- 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 for felodipine
-
The invention discloses a preparation method for felodipine. The method includes the following steps: taking 2,3-dichlorobenzaldehyde, beta-ethyl amino crotonate and methyl acetoacetate as raw materials and putting the raw materials into a reaction vessel; adding a catalyst; starting heating, and keeping the reaction at a stable temperature after slow heating; adding absolute ethanol while hot after the reaction time arrives; and obtaining a high-quality product of felodipine after cooling. The raw materials, solvents and catalysts used by the method are all commercial products, so that pricesare cheap and costs are low; toxic or dangerous reagents are not used, so that production safety is high; synthetic routes are short, and total yield is high; the method is simple in operation and convenient for industrialization; and waste water is not generated, and the method can be applied after solvent recovery.
- -
-
Paragraph 0014; 0040-0042; 0045-0048; 0051-0053
(2018/12/13)
-
- Evaluation of the chiral recognition properties and the column performances of three chiral stationary phases based on cellulose for the enantioseparation of six dihydropyridines by high-performance liquid chromatography
-
Separations of six dihydropyridine enantiomers on three commercially available cellulose-based chiral stationary phases (Chiralcel OD-RH, Chiralpak IB, and Chiralpak IC) were evaluated with high-performance liquid chromatography (HPLC). The best enantioseparation of the six chiral drugs was obtained with a Chiralpak IC (250?×?4.6?mm i.d., 5?μm) column. Then the influence of the mobile phase including an alcohol-modifying agent and alkaline additive on the enantioseparation were investigated and optimized. The optimal mobile phase conditions and maximum resolution for every analyte were as follows respectively: n-hexane/isopropanol (85:15, v/v) for nimodipine (R?=?5.80) and cinildilpine (R?=?5.65); n-hexane/isopropanol (92:8, v/v) for nicardipine (R?=?1.76) and nisoldipine (R?=?1.92); and n-hexane/isopropanol/ethanol (97:2:1, v/v/v) for felodipine (R?=?1.84) and lercanidipine (R?=?1.47). Relative separation mechanisms are discussed based on the separation results, and indicate that the achiral parts in the analytes' structure showed an important influence on the separation of the chiral column.
- Yu, Jia,Tang, Jing,Yuan, Xiaowei,Guo, Xingjie,Zhao, Longshan
-
p. 147 - 154
(2017/04/24)
-
- 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)
-
- Metal-free-mediated oxidation aromatization of 1,4-dihydropyridines to pyridines using visible light and air
-
A metal-free and environmentally friendly aerobic aromatization photosensitized by organic dye eosin Y bis(tetrabutyl ammonium salt) (TBA-eosinY) has been developed. With the aid of K2CO3, the aerobic catalytic system converts 1,4-dihydropyridines to their corresponding pyridine derivatives efficiently under visible light irradiation (λ=450 nm) at room temperature.
- Wei, Xiaojing,Wang, Lin,Jia, Wenliang,Du, Shaofu,Wu, Lizhu,Liu, Qiang
-
supporting information
p. 1245 - 1250
(2015/02/05)
-
- PROCESS FOR THE PREPARATION OF 4 -SUBSTITUTED -1, 4-DIHYDROPYRIDINES
-
4-Substituted-l,4-dihydropyridines of formula I are prepared by a cycloaddition reaction in which the cyclization is driven to completion at ambient temperature optionally in water without any catalyst. For exemplary purposes, the invention is described in particular detail with respect to the preparation of felodipine of formula II. Felodipine, a vasodilator, is prepared by a cycloaddition reaction of alkyl 3- aminocrotonate with dichlorobenzylidene under reaction conditions whereby the product crystallizes out of the reaction solution and may be directly isolated by filtration.
- -
-
Page/Page column 29
(2012/10/07)
-
- OSMOTIC PUMP CONTROLLED RELEASE TABLET AND PREPARATION METHOD THEREOF
-
An osmotic pump controlled release tablet and the preparation method thereof are disclosed. The osmotic pump controlled release tablet is composed of tablet core, semipermeable membrane and optional film coating. The material of said semipermeable membrane is composed of ethyl cellulose and povidone in the ratio of 1:1?1:4 by weight. Said tablet core comprises drug containing layer and push layer. The osmotic pump controlled release tablet also characterizes in that; (1) the angle θ1 formed by the outer curved surface of the drug containing layer and the lateral surface is 120°-180°; and/or (2) the ratio of L1 to r is 0.27-1.0, wherein L1 is the vertical distance from the central vertex of the outer curved surface of the drug containing layer to the plane formed by the intersection line between the outer curved surface of the drug containing layer and the lateral surface, and r is the radius of the tablet core.
- -
-
-
- OSMOTIC PUMP CONTROLLED RELEASE TABLET AND PREPARATION METHOD THEREOF
-
An osmotic pump controlled release tablet and the preparation method thereof are disclosed. The osmotic pump controlled release tablet is composed of tablet core, semipermeable membrane and optional film coating. The material of said semipermeable membrane is composed of ethyl cellulose and povidone in the ratio of 1:1~1:4 by weight. Said tablet core comprises drug containing layer and push layer. The osmotic pump controlled release tablet also characterizes in that; (1) the angle θ1 formed by the outer curved surface of the drug containing layer and the lateral surface is 120°-180°; and/or (2) the ratio of L1 to r is 0.27-1.0, wherein L1 is the vertical distance from the central vertex of the outer curved surface of the drug containing layer to the plane formed by the intersection line between the outer curved surface of the drug containing layer and the lateral surface, and r is the radius of the tablet core.
- -
-
-
- Solid Pharmaceutical Preparations Containing Copolymers Based On Polyethers Combined With Poorly Water-Soluble Polymers
-
The invention relates to dosage forms which contain preparations of poorly water-soluble substances in a polymer matrix of polyether copolymers, said polyether copolymers being obtained by the radically initiated polymerization of a mixture from 30 to 80% by weight of N-vinyl lactam, 10 to 50% by weight of vinyl acetate and 10 to 50% by weight of a polyether, and at least one poorly water-soluble polymer, the poorly water-soluble substance being present in the polymer matrix as an amorphous substance.
- -
-
-
- A facile synthesis of (S)-felodipine
-
A short and facile synthesis of (S)-felodipine was developed starting from (R)-glycidol as the source of the chiral auxiliary. 2-Hydroxyethyl esters were found to undergo selective transesterification reactions in the presence of other esters. This selective transesterification reaction was applied to the synthesis of (S)-felodipine through selective substitution of the 2-hydroxyethyl group possessing chiral ester with sodium methoxide.
- Kwon, Kuktae,Shin, Jung A.,Lee, Hee-Yoon
-
experimental part
p. 10222 - 10228
(2012/01/05)
-
- 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)
-
- 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.
- -
-
-
- Preparation of micron-size felodipine particles by microfluidization
-
The present invention provides the components for a stable felodipine composition and a process for preparing the composition. The composition includes felodipine, non-covalently bound to β-cylodextrin, and an optional binder as a moisture carrier component for the migration of hydroxide ions to the non-covalently bound felodipine and β-cylodextrin. The felodipine composition is combined with a carrier comprising cyclodextrin particles, a water-insoluble alkaline component and a swellable polymer.
- -
-
-
- Enantioselective retention of 4-aryl-1,4-dihydropyridine calcium-channel blockers on human serum albumin and α1-acid glycoprotein HPLC columns: Relationships with different scales of lipophilicity
-
The enantioselective retention of eight 4-aryl-1,4-dihydropyridine (DHP) calcium-channel blockers on HPLC stationary phases supporting human serum albumin (HSA) or α1-acid glycoprotein (AGP) was investigated. All chiral neutral DHPs were resolved on the AGP column, whereas, on the HSA column, only isradipine showed a split chromatographic peak. Analyses performed on AGP with eluents containing dimethyloctylamine (DMOA) as thc displacer demonstrated that the protein has at least two binding sites for DHPs. The first family of binding sites is enantioselective, binds exclusively to the (R)-forms, and presumably interacts competitively with DMOA. The second family of binding sites appears to be non-enantioselective and is affected by a cooperative interaction with DMOA. For the selected set of DHPs, the lipophilicity scale in octan-1-ol/H2O (log P) was not collinear with log k(w)(IAM) values obtained with immobilized artificial membranes (IAM-HPLC) due to the inclusion of both neutral and basic congeners. Only for the neutral DHPs did log k(w)(IAM) behave as a better descriptor than log P for retention date on HSA and AGP. In fact, the behavior of the basic DHPs amlodipine and nicardipine on both proteins correlated better with the octan- 1-ol/H2O log P values. We, therefore, infer that the amphipathic nature of the IAM phase only mimics the interaction of non-ionizable compounds with serum proteins. In contrast, the IAM-HPLC retention data of protonated bases encode additional interaction mechanisms that are specific for phospholipids and not involved in ligand-protein interactions.
- Barbato, Francesco,Quaglia, Fabiana,Quercia, Maria Tiziana,La Rotonda, Maria Immacolata
-
p. 767 - 776
(2007/10/03)
-
- Process to prepare dihydropyridine and derivatives thereof
-
A novel process is disclosed for the preparation of dihydropyridine compounds and derivatives thereof, and more particularly felodipine. The process to prepare felodipine involves a two step procedure condensing 2,3-dichlorobenzaldehyde with methyl acetoacetate in the presence of a catalyst system. The resultant benzylidine intermediate is sequentially reacted with ethyl aminocrotonate to provide felodipine. The novelty of the present invention resides in part on (1) a new catalyst system not previously disclosed for the preparation of felodipine, (2) the absence of acid(s), (3) the control of reaction conditions to yield lower amounts of unreacted aldehyde compared to known reactions, (4) a simplified purification process, and (5) formation of negligible quantities of symmetrical diester byproducts.
- -
-
-
- Synthesis of unsymmetrically substituted 1,4-dihydropyridines and analogous calcium antagonists by microwave heating
-
Rapid and efficient synthesis of 3,5-unsymmetrically substituted 1,4-dihydropyridines and imidazopyrimidine derivatives can be achieved under microwave irradiation using a household microwave oven.
- Alajarin,Jordan,Vaquero,Alvarez-Builla
-
p. 389 - 391
(2007/10/02)
-
- Determination of the absolute configuration of biologically active (S)-(-)-NB 818 and its structural correlation with the stereoselectivity of the channel blocking action
-
The absolute configuration of 4-(2,3-dichlorophenyl)-1,4-dihydropyridines was established by chemical correlation with (S)-(-)-felodipine, the absolute configuration of which had been determined by X-ray analysis.
- Yamazaki,Ebiike,Achiwa
-
p. 1968 - 1970
(2007/10/02)
-
- Process for the preparation of 4-substituted-1,4-dihydropydrines
-
4-Substituted-1,4-dihydropyridines are prepared by a cycloaddition reaction in which the cyclization is driven to completion, after thermal reaction, by addition of an acid. Felodipine, a vasodilator, is prepared by a cycloaddition reaction of ethyl 3-aminocrotonate with a suitably substituted dichlorobenzylidine under reaction conditions whereby the product crystallizes out of the reaction solution and may be directly isolated by filtration.
- -
-
-
- 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.
- -
-
-
- SYNTHESIS OF THE ENANTIOMERS OF FELODIPINE AND DETERMINATION OF THEIR ABSOLUTE CONFIGURATION
-
The pure enantiomers of felodipine, 1, have been synthesized by chromatographic separation of diastereomeric esters with (R)-1-(p-toluenesulfonyl)-3-trityloxypropan-2-ol, 3, as an easily removable chiral auxiliary.Absolute configurations have been deduced
- Lamm, Bo,Simonsson, Roger,Sundell, Staffan
-
p. 6423 - 6426
(2007/10/02)
-
- 2,6-Dimethyl-4-2,3-disubstituted phenyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid-3,5-asymmetric diesters having hypotensive properties, as well as method for treating hypertensive conditions and pharmaceutical preparations containing same
-
The present invention relates to new compounds having antihypertensive effect, which compounds are of the formula I, STR1 wherein R1 is selected from the group consisting of --CH3, --C2 H5, --CH2 CH2 OCH3, and --CH2 CH2 OC2 H5, and R2 is selected from the group consisting of --C2 H5, --CH(CH3)2, --C(CH3)3, --CH(CH3)CH2 OCH3, C(CH3)2 CH2 OCH3, and --CH2 C(CH3)=CH2, whereby R1 and R2 are not the same, R3 is selected from the group consisting of chloro, and R4 is selected from the group consisting of chloro, and methyl, a method for lowering the blood pressure in mammals including man using said compounds, and pharmaceutical preparations containing said compounds.
- -
-
-
