- ANTHELMINTIC HETEROCYCLIC COMPOUNDS
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This invention provides for compounds of the formula (I): wherein the variables are defined herein, or salt thereof, compositions comprising these compounds, and method for the treatment, control or prevention of a parasitic infestation or infection in an animal in need thereof by administering an effective amount of these compounds to said animal.
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- BICYCLIC DERIVATIVES FOR TREATING ENDOPARASITES
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The present invention provides compounds of formula (I): which are useful in the control of endoparasites, for example heartworms, in warm-blooded animals.
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Page/Page column 40; 73
(2020/12/29)
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- TRICYCLIC INDOLE MCL-1 INHIBITORS AND USES THEREOF
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The present invention provides for compounds that inhibit the activity of an anti-apoptotic Bcl-2 family member Myeloid cell leukemia-1 (Mcl-1) protein. The present invention also provides for pharmaceutical compositions as well as methods for using compounds for treatment of diseases and conditions (e.g., cancer) characterized by the over-expression or dysregulation of Mcl-1 protein.
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Paragraph 0429; 0443
(2016/05/19)
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- Ruthenium(II)-Catalyzed Traceless C?H Functionalization Using an N?N Bond as an Internal Oxidant
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A previously elusive RuII-catalyzed N?N bond-based traceless C?H functionalization strategy is reported. An N-amino (i.e., hydrazine) group is used for the directed C?H functionalization with either an alkyne or an alkene, affording an indole derivative or olefination product. The synthesis features a broad substrate scope, superior atom and step economy, as well as mild reaction conditions.
- Zhou, Shuguang,Wang, Jinhu,Chen, Pei,Chen, Kehao,Zhu, Jin
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supporting information
p. 14508 - 14512
(2016/10/03)
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- Discovery of a tetracyclic quinoxaline derivative as a potent and orally active multifunctional drug candidate for the treatment of neuropsychiatric and neurological disorders
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We report the synthesis and structure-activity relationships of a class of tetracyclic butyrophenones that exhibit potent binding affinities to serotonin 5-HT2A and dopamine D2 receptors. This work has led to the discovery of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H,7H- pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8-yl) -1-(4-fluorophenyl)-butan-1-one 4-methylbenzenesulfonate (ITI-007), which is a potent 5-HT2A antagonist, postsynaptic D2 antagonist, and inhibitor of serotonin transporter. This multifunctional drug candidate is orally bioavailable and exhibits good antipsychotic efficacy in vivo. Currently, this investigational new drug is under clinical development for the treatment of neuropsychiatric and neurological disorders.
- Li, Peng,Zhang, Qiang,Robichaud, Albert J.,Lee, Taekyu,Tomesch, John,Yao, Wei,Beard, J. David,Snyder, Gretchen L.,Zhu, Hongwen,Peng, Youyi,Hendrick, Joseph P.,Vanover, Kimberly E.,Davis, Robert E.,Mates, Sharon,Wennogle, Lawrence P.
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p. 2670 - 2682
(2014/04/17)
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- Design and synthesis of a metabolically stable and potent antitussive agent, a novel δ opioid receptor antagonist, TRK-851
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We have previously reported on antitussive effect of (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5′,6′-dihydro-3-methoxy-4′H-pyrrolo[3,2,1-ij]quinolino[2′,1′:6,7]morphinan-14-ol(1b) methanesulfonate (TRK-850), a selective δ opioid receptor antagonist which markedly reduced the number of coughs in a rat cough model. We designed TRK-850 based on naltrindole (NTI), a typical δ opioid receptor antagonist, to improve its permeability through the blood-brain barrier by introducing hydrophobic moieties to NTI. The ED50 values of NTI and compound 1b by intraperitoneal injections were 104 μg/kg and 2.07 μg/kg, respectively. This increased antitussive potency probably resulted from the improved brain exposure of compound 1b. However, 1b was extremely unstable toward metabolism by cytochrome P450. In this study, we designed and synthesized compound 1b derivatives to improve the metabolic instability, which resulted in affording highly potent and metabolically stable oral antitussive agent (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-8′-fluoro-5′,6′-dihydro-4′H-pyrrolo[3,2,1-ij]quinolino[2′,1′:6,7]morphinan-3,14-diol (1c) methanesulfonate (TRK-851).
- Sakami, Satoshi,Kawai, Koji,Maeda, Masayuki,Aoki, Takumi,Fujii, Hideaki,Ohno, Hiroshi,Ito, Tsuyoshi,Saitoh, Akiyoshi,Nakao, Kaoru,Izumimoto, Naoki,Matsuura, Hirotoshi,Endo, Takashi,Ueno, Shinya,Natsume, Kazuto,Nagase, Hiroshi
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p. 7956 - 7967
(2008/12/23)
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- Indole derivatives and medical application thereof
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The present invention relates to indole derivatives represented by the following compound 1 and the pharmacologically acceptable acid addition salt thereof. STR1 The compounds of the present invention were found to exhibit strong antitussive and analgesic actions as a result of pharmacological evaluation, and can be used in the pharmaceutical field as effective antitussives and analgesics.
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- Development of high-affinity 5-HT3 receptor antagonists. Structure- affinity relationships of novel 1,7-annelated indole derivatives. 1
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On the basis of the structures of ondansetron and GR 65,630, its ring- opened C-linked methylimidazole analogue, novel 1,7-annelated indole derivatives were synthesized as potential 5-HT3 antagonists. Receptor binding studies show that all compounds display a high affinity for the 5- HT3 receptors. In both series annelation results in compounds being 7 and 4 times more potent than the references ondansetron and GR 65,630, respectively. Similar to ondansetron, the 1,7-annelated indoles show little stereoselectivity. The (-)-isomers are only slightly more potent than the (+)-isomers. The receptor binding profile of l-10-[(2-methyl-1H-imidazol-1- yl)methyl]-5,6,8,9,10,11-hexahydro-4H-pyrido[3,2,1-jk]carbazol-11-one hydrochloride (24b) (INN cilansetron) shows that the compound displays, besides a high affinity for 5-HT3 receptors (K(i) = 0.19 nM), a weak affinity for σ-receptors (K(i) = 340 nM), muscarine M1 receptors (K(i) = 910 nM), and 5-HT4 receptors (K(i) = 960 nM) and no affinity (K(i) ≥ 5000 nM) for all the other receptor types tested (n = 37). The new compounds fit the proposed necessary chemical template for binding: a heteroaromatic ring system, a coplanar carbonyl group, and a nitrogen center at well-defined distances. The enhanced potency of the annelated 1,7-indole derivatives indicates that the extra ring provides a favorable hydrophobic area for interaction with the 5-HT3 receptor site. In vivo cilansetron is more potent and induces less central side effects than ondansetron. At present cilansetron is in clinical trials.
- Van Wijngaarden,Hamminga,Van Hes,Standaar,Tipker,Tulp,Mol,Olivier,De Jonge
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p. 3693 - 3699
(2007/10/02)
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