171489-59-1Relevant academic research and scientific papers
Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease
Sánchez-Arias, Juan A.,Rabal, Obdulia,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,Ugarte, Ana,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
, p. 638 - 661 (2017)
A novel systems therapeutics approach, involving simultaneous inhibition of phosphodiesterase 5 (PDE5) and histone deacetylase (HDAC), has been validated as a potentially novel therapeutic strategy for the treatment of Alzheimer’s disease (AD). First-in-class dual inhibitors bearing a sildenafil core have been very recently reported, and the lead molecule 7 has proven this strategy in AD animal models. Because scaffolds may play a critical role in primary activities and ADME-Tox profiling as well as on intellectual property, we have explored alternative scaffolds (vardenafil- and tadalafil-based cores) and evaluated their impact on critical parameters such as primary activities, permeability, toxicity, and in vivo (pharmacokinetics and functional response in hippocampus) to identify a potential alternative lead molecule bearing a different chemotype for in vivo testing.
The discovery of tadalafil: A novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-Hexahydropyrazino[1′,2′ :1,6]pyrido[3,4-b]indole-1,4-dione analogues
Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier de Gouville, Anne-Charlotte,Coste, Hervé,Linget, Jean Michel,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinièret, Richard
, p. 4533 - 4542 (2003)
Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1. 12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/>7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
Synthesis of tadalafil (Cialis) from l-tryptophan
Xiao, Sen,Shi, Xiao-Xin,Xing, Jing,Yan, Jing-Jing,Liu, Shi-Ling,Lu, Wei-Dong
, p. 2090 - 2096 (2009)
The first synthesis of tadalafil 1 (Cialis) from l-tryptophan is described. The title compound 1 was synthesized via seven steps from l-tryptophan methyl ester hydrochloride in 42.3% overall yield. Two characteristic steps involved in this synthesis are t
Two Concise syntheses of cialis via the N-acyliminium pictet-spengler reaction
Revell, Jefferson D.,Srinivasan, Natarajan,Ganesan
, p. 1428 - 1430 (2004)
The imine derived from piperonal and D-tryptophan methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.
Highly stereoselective Pictet-Spengler reaction of d-tryptophan methyl ester with piperonal: convenient syntheses of Cialis (Tadalafil), 12a-epi-Cialis, and their deuterated analogues
Shi, Xiao-Xin,Liu, Shi-Ling,Xu, Wei,Xu, Yu-Lan
, p. 435 - 442 (2008)
The acid-catalyzed Pictet-Spengler reaction of d-tryptophan methyl ester with piperonal in acetic acid has been reported, the best stereoselectivity (cis/trans = 92:8) was obtained with benzoic acid as the catalyst. The Pictet-Spengler reaction of d-tryptophan methyl ester hydrochloride with piperonal in various solvents has been extensively studied, the solvent-dependence of stereoselectivities could be principally attributed to the solubility-difference between cis and trans products 5-HCl in the used solvent, the best stereoselectivity (cis/trans = 99:1) was obtained using nitromethane or acetonitrile as the solvent. A base-catalyzed epimerization at 12a-position of Cialis 1 (tadalafil) in a DMSO-containing solvent was also exploited. Cialis, 12a-epi-Cialis 2, deuterium-labeled 3,3,12a-d3-Cialis 3, and 3,3,12a-d3-12a-epi-Cialis 4 were efficiently synthesized from d-tryptophan methyl ester hydrochloride.
Preparation method of tadalafil
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Paragraph 0052-0055; 0059-0060; 0064-0065, (2022/01/12)
The invention provides a preparation method of tadalafil, and relates to the technical field of medicines. The preparation method comprises the steps of taking D-cis-carboline hydrochloride as an initial raw material, carrying out acylating chlorination reaction on the D-cis-carboline hydrochloride and chloroacetyl chloride under the action of an acid-binding agent, carrying out primary refining on an obtained chloroacetylate intermediate crude product, carrying out aminolysis cyclization reaction on the obtained high-purity chloroacetylate intermediate and methylamine, adding a pulping solvent into the obtained tadalafil crude product for pulping, carrying out solid-liquid separation, washing the obtained solid product, and drying to obtain the high-purity tadalafil. Moreover, the D-cis-carline hydrochloride raw material is cheap, easy to obtain and stable in quality, the D-cis-carline hydrochloride raw material is used as a starting raw material, the production period of tadalafil is short, and the production cost is low.
Preparation method of phosphodiesterase inhibitor
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Paragraph 0016; 0041-0055, (2021/11/03)
The invention discloses a preparation method of a phosphodiesterase inhibitor and belongs to the field of medicinal chemistry. The preparation method comprises the following steps: starting the raw material 1 and methanol to prepare the intermediate I without adding organic solvent crystallization. After the series of centrifugation, washing and drying, the intermediate II is directly condensed and cyclized with piperonal, and a final product tadalafil is prepared by chloroacetylation, aminolysis and refining steps. The method improves the product yield and quality, greatly shortens the reaction period, reduces the operation steps and the production cost, and is suitable for industrial mass production.
NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
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Page/Page column 89, (2021/12/28)
The present invention relates to compounds of formula (I), or pharmaceutically acceptable salt, solvate or hydrate thereof, wherein said compound of formula (I) comprises at least one covalently bound -ONO2 or -ONO moiety and at most four covalently bound -ONO2 or -ONO moieties, and wherein AR, R1, X, R3 and R4 are as defined in claim 1; and pharmaceutical compositions thereof, and their use in methods of treating or preventing a disease alleviated by inhibition of PDE5 in a human or in a non-human mammal.
Production process of tadalafil bulk drug
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, (2020/07/02)
The invention belongs to the technical field of medicines, and particularly relates to a production process of a tadalafil bulk drug. The production process of the tadalafil bulk drug comprises the following steps: A1, carrying out an esterification reaction on methanol and D-tryptophan to obtain an intermediate I; A2, performing a condensation reaction on the intermediate I and heliotropin to obtain an intermediate II; A3, performing an acylation reaction on the intermediate II and chloroacetyl chloride to obtain an intermediate III; and A4, carrying out a cyclization reaction on the intermediate III and monomethylamine to obtain the tadalafil bulk drug. According to the method, a reaction path is reasonably selected, and meanwhile, the process details of each reaction step are deeply optimized, so high purity and yield of a product of each step of reaction can be obtained, the prepared tadalafil bulk drug is low in cost and good in stability, the economical efficiency of the whole reaction path is improved, and production cost is reduced.
Method for purifying tadalafil intermediates
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Paragraph 0033; 0035-0072, (2019/04/29)
The invention relates to a method for purifying a Tadalafil intermediate as shown in a formula I. The method comprises the following steps: (a) completely dissolving a compound I crude product in amides through stirring, adding an adsorbent, stirring while keeping temperature, and filtering; (b) dropwise adding an anti-solvent to filter liquor, and reducing the temperature for devitrification; and (c) filtering, and drying to obtain a compound I. The method provided by the invention is easy and convenient to operate; and the obtained product has good quality.
