] was also prepared. Antihypertensive activities of (±)-5 and (?)-5 in SHR were compared. The results showed that (±)-5 and (?)-5 had a higher potency than nitrendipine, and (+)-isomer was 1.79-fold the raceme at a dose of 2 mg/kg. Springer Science+Business Media, LLC 2010.
- Zhou, Kai,Wang, Xiao-Meng,Zhao, Yi-Zhi,Cao, Yong-Xiao,Fu, Qiang,Zhang, San-Qi
-
p. 1325 - 1330
(2012/06/04)
-
- Catalytic effect of nanosized metal oxides on the Hantzsch reaction
-
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
-
experimental part
p. 566 - 572
(2011/01/07)
-
- Synthesis and application of ionic liquid phase-supported β-aminocrotonate for access to asymmetric 1,4- dihydropyridines
-
Ethyl methyl 2,6-dimethyl-4-(3-nitrophenyl)-l,4-dihydropyridine-3, 5dicarboxylate or nitrendipine was prepared in four steps with high overall yield from ionic liquid phase bound b-aminocrotonate. The asymmetric 1,4-dihydropyridine scaffolds were built using a sequential approach according to ionic liquid-phase organic synthesis (IoLiPOS) methodology.
- Bazureau, Jean Pierre,Legeay, Jean-Christophe,Carrie, Daniel,Paquin, Ludovic,Jacques, Jean,Eynde, Vanen
-
scheme or table
p. 91 - 96
(2010/06/19)
-
- THERAPY FOR COMPLICATIONS OF DIABETES
-
A method for enhancing glycemic control and/or insulin sensitivity in a human subject having diabetic nephropathy and/or metabolic syndrome comprises administering to the subject a selective endothelin A (ETA) receptor antagonist in a glycemic control and/or insulin sensitivity enhancing effective amount. A method for treating a complex of comorbidities in an elderly diabetic human subject comprises administering to the subject a selective ETA receptor antagonist in combination or as adjunctive therapy with at least one additional agent that is (i) other than a selective ETA receptor antagonist and (ii) effective in treatment of diabetes and/or at least one of said comorbidities other than hypertension. A therapeutic combination useful in such a method comprises a selective ETA receptor antagonist and at least one antidiabetic, anti-obesity or antidyslipidemic agent other than a selective ETA receptor antagonist.
- -
-
-
- ANTIHYPERTENSIVE THERAPY
-
A new use of darusentan is provided in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy with one or more drugs. The composition comprises darusentan in an amount providing a therapeutically effective daily dose; wherein (a) the composition is orally deliverable and/or (b) the daily dose of darusentan is effective to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures. Further provided is a new use of darusentan in preparation of a pharmaceutical composition for lowering blood pressure in a patient exhibiting resistance to a baseline antihypertensive therapy, wherein the composition is administered adjunctively with at least one diuretic and at least one antihypertensive drug selected from ACE inhibitors, angiotensin II receptor blockers, beta-adrenergic receptor blockers and calcium channel blockers.
- -
-
-
- Regioselective synthesis of pyridines and dihydropyridines derived from β-amino acids and aminophosphonates by reaction of N-vinylic phosphazenes with α,β-unsaturated ketones
-
Reaction of N-vinylic phosphazenes with α,β-unsaturated ketones leads to the formation of pyridines derived from β-amino acids in a regioselective fashion. The use of functionalized enones derived from α-acylstyryl-carboxylates or -phosphonates affords biologically active asymmetrical and symmetrical dihydropyridines substituted with carboxylate or phosphonate groups including nitrendipine, felodipine, MRS 1097, and efonidipine analogs.
- Palacios, Francisco,Herrán, Esther,Rubiales, Gloria,Alonso, Concepción
-
p. 5669 - 5676
(2008/01/01)
-
- Method for treating resistant hypertension
-
A method is provided for lowering blood pressure in a patient having clinically diagnosed resistant hypertension. The method comprises administering darusentan to the patient adjunctively with a baseline antihypertensive regimen that comprises administration of at least one diuretic and at least two antihypertensive drugs selected from at least two of (a) ACE inhibitors and angiotensin II receptor blockers, (b) beta-adrenergic receptor blockers and (c) calcium channel blockers. The darusentan is orally administered at a dose and frequency effective, in combination with the baseline regimen, to provide a reduction of at least about 3 mmHg in one or more blood pressure parameters selected from trough sitting systolic, trough sitting diastolic, 24-hour ambulatory systolic, 24-hour ambulatory diastolic, maximum diurnal systolic and maximum diurnal diastolic blood pressures.
- -
-
-
- Process to prepare 1,4-dihydropyridine intermediates and derivatives thereof
-
An improved catalyst is disclosed for a process involving the preparation of benzylidene intermediates useful in the preparation of 1,4-dihydropyridine compounds and derivatives thereof useful as medicines such as for example felodipine. This is accomplished by the condensation of an aldehyde and an acetoacetate in the presence of a novel catalyst system that includes a pyridyl carboxylic acid and a secondary amine. It has been found that through the use of the present invention the purity and yield of the desired isomer of the benzylidene intermediate can be maximized, thus avoiding the requirement of additional purification steps. The use of these intermediates can then be further reacted to form the required dihydropyridines, again having a very high purity and yield compared with the prior art.
- -
-
-
- PROCESS FOR THE PREPARATION OF 1,4-DIHYDROPYRIDINES AND NOVEL 1,4-DIHYDROPYRIDINES USEFUL AS THERAPEUTIC AGENTS
-
The present invention provides a process for the preparation of 1,4-dihydropyridines of the formula (1), wherein R1 is H, NO2, Cl, OAc, OH, R2 is H, NO2, Cl, -O-CH2-O-, OMe, OAc, OEt, OH, R3 is H, NO2, Cl, N(Me)2, -O- CH2 -O-, OMe, OAc, OH, R4 is H, OMe, OAc, OH, R5 is H, Cl, I, and R6 and R7 are either methyl, ethyl or both by preparing a mixture of an aromatic aldehyde, alkyl acetoacetate and a source of ammonia, adsorbing the prepared mixture and adsorbent till adsorbent becomes free flowing, heating the material so obtained under microwave irradiation, cooling the reaction mixture and recovering the compound of formula (1). The present invention also relates to novel 1,4-dihydropyridines with cardiovascular activity.
- -
-
-
- Chemical compounds having ion channel blocking activity for the treatment of immune dysfunction
-
The present invention relates to chemical compounds having inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca), and the use of such compounds for the treatment or alleviation of diseases or conditions relating to immune dysfunction. Moreover, the invention relates to a method of screening a chemical compound for inhibitory activity on an intermediate conductance Ca 2+ activated potassium channel (IK Ca).
- -
-
-
- Scaling up of dihydropyridine ester synthesis by using aqueous hydrotrope solutions in a continuous microwave reactor
-
We report here the scaling up of clinically important dihydropyridine by using a continuous microwave reactor (CMR). We also report the use of aqueous hydrotrope solution as a cheap, safe and "green" alternative to organic solvent to carry out homogeneous reactions under microwave heating. We have studied different aqueous hydrotrope solutions for the reaction in batch as well as continuous-flow process.
- Khadilkar, Bhushan M.,Madyar, Virendra R.
-
p. 452 - 455
(2013/09/07)
-
- Inclusion complexes of optically active 1,4-dihydropyridines with methyl-β-cyclodextrin
-
Novel inclusion complexes of racemic 1,4-dihydropyridines and enantiomers thereof of the formula STR1 wherein R represents a phenyl group, substituted with nitro, trifluoromethyl, difluoromethoxy group or with one or two halo atoms (especially chlorine), R1 and R2, if the same, represent methyl groups and if one of them has the meaning of a 2-aminoethoxymethyl or cyano group, the other represents a methyl group, R3 and R4, if different, stand each time for a hydrogen, linear or branched C1 -C6 -alkyl, 2-methoxyethyl, 1-(phenylmethyl)-3-piperidinylphenyl, styryl, furyl, piperidino, 4-diphenylmethyl-1-piperazinylethyl, 5-phenyl-3-pirazolyloxy, 1-phenyl-methyl-3-pyrrolidinyl group or a group of the formula STR2 or, if the same, stand each time C1 -C4 alkyl group, and of acid addition salts thereof with methyl-β-cyclodextrin, hydroxy-ethyl-β-cyclodextrin or hydroxypropyl-β-cyclodextrin, with the exception of inclusion complexes of racemic dihydropyridines with HP-β-CD, or, in case of amlodipine and enantiomeric nicardipine, also with β-cyclodextrin, are disclosed. Whilst inclusion complexes of racemic dihydropyridines with the cites cyclodextrins are prepared in a well-known manner disclosed in the literature, enantiomerically pure dihydropyridines and inclusion complexes thereof with cyclodextrins are prepared in a novel way by means of preparative column chromatography. The invention also relates to a pharmaceutical formulation containing novel inclusion complexes and to the use thereof as calcium antagonists for the treatment of hypertension, angina pectoris and cerebrovascular disorders.
- -
-
-
- Approaches to combinatorial synthesis of heterocycles: A solid-phase synthesis of 1,4-dihydropyridines
-
N-Immobilized enamino esters 2 derived from amine-functionalized PAL or Rink polystyrene resins react with preformed 2-arylidene β-keto esters or directly with β-keto esters and aldehydes to afford, upon trifluoroacetic acid cleavage, 1,4-dihydropyridine (DHP) derivatives in good yields. The mechanism of this transformation on solid support has been studied using 13C NMR and IR spectroscopies. This new solid-phase synthesis has been applied to the preparation of several bioactive DHPs and is designed to be amenable to the 'split and pool' protocol for combinatorial library synthesis.
- Gordeev, Mikhail F.,Patel, Dinesh V.,Gordon, Eric M.
-
p. 924 - 928
(2007/10/03)
-
- Aqueous hydrotrope solution as a safer medium for microwave enhanced Hantzsch dihydropyridine ester synthesis
-
Hantzsch esters are prepared for the first time, by condensing alkyl β-aminocrotonate, aldehyde and alkyl acetoacetate in aqueous sodium butylmonoglycosulphate (NaBMGS) as a safe reaction medium in an unmodified domestic microwave oven.
- Khadilkar, Bhushan M.,Gaikar, Vilas G.,Chitnavis, Ashish A.
-
p. 8083 - 8086
(2007/10/02)
-
- Process for preparation of enantiomerically pure polysubstituted 1,4-dihydropyridines
-
A process for the optical resolution of racemic 1,4-dihydropyridines, containing isothioureido groups. Salification of racemic isothioureas with optically active acids produces diasteroisomeric mixtures of isothiouronium salts, that, using conventional techniques, are separated in the individual components to give optically pure isothioureides of 1,4-dihydropyridines and salts thereof with conventional acids. Said optically pure 1,4-dihydropyridines can then be subjected to desulphuration and to different transformations to give to other enantiomerically pure and therapeutically useful 1,4-dihydropyridines.
- -
-
-
- Intermediates of optically active 1,4-dihydropyridines
-
STR1 in which optically pure products are obtained. The process is novel, as is II. I is known as being active on the blood circulation system.
- -
-
-
- Synthesis and comparative pharmacological studies of 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylates with non-identical ester functions
-
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
-
p. 407 - 409
(2007/10/02)
-
- Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acid
-
Pharmaceutical compositions containing unsymmetrical esters of 1,4-dihydropyridine 3,5-dicarboxylic acids as the active ingredient and methods of using same. The said ingredients are unsymmetrical 1,4-dihydropyridine 3,5-dicarboxylates which are substituted at position-4 of the dihydropyridine nucleus by phenyl which contains at least one nitro, cyano, azido, alkylthio, or alkylsulphonyl substituent. The compositions have a cardiovascular activity which makes them useful for effecting coronary vascular dilation and, also, they have utility in the treatment of hypertension.
- -
-
-
