- METHYL OXAZOLE OREXIN RECEPTOR ANTAGONISTS
-
The present invention is directed to methyl oxazole compounds which are antagonists of orexin receptors. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which orexin receptors are involved.
- -
-
Page/Page column 45
(2016/06/28)
-
- Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols
-
The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by l-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-l-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-l-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis. The Royal Society of Chemistry 2012.
- Gómez, Livia,Garrabou, Xavier,Joglar, Jesús,Bujons, Jordi,Parella, Teodor,Vilaplana, Cristina,Cardona, Pere Joan,Clapés, Pere
-
experimental part
p. 6309 - 6321
(2012/09/05)
-
- Non-nucleoside inhibitors of the measles virus RNA-dependent RNA polymerase: Synthesis, structure-activity relationships, and pharmacokinetics
-
The measles virus (MeV), a member of the paramyxovirus family, is an important cause of pediatric morbidity and mortality worldwide. In an effort to provide therapeutic treatments for improved measles management, we previously identified a small, non-nucl
- Ndungu, J. Maina,Krumm, Stefanie A.,Yan, Dan,Arrendale, Richard F.,Reddy, G. Prabhakar,Evers, Taylor,Howard, Randy,Natchus, Michael G.,Saindane, Manohar T.,Liotta, Dennis C.,Plemper, Richard K.,Snyder, James P.,Sun, Aiming
-
supporting information; experimental part
p. 4220 - 4230
(2012/06/30)
-
- Synthesis of new analogues of the tetraponerines
-
To evaluate the influences of the tetraponerine alkyl chains and tricyclic ring systems on their cytotoxic activities, we have prepared a series of alkyl derivatives (3a, 3b and 4a-f) of the non-natural tricyclic skeletons d.ecahyd.ro-2H,6fi-dipyrido[1.,2-a:1.2'-c]pyrimidine (3, 6-6-6 skeleton) and. dodecahydro-2W-l,8a-diazaphenanthrene (4, iso-6-6-6 skeleton). In this study, two ways to synthesise the 6-6-6 analogues have been developed and compared. One is based, on the condensation of a-tripiperideme with diethyl malonate (DBM) in. water at pH11. This yielded, oxo ester 11, precursor of the amino nitrile 8, but only in moderate yield. In the second pathway, the key intermediate 8 was more efficiently synthesised by starting from. 2-(2-piperidyl)ethanol. Treatment of 8 with alkyl Grignard reagents led to the 6-6-6 analogues 3a and 3b. When the one-pot reaction between a-tripiperideine and DEM was performed in water at pH 8, the lactam 12, precursor of the iso-6-6-6 skeleton, was obtained, in a yield of 76 %. The same lactam was also obtained in a yield of 86 % by treatment of tetrahydroanabasine 14 with DEM in water at pH 8. Lactam 12 was transformed into the iso-6-6-6 analogues 4a-4f. The cytotoxic activities of the 6-6-6 and. i.so-66-6 analogues against H.T29 cancer cells were compared with those of the 5-6-5 and 6-6-5 tetraponerines and. with those of solenopsin analogues. 2009 Wiley-VCH Verlag GmbH & Co. KGaA.
- Rouchaud, Anne,Braekman, Jean-Claude
-
experimental part
p. 2666 - 2674
(2009/10/01)
-
- 2-substituted piperidines that are ligands for monoamine receptors and transporters
-
One aspect of the present invention relates to heterocyclic compounds. A second aspect of the present invention relates to the use of the heterocyclic compounds as ligands for various mammalian cellular receptors, including dopamine, serotonin, or norepinephrine transporters. The compounds of the present invention will find use in the treatment of numerous ailments, conditions and diseases which afflict mammals, including but not limited to addiction, anxiety, depression, sexual dysfunction, hypertension, migraine, Alzheimer's disease, obesity, emesis, psychosis, analgesia, schizophrenia, Parkinson's disease, restless leg syndrome, sleeping disorders, attention deficit hyperactivity disorder, irritable bowel syndrome, premature ejaculation, menstrual dysphoria syndrome, urinary incontinence, inflammatory pain, neuropathic pain, Lesche-Nyhane disease, Wilson's disease, and Tourette's syndrome. An additional aspect of the present invention relates to the synthesis of combinatorial libraries of the heterocyclic compounds, and the screening of those libraries for biological activity, e.g., in assays based on dopamine transporters.
- -
-
-
- Remote Stereocenter Discrimination in the Enzymatic Resolution of Piperidine-2-ethanol. Short Enantioselective Synthesis of Sedamine and Allosedamine
-
Kinetic resolution of N-Boc-piperidine-2-ethanol (2), a case of remote stereocenter discrimination, was accomplished by sequential transesterification mediated by two enzymes, Lipase PS and porcine pancreatic lipase, showing opposite enantioselectivity. The gram-scale availability of the two enantiomeric N-Boc alcohols 2a (R) and 2c (S) enlarges their synthetic exploitation for the enantioselective preparation of piperidine alkaloids. As an example, the convenient three-step synthesis of both the enantiomers of sedamine and allosedamine is described.
- Angoli, Marco,Barilli, Alessio,Lesma, Giordano,Passarella, Daniele,Riva, Sergio,Silvani, Alessandra,Danieli, Bruno
-
p. 9525 - 9527
(2007/10/03)
-
- Design of selective thrombin inhibitors based on the (R)-Phe-Pro-Arg sequence
-
Potent and selective inhibitors of thrombin were sought based on the (R)-Phe-Pro-Arg sequence. The objective was to generate similar binding interactions to those achieved by potent competitive inhibitors of the argatroban type, so eliminating the need for covalent interaction with the catalytic serine function, as utilized by aldehyde and boronic acid type inhibitors. Improving the S1 subsite interaction by substitution of arginine with a 4-alkoxybenzamidine residue provided potent lead 2 (Ki = 0.37 nM). Though an amide bond, which H-bonds to the active site, is lost, modeling indicated that a new H-bond is generated between the alkoxy oxygen atom and the catalytic Ser-195 hydroxyl group. Substitution of the benzamidine system by 1-amidinopiperidine then gave compound 4, which provided a further gain in selectivity over trypsin. However, previous work had shown that these compounds were likely to be too lipophilic (Log D +0.4 and +0.2, respectively) and to suffer rapid hepatic extraction, presumably via biliary elimination. Accordingly, both proved short-acting when administered intravenously to rats and showed poor activity when given intraduodenally. The aim was then to reduce lipophilicity below a log D of - 1.2, which in a previously reported series had been effective in preventing rapid clearance. It was anticipated that compounds of this type would rely on the cation selective paracellular route of absorption from the gastrointestinal tract. Potent polar analogues with selectivity >1000 over trypsin were obtained. The best in vivo activity was shown by compound 12. However, in the final analysis, its oral bioavilability proved poor, relative to analogues with similar physicochemical properties derived from argatroban, consistent with the hypothesis that molecular shape is an additional important determinant of paracellular absorption.
- Danilewicz, John C.,Abel, Stuart M.,Brown, Alan D.,Fish, Paul V.,Hawkeswood, Edward,Holland, Stephen J.,James, Keith,McElroy, Andrew B.,Overington, John,Powling, Michael J.,Rance, David J.
-
p. 2432 - 2453
(2007/10/03)
-
- Antagonists of gonadotropin releasing hormone
-
PCT No. PCT/US97/08479 Sec. 371 Date Nov. 12, 1998 Sec. 102(e) Date Nov. 12, 1998 PCT Filed May 16, 1997 PCT Pub. No. WO97/44321 PCT Pub. Date Nov. 27, 1997There are disclosed compounds of formula (I) and pharmaceutical acceptable salts thereof which are useful as antagonists of GnRH and as such may be useful for the treatment of a variety of sex-hormone related conditions.
- -
-
-
- Heterocyclisation via 1,3-Cyclic Sulfates. Asymmetric Synthesis of (+)-Sedridine
-
1,3-Cyclic sulfates (1b-d) participate in heterocyclisation reactions to give pyrrolidines (2b) and piperidines (2c/d). Cyclic sulfate activation, when coupled to the enantio- and diastereoselective generation of 1,3-diols, provides a synthesis of (+)-sedridine (9).
- Littler, Benjamin J.,Gallagher, Timothy,Boddy, Ian K.,Riordan, Peter D.
-
-
- Highly stereoselective total syntheses of (+)-allopumiliotoxins 267A and 339A via intramolecular nickel(II)/chromium(II)-mediated cyclization
-
Remarkably high regio- and stereoselective approaches for the syntheses of dendrobatid alkaloids (+)allopumiliotoxin 267A and 339A have been develop. As a model study for these alkaloids, we initially undertook intramolecular chromium(II)-mediated cycliza
- Aoyagi, Sakae,Wang, Tzu-Chueh,Kibayashi, Chihiro
-
p. 11393 - 11409
(2007/10/02)
-