- N-Trifluoromethyl Amines and Azoles: An Underexplored Functional Group in the Medicinal Chemist's Toolbox
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Introducing trifluoromethyl groups is a common strategy to improve the properties of biologically active compounds. However, N-Trifluoromethyl moieties on amines and azoles are very rarely used. To evaluate their suitability in drug design, we synthesized a series of N-Trifluoromethyl amines and azoles, determined their stability in aqueous media, and investigated their properties. We show that N-Trifluoromethyl amines are prone to hydrolysis, whereas N-Trifluoromethyl azoles have excellent aqueous stability. Compared to their N-methyl analogues, N-Trifluoromethyl azoles have a higher lipophilicity and can show increased metabolic stability and Caco-2 permeability. Furthermore, N-Trifluoromethyl azoles can serve as bioisosteres of N-iso-propyl and N-Tert-butyl azoles. Consequently, we suggest that N-Trifluoromethyl azoles are valuable substructures to be considered in medicinal chemistry.
- Schiesser, Stefan,Chepliaka, Hanna,Kollback, Johanna,Quennesson, Thibaut,Czechtizky, Werngard,Cox, Rhona J.
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p. 13076 - 13089
(2020/11/13)
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- Design, synthesis and biological activity evaluation of benzoate compounds as local anesthetics
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Tetracaine and pramocaine were used as the lead compounds to design benzoate compounds. The combination principle was used to design the target molecule, and the target molecule was modified by bioisostere formation and modification with alkyl groups. In this research, a total of 16 compounds were designed and synthesized. In the process of synthesis, we selected a route with high total yields, mild conditions and simple operation. Three steps were used in the synthesis of the new target compounds, namely, alkylation, esterification and alkylation. The newly designed target compounds were evaluated via surface anesthesia, infiltration anesthesia, block anesthesia and acute toxicity tests. The results of biological activity experiments showed that compounds 4d, 4g, 4j, 4k, 4n, and 4o had a good local anesthetic effect, and the results of acute toxicity tests showed that the target compounds had low toxicity.
- Zou, Huiying,Chen, Guangying,Zhou, Shiyang
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p. 6627 - 6635
(2019/03/14)
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- Method for preparing tetracaine hydrochloride
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The invention discloses a method for preparing tetracaine hydrochloride. The method comprises the following steps: (1) preparing 4-n-butyl aminobenzoic acid, namely adding a solvent, 4-halogen-benzoicacid, n-butylamine and copper catalyst into a high pressure reactor to obtain the 4-n-butyl aminobenzoic acid; (2) preparing tetracaine, namely adding the 4-n-butyl aminobenzoic acid prepared in thestep (1), N,N-dimethylethanolamine, concentrated sulfuric acid and a solvent into a reaction bottle, heating, refluxing and diverting to obtain the tetracaine; and (3) preparing tetracaine hydrochloride, namely reacting the tetracaine prepared in the step (2) with concentrated hydrochloric acid in a solvent at a certain temperature to obtain the tetracaine hydrochloride. The method has the advantages that 1, the copper catalyst has smaller toxicity, is low in price and easily available while the copper catalyst is much safer, and the cost for raw materials and operation can be greatly reduced;2, the raw materials are easily available, the reaction has few steps, the intermediate reacting process can be easily controlled, few byproduct is generated, and large-scale production is easy to implement; and 3, the product has high purity and high total yield.
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Paragraph 0041
(2019/01/21)
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- DERIVATIVES OF TETRACAINE
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Disclosed herein are derivatives of tetracaine that, among other things, block cyclic nucleotide gated (CNG) channels and are useful in the treatment of diseases characterized by overactive CNG channels such as retinal degeneration diseases.
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Paragraph 0098
(2014/02/16)
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- Cyclic nucleotide-gated channel block by hydrolysis-resistant tetracaine derivatives
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To meet a pressing need for better cyclic nucleotide-gated (CNG) channel antagonists, we have increased the biological stability of tetracaine-based blockers by synthesizing amide and thioamide linkage substitutions of tetracaine (1) and a higher affinity
- Andrade, Adriana L.,Melich, Kenneth,Whatley, G. Gregory,Kirk, Sarah R.,Karpen, Jeffrey W.
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experimental part
p. 4904 - 4912
(2011/09/19)
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- Block of cyclic nucleotide-gated channels by tetracaine derivatives: Role of apolar interactions at two distinct locations
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A series of new tetracaine derivatives was synthesized to explore the effects of hydrophobic character on blockade of cyclic nucleotide-gated (CNG) channels. Increasing the hydrophobicity at either of two positions on the tetracaine scaffold, the tertiary amine or the butyl tail, yields blockers with increased potency. However, shape also plays an important role. While gradual increases in length of the butyl tail lead to increased potency, substitution of the butyl tail with branched alkyl or cyclic groups is deleterious.
- Strassmaier, Timothy,Kirk, Sarah R.,Banerji, Tapasree,Karpen, Jeffrey W.
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p. 645 - 649
(2008/09/19)
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- One-pot reductive mono-N-alkylation of aniline and nitroarene derivatives using aldehydes
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(Chemical Equation Presented) One-pot reductive mono-N-alkylation of aniline and nitroarene derivatives using various aldehydes by Pd/C catalyst in aqueous 2-propanol solvent with ammonium formate as in situ hydrogen donor is illustrated. The reaction proceeded smoothly and selectively with excellent yield at room temperature. Our protocol presents a facile, economical, and environmentally benign alternative for reductive amination.
- Byun, Eunyoung,Hong, Bomi,De Castro, Kathlia A.,Lim, Minkyung,Rhee, Hakjune
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p. 9815 - 9817
(2008/03/27)
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- The Chemistry of N-Substituted Benzotriazoles. Part 4. A Novel and Versatile Method for the Mono-N-alkylation of Aromatic and Heteroaromatic Amines
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Mono-N-alkylation of aromatic and heteroaromatic amines is achieved in high yield by NaBH4 reduction of the adducts formed from benzotriazole, aliphatic aldehydes and the amines.Reaction of the same adducts with Grignard reagents gives N-(secondary alkyl)arylamines.Carboxy groups need no protection and nitro groups are unaffected.Adenine is mono-N-alkylated in high yield.
- Katritzky, Alan R.,Rachwal, Stanislaw,Rachwal, Bogumila
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p. 805 - 810
(2007/10/02)
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- Liquid Crystalline 4-Cyanobiphenyl-4-Alkylaminobenzoates
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The mesomorphic and dielectric properties of homolo new compounds 4-cyanobiphenyl-4-alkylaminobenzoates are presented.
- Gureviciene, J.-J.,Adomenas, P.
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p. 177 - 180
(2007/10/02)
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