3066-44-2Relevant articles and documents
Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas
Krska, Shane W.,Lin, Shishi,Nkulu, Leah E.,Stahl, Shannon S.,Suh, Sung-Eun
, p. 10380 - 10387 (2021/08/12)
C(sp3)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2′-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, andN-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.
The Reactivity of Difluorocarbene with Hydroxylamines: Synthesis of Carbamoyl Fluorides
Baars, Hannah,Engel, Julien,Mertens, Lucas,Meister, Daniela,Bolm, Carsten
, p. 2293 - 2299 (2016/07/29)
Carbamoyl fluorides are formed in reactions of hydroxylamines with difluorocarbene generated from sodium bromodifluoroacetate as readily available and non-toxic carbene precursor. The process shows a high functional group tolerance, and the reaction path has been rationalized by computational calculations. (Figure presented.) .
N-methylimidazole-catalyzed synthesis of carbamates from hydroxamic acids via the lossen rearrangement
Yoganathan, Sabesan,Miller, Scott J.
, p. 602 - 605 (2013/04/11)
An efficient, one-pot, N-methylimidazole (NMI) accelerated synthesis of aromatic and aliphatic carbamates via the Lossen rearrangement is reported. NMI is a catalyst for the conversion of isocyanate intermediates to the carbamates. Moreover, the utility of arylsulfonyl chloride in combination with NMI minimizes the formation of often-observed hydroxamate-isocyanate dimers during the sequence. Under the present conditions, lowering of temperatures is also possible, enabling a mild protocol.
Direct synthesis of acyl azides from carboxylic acids using 2-azido-l,3-dimethylimidazolinium chloride
Kitamura, Mitsuru,Tashiro, Norifumi,Takamoto, Yusuke,Okauchi, Tatsuo
scheme or table, p. 731 - 733 (2011/01/08)
Acyl azides were directly synthesized from carboxylic acids by the treatment with 2-azido-l,3-dimethylimidazolinium chloride (ADMC, 1) and amine. This procedure resulted in acyl azides in good yields and was applied to the amidation of amino acid derivatives without racemization of the products.
Triphenylphosphine/2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)/[n-Bu4N]OCN as a useful system for the efficient conversion of tetrahydropyranyl (THP) ethers to the corresponding alkyl isocyanates
Akhlaghinia, Batool,Samiei, Sima
experimental part, p. 2525 - 2529 (2010/03/31)
Triphenylphosphine/2,3-dichloro-5,6-dicyanobenzoquinone/tetrabutylammonium cyanate was used as an efficient system for the conversion of tetrahydropyranyl ethers to the corresponding alkyl isocyanates. Taylor & Francis Group, LLC.
Discovering potent small molecule inhibitors of cyclophilin A using de novo drug design approach
Ni, Shuaishuai,Yuan, Yaxia,Huang, Jin,Mao, Xiaona,Lv, Maosheng,Zhu, Jin,Shen, Xu,Pei, Jianfeng,Lai, Luhua,Jiang, Hualiang,Li, Jian
supporting information; experimental part, p. 5295 - 5298 (2010/02/28)
This work describes an integrated approach of de novo drug design, chemical synthesis, and bioassay for quick identification of a series of novel small molecule cyclophilin A (CypA) inhibitors (1-3). The activities of the two most potent CypA inhibitors (3h and 3i) are 2.59 and 1.52 nM, respectively, which are about 16 and 27 times more potent than that of cyclosporin A. This study clearly demonstrates the power of our de novo drug design strategy and the related program LigBuilder 2.0 in drug discovery.
A new and convenient method of generating alkyl isocyanates from alcohols, thiols and trimethylsilyl ethers using triphenylphosphine/2,3-dichloro-5,6- dicyanobenzoquinone/Bu4NOCN
Akhlaghinia, Batool
, p. 1955 - 1958 (2007/10/03)
Alkyl isocyanates are prepared in good to excellent yields by treatment of alcohols, thiols and trimethylsilyl ethers with triphenylphosphine/2,3-dichloro- 5,6-dicyanobenzoquinone/ Bu4NOCN in acetonitrile. This method is highly selective for conversion of primary alcohols to alkyl isocyanates in the presence of secondary and tertiary alcohols, thiols and trimethysilyl ethers. Georg Thieme Verlag Stuttgart.
Manipulation of N,O-nucleophilicity: Efficient formation of 4-N-substituted 2,4-dihydro-3H-1,2,4-triazolin-3-ones
Huang, Xianhai,Palani, Anandan,Xiao, Dong,Aslanian, Robert,Shih, Neng-Yang
, p. 4795 - 4798 (2007/10/03)
(Chemical Equation Presented) A new efficient two-step synthesis of 2,4-dihydro-3H-1,2,4-triazolin-3-ones (triazolinones) from readily available amines is reported. Our novel conditions using hexamethyl disilazane, bromotrimethylsilane, and a catalytic amount of ammonium sulfate smoothly cyclize 1-formyl and 1-acetyl semicarbazides to the target triazolinones. This transformation features simultaneous manipulation of N- and O-nucleophilicity as well as differentiation of the nucleophilicity of a urea and an acyl carbonyl.
Nonpeptide bradykinin B2 receptor antagonists: Conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists
Dziadulewicz, Edward K.,Ritchie, Timothy J.,Hallett, Allan,Snell, Christopher R.,Davies, John W.,Wrigglesworth, Roger,Dunstan, Andrew R.,Bloomfield, Graham C.,Drake, Gillian S.,McIntyre, Peter,Brown, Michael C.,Burgess, Gillian M.,Lee, Wai,Davis, Clare,Yaqoob, Mohammed,Phagoo, Steve B.,Phillips, Elsa,Perkins, Martin N.,Campbell, Elizabeth A.,Davis, Andrew J.,Rang, Humphrey P.
, p. 2160 - 2172 (2007/10/03)
The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-l-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl] pyrrolidine-2-carboxylic acid {2-[(2-dimethylaminoethyl)methylamino]ethyl} amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a Ki of 0.5 ± 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 μmol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with Ki ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 μmol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.
Design, synthesis and pharmacological evaluation of 3-benzylazetidine-2-one-based human chymase inhibitors
Aoyama, Yasunori,Uenaka, Masaaki,Kii, Makoto,Tanaka, Mamoru,Konoike, Toshiro,Hayasaki-Kajiwara, Yoko,Naya, Noriyuki,Nakajima, Masatoshi
, p. 3065 - 3075 (2007/10/03)
3-Benzylazetidine-2-one derivatives were designed and evaluated as a novel series of chymase inhibitors. Structure-activity relationship studies of 3-benzylazetidine-2-ones led to compounds 23, which exhibited 3.1nM inhibition of human chymase and enhancement of stability in human plasma (t1/2 6 h). Copyright
