211692-42-1Relevant academic research and scientific papers
Alkyl Carbagermatranes Enable Practical Palladium-Catalyzed sp2-sp3 Cross-Coupling
Xu, Meng-Yu,Jiang, Wei-Tao,Li, Ying,Xu, Qing-Hao,Zhou, Qiao-Lan,Yang, Shuo,Xiao, Bin
, p. 7582 - 7588 (2019/05/16)
Pd-catalyzed cross-coupling reactions have achieved tremendous accomplishments in the past decades. However, C(sp3)-hybridized nucleophiles generally remain as challenging coupling partners due to their sluggish transmetalation compared to the C(sp2)-hybridized counterparts. While a single-electron-transfer-based strategy using C(sp3)-hybridized nucleophiles had made significant progress recently, fewer breakthroughs have been made concerning the traditional two-electron mechanism involving C(sp3)-hybridized nucleophiles. In this report, we present a series of unique alkyl carbagermatranes that were proven to be highly reactive in cross-coupling reactions with our newly developed electron-deficient phosphine ligands. Generally, secondary alkyl carbagermatranes show slightly lower, yet comparable activity to its Sn analogue. Meanwhile, primary alkyl carbagermatranes exhibit high activity, and they were also proved stable enough to be compatible with various reactions. Chiral secondary benzyl carbagermatrane gave the coupling product under base/additive-free conditions with its configuration fully inversed, suggesting that transmetalation was carried out in an "SE2(open) Inv" pathway, which is consistent with Hiyama's previous observation. Notably, the cross-coupling of primary alkyl carbagermatranes could be performed under base/additive-free conditions with excellent functional group tolerance and therefore may have potentially important applications such as stapled peptide synthesis.
Copper-Catalyzed Boron-Selective C(sp2)-C(sp3) Oxidative Cross-Coupling of Arylboronic Acids and Alkyltrifluoroborates Involving a Single-Electron Transmetalation Process
Ding, Siyi,Xu, Liang,Li, Pengfei
, p. 1329 - 1333 (2016/02/18)
A rapid and highly selective oxidative cross-coupling reaction between readily available and shelf-stable arylboronic acids and primary or secondary potassium alkyltrifluoroborates was devised and developed, which works under mild conditions using copper(II) acetate as the catalyst and silver oxide as the oxidant. Initial experimental results indicate that a single-electron transmetalation process is involved. This approach effectively bypasses the problems associated with the traditional cross-coupling reactions of alkylboronates and thus provides a complementary method in building C(sp2)-C(sp3) bonds.
BENZOXAZOLONE DERIVATIVES AS ACID CERAMIDASE INHIBITORS, AND THEIR USE AS MEDICAMENTS
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Page/Page column 42; 56, (2015/12/11)
The present invention relates to benzoxazolone derivatives as acid ceramidase inhibitors, pharmaceutical compositions containing these inhibitors and methods of inhibiting acid ceramidase for the treatment of disorders in which modulation of the levels of ceramide is clinically relevant. The invention also provides benzoxazolone derivatives for use as a medicament in the treatment of cancer, inflammation, pain, inflammatory pain or pulmonary diseases.
Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
Bach, Anders,Pizzirani, Daniela,Realini, Natalia,Vozella, Valentina,Russo, Debora,Penna, Ilaria,Melzig, Laurin,Scarpelli, Rita,Piomelli, Daniele
, p. 9258 - 9272 (2015/12/23)
Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
Asymmetric hydrogenation of α-primary and secondary amino ketones: Efficient asymmetric syntheses of (-)-arbutamine and (-)-denopamine
Shang, Gao,Liu, Duan,Allen, Scott E.,Yang, Qin,Zhang, Xumu
, p. 7780 - 7784 (2008/04/03)
Two ss-receptor agonists (-)-denopamine and (-)-arbutamine were prepared in good yields and enantioselectivities by asymmetric hydrogenation of unprotected amino ketones for the first time by using Rh catalysts bearing electron-donating phosphine ligands. A series of α-primary and secondary amino ketones were synthesized and hydrogenated to produce various 1,2-amino alcohols in good yields and with good enantioselectivies. This Rh electron-donating phosphine-catalyzed asymmetric hyderogenation repI resents one of the most promising and convenient approaches towards the asymmetric synthesis of chiral amino alcohols.
Search for histamine H3 receptor antagonists with combined inhibitory potency at Nτ-methyltransferase: Ether derivatives
Apelt,Grassmann,Ligneau,Pertz,Ganellin,Arrang,Schwartz,Schunack,Stark, Holger
, p. 97 - 106 (2007/10/03)
With the recent development of new hybrid compounds having histamine H 3 receptor antagonist with combined histamine Nτ- methyltransferase (HMT) inhibitory potency an innovative approach was described in the research of novel lead compounds modulating histaminergic neurotransmission. Several compounds containing an ether moiety derived from the recently published 4-(3-piperidinopropoxy)phenylaminoquinoline derivatives (like FUB 836), were synthesized in this study and tested for their affinity at cloned human histamine H3 (hH3) receptors and on the inhibition of rat HMT. Besides different heterocycles, e.g. nitro- or amino-substituted pyridines, quinolines, benzothiazole or pyrroline, three classes of compounds were produced: heteroaromatic 3-piperidinopropyl ethers, keto- or imino-substituted 4-(3-piperidinopropyl)phenyl ethers and 4-(3-piperidinopropyl)phenyl ethers with substituted (alkyl)aminopyridines. Whereas the (3-piperidinopropoxy)heterocycles showed only moderate activities on both test models, the 4-(3-piperidinopropoxy)phenyl derivatives were identified as potent histamine H3 receptor ligands and/or HMT inhibitors. Ki values up to 0.42 nM were found for the affinity to the hH 3 receptor. HMT inhibitory potency was identified with IC 50 values about 0.3 μM for the most potent compounds in this series. Comparison of the pyridine-containing derivatives to recently published quinoline analogues showed a decrease in potencies for the pyridines. The dual activity, H3 receptor affinity and HMT inhibition, was moderate to good. For all compounds affinities at hH3 receptors were higher than their inhibitory HMT potencies. The described new histamine H3 receptor antagonists with an ether moiety represent a further promising step in our investigations for a dual activity.
Development of a new class of nonimidazole histamine H3 receptor ligands with combined inhibitory histamine N-methyltransferase activity
Apelt, Joachim,Ligneau, Xavier,Pertz, Heinz H.,Arrang, Jean-Michel,Ganellin, C. Robin,Schwartz, Jean-Charles,Schunack, Walter,Stark, Holger
, p. 1128 - 1141 (2007/10/03)
In search of novel ways to enhance histaminergic neurotransmission in the central nervous system, a new class of nonimidazole histamine H3 receptor ligands were developed that simultaneously possess strong inhibitory activity on the main histamine metabolizing enzyme, histamine N-methyltransferase (HMT). The novel compounds contain an aminoquinoline moiety, which is an important structural feature for HMT inhibitory activity, connected by different spacers to a piperidino group (for H3 receptor antagonism). Variation of the spacer structure provides two different series of compounds. One series, having only an alkylene spacer between the basic centers, led to highly potent HMT inhibitors with moderate to high affinity at human histamine H3 receptors. The second series possesses a p-phenoxypropyl spacer, which may be extended by another alkylene chain. This latter series also showed strong inhibitory activity on HMT, and in most cases, the H3 receptor affinity even surpassed that of the first series. One of the most potent compounds with this dual mode of action is 4-(4-(3-piperidinopropoxy)phenylamino)quinoline (34) (hH3, Ki = 0.09 nM; HMT, IC50 = 51 nM). This class of compounds showed high antagonist potency and good H3 receptor selectivity in functional assays in guinea pig on H1, H2, and H3 receptors. Because of low or missing in vivo activity of two selected compounds, the proof of concept of these valuable pharmacological tools for the supposed superior overall enhancing effect on histaminergic neurotransmission failed to appear hitherto.
Synthesis and pharmacological characterization of novel 6-fluorochroman derivatives as potential 5-HT(1A) receptor antagonists
Yasunaga, Tomoyuki,Kimura, Takenori,Naito, Ryo,Kontani, Toru,Wanibuchi, Fumikazu,Yamashita, Hiroshi,Nomura, Tamako,Tsukamoto, Shin-Ichi,Yamaguchi, Tokio,Mase, Toshiyasu
, p. 2765 - 2778 (2007/10/03)
A series of novel 6-fluorochroman derivatives was prepared and evaluated as antagonists for the 5-HT(1A) receptor. N-2-[[(6-Fluorochroman-8- yl)oxy]ethyl]-4-(4-methoxyphenyl)butylamine (3; J. Med. Chem. 1997, 40, 1252- 1257) was chosen as a lead, and structural modifications were done on the aliphatic portion of the chroman ring, the tether linking the middle amine and the terminal aromatic ring, the aromatic ring, and lastly the amine. Radioligand binding assays proved that the majority of the novel compounds behaved as good to excellent ligands at the 5-HT(1A) receptor, some of which were selective with respect to α1-adrenergic and D2-dopaminergic receptors. The antagonist activity of the compounds was assessed in the forskolinstimulated adenylate cyclase assays in CHO cells expressing the human 5-HT(1A) receptors. Among the modifications attempted, introduction of an oxo or an optically active hydroxy moiety at the chroman C-4 position was effective in ameliorating the receptor selectivity. Six analogues were selected through the in vitro screens and further evaluated for their in vivo activities. A 4-oxochroman derivative (31n), having a terminal 1,3- benzodioxole ring, demonstrated antagonist activities toward 8-OH-DPAT- induced behavioral and electrophysiological responses in rats.
