- Preparation methods of antihypertensive Fosinopril sodium and key intermediate thereof
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The invention relates to preparation methods of an antihypertensive Fosinopril sodium and a key intermediate thereof trans-4-phenyl-L-proline suitable for industrial production. Synthesis of the key intermediate trans-4-phenyl-L-proline has high chiral selectivity, and the method is simple and easy to operate.
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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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p. 1368 - 1381
(2012/04/04)
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- Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines
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Analogues of captopril, enalaprilat, and the phosphinic acid [[hydroxy(4-phenylbutyl)phosphinyl]acetyl)-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.
- Krapcho,Turk,Cushman,Powell,DeForrest,Spitzmiller,Karanewsky,Duggan,Rovnvak,Schwartz,Natarajan,Godfrey,Ryono,Neubeck,Atwa,Petrillo Jr.
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p. 1148 - 1160
(2007/10/02)
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- LITHIUM DIPHENYLCUPRATE REACTIONS WITH 4-TOSYLOXY-L-PROLINES; AN INTERESTING STEREOCHEMICAL OUTCOME. A SYNTHESIS OF TRANS-4-PHENYL-L-PROLINE.
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The reaction of lithium diphenylcuprate with trans-4- and cis-4-tosyloxy-L-prolines gives excellent yields of 4-phenyl substituted L-prolines and the reaction proceeds with net retention of configuration at the carbon center bearing the tosyloxy group.
- Thottathil, John K.,Moniot, Jerome L.
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p. 151 - 154
(2007/10/02)
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- Method for making substituted prolines
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A method is provided for making substituted prolines of the structure STR1 wherein X is lower alkyl or aryl, R is H, lower alkyl or an alkali metal and Z is an N-protecting group, which method includes the step of reacting a compound of the structure STR2
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