- One-pot pictet-spengler reaction and esterification for the preparation of a key tadalafil synthetic intermediate
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A new method is reported for the preparation of 2,3,4,9-tetrahydro-1H- β-carboline-3-carboxylic acid methyl ester, a key intermediate in the synthesis of Tadalafil which is used for the treatment of male erectile dysfunction, via one-pot esterification and Pictet-Spengler reaction.
- Scarpi, Dina,Occhiato, Ernesto G.,Guarna, Antonio,Borzatta, Valerio
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Read Online
- NOVEL DUAL MODE OF ACTION SOLUBLE GUANYLATE CYCLASE ACTIVATORS AND PHOSPHODIESTERASE INHIBITORS AND USES THEREOF
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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.
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Page/Page column 89
(2021/12/28)
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- Production process of tadalafil bulk drug
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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.
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- Preparation method of tadalafil and intermediate of tadalafil
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The invention relates to a preparation method of a selective and reversible inhibitor tadalafil of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase 5 (PDE5). The method comprises the following steps: carrying out an esterification reaction on D-tryptophan as an initial raw material and methanol under catalysis of sulfuric acid to generate D-tryptophan methyl ester (an intermediate1); carrying out a Pictet-Spengler (P-S) reaction on the D-tryptophan methyl ester and heliotropin to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride (an intermediate 2); carrying out an amidation reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester hydrochloride and chloroacetyl chloride to prepare (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester (an intermediate 3); andfinally carrying out a cyclization reaction on the (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid methyl ester and a methylamine alcohol solution to obtain the tadalafil. The method provided by the invention has the advantages of easily available raw materials, simple operation, greenness, environmental protection and low costs, andis suitable for industrial production.
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- Discovery of in Vivo Chemical Probes for Treating Alzheimer's Disease: Dual Phosphodiesterase 5 (PDE5) and Class i Histone Deacetylase Selective Inhibitors
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In order to determine the contributions of histone deacetylase (HDAC) isoforms to the beneficial effects of dual phosphodiesterase 5 (PDE5) and pan-HDAC inhibitors on in vivo models of Alzheimer's disease (AD), we have designed, synthesized, and tested novel chemical probes with the desired target compound profile of PDE5 and class I HDAC selective inhibitors. Compared to previous hydroxamate-based series, these molecules exhibit longer residence times on HDACs. In this scenario, shorter or longer preincubation times may have a significant impact on the IC50 values of these compounds and therefore on their corresponding selectivity profiles on the different HDAC isoforms. On the other hand, different chemical series have been explored and, as expected, some pairwise comparisons show a clear impact of the scaffold on biological responses (e.g., 35a vs 40a). The lead identification process led to compound 29a, which shows an adequate ADME-Tox profile and in vivo target engagement (histone acetylation and cAMP/cGMP response element-binding (CREB) phosphorylation) in the central nervous system (CNS), suggesting that this compound represents an optimized chemical probe; thus, 29a has been assayed in a mouse model of AD (Tg2576).
- Rabal, Obdulia,Sánchez-Arias, Juan A.,Cuadrado-Tejedor, Mar,De Miguel, Irene,Pérez-González, Marta,García-Barroso, Carolina,Ugarte, Ana,Estella-Hermoso De Mendoza, Ander,Sáez, Elena,Espelosin, Maria,Ursua, Susana,Haizhong, Tan,Wei, Wu,Musheng, Xu,Garcia-Osta, Ana,Oyarzabal, Julen
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p. 1765 - 1782
(2019/01/08)
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- Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer's Disease
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Through drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer's disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier (BBB) penetrability. Importantly, 1w·Cit (citrate of 1w) could reverse the cognitive dysfunction of scopolamine-induced AD mice and exhibited an excellent effect on enhancing cAMP response element-binding protein (CREB) phosphorylation in vivo, a crucial factor in memory formation and synaptic plasticity. Moreover, the molecular docking simulations of 1w with hAChE and hPDE5A confirmed that our design strategy was rational. In summary, our research provides a potential selective dual-target AChE/PDE5 inhibitor as a good candidate drug for the treatment of AD, and it could also be regarded as a small molecule probe to validate the novel AD therapeutic approach in vivo.
- Mao, Fei,Wang, Huan,Ni, Wei,Zheng, Xinyu,Wang, Manjiong,Bao, Keting,Ling, Dazheng,Li, Xiaokang,Xu, Yixiang,Zhang, Haiyan,Li, Jian
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p. 328 - 345
(2018/03/01)
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- 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof
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The present invention relates to a 3,4-methylenedioxyphenyl substituted tetrahydro-beta-carboline piperazine dione derivative and uses thereof, and specifically discloses a compound represented by a formula I, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein each group is defined in the specification. According to the present invention, the compound has dual inhibitory activity on acetylcholinesterase and phosphodiesterase 5, and has good blood-brain barrier permeability, such that the compound can be used for preparing drugs for treatment and/or prevention ofAlzheimer's diseases. The formula I is defined in the specification.
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- Preparation of tadalafil intermediate
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The invention provides a method for preparing a tadalafil intermediate in different solvents by adopting different catalysts. (The formula II is described in the specification.).
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Paragraph 0012; 0014-0017
(2018/03/24)
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- Preparation method of tadalafil
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The invention discloses a preparation method of tadalafil, starting material D-Tryptophan methyl ester hydrochloride is reacted with oxalyl chloride to obtain an intermediate III, and the final product tadalafil (I) is obtained through cyclization, Grignard reaction, asymmetric reduction, substitution and condensation reaction. The use of national control chemical piperonal is avoided, an intermediate VI can be highly-selectively obtained by the asymmetric reduction, and the method has the advantages of simple postprocessing, short synthesis steps and high product total yield, and is suitable for industrialized production.
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Paragraph 0053; 0054
(2017/08/29)
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- Impact of Scaffold Exploration on Novel Dual-Acting Histone Deacetylases and Phosphodiesterase 5 Inhibitors for the Treatment of Alzheimer’s Disease
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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.
- 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
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p. 638 - 661
(2017/03/20)
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- A tadalafil intermediate preparation method
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The invention relates to an improved method of preparing a compound (II). The improved method comprises the following steps: (the formula is shown in the description) 1, mixing D-tryptophan, methanol and toluene, adding thionyl chloride dropwise, and then carrying out reaction at the temperature of 70-85 DEG C to obtain D-tryptophan ester hydrochloride, wherein the structure is shown in a formula (III):(the formula is shown in the specification); and 2, mixing the D-tryptophan ester hydrochloride, a compound (IV) and a nitrile solvent, uniformly stirring, then raising the temperature to 75-85 DEG C, and carrying out reaction, (the formula is shown in the description). The improved preparation method of the compound shown by the D-tryptophan ester hydrochloride (II) has the following beneficial effects: 1, the dosage of the thionyl chloride in the first step is greatly reduced, so that the risk and the corrosion of the reaction are lowered, the post-processing is simple, and the yield is above 90 percent; 2, in the second step, the nitrile solvent is adopted to improve the stereoselectivity, and the enantiomer extra amount (ee %) is above 99 percent.
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Paragraph 0028; 0029; 0030
(2017/05/27)
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- Improved synthesis of tadalafil using dimethyl carbonate and ionic liquids
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An improved synthesis of tadalafil, a drug for the treatment of male erectile dysfunction, involves the use of safer solvents and reagents as well as a reduced number of steps.
- Earle, Martyn J.,Noe, Marco,Perosa, Alvise,Seddon, Kenneth R.
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p. 1204 - 1211
(2014/01/06)
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- Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs
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In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1.
- Ochiana, Stefan O.,Gustafson, Alden,Bland, Nicholas D.,Wang, Cuihua,Russo, Michael J.,Campbell, Robert K.,Pollastri, Michael P.
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scheme or table
p. 2582 - 2584
(2012/05/05)
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- Drug to genome to drug: Discovery of new antiplasmodial compounds
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Figure Presented. The dominant strategy for discovery of new antimalarial drugs relies on cell-free assays on specific biochemical pathways of Plasmodium falciparum. However, it appears that screening directly on the parasite is a more rewarding approach. The drug to genome to drug approach consists of testing a small set of structural analogues of a drug acting on human proteins that have plasmodial orthologues. Both man and plasmodium possess cyclic nucleotide phosphodiesterases (PDEs) that are key players of cell homeostasis. We synthesized and tested 40 analogues of tadalafil, a human PDE5 inhibitor, on P. falciparum in culture and obtained potent inhibitors of parasite growth. We discuss the structure-activity relationships, which support the hypothesis that our compounds kill the parasite via inhibition of plasmodial PDE activity. We also prove that antiplasmodial derivatives inhibit the hydrolysis of cyclic nucleotides of the parasite, validating the cAMP/cGMP pathways as therapeutic targets against Plasmodium falciparum.
- Beghyn, Terence B.,Charton, Julie,Leroux, Florence,Laconde, Guillaume,Bourin, Arnaud,Cos, Paul,Maes, Louis,Deprez, Benoit
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experimental part
p. 3222 - 3240
(2011/06/27)
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- Synthesis of tadalafil (Cialis) from l-tryptophan
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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
- Xiao, Sen,Shi, Xiao-Xin,Xing, Jing,Yan, Jing-Jing,Liu, Shi-Ling,Lu, Wei-Dong
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experimental part
p. 2090 - 2096
(2010/03/04)
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- Conversion of tryptophan into ?-carboline derivatives
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The invention belongs in the field of organic chemistry and relates to a new shortened Pictet-Spengler type reaction for preparing isomerically pure β-carboline compounds useful for the synthesis of tadalafil.
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(2009/10/18)
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- A PROCESS FOR THE PREPARATION OF INTERMEDIATES OF TETRACYCLIC COMPOUNDS
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The present invention relates to a process for the preparation of cis-intermediates of Formula II, (Formula II) wherein R1 represents hydrogen, (un)substituted alkyl, alkenyl, aryl, and X represents a leaving group, which are useful synthetic intermediates in the preparation of tetracyclic compounds having phosphodiesterase inhibitory activity.
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(2009/03/07)
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- PROCESS FOR PREPARATION OF TADALAFIL
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It has been found that tadalafil can be obtained in high purity when (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyL-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate is reacted with methylamine in methanol in specific quantities for a specific reaction time. It has also been found that (6R,12aR)-methyl-1,2,3,4-tertahydro-2-chloroacetyl-1-(3,4-methylenedioxy- phenyl)-9H-pyrido[3,4-b]indole-3-carboxylate, the key intermediate in the preparation of tadalafil, may be obtained in higher yield from D-Tryptophan methyl ester without isolationg intermediate as solid.
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Page/Page column 2-3; 6-7
(2009/12/27)
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- CHIRAL TETRA-HYDRO BETA-CARBOLINE DERIVATIVES AND APPLICATIONS THEREOF AS ANTIPARASITIC COMPOUNDS
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The invention relates to the use of chiral tetra-hydro β-carboline derivatives of formula (I) for the preparation of pharmaceutical composition for the prevention and/or the treatment of parasitic diseases involving parasites having a phosphodiesterase activity: or a pharmaceutically acceptable salt thereof, in which: - R1 and R2, identical or different, represent a hydrogen atom or a fluorine atom; - k is an integer equal to 0 or 1; - R3 is selected from the group consisting of: ■ a phenyl ring optionally substituted ■ a 3'-N-pyridine ring optionally substituted - R4 is a group selected in the group consisting of the following groups: -NH-A-R5, -NHC(O)-R5 and the groups of formulas (II-a) to (II-c) below: The invention also relates to some new chiral tetra-hydro β-carboline derivatives.
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(2008/06/13)
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- Highly stereoselective Pictet-Spengler reaction of d-tryptophan methyl ester with piperonal: convenient syntheses of Cialis (Tadalafil), 12a-epi-Cialis, and their deuterated analogues
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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.
- Shi, Xiao-Xin,Liu, Shi-Ling,Xu, Wei,Xu, Yu-Lan
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p. 435 - 442
(2008/09/19)
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- PDE5 inhibitors: An original access to novel potent arylated analogues of tadalafil
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A method to access totally new analogues of tadalafil was explored. The Buchwald reaction was adapted and used to replace the methyl group of tadalafil by various aryl groups. Inhibition potencies on PDE5 of these analogues were determined and proved to be comparable to the one of tadalafil. Using the same route, compounds with the same level of activity but improved water solubility were produced by introducing a pyridine or a pyrimidine ring. This original route also opens access to new unpatented compounds.
- Beghyn, Terence,Hounsou, Candide,Deprez, Benoit P.
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p. 789 - 792
(2007/10/03)
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- AN IMPROVED PROCESS FOR PREPARING TADALAFIL AND ITS INTERMEDIATE
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The present invention relates an improved process for the preparation of tetrahydro-?-carboline derivative of formula (V) which is useful as an intermediate for the preparation of Tadalafil of formula (I). Moreover, the present invention relates to the process for the preparation of Tadalafil of formula (I): Formula (V) and Formula (I).
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Page/Page column 11; 12; 12-13
(2008/06/13)
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- Process for preparing Tadalafil and its intermediate
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The present invention relates an improved process for the preparation of tetrahydro-β-carboline derivative of formula (V) which is useful as an intermediate for the preparation of Tadalafil of formula (I). Moreover, the present invention relates to the process for the preparation of Tadalafil of formula (I)
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Page/Page column 2; 6-7
(2008/06/13)
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- Preparation of tadalafil intermediates
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Provided is a process for preparing tadalafil intermediates in various solvents. Also provided is a method for converting said intermediates to tadalafil.
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(2008/06/13)
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- Synthesis of tadalafil analogues
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Five novel compounds as potential phosphodiesterase type 5 (PDE-5) inhibitors were synthesized from D-tryptophan methyl ester via the Pictet-Spengler reaction and cyclization reaction. The structures of those compounds were confirmed by elemental analyses
- Wang, Liu-Tang,Huang, Hao,Ye, Zhong-Lin,Wu, Yong,Wang, Xue-Chao
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p. 2627 - 2632
(2007/10/03)
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- Pictet-Spengler cyclization in room temperature ionic liquid: A convenient access to tetrahydro β-carbolines
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1,2,3,4-Tetrahydro-β-carbolines have been synthesized in moderate to good yields in short reaction time using the ionic liquid [bbim] BF4 as reaction medium and promoter. There was no need for the use of an additional catalyst normally employed
- Muthukrishnan,More, Shivaji V.,Garud, Dinesh R.,Ramana,Joshi,Joshi
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p. 767 - 772
(2007/10/03)
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- PROCESS FOR PREPARING TADALAFIL AND ITS INTERMEDIATES
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The present invention relates to two novel forms of Tadalafil which differ in their bulk densities. The invention also relates to an improved process for the preparation of Tadalafil and its intermediates.
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Page/Page column 4; 9-11; 17
(2008/06/13)
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- Synthesis and SAR of tetracyclic pyrroloquinolones as phosphodiesterase 5 inhibitors
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The synthesis of the fused tetracyclic pyrroloquinolones 9a-i in four steps is described. The PDE5 inhibitory activities of these compounds, their selectivities against PDE1, PDE2, PDE3, PDE4 and PDE6, the preclinical pharmacokinetic assessments and the in vivo efficacy in increasing intracavernosal pressure are presented and discussed.
- Jiang, Weiqin,Alford, Vernon C.,Qiu, Yuhong,Bhattacharjee, Sheela,John, T. Matthew,Haynes-Johnson, Donna,Kraft, Patricia J.,Lundeen, Scott G.,Sui, Zhihua
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p. 1505 - 1515
(2007/10/03)
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- Indole derivatives as pde5-inhibitors
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Compounds of the general structural formula and use of the compounds and salts and solvates thereof, as therapeutic agents.
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- Design, synthesis and biological activity of β-carboline-based type-5 phosphodiesterase inhibitors
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The SAR of a series of β-carboline derived type 5 phosphodiesterase inhibitors has been explored and we have discovered compounds with excellent levels of PDE5 potency and selectivity over PDE6. However, the series exhibits low levels of selectivity over PDE11, a phosphodiesterase with unknown function.
- Maw, Graham N.,Allerton, Charlotte M. N.,Gbekor, Eugene,Million, William A.
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p. 1425 - 1428
(2007/10/03)
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- 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
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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).
- Daugan, Alain,Grondin, Pascal,Ruault, Cécile,Le Monnier de Gouville, Anne-Charlotte,Coste, Hervé,Linget, Jean Michel,Kirilovsky, Jorge,Hyafil, Fran?ois,Labaudinièret, Richard
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p. 4533 - 4542
(2007/10/03)
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- Cyclic gmp-specific phosphodiesterase inhibitors
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Compounds of general structural formula (I) and use of the compounds and salts and solvates thereof, as therapeutic agents.
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- Chemical compounds
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Compounds of the general structural formula and use of the compounds and salts and solvates thereof, as therapeutic agents.
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