- Orienting the heterocyclic periphery: A structural model for chloroquine's antimalarial activity
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The antimalarial drug chloroquine binds to gallium proto-porphyrin-IX in methanol and in the solid state and represents a unique drug-heme model.
- Dodd, Erin L.,Bohle, D. Scott
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- Multiple spectroscopic and magnetic techniques show that chloroquine induces formation of the μ-oxo dimer of ferriprotoporphyrin IX
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Interaction of the antimalarial chloroquine (CQ) with ferriprotoporphyrin IX, Fe(III)PPIX, was investigated in aqueous solution (pH 7.4) and as a precipitate from aqueous medium at pH 5.0. In solution, spectrophotometric titrations indicated strong association (logKobs 13.3 ± 0.2) and a Job plot gave a stoichiometry of 1:2 CQ:Fe(III)PPIX. UV-visible absorbance and magnetic circular dichroism spectra of the complex were compared to various Fe(III)PPIX species. Close similarity to the spectra of the μ-oxo dimer, μ-[Fe(III)PPIX]2O, was revealed. The induction of this species by CQ was confirmed by magnetic susceptibility measurements using the Evans NMR method. The observed low-magnetic moment (2.25 ± 0.02 μB) could only be attributed to antiferromagnetically coupled Fe(III) centers. The value was comparable to that of μ-[Fe(III)PPIX]2O (2.0 ± 0.1 μB). In the solid-state, mass spectrometry confirmed the presence of CQ in the complex. Dissolution of this solid in aqueous solution (pH 7.4) resulted in a solution with a UV-visible spectrum consistent with the same 1:2 stoichiometry observed in the Job plot. Magnetic susceptibility measurements made on the solid using an Evans balance produced a magnetic moment (2.3 ± 0.1 μB) consistent with that in solution. Diffusion coefficients of CQ and its complex with Fe(III)PPIX were measured in aqueous solution (3.3 ± 0.3 and 0.6 ± 0.2 × 10- 10 m 2·s- 1, respectively). The latter was used in conjunction with an empirical relationship between diffusion coefficient and molar volume to estimate the degree of aggregation. The findings suggest the formation of a 2:4 CQ:Fe(III)PPIX complex in aqueous solution at pH 7.4.
- Kuter, David,Benjamin, Stefan J.,Egan, Timothy J.
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- UV-Visible and Carbon NMR Studies of Chloroquine Binding to Urohemin I Chloride and Uroporphyrin I in Aqueous Solutions
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Interactions of the antimalaria drug chloroquine with urohemin I and uroporphyrin I have been studied in aqueous solutions at pH 6.0 and 22 +/- 1 deg C with UV-visible and natural abundance carbon NMR spectroscopies.Both tetrapyrroles are water soluble and were chosen because their aggregation properties are understood and can be regulated by concentration and ionic strength.Chloroquine binding to urohemin I monomer has a stoichiometry of two urohemin molecules to one chloroquine molecule with an apparent association equilibrium constant of (7.8 +/- 0.4) * 108 M-2 at pH 6.0 and a urohemin concentration of 10-6 M.This stoichiometry is identical with that recently reported for complexes of urohemin I with another antimalarial, quinine.In that case, the binding was found to be cooperative, whereas in this case drug binding is noncooperative.Uroporphyrin binds to chloroquine with 1:1 stoichiometry and an apparent equilibrium constant of (2.8 +/- 0.2) * 106 M-1 at a uroporphyrin concentration 10-6 M.Carbon NMR spectroscopy and optical methods best describe these complexes as cofacial ? - ? dimers with structures different from the quinine complexes of the same tetrapyrroles.
- Constantinidis, I.,Satterlee, James D.
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- Enantioselective analyses of chloroquine and hydroxychloroquine in rat liver microsomes through chiral liquid chromatography–tandem mass spectrometry
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An efficient, sensitive and selective liquid chromatography–tandem mass spectrometry (LC–MS/MS) chiral analysis method was established for determination of chloroquine and hydroxychloroquine enantiomers in rat liver microsomes. Effects of polysaccharide c
- Fan, Jun,Guo, Dong,He, Rujian,Liang, Ziqing,Su, Wenxia,Zhang, Weiguang
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supporting information
p. 126 - 133
(2021/11/09)
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- Synthesis method of high-purity chloroquine phosphate
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The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of chloroquine phosphate, and particularly provides a synthesis method of high-purity chloroquine phosphate. The synthesis method comprises the following steps: (1) condensation: reacting 4, 7-dichloroquinoline with 2-amido-5-diethylamine pentane to obtain a chloroquine crude product; and (2) refining: recrystallizing to obtain chloroquine with higher purity. (3) salifying: stirring and crystallizing the refined chloroquine and phosphoric acid for 2-3 hours, and filtering to obtain a chloroquine phosphate crude product; and (4) purification: recrystallizing the chloroquine phosphate crude product to obtain high-purity chloroquine phosphate. The method is high in atom utilization rate, high in yield, high in product purity, less in solid waste, beneficial to environmental protection and convenient for industrial application, and has a relatively good industrial prospect.
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Paragraph 0043-0047; 0053-0057; 0062-0066; 0076-0081; 0087
(2021/02/10)
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- Preparation method of chloroquine phosphate
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The invention discloses a preparation method of chloroquine phosphate, namely 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline diphosphate. The preparation method comprises the following steps: (1) carrying out a condensation reaction on 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, and carrying out alkalization extraction, concentration and crystallization to obtain chloroquine; and (2) salifying the chloroquine obtained in the step (1) and phosphoric acid to obtain chloroquine phosphate. The method avoids the use of phenol, is simple in reaction, and is beneficial to industrial production; and the chloroquine is crystallized to improve the purity and then salified with the phosphoric acid, so product appearance is good, the purity of the produced chloroquine phosphate is greater than or equal to 99.5%, and a single impurity is less than 0.1% (according to an HPLC area normalization method).
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Paragraph 0030-0036; 0039-0045; 0048-0054
(2021/05/26)
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- Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine
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The invention provides a rapid and simple method for preparing optically active chloroquine, hydroxychloroquine and analogues thereof, which comprises the following steps: reacting racemates of chloroquine, hydroxychloroquine and analogues thereof with an acidic chiral resolution reagent to generate corresponding salts, and separating and purifying to obtain optically pure salts of chloroquine, hydroxychloroquine and analogues thereof, and reacting with alkali to obtain (R)- or (S)- chloroquine with high optical purity and (R)- or (S)- hydroxychloroquine and analogues thereof. The method is simple and convenient to operate and low in cost, the enantiomer purity can reach 99.9% ee, and industrial production of chloroquine, hydroxychloroquine and analogues thereof with single chiral configuration is easy to realize. The invention also provides (R)- or (S)- chloroquine and (R)- or (S)- hydroxychloroquine and analogues thereof, pharmaceutical compositions and uses thereof, optically activechloroquine and hydroxychloroquine and analogues thereof reduce toxic and side effects, and have better treatment effects on coronavirus, influenza virus and autoimmune diseases.
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Paragraph 0158-0164
(2021/03/11)
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- Preparation method and application of chiral chloroquine and phosphate thereof
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The invention discloses a preparation method and application of chiral chloroquine and phosphate thereof. The method comprises the following steps: in a resolving solvent, salifying and crystallizing chloroquine racemate and a resolving agent to separate out crystals; performing primary recrystallizing, dissociating the crystals in an alkaline solution; filtering and separating out the resolving agent; performing extracting with an organic solvent, and drying and concentrating organic phases to respectively obtain corresponding (R)/(S)-chloroquine; and further salifying the (R)/(S)-chloroquine with phosphoric acid in the solvent to respectively obtain corresponding (R)/(S)-chloroquine phosphate. By adopting the method provided by the invention, the optical purity ee value of a finished product can be greater than 80% after primary crystallization, and the product with higher purity can be obtained by primary recrystallization. The crystals are good in crystal form and easy to filter and separate; the method is simple and convenient in resolution operation, free of tedious purification processes such as column separation, high in product optical purity, and relatively high in yield; and the resolving agent is reusable, so that production cost is low, and the method has a good industrial application prospect.
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Paragraph 0080-0086; 0106-0110; 0115-0118; 0121; 0124; ...
(2021/09/08)
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- Preparation method of enantiomer pure chloroquine and chloroquine phosphate
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The invention discloses a preparation method of enantiomer pure chloroquine and chloroquine phosphate, which comprises the following steps of: salifying racemic 2-amino-5-diethylaminopentane under theaction of single-configuration acid to form diastereomer salt, separating out the diastereomer salt from the solution to obtain single-configuration 2-amino- 5-diethylaminopentane intermediate salt,and the like. According to the method, racemic 2-amino- 5-diethylaminopentane is salified under the action of single-configuration acid to form diastereomer salt. On the basis of synthesizing chloroquine/chloroquine phosphate in the prior art, 2-amino-5-diethylaminopentane is used as a raw material to form diastereomer salt to resolve chiral raw materials. The method is high in purity, green and suitable for large-scale production, hazardous chemicals do not need to be introduced, salifying resolution is achieved, reaction energy barriers are reduced through catalyst application, the reactionrate is increased, side reactions are reduced, the optical purity of the product is improved through HPLC determination, the resolution cost is reduced, and the method is suitable for large-scale production.
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- Preparation process of chloroquine phosphate (by machine translation)
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The invention discloses a preparation process of chloroquine phosphate. The preparation process of the chloroquine phosphate comprises the following steps: (1) condensation reaction with 4,7 -amino 2 - diethylamino-pentane, and basifying and extracting to obtain chloroquine; (-5 -) synthesizing chloroquine and phosphoric acid obtained in the step (2 1) to obtain chloroquine phosphate. To the preparation process of chloroquine phosphate provided by the invention, the use of other catalysts such as benzene and other catalysts is avoided in the preparation process, the product purity is high, the single impurity is less than 0.1%, the operation is simple, the procedures are simplified, the production efficiency is improved, and the method is suitable for industrial production. (by machine translation)
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Paragraph 0041-0042; 0045-0046; 0049-0050; 0053-0054; 0057
(2020/09/23)
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- Preparation method of chiral aminochloroquinoline
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The invention discloses a preparation method of chiral aminochloroquinoline, which comprises the following steps: splitting a chiral side chain, preparing enantiomer salt, splitting the side chain andchiral acid crystals to obtain chiral acid salt, neutralizing the chiral acid salt to obtain free basic groups, and reacting the free basic groups with 4, 7-dichloroquinoline to obtain chiral aminochloroquinoline. The yield of the chiral aminochloroquinoline obtained by the method is high, and the purity reaches 99.7%.
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Paragraph 0028-0029; 0031; 0033-0034; 0036-0037
(2020/11/23)
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- Application of chiral chloroquine, hydroxychloroquine or salt of the chiral chloroquine and hydroxychloroquine as anti-coronavirus drug target 3CL hydrolase inhibitor for reducing cardiotoxicity
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The invention discloses an application of chiral chloroquine, hydroxychloroquine or pharmaceutically acceptable salts of the chiral chloroquine and hydroxychloroquine in preparation of drugs used forpreventing and/or treating coronavirus pneumonia by using a coronavirus key drug target 3CL hydrolase (Mpro) as an action target. The chiral chloroquine and hydroxychloroquine have high bonding strength with the Mpro causing inflammation of the lung and the like; the activity of the Mpro can be significantly inhibited; and the chiral chloroquine and hydroxychloroquine are indicated to have the effect of preventing and treating pneumonia caused by coronaviruses and be able to be used as anti-pneumonia drugs. Through evaluation on the inhibitory activity of an hERG potassium ion channel, the concentration at which the chloroquine, hydroxychloroquine and enantiomers of the chloroquine and hydroxychloroquine are likely to generate cardiotoxicity to the hERG potassium ion channel is provided. The chiral chloroquine and hydroxychloroquine are prepared through chiral high-performance liquid chromatography and chiral synthesis; S-configuration chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine can be selected as a drug independently, or form a pharmaceutical composition for treating diseases caused by the coronaviruses; and due to higher activity and low cardiotoxicity of the chloroquine, hydroxychloroquine or salts of the chloroquine and hydroxychloroquine, the administration dosage range is greatly widened.
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- Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
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The invention belongs to the field of drug synthesis, and discloses a compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt, tautomer, polymorphic substance, isomer and solvate thereof. Secondly, the invention discloses a method for preparing chiral chloroquine and hydroxychloroquine through chiral high performance liquid chromatography. Finally, the invention discloses application of chiral chloroquine, hydroxychloroquine and salt derivatives thereof in preparation of drugs for treating novel coronavirus pneumonia.
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Paragraph 0163; 0170
(2020/09/16)
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- Mono/Dual Amination of Phenols with Amines in Water
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We herein describe a practical direct amination of phenols through a palladium-catalyzed hydrogen-transfer-mediated activation method to synthesize the secondary and tertiary amines. In this conversion, environmentally friendly water and inexpensive ammonium formate were used as solvent and reductant, respectively. A range of amines, including aliphatic amines, aniline, secondary amines, and diamines, could be coupled effectively by this method to achieve mono/dual amination and cyclization of phenols. This study not only provides a green and mild strategy for the synthesis of secondary and tertiary naphthylamines but also expands the synthesis of chloroquine in organic chemistry.
- Liang, Wanyi,Xie, Feng,Yang, Zhihai,Zeng, Zheng,Xia, Chuanjiang,Li, Yibiao,Zhu, Zhongzhi,Chen, Xiuwen
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supporting information
p. 8291 - 8295
(2020/10/12)
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- USE OF CHLOROQUINE AND CLEMIZOLE COMPOUNDS FOR TREATMENT OF INFLAMMATORY AND CANCEROUS CONDITIONS
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Disclosed herein are methods for use of R-chloroquine or clemizole or combinations of R- chloroquine and clemizole for the treatment of a subject in need thereof. Uses include methods of treating inflammatory' conditions, treating liver cancer or reducing the risk of developing liver cancer in a subject. Uses also include methods of treating non-alcoholic steatohepatitis in a subject.
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- Asymmetric synthesis method of optically pure (R)/(S)-chloroquine
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The invention discloses an asymmetric synthesis method of optically pure (R)/(S)-chloroquine. 4-amino-7-chloroquinoline and 5-diethylin-2-pentanone are taken as starting raw materials and are subjected to an asymmetric reductive ammoniation reaction under the catalysis of chiral acid, optically pure chloroquine is obtained, and the spatial configuration of a product is controlled through spatial configuration of the chiral acid. The method adopts simple steps, the raw materials are easy to obtain, the yield is higher, the stereoselectivity is good, the chiral construction cost is relatively lower, the operation is simple, and the method is environment-friendly and suitable for large-scale production.
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Paragraph 0037; 0038; 0039
(2016/10/08)
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- Lewis acid-catalyzed generation of C-C and C-N bonds on π-deficient heterocyclic substrates
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Focused microwave irradiation of a series of halogenated nitrogen heterocycles and different kinds of nucleophiles in the presence of a catalytic amount of indium trichloride leads to the efficient and completely regioselective generation of aromatic C-C and C-N bonds. The method is simple, rapid, general and inexpensive, and can be performed without the use of dried solvents. Most of the synthetized compounds are new and in many cases the work-up required only filtration. Furthermore, this is the first example of the use of a Lewis acid as a catalyst for heteroarylation, vinylation and amination reactions on π-deficient heterocyclic substrates.
- Staderini, Matteo,Bolognesi, Maria Laura,Menndez, J. Carlos
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supporting information
p. 185 - 195
(2015/01/30)
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- Assembly of 4-aminoquinolines via palladium catalysis: A mild and convenient alternative to SNAr methodology
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4-Aminoquinolines, classically prepared via SNAr chemistry from an amine and 4-haloquinoline, are important scaffolds in medicinal chemistry. Interest in these compounds prompted us to explore palladium catalysis as an alternative to the existing methods for their preparation. Initial results followed by an iterative screening paradigm confirmed Pd(OAc)2/ DPEphos/K3PO4 as a mild and convenient alternative for the formation of the C-N bond in 4-aminoquinolines. A description of the screen and the scope of this methodology are discussed herein.
- Margolis, Brandon J.,Long, Kimberly A.,Laird, Dana L. T.,Ruble, J. Craig,Pulley, Shon R.
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p. 2232 - 2235
(2007/10/03)
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- Method of using deuterated calcium channel blockers
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Therapeutic methods and compositions using deuterated enriched 2-[(2-aminoethoxy)methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylic acid 3-ethyl 5-methyl ester and other deuterated dihydropyridine compounds are described. The deuterated compounds exhibit enhanced efficacy in blocking calcium channels over non-deuterated dihydropyridines.
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- Enhancement of the efficacy of nifedipine by deuteration
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A method of enhancing the efficiency and increasing the duration of action of drugs (e.g. dihydropyridines and anti-bacterials) and particularly of nifedipine and penicillins wherein one or more hydrogen atoms are deuterated and wherein the deuterated drug has unexpectedly improved properties when used in much lower concentrations than unmodified drug. A method for determining the identity and bioequivalency of a new drug is also disclosed wherein the molecular and isotope structure of a new drug is determined by isotope ratio mass spectrometry and compared with the molecular and isotope structure of a known human drug.
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- Antimalarials: Synthesis of 4-aminoquinolines that circumvent drug resistance in malaria parasites
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The strategies described here have permitted the synthesis of a series of 4-aminoquinoline antimalarials. Substantive improvements over previous syntheses include nucleophilic substitution with neat amine rather than in phenol, regioselective reductive alkylation to convert the terminal primary amine (12a-20a) on the diaminoalkane side chain to a diethylamino group, and purification by column chromatography with basic alumina. The 1H nmr spectra obtained after regioselective reductive alkylation with sodium borodeuteride (in comparison with sodium borohydride) demonstrated that this reductive alkylation proceeds via formation and subsequent reduction of the corresponding diamides in situ.
- De,Byers,Krogstad
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p. 315 - 320
(2007/10/03)
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