- Substituted 5-oxo-pyrrolidine derivative, and preparation method and applications thereof
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The invention belongs to the technical field of medicine, relates to a substituted 5-oxo-pyrrolidine derivative disclosed in generation formula I, and a preparation method and applications thereof, and more specifically relates to applications of the substituted 5-oxo-pyrrolidine derivative in preparation of anti-cerebral ischemia medicines as a nerve protective agent, and a pharmaceutical composition taking the substituted 5-oxo-pyrrolidine derivative and a pharmaceutically acceptable salt of the substituted 5-oxo-pyrrolidine derivative as active components. The pharmaceutical composition contains the substituted 5-oxo-pyrrolidine derivative and a pharmaceutical excipient and/or a diluent of the substituted 5-oxo-pyrrolidine derivative. In the general formula I, R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, X, Y, and n are defined in the patent specification and patent claims.
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- Discovery of ABT-957: 1-Benzyl-5-oxopyrrolidine-2-carboxamides as selective calpain inhibitors with enhanced metabolic stability
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Aberrant activation of calpain has been observed in various pathophysiological disorders including neurodegenerative diseases such as Alzheimer's Disease. Here we describe our efforts on ketoamide-based 1-benzyl-5-oxopyrrolidine-2-carboxamides as a novel series of highly selective calpain inhibitors mitigating the metabolic liability of carbonyl reduction. The most advanced compound from this new series, namely A-1212805 (ABT-957, Alicapistat) proceeded to clinical phase I studies.
- Jantos, Katja,Kling, Andreas,Mack, Helmut,Hornberger, Wilfried,Moeller, Achim,Nimmrich, Volker,Lao, Yanbin,Nijsen, Marjoleen
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supporting information
p. 1968 - 1973
(2019/05/29)
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- CALPAIN MODULATORS AND THERAPEUTIC USES THEREOF
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Disclosed herein are small molecule calpain modulator compositions, pharmaceutical compositions, the use and preparation thereof.
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- ANTIVIRAL COMPOUNDS
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The present invention relates to novel compounds of general formula (I) wherein the groups X, and R1 to R4 have the meanings given in the description and claims, process for preparing these compounds and their use as for treating, preventing or ameliorating viral infections and their use for treating, preventing or ameliorating diseases which are associated with PLA2G16.
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Paragraph 0718; 0733
(2018/04/13)
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- A the non-peptide class perishes weakly inhibiting protein antagonists and its synthetic method and application (by machine translation)
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This invention discloses a kind of the non-peptide class perishes weakly inhibiting protein antagonist and method for preparing the same and application, which aims to provide a better anticancer effect with the non-peptide class perishes weakly inhibitin
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- 3,7-DIAZABICYCLO[3.3.1 ]NONANE CARBOXAMIDES AS ANTITHROMBOTIC AGENTS
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The present invention relates to the 3,7-diazabicyclo[3.3.1]nonane carboxamides and process for preparation thereof. The present invention further relates to the compounds of general formula (1) possessing anti-thrombotic (anti-platelet) activities. The invention also relates to use of these moieties as inhibitors of collagen induced platelet adhesion and aggregation mediated through collagen receptors both in vitro and in vivo. Further, invention also relates these class of compounds exhibiting anti-platelet efficacy through dual mechanism inhibited both collagen as well as U46619 (thromboxane receptor agonist) induced platelet aggregation. General formula (1) Wherein, R' is; wherein R is selected from alkyl, acyl, tosyl, tert-butyloxycarbonyl, araalkyl or substituted araalkyl groups; R'' is selected preferably from halogen, cyano, lower alkyl, aryl, substituted aryl, and tosyl groups; R1 is selected from hydrogen and lower alkyl groups; R2 is selected from lower alkyl and aryl groups; R3 is selected from tert-butyloxycarbonyl and bezyloxycarbonyl groups; n = 0,1.
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- An efficient and straight forward strategy for the synthesis of enantiomerically pure (S)-1-benzyl-5-(alkyl/aryl amino) methyl-pyrrolidin-2-ones
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A simple, efficient and straightforward strategy for the synthesis of enantiomerically pure (S)-5-((alkyl/aryl amino) methyl)-pyrrolidin-2-ones from N-benzyl-5(S)-pyroglutaminol through Mitsunobu reaction has been described. These pyrrolidin-2-ones have great potential to act as asymmetric precursors for the synthesis of bioactive compounds/ natural products requiring suitably substituted aminomethyl group at C-5 of native pyrrolidin-2-ones.
- Panday, Sharad Kumar,Pathak, Manoher Bhushan,Prasad, Jagdish
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p. 936 - 939
(2015/08/06)
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- Synthesis and identification of chiral aminomethylpiperidine carboxamides as inhibitor of collagen induced platelet activation
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A series of chiral lactam carboxamides of aminomethylpiperidine were synthesized and investigated for the collagen induced in vitro anti-platelet efficacy and collagen plus epinephrine induced in vivo pulmonary thromboembolism. The compound 31a (30 μM/kg) displayed a remarkable antithrombotic efficacy (60% protection) which was sustained for more than 24 h and points to its excellent bioavailability. The compounds 31a (IC50 = 6.6 μM) and 32a (IC50 = 37 μM), as well as their racemic mixture 28i (IC50 = 16 μM) significantly inhibited collagen-induced human platelet aggregation in vitro. Compound 34c displayed dual mechanism of action against both collagen (IC50 = 3.3 μM) and U46619 (IC50 = 2.7 μM) induced platelet aggregation. The pharmacokinetic study of 31a indicated very faster absorption, prolonged and constant systemic exposure and thereby exhibiting better therapeutic response.
- Anil Kumar,Misra, Ankita,Siddiqi, Tanveer Irshad,Srivastava, Stuti,Jain, Manish,Bhatta, Rabi Sankar,Barthwal, Manoj,Dikshit, Madhu,Dikshit, Dinesh K.
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p. 456 - 472
(2014/06/09)
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- An efficient and straight forward synthesis of (5S)-1-benzyl-5-(1H- imidazol-1-ylmethyl)-2-pyrrolidinone (MM1): A novel antihypertensive agent
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(5S)-1-benzyl-5-(1H-imidazol-1-ylmethyl)-2-pyrrolidinone and its closely related analog was synthesized from (S)-pyroglutaminol and imidazole or substituted imidazole using Mitsunobu reaction as the key step. Springer Science+Business Media, LLC 2010.
- Prasad, Jagdish,Pathak, Manoher Bhushan,Panday, Sharad Kumar
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experimental part
p. 321 - 324
(2012/08/28)
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- Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor
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A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X7 receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X7 antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.
- Abdi, Muna H.,Beswick, Paul J.,Billinton, Andy,Chambers, Laura J.,Charlton, Andrew,Collins, Sue D.,Collis, Katharine L.,Dean, David K.,Fonfria, Elena,Gleave, Robert J.,Lejeune, Clarisse L.,Livermore, David G.,Medhurst, Stephen J.,Michel, Anton D.,Moses, Andrew P.,Page, Lee,Patel, Sadhana,Roman, Shilina A.,Senger, Stefan,Slingsby, Brian,Steadman, Jon G.A.,Stevens, Alexander J.,Walter, Daryl S.
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scheme or table
p. 5080 - 5084
(2010/10/04)
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- Pyroglutamic acid derivatives and related compounds which inhibit leukocyte adhesion mediated by VLA-4
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Disclosed are pyroglutamic acid derivatives and related compounds which bind VLA-4. Certain of these compounds also inhibit leukocyte adhesion and, in particular, leukocyte adhesion mediated by VLA-4. Such compounds are useful in the treatment of inflamma
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- Di-μ-hydroxy-bis(N,N,N′,N′-tetramethylenediamine)-copper(II) chloride [Cu(OH)·TMEDA]2Cl2: An efficient, practical catalyst for benzylation and allylation of amides
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An efficient protocol for the benzylation or allylation of amides using the corresponding benzyl or allyl chlorides as electrophiles under basic conditions with commercially available 5 mol % of [Cu(OH)TMEDA]2Cl2 as catalyst was developed. Under these conditions, unprotected amino acids were benzylated without any racemization.
- Kumaraswamy,Pitchaiah,Ramakrishna,Ramakrishna,Sadaiah
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p. 2013 - 2015
(2007/10/03)
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- STEROID SPARING AGENTS AND METHODS OF USING SAME
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This invention relates generally to the use of a steroid sparing agent for the preparation of a medicament for the treatment of inflammatory bowel diseases (IBD), asthma, multiple sclerosis (MS), rheumatoid arthritis (RA), graft versus host disease (GVHD), host versus graft disease, and various spondyloarthropathies, comprising administering a steroid sparing immunoglobulin or small molecule composition to a patient in need thereof. The invention also relates generally to combination therapies for the treatment of these conditions.
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Page/Page column 625-626
(2010/02/14)
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- Dimethylaluminum methyltellurate, a new reagent for the cleavage of hindered methyl esters under exceptionally mild conditions by a novel mechanism
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An efficient and effective new reagent (Me2AlTeMe)2 has been developed for the conversion of methyl esters to the corresponding carboxylic acids in toluene solution at 23°C.
- Reddy, B.V. Subba,Reddy, Leleti Rajender,Corey
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p. 4589 - 4593
(2007/10/03)
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- An efficient, stereocontrolled synthesis of a potent omuralide-salinosporin hybrid for selective proteasome inhibition
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A short and highly stereocontrolled synthesis of the potent proteasome inhibitor 3 from the (S)-threonine-derived oxazoline 4 has been developed. The synthetic sequence is summarized in Scheme 1. Aldol coupling of the zinc enolate of 4 with isobutyraldehyde and subsequent silylation provided the TBS ether 5 diastereoselectively (10:1). Reductive cleavage of the oxazoline ring of 5 followed by Swern oxidation of the resulting amino alcohol afforded amino ketone 6, converted further by N-acylation to the acrylamide 7, whose structure was confirmed by X-ray crystallographic analysis. Acrylamide 7 was cyclized to 8 by a novel application of the Kulinkovich Ti(II)-cyclopentene complex. Silylation of 8 to 9 and radical cyclization at low temperature produced the bicyclic lactam 10 with complete control of all stereocenters. Hydroxy desilylation and N-deprotection of 10 gave the dihydroxy ester 11, which was converted to 3 by a novel three-step sequence: (1) demethylation with [Me2AlTeMe]2, (2) combined β-lactonization and chlorination, and (3) desilylation to effect cleavage of the TBS ether. Copyright
- Reddy, Leleti Rajender,Fournier, Jean-Francois,Reddy, B. V. Subba,Corey
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p. 8974 - 8976
(2007/10/03)
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- A general method for the asymmetric synthesis of both enantiomers of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing pyroglutamic acid derivatives as chiral auxiliaries
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9-(S)-Pyroglutaminyl-β-carbolines were allowed to react with a nucleophile (allyltributyltin or a silyl enol ether) in the presence of 2,2,2-trichloroethyl chloroformate to give 1,2-addition products in good yields and high diastereoselectivity. The chiral auxiliary at N-9 was readily removed by a mild hydrolysis. The same chiral source afforded both enantiomers by simply altering a protecting group of the amide nitrogen. That is, (S)-pyroglutaminyl groups which had an N-alkyl group afforded the (S) isomer, whereas the ones having an N-acyl group produced the (R) isomer of the addition products.
- Itoh, Takashi,Miyazaki, Michiko,Ikeda, Sachiko,Nagata, Kazuhiro,Yokoya, Masashi,Matsuya, Yuji,Enomoto, Yasuko,Ohsawa, Akio
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p. 3527 - 3536
(2007/10/03)
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- A new entry to asymmetric synthesis of 1-substituted 1,2,3,4-tetrahydro-β-carbolines employing a pyroglutamic acid derivative as a chiral auxiliary
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β-Carboline which was protected at N-9 by an acyl group derived from L-pyroglutamic acid reacted with allyltributyltin or silyl enol ethers in the presence of an alkyl chloroformate in a highly diastereoselective manner to give 1-substituted 1,2-dihydro-β
- Itoh, Takashi,Nagata, Kazuhiro,Yokoya, Masashi,Miyazaki, Michiko,Ikeda, Sachiko,Matsuya, Yuji,Enomoto, Yasuko,Ohsawa, Akio
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p. 1005 - 1007
(2007/10/03)
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- Preparation of both enantiomers of 1-allyl-1,2,3,4-tetrahydro-β-carboline using allyltin reagents and a chiral auxiliary derived from L-proline
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β-Carboline, which had an acyl group derived from L-proline at the 9-position, reacted with allyltributyltin and 2,2,2-trichloroethyl chloroformate to afford an 1-allyl-1,2-dihydro-β-carboline derivative in a diastereoselective manner. The chiral acyl group at N-9 was readily eliminated by aqueous alkali to give a corresponding carboxylic acid. The formed 1-allyl-1,2-dihydro-β-carboline was transformed via two reduction steps to 1-allyl-1,2,3,4-tetrahydro-β-carboline in high ee. When the allylation was carried out using tetraallyltin instead of allyltributyltin, the stereoselectivity was reversed, and the antipode of the allyl adduct was obtained in high yield and ee in the presence of tin(IV) tetraiodide. Thus, it was found that both enantiomers of 1-allyl-β-carboline were obtained in good enantioselectivities by the use of the same chiral auxiliary.
- Itoh, Takashi,Matsuya, Y?ji,Enomoto, Yasuko,Ohsawa, Akio
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p. 7277 - 7289
(2007/10/03)
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- The improved synthesis of enantiopure (s)-N-arylmethyl-5-oxoprolines
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A mild procedure for the preparation of enantiopure N-alkylated (S)- (+)-5-oxoprolines 3a-r is described. The method starting from (S)-glutamic acid appears generally applicable to substrates with a wide range of substituents.
- Marchalin, Stefan,Kadlecikova, Katarina,Bar, Nathalie,Decroix, Bernard
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p. 3619 - 3624
(2007/10/03)
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- Peptide Mimetics of Thyrotropin-Releasing Hormone Based on a Cyclohexane Framework: Design, Synthesis, and Cognition-Enhancing Properties
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The design and synthesis of peptide mimetics of thyrotropin-releasing hormone (TRH) in which the peptide backbone is entirely replaced by a cyclohexane framework are described.The cis-1,3,5-trisubstituted ring was expected to permit key pharmacophoric gro
- Olson, Gary L.,Cheung, Ho-Chuen,Chiang, Elliot,Madison, Vincent S.,Sepinwall, Jerry,et al.
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p. 2866 - 2879
(2007/10/02)
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- NEW STRATEGY FOR THE CONSTRUCTION OF CARBAPENEMS. TOTAL SYNTHESIS OF 6-epi PS-5 AND PS-5
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A strategically novel approach to carbapenems has been developed.The pyrrolidine ring is first constructed, appended with the required side chains, and the β-lactam ring is then annealed.We have demonstrated the utility of the approach to the asymmetric s
- Koskinen, Ari M. P.,Ghiaci, Mehran
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p. 3209 - 3212
(2007/10/02)
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- Protection by pyroglutamic acid and some of its newly synthesized derivatives against glutamate-induced seizures in mice
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The protection by pyroglutamic acid (CAS 98-79-3) and derivatives Ia-i (injected i.p.) against glutamate- and NMDA (N-methyl-D-aspartate) (i.c.v.) induced seizures in mice has been studied in comparison with known antiepileptics and antagonists of excitatory aminoacids. The potency of pyroglutamic acid and some derivatives (Id,f,g,h) against glutamate-induced convulsions was similar to that shown by glutamic acid diethylester and by valproic acid. Interestingly, pyroglutamic acid did not affect NMDA-induced convulsions which were well antagonized by both 2-amino-5-phosphono valeric acid and by diazepam. Thus, pyroglutamic acid may represent the starting for synthesis of excitatory aminoacid antagonists acting at non NMDA receptors.
- Beani,Bianchi,Baraldi,Manfredini,Pollini
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p. 1187 - 1191
(2007/10/02)
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- Antibacterial amide compounds and means for using the same
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Novel organic amide compounds which are N-[6-[(acylaminoacylamino or aminoacylamino)phenyl]-1,2-dihydro-2-oxonicotinyl] penicillin compounds having broad spectrum antibacterial utility are provided by (a) reacting the free amino acid of the appropriate penicillin or the acid salt or silylated derivative or complex thereof with a reactive derivative of the corresponding N-6-[(acylaminoacylamino or aminoacylamino)-phenyl]-1,2-dihydro-2-oxonicotinic acid or (b) reacting the free amino acid 6-aminopenicillanic acid or a related compound or the acid salt or silylated derivative thereof with a reactive derivative of the corresponding D-N-[6-[(acylaminoacylamino or aminoacylamino) phenyl]-1,2-dihydro-2-oxonicotinyl]-2-substituted glycine. Pharmaceutical compositions containing said compounds and methods for treating infections using said compositions are also disclosed.
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