- Diastereoselective synthesis and biological evaluation of enantiomerically pure tricyclic indolines
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Tricyclic indolines are common in both natural products and synthetic chemical probes. In this study we demonstrated that enantiomerically pure tricyclic indolines can be prepared from an inexpensive commercially available chiral starting material, pyroglutamic acid. The synthesis features a highly diastereoselective gold-catalyzed cyclization of alkyne-tethered indoles and subsequent diastereoselective reductive ring-opening reaction. Using this approach, we synthesized analogs of our previously discovered tricyclic indoline probes that possess antibacterial and resistance-modifying activity. The biological activity against methicillin-resistant Staphylococcus aureus (MRSA) of these analogues was evaluated and reported. The synthetic approach reported may be leveraged in the future to prepare diastereopure chemical probes for the determination of biological targets for drug discovery.
- He,Griffiths,Wang,Wang
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supporting information
p. 4241 - 4245
(2017/07/10)
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- CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
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There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP4 subtype of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and their use as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
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Paragraph 0410; 0411; 0412
(2015/03/31)
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- PROCESS FOR THE SYNTHESIS OF SUBSTITUTED GAMMA LACTAMS
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The present invention provides synthetic processes for the preparation of a variety of well-defined substituted gamma lactams. The compounds that can be prepared by the process of the invention are useful for treating a variety of conditions. In some embodiments of the invention, the compounds are useful for treating ocular disorders, such as, for example, glaucoma, lowering of elevated intraocular pressure, and the like. In other embodiments, the compounds are useful for treating irritable bowel disease. In further embodiments, the compounds are useful in promoting hair growth. In still further embodiments, the compounds are useful in promoting wound healing, scar reduction, and the like.
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Paragraph 0049-0050
(2014/03/24)
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- PROCESS FOR THE SYNTHESIS OF SUBSTITUTED GAMMA LACTAMS
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The present invention provides synthetic processes for the preparation of a variety of well-defined substituted gamma lactams. The compounds that can be prepared by the process of the invention are useful for treating a variety of conditions. In some embodiments of the invention, the compounds are useful for treating ocular disorders, such as, for example, glaucoma, lowering of elevated intraocular pressure, and the like. In other embodiments, the compounds are useful for treating irritable bowel disease. In further embodiments, the compounds are useful in promoting hair growth. In still further embodiments, the compounds are useful in promoting wound healing, scar reduction, and the like.
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Page/Page column 11
(2014/03/25)
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- CYCLIC AMINE DERIVATIVES AS EP4 RECEPTOR ANTAGONISTS
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There is described a novel group of cyclic amine derivative compounds, having an EP4 receptor antagonistic activity and specifically pharmaceutical compounds which are useful for the treatment or alleviation of Prostaglandin E mediated diseases. The present invention therefore relates to novel compounds which are selective antagonists of the EP 4 sub type of PGE2 receptors with analgesic and antinflammatory activity, processes for their preparation, pharmaceutical compositions containing them and theiruse as medicaments, inter alia for the treatment or alleviation of Prostaglandin E mediated diseases such as acute and chronic pain, osteoarthritis, inflammation-associated disorder as arthritis, rheumatoid arthritis, cancer, migraine and endometriosis.
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Page/Page column 51; 52
(2013/03/26)
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- Discovery of a novel class of potent and orally bioavailable sphingosine 1-phosphate receptor 1 antagonists
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A series of subtype selective sphingosine 1-phosphate receptor 1 (S1P 1) antagonists are disclosed. Our high-throughput screening campaign revealed hit 1 for which an increase in potency and mouse oral exposure was achieved with minor modifications to the chemical scaffold. In vivo efficacy revealed that at high doses compounds 12 and 15 inhibited tumor growth. Further optimization of our lead series led to the discovery of proline derivatives 37 (XL541) and 38 which had similar efficacy as our first generation analogues at significantly lower doses. Analogue 37 displayed excellent pharmacokinetics and oral exposure in multiple species.
- Ibrahim, Mohamed A.,Johnson, Henry W. B.,Jeong, Joon Won,Lewis, Gary L.,Shi, Xian,Noguchi, Robin T.,Williams, Matthew,Leahy, James W.,Nuss, John M.,Woolfrey, John,Banica, Monica,Bentzien, Frauke,Chou, Yu-Chien,Gibson, Anna,Heald, Nathan,Lamb, Peter,Mattheakis, Larry,Matthews, David,Shipway, Aaron,Wu, Xiang,Zhang, Wentao,Zhou, Sihong,Shankar, Geetha
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experimental part
p. 1368 - 1381
(2012/04/04)
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- Synthesis of 3-guaninyl- and 3-adeninyl-5-hydroxymethyl-2-pyrrolidinone nucleosides
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l- And d-glutamic acids, as well as trans-4-hydroxy-l-proline, are converted to the corresponding 3-guaninyl-5-hydroxymethyl-2-pyrrolidinone (4) or 3-adeninyl-5-hydroxymethyl-2-pyrrolidinone (5) nucleoside analog. The protecting group used to block the lactam nitrogen in key intermediates has a significant effect on the diastereoselectivity of the coupling reaction with adenine or guanine.
- Saleh, Abdullah,D'Angelo, John G.,Morton, Martha D.,Quinn, Jesse,Redden, Kendra,Mielguz, Rafal W.,Pavlik, Christopher,Smith, Michael B.
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scheme or table
p. 5574 - 5583
(2011/10/02)
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- PTERIDINONES AS INHIBITORS OF POLO - LIKE KINASE
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The present invention provides compounds having a structure according to Formula (I) or a salt or solvate thereof, wherein ring A, X, R1, R2, R3, R4, R5 and R6, are defined herein. The invention further provides pharmaceutical compositions including the compounds of the invention and methods of making and using the compounds and compositions of the invention, e.g., in the treatment and prevention of various disorders, such as Parkinson's disease.
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Page/Page column 81
(2011/07/09)
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- Synthesis and uses of pyroglutamic acid derivatives
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Novel pyroglutamic acid derivatives (I), wherein R1 is -OH, -ORa, wherein Ra is alkyl, cycloalkyl, alkenyl, cycloalkenyl, aryl, aralkyl or heterocyclyl; R2, R3 and R4 are independently H, a nitrogen protecting group which hydrolyzes under acidic conditions or phtalamide; X is a pharmaceutically acceptable anion; and Y is a N-containing group; either in the form of their isolated optically active stereoisomers or in the form of mixtures thereof, are useful compounds for enhancing an immuneresponse in a subject and/or for treating tumours, bacterial, fungal or viral infections, or autoimmune diseases.
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Page/Page column 28
(2008/06/13)
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- Efficient total synthesis of AI-77-B, a gastroprotective substance from Bacillus pumilus AI-77
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First total synthesis of AI-77-B (1), a gastroprotective substance from Bacillus pumilus AI-77, was achieved in a stereoselective and convergent manner. In this synthesis, the dihydroisocoumarin part 2 was constructed in one step through 1,2-addition of the benzylic anion 17b to Boc-L-leucinal 7b. The hydroxy amino acid 4 was elaborated from (R)-glutamic acid in a highly stereoselective manner. Condensation of 2·HCl and 4, intramolecular Pinner reaction, followed by mild hydrolysis afforded AI-77-B (1).
- Hamada,Hara,Kawai,Kohno,Shioiri
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p. 8635 - 8652
(2007/10/02)
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- Stereoselectivity of muscarinic receptors in vivo and in vitro for oxotremorine analogues. N-[4-(Tertiary amino)-2-butynyl]-5-methyl-2-pyrrolidones
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The enantiomers of three 5-methyl-2-pyrrolidone analogues of the muscarinic agent oxotremorine were synthesized. The pyrrolidine derivative (R)-13 was an antagonist to carbachol in the guinea pig ileum and also showed central and peripheral antimuscarinic activity in vivo. It was more potent and more selective than atropine in antagonizing the central effects of 1. The dimethylamino analogue (R)-14 and the trimethylammonium salt (R)-15 were potent agonists in the guinea pig ileum. (R)-14 showed both central muscarinic (hypothermia) and central antimuscarinic activity (antagonism of oxotremorine-induced tremor) in vivo. The R enantiomers of 13-15 were considerably more potent than the S enantiomers in vivo and in vitro irrespective of whether agonist or antagonist activity was measured. From a comparison of the contribution of the methyl group at the chiral center to the overall affinities it is suggested that agonists and antagonists in this series bind in an essentially identical manner to the muscarinic receptor.
- Amstutz,Ringdahl,Karlen,Roch,Jenden
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p. 1760 - 1765
(2007/10/02)
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