- CONJUGATES
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The present invention provides a conjugate of formula (I) and itsuse in methods of treatment, and also methods for delivering an active agent into a cell. The methods may be used to deliver an active agent into a nematode, flatworm, parasite or bacterium. The conjugate of formula (I) is: (formula (I)), wherein -D- is C1-4 alkylene or C2-4 alkenylene, preferably C2-4 alkenylene, where the alkylene or alkenylene is optionally substituted with alkyl or halo; A- is an active agent for delivery; and -RA, -RB, -RT1, -RT2, -R1, -R2, -R3, -X- and -L- are as defined herein.
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Page/Page column 77
(2020/07/14)
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- A preparation method of praziquantel (by machine translation)
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The invention discloses a method for preparation of praziquantel, comprises the following steps: S1, β - phenethylamine with chloroacetyl chloride in a polar aprotic solvent, under alkaline compound to promote the acylation reaction is carried out, to produce intermediate I: 2 - chloro - N - (2 - phenyl-ethyl) - acetamide; S2, intermediate I in ethanolamine in the condensation reaction, an intermediate II: 2 - (2 - hydroxy - ethylamino) - N - phenethyl - acetamide; S3, using the intermediate II and TEMPO as raw materials, after oxidation is carried out after the cyclization reaction to prepare the intermediate III: 4 - carbon yl - 1, 2, 3, 6, 7, 11b - hexahydro - 4 H - pyrazinyl [2, 1 - a] isoquinoline; S4, the intermediate III with the cyclohexyl chloride in a polar aprotic solvent, a basic compound for promoting the next, react to generate the target product pqt. The preparation method has the raw materials are easy, the price is cheap; the process is simple, the production safety; high yield, low cost and the like. (by machine translation)
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Paragraph 0028; 0034; 0035
(2019/02/27)
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- Recovery preparation method of racepiquamine
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The invention discloses a recovery preparation method of racepiquamine-1. The preparation method comprises the following steps: dissolving a waste material S-piquamine intermediate-1 as an initial rawmaterial in a solvent; and carrying out reaction at a proper temperature in the presence of a catalyst and hydrogen at a certain pressure to prepare the piquamine intermediate-1 of racemate. The formula is as shown in the description. The configured piquamine S-1 which is not needed is efficiently, conveniently and fully operated and recovered with a high yield to obtain a racemate compound 1, and then the racemate compound is used again to prepare levopraziquantel, so that wastes can be turned into wealth, and therefore, the generation cost of the levopraziquantel is saved greatly.
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Paragraph 0080; 0081; 0082; 0085; 0087; 0089; 0091; 0093
(2018/06/12)
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- Racemic praziquanamine recovery and preparation method
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The present invention discloses a racemic praziquanamine-1 recovery and preparation method, which comprises: 1) preparing a compound 2 by using a waste material S-praziquanamine intermediate-1 as a starting raw material under the action of a catalyst or a dehydrogenation reagent; and 2) carrying out hydrogenation reduction on the compound 2 to obtain the racemic praziquanamine-1, wherein the formulas S-1, 1 and 2 are defined in the specification, the operations of the step 1) specifically comprise dissolving S-praziquanamine-1 in a first solvent, adding a first catalyst or a dehydrogenation reagent, and carrying out a reaction at a proper temperature to obtain the compound 2, and the operations of the step 2) specifically comprise dissolving the compound 2 in a second solvent, adding a second catalyst or a dehydrogenation reagent, and carrying out a reaction at a proper temperature to obtain the racemic praziquanamine-1. According to the present invention, the unwanted configuration praziquanamine S-1 is completely recovered and utilized to obtain the racemic compound 1, and the L-praziquantel is prepared by using the racemic compound 1 through the resolution method, such that the waste can be turned into treasure, and the L-praziquantel production cost can be substantially saved.
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Paragraph 0114; 0115; 0116; 0117; 0118; 0119; 0120-0141
(2017/09/19)
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- Br?nsted acid-mediated cyclization-dehydrosulfonylation/reduction sequences: An easy access to pyrazinoisoquinolines and pyridopyrazines
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An efficient and alternative synthetic approach has been developed to prepare various N-(arylethyl)piperazine-2,6-diones from 4-benzenesulfonyliminodiacetic acid and primary amines using carbonyldiimidazole in the presence of a catalytic amount of DMAP at ambient temperature. Piperazine-2,6-diones are successfully transformed to pharmaceutically useful pyridopyrazines or pyrazinoisoquinolines and ene-diamides via an imide carbonyl group activation strategy using a Br?nsted acid. Subsequent dehydrosulfonylation reactions of the ene-diamides, in a one pot manner, smoothly transformed them to substituted pyrazinones. A concise synthesis of praziquantel (1) has also been achieved through this method.
- Rao, Ramana Sreenivasa,Ramanathan, Chinnasamy Ramaraj
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p. 428 - 440
(2017/03/14)
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- One-pot palladium-catalyzed racemization of (S)-praziquanamine: A key intermediate for the anthelmintic agent (R)-praziquantel
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An one-pot palladium-catalyzed procedure for racemization of (S)-praziquanamine, which is the undesired enantiomer and produced during the resolution step for preparing the anthelmintic drug (R)-praziquantel, has been developed through dehydrogenation of
- Yang, Zhezhou,Guo, Xiang,Xu, Shanghu,Jiao, Huirong,Tan, Zhinmin,Zhang, Fuli
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p. 122 - 130
(2017/03/01)
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- A method for synthesizing metabolite pqt (by machine translation)
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The invention relates to two kinds of pqt of the synthetic method of metabolic product, belongs to the technical field of medicament, are respectively to pqt and 4 the hydroxy [...] cyclohexane carboxylic acid methyl ester as the raw material, pqt and cyclohexenols -3 the [...] formic acid as the raw material to synthesize the pqt two metabolic product. The advantages of: the invention the first time the two portions metabolic product. And, these two kinds of pqt metabolic product of simple synthesis technology, high purity of the product. (by machine translation)
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Paragraph 0029; 0030
(2017/01/02)
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- Praziquantel synthetic technology
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The invention discloses a praziquantel synthetic technology; beta-phenylethylamine, amino acetyl halide hydrochloride, halogenated acetaldehyde alcohol and cyclohexyl formyl chloride are used as raw materials and subjected to condensation, cyclization and acylation to synthesize praziquantel. The method has the advantages of cheap and easily available raw materials, low toxicity, safe production and simple process; amino acetyl halide hydrochloride and beta-phenylethylamine are condensed, the activity is moderate and the yield is relatively high; with reaction of halogenated aldehyde alcohol and an intermediate A, because halogen of halogenated aldehyde alcohol is easy to remove, the reaction is easy to implement, and the yield is favorable to improve; secondly, the synthetic technology has the advantages of mild synthetic reaction conditions, atmospheric pressure operation, safe operation and concise synthetic steps, and the total yield can be more than 50%; and the synthetic process has less waste emissions, pollution is low, the technology is a clean and highly efficient synthetic technology, and the production cost can be reduced by about 30%.
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Paragraph 0011
(2016/11/28)
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- METHOD FOR THE PRODUCTION OF PRAZIQUANTEL AND PRECURSORS THEREOF
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The present invention relates to methods for the production of enantiopure or enantioenriched Praziquantel precursors and to methods for the production of enantiopure or enantioenriched Praziquantel comprising the methods for the production of the Praziquantel precursors. The present invention further relates to compounds or intermediates useful in such methods.
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Page/Page column 28-29
(2016/06/15)
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- Development of chiral praziquantel analogues as potential drug candidates with activity to juvenile Schistosoma japonicum
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A series of chiral praziquantel analogues were synthesized and evaluated against Schistosoma japonicum both in vitro and in vivo. All compounds exhibited low to considerable good activity in vivo. Remarkably, worm reduction rate of R-3 was 60.0% at a sing
- Zheng, Yang,Dong, Lanlan,Hu, Changyan,Zhao, Bo,Yang, Chunhua,Xia, Chaoming,Sun, Dequn
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supporting information
p. 4223 - 4226
(2014/11/07)
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- Design and synthesis of molecular probes for the determination of the target of the anthelmintic drug praziquantel
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Schistosomiasis is a highly prevalent neglected tropical disease caused by blood-dwelling helminths of the genus Schistosoma. Praziquantel (PZQ) is the only drug available widely for the treatment of this disease and is administered in racemic form, even
- Sharma, Lalit Kumar,Cupit, Pauline M.,Goronga, Tino,Webb, Thomas R.,Cunningham, Charles
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supporting information
p. 2469 - 2472
(2014/05/20)
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- Synthesis and SAR studies of praziquantel derivatives with activity against Schistosoma japonicum
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The synthesis and structure-activity relationship (SAR) studies of praziquantel derivatives with activity against adult Schistosoma japonicum are described. Several of them showed better worm killing activity than praziquantel and could serve as leads for further optimization.
- Wang, Wen-Long,Song, Li-Jun,Chen, Xia,Yin, Xu-Ren,Fan, Wen-Hua,Wang, Gu-Ping,Yu, Chuan-Xin,Feng, Bainian
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p. 9163 - 9178
(2013/09/23)
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- PROCESS FOR THE PREPARATION OF PRAZIQUANTEL
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The present disclosure describes a novel, cost-effective process for preparation of a 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino-[2,1-a]isoquinoline derivatives. Specifically, it discloses a process for the preparation of the anthelmintic drug praziquantel through the use of a novel intermediate, 2-[(2,2-dimethoxyethyl)benzyl amino]-N-phenethylacetamide. This present disclosure also describes a novel crystalline form of 4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline.
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Paragraph 0056; 0057; 0058
(2013/11/06)
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- Praziquantel analogs with activity against juvenile Schistosoma mansoni
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Six amide and four urea derivatives of praziquantel were synthesized and tested for antischistosomal activity against juvenile and adults stages of Schistosoma mansoni in infected mice. Only one of these had significant activity against adult worms, but,
- Dong, Yuxiang,Chollet, Jacques,Vargas, Mireille,Mansour, Nuha R.,Bickle, Quentin,Alnouti, Yazen,Huang, Jiangeng,Keiser, Jennifer,Vennerstrom, Jonathan L.
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scheme or table
p. 2481 - 2484
(2010/07/16)
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- Design and synthesis of novel pyrazino[2,1-a]isoquinoline derivatives with potent antifungal activity
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A series of novel pyrazino[2,1-a]isoquinoline compounds were designed, synthesized, and their antifungal activities in vitro were evaluated. The results showed that all of the title compounds exhibited antifungal activities. Most of them exhibited stronge
- Tang, Hui,Zheng, Can-Hui,Zhu, Ju,Fu, Bing-Yue,Zhou, You-Jun,Lv, Jia-Guo
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p. 360 - 366
(2011/07/09)
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- Synthesis of "Trioxaquantel" derivatives as potential new antischistosomal drugs
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Over the past 20 years, praziquantel, a pyrazinoisoquinoline derivative, has become the mainstay for morbidity control of human and animal schistosomiasis. From early in their lives in vertebrate hosts, schistosomes ingest hemoglobin and aggregate the released heme as a dark pigment very similar to the hemozoin produced by Plasmodium in malaria infection. The antimalarial artemisinin derivatives have real, though low, schistosomicide activity. Because of the complementarity of the two drug classes - praziquantel and artemisinin derivatives - we designed new molecules, named trioxaquantels, that combine the 1,2,4-trioxane unit responsible for the activity of artemisinin, and the pyrazinoisoquinoline moiety of praziquantel within a single drug. The synthesis of these new drugs and their preliminary evaluation in mice infected with Schistosoma mansoni is reported here. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.
- Laurent, Sophie A.-L.,Boissier, Jerome,Cosledan, Frederic,Gornitzka, Heinz,Robert, Anne,Meunier, Bernard
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experimental part
p. 895 - 913
(2009/04/08)
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- 2-(CYCLIC AMINO)-PYRIMIDONE DERIVATIVES AS TPK1 INHIBITORS
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A compound represented by the formula (I), an optically active isomer thereof, or a pharmaceutical acceptable salt thereof (I) wherein R2 represents a hydrogen or the like; R3 represents methyl group or the like; R20 represents a halogen atom or the like; q represents an integer of 0 to 3; Z represent nitrogen atom, CH, or the like; R4 represents hydrogen or the like; R5 represents hydrogen or the like; R6 represents a substituted alkyloxy and the like; p represents an integer of 0 to 3; X represents bond, CH2, oxygen atom, NH, or the like; any one or more of R5 and R6, R5 and R4, R6 and R4, X and R5, X and R4, X and R6, and R6 and R6 may combine to each other to form a ring, which is used for preventive and/or therapeutic treatment of a disease caused by tau protein kinase 1 hyperactivity such as a neurodegenerative diseases (e.g. Alzheimer disease).
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Page/Page column 178; 179
(2008/06/13)
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- Formation of pyrazinoisoquinoline ring system by the tandem amidoalkylation and N-acyliminium ion cyclization: An efficient synthesis of Praziquantel
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An efficient synthesis of pyrazinoisoquinoline derivatives including Praziquantel has been accomplished by the tandem amidoalkylaion and N- acyliminium ion cyclization of amido-acetals.
- Kim, Joong Hyup,Lee, Yong Sup,Park, Hokoon,Kim, Choong Sup
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p. 7395 - 7400
(2007/10/03)
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- Synthesis and Anthelmintic Activity of a Series of Pyrazinobenzazepine Derivatives
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A series of 1,2,3,4,6,7,8,12b-octahydropyrazinobenzazepine derivatives was prepared and the cestocidal activity of the compounds evaluated in an in vitro Taenia crassiceps screen.Many of these derivatives proved to be highly active, and 2-(cyclohexylcarbonyl)-4-oxo-1,2,3,4,6,7,8,12b-octahydropyrazinobenzazepine, epsiprantel (BAN) (22), was selected for further development.The structure-activity relationships are discussed.
- Brewer, Malcolm D.,Burgess, Malcolm N.,Dorgan, Roderick J. J.,Elliott, Richard L.,Mamalis, Patrick,et al.
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p. 2058 - 2062
(2007/10/02)
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- Process for the production of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives
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This invention discloses a process for the preparation of (±)-4-oxo-1,2,3,6,7,11b-hexahydro-4H-pyrazino[2,1-a]isoquinoline derivatives which comprises conducting an intramolecular cyclization reaction of the compounds of formulas II III in an acid medium. STR1
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- NEW SYNTHESES OF PRAZIQUANTEL : 2-(CYCLOHEXYLCARBONYL)-1,2,3,6,7,11b-HEXAHYDRO-4H-PYRAZINOISOQUINOLIN-4-ONE
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This paper describes two different synthetic pathways for praziquantel, a new broad spectrum schistosomicide and cestocide.Easy to apply on an industrial scale, they involve a selective reduction of 4-acyl-1-phenethylpiperazine-2,6-dione in 4-acyl-6-hydroxy-1-phenethylpiperazin-2-one, the cyclisation of wchich in acetic medium gives tricyclic compounds 2-acyl-1,2,3,6,7,11b-hexahydro-4H-pyrazinisoquinolin-4-one.
- Frehel, Daniel,Maffrand, Jean-Pierre
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p. 1731 - 1735
(2007/10/02)
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- Process for the preparation of 4-oxo-hexahydro-pyrazinoisoquinoline derivatives
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4-OXO-HEXAHYDRO-PYRAZINOISOQUINOLINE DERIVATIVES ARE OBTAINED IN GOOD YIELD BY A SINGLE-STEP PROCESS WHICH COMPRISES HYDROLYZING A 2-ACYL-4-OXO-1,2,3,6,7,11B-HEXAHYDRO-4H-pyrazino[2,1-a]isoquinoline with an oxygen-containing acid or acid salt of inorganic
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