- Ligand-Phospholipid Conjugation: A Versatile Strategy for Developing Long-Acting Ligands That Bind to Membrane Proteins by Restricting the Subcellular Localization of the Ligand
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We hypothesized that if drug localization can be restricted to a particular subcellular domain where their target proteins reside, the drugs could bind to their target proteins without being metabolized and/or excreted, which would significantly extend the half-life of the corresponding drug-target complex. Thus, we designed ligand-phospholipid conjugates in which the ligand is conjugated with a phospholipid through a polyethylene glycol linker to restrict the subcellular localization of the ligand in the vicinity of the lipid bilayer. Here, we present the design, synthesis, pharmacological activity, and binding mode analysis of ligand-phospholipid conjugates with muscarinic acetylcholine receptors as the target proteins. These results demonstrate that ligand-phospholipid conjugation can be a versatile strategy for developing long-acting ligands that bind to membrane proteins in drug discovery.
- Kawamura, Shuhei,Ito, Yoshihiko,Hirokawa, Takatsugu,Hikiyama, Eriko,Yamada, Shizuo,Shuto, Satoshi
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p. 4020 - 4029
(2018/05/07)
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- Computationally-Led Ligand Modification using Interplay between Theory and Experiments: Highly Active Chiral Rhodium Catalyst Controlled by Electronic Effects and CH–π Interactions
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A chiral ligand for the rhodium-catalyzed asymmetric 1,4-addition of an arylboronic acid to a coumarin substrate that could markedly reduce catalyst loading was developed using interplay between theoretical and experimental approaches. Evaluation of the transition states for insertion and for hydrolysis of intermediate complexes (which were emphasized in response to the experimental results) using DFT calculations at the B97D/6-31G(d) level with the LANL2DZ basis set for rhodium revealed that: (i) the electron-poor nature of the ligands and (ii) CH–π interactions between the ligand and coumarin substrates played significant roles in both acceleration of insertion and inhibition of ArB(OH)2 decomposition (protodeboronation). The computationally-designed ligand, incorporating the above information, enabled a decrease in the catalyst loading to 0.025 mol% (S/C=4,000), which is less than one one-hundredth relative to past catalyst loadings of typically 3 mol%, with almost complete enantioselectivity. Furthermore, the gram-scale synthesis of the urological drug, (R)-tolterodine (l)-tartrate, was demonstrated without the need of intermediate purification. (Figure presented.).
- Korenaga, Toshinobu,Sasaki, Ryo,Takemoto, Toshihide,Yasuda, Toshihisa,Watanabe, Masahito
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supporting information
p. 322 - 333
(2018/01/22)
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- PROCESS FOR THE PREPARATION OF N,N-DIISOPROPYL-3-(2-HYDROXY-5-METHYLPHENYL)- 3-PHENYL PROPYLAMINE AND ITS SALTS STARTING FROM A NOVEL INTERMEDIATE
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The invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propyl amine) and its salts, in particular for the preparation of the tartrate salt, and more particularly for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenyl-2-propenamide, which can be used as pure Z or E isomer or as a mixture of Z and E isomers. When the target is the preparation of the enantiomer (R)-(+)-(N,N- diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine) and diastereomeric crystallization of suitable compound is applied, the present invention covers also the use of racemisation of undesired (S)-(-)- (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propylamine) enantiomer and its recycle in the process.
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- Process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)- 3-phenyl propylamine and its salts starting from a novel intermediate
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The invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine) and its salts, in particular for the preparation of the tartrate salt, and more in particular for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl-2-propenamide which can be used as pure Z or E isomer or as a mixture of Z and E isomers.
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Page/Page column 11
(2012/07/28)
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- IMPROVED PROCESS FOR THE PREPARATION OF (R)-2-(3-DIISOPROPYLAMINO)-1-PHENYLPROPYL)-4METHYLPHENOL AND SALTS THEREOF
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The present invention relates to an improved process for the preparation of Tolterodine or salts thereof, which comprises the use of 3-(2-methoxy-5-methylphenyl)-3-phenylpropyl methane sulfonate.
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Page/Page column 8
(2010/09/17)
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- A PROCESS FOR THE PREPARATION OF TOLTERODINE TARTRATE
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The present invention relates to provide an improved process for the preparation of tolterodine or salt thereof, comprises a step of reducing 3-(2-methoxy-5-methylphenyl) -3-phenyl propionic acid of formula (III) in the presence of a reducing agent, an acidic reagent and a solvent to obtain 3-(2-methoxy-5-methylphenyl) -3-phenyl propanol of formula (IV).
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Page/Page column 19-20; 10
(2010/05/13)
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- A PROCESS FOR THE PREPARATION OF TOLTERODINE TARTRATE
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The present invention relates to provide a process for the preparation of (+)-(R)-Tolterodine-L-tartrate, comprises a step of aminating hydroxyl protected 3-(2-methoxy-5-methylphenyl)-3-phenyl propanol of formula (V) with diisopropylamine in the presence of water to obtain N, N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenylpropyl amine of formula (VI).
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Paragraph 213-222
(2010/09/03)
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- CRYSTALLINE TOLTERODINE TARTARATE AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME
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A crystalline salt of 2-[(1R)-3-[bis(l-methylethyl)amino]-1-ρhenylρropyl]-4-methyl-phenol with (2R,3R)-2,3-dihydroxybutanedioic acid, known under the name R-tolterodine tartarate, wherein: a) at least 90 % of all crystals are present in a size smaller than 30 μm, b) at least 40 % of crystalline matter are smaller than 250 μm, c) the maximum size of crystals does not exceed 800 μm, d) the salt contains less than 0.1 weight % of the undesirable enantiomer S-tolterodine tartarate, e) analytical test for sulfate ashes (Pharm. Eur.) provides a value lower than 0.1%. The method of its preparation involves at least one crystallization from water. A pharmaceutical composition containing tolterodine or its pharmaceutically acceptable salts further contains a filler, a disintegrant and a lubricant, said composition being free of ions of alkaline earth metals.
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Page/Page column 18-20
(2008/06/13)
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- Reduction of ethyl benzoylacetate and selective protection of 2-(3-hydroxy-1-pheny|propyl)4-methylphenol: A new and facile synthesis of tolterodine
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A new and facile synthesis of tolterodine using ethyl benzoylacetate as the starting material was developed. Reduction using sodium borohydride in methanol followed by Friedel-Crafts alkylation utilizing FeCl3 ·6H2O as catalyst lead to the known 2-(3-hydroxyl- phenylpropyl)-4-methylphenol intermediate. Consecutive protection of phenolic OH withp-toluenesulfonyl chloride via two-phase reaction and conversion of aliphatic OH using p-nitrobenzenesulfonyl chloride facilitates direct substitution of duesopropylamine. After simultaneous deprotection of the tosyl group, optically pure (R)-tolterodine·L-tartrate was obtained by resolution using L-tartaric acid with 99.99% purity.
- De Castro, Kathlia A.,Jungnam, Ko,Daejong, Park,Sungdae, Park,Hakjune, Rhee
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p. 918 - 921
(2012/12/30)
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- PROCESS FOR THE PRODUCTION OF BENZOPYRAN-2-OL DERIVATIVES
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The invention provides a process for the production of a compound of formula (I), wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of: (i) reacting a compound of formula (II), wherein OX is hydroxy or O- M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with trans-cinnamaldehyde (III), in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). The above process may be used in the production of tolterodine and fesoterodine, which are useful in the treatment of overactive bladder.
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Page/Page column 11-12; 13-14
(2008/06/13)
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- SUBSTANTIALLY PURE TOLTERODINE TARTRATE AND PROCESS FOR PREPARING THEREOF
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The present invention provides substantially pure Tolterodine.
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Page/Page column 16-18
(2008/06/13)
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- Process for preparing tolterodine
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A process for preparing tolterodine with high purity.
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Page/Page column 7
(2010/11/08)
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- METHOD OF OBTAINING TOLTERODINE
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The process comprises reacting a compound of formula (II), where R is a hydroxyl protecting group, and the asterisk indicates an asymmetric carbon atom, with diisopropylamine in the presence of a reducing agent; optionally converting the resulting intermediate into a salt and, if so desired, isolating it; removing the hydroxyl protecting group; and if so desired, separating the desired (R) or (S) enantiomer, or the mixture of enantiomers and/or converting the obtained compound into a pharmaceutically acceptable salt thereof. Tolterodine is a muscarinic receptor antagonist useful in treating urinary incontinence and other symptoms of urinary bladder hyperactivity.
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Page/Page column 10
(2008/06/13)
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