A series of fluoroglycosylated fluoroindolocarbazoles was examined with respect to their topoisomerase I activity, cytotoxicity, and selectivity. The lead clinical candidate from this series, BMS-250749, displays broad spectrum antitumor activity superior to CPT-11 against some preclinical xenograft models, including curative antitumor activity against Lewis lung carcinoma.

A series of fluoroindolocarbazoles were studied with respect to their topoisomerase I activity, cytotoxicity, selectivity, and in vivo antitumor activity. Emerging from this series was BMS-251873, a potential clinical candidate possessing a robust pharmacological profile including curative antitumor activity against prostate carcinoma.

A compound of Formula I, including pharmaceutically acceptable salts thereof, ** ** Formula wherein: Z is Q is selected from the group consisting of: -W- is R1, R2, R3, R4 and R5 are independently selected from the group consisting of hydrogen, halogen, cyano, nitro, COOR 8, XR 9 and B; m is 2; R6 is O or does not exist; R7 is (CH2) nR10; n is 0-6; R10 is selected from the group consisting of H, (1-6C) alkyl, -C (O) -C (C1-6), C (O) -phenyl and CONR11R12; R11 and R12 are each independently H, alkyl (1-6C) or phenyl; - - represents a carbon-carbon bond or does not exist; D is selected from the group consisting of hydrogen, (1-6C) alkyl, (C2-6) alkynyl, (3-6C) cycloalkyl, halogen, cyano, -CONR32R33, -SO2R32, COR32, COOR 8, tetrahydrofuryl, pyrrolidinyl, phenyl and heteroaryl; wherein said alkyl (C1-6), (C2-6) alkynyl, phenyl and heteroaryl are each independently optionally substituted with one to three same or different members selected from the group G; heteroaryl is selected from the group consisting of furanyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyrazolyl, tetrazolyl, triazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl;

La presente invention porte sur des derives fluoro sucres et autres derives sucres d'indolopyrrolocarbazoles, sur leurs sels et hydrates qui presentent une activite selective contre la topoisomerase I (topo I). Ces derives sont utiles pour inhiber la proliferation de cellules tumorales et presentent un effet antitumoral. L'invention porte egalement sur leurs procedes de preparation.

A series of potent inhibitors of P-selectin as potential anti-inflammatory agents is reported. These compounds are derivatives of galactocerebrosides bearing a malonate side chain in positions 2 and 3 of the galactose moiety. Based on the binding mode of sialyl Lewis X, the two acidic groups of the malonate are designed to form ionic interactions with two important lysines in the active site of P-selectin, Lys113 and Lys111. On the other hand, the 4- and 6-hydroxy groups on the galactose ring are arranged to chelate the calcium ion in the P-selectin active site. The synthesis and the biological activity of this series of compounds are described. Lead compounds having a greater potency than sialyl Lewis X are identified.

Native sulfatides, as well as many sulfated glycolipids, have been shown to avidly bind to the selectin receptors. In vivo, native sulfatides significantly block activity in selectin-dependent inflammatory responses. The fact that nonsulfated galactocerebrosides did not inhibit selectin-mediated adhesion identified a critical role for the anionic sulfate residue. We therefore initiated a program to evaluate the activity of position isomers. This study showed a binding selectivity for the positions 2 and 3 of the sulfate group on the carbohydrate ring as well as enhanced activity for the disulfated analogs, Furthermore, it was discovered that the attachment of lipophilic substituents on the carbohydrate ring was tolerated, consistent with the presence of a lipophilic pocket in the binding cavity. This resulted in compounds with a 6-fold increased potency.

Selectin binding is the first step in extravasation of leukocytes through the endothelium. Infiltration of leukocytes is a hallmark of an inflammatory response. Blockade of selectin-dependent adhesion, therefore, represents a specific mechanism-based anti-inflammatory strategy. We have used the natural product sulfatide, one of the selectin ligands, as a template to design a novel selectin antagonist. BMS-190394, a structural analog of sulfatide, is an inhibitor of cell binding to P-, E- and L-selectin-Ig fusion proteins. BMS-190394 also inhibits binding mediated by native P-selectin expressed on the surface of activated platelets. Pharmacokinetic analysis of BMS-190394 showed that the compound remained in circulation with a T1/2 of 7 hr, long enough to inhibit the development of an acute inflammatory response. The in vitro activity and pharmacokinetic profile of this selectin-blocking compound led to the determination of its in vivo anti-inflammatory activity. BMS-190394 was a potent inhibitor of the dermal immune complex-induced reverse passive Arthus reaction in rats when delivered by the i.v. or i.p. route. The ED50 of the compound in the reverse passive Arthus reaction compares favorably to that for dexamethasone. BMS-190394 was also an effective inhibitor of the delayed-type hypersensitivity reaction in the rat. Compared with previous reports of the use of antibodies and complex oligosaccharides to inhibit the activity of the selectins, this low-molecular-weight inhibitor of the selectins presents a novel class of anti-inflammatory agents.

An efficient and stereocontrolled preparation of the key a/etidinone-acid 5a is described.

In this study, a highly stereoselective preparation of (3S,4S)-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]-4-[(1R)-1-carboxy-ethyl]-azetidin-2-one (2) is reported. It involves a Lewis acid mediated condensation of (3S,4R)-4-acetoxy-3-[(1R)-1-tert-butyldimethylsilyloxyethyl]azetidin-2-one (3) with simple O-silylenol ethers of thiopropionates. From all the examples reported in this paper the 2-picolyl thiopropionate or similar arrangements were found to be essential for this stereoselection. Finally, a mechanism involving chelation control seems to be operative.

Aldol condensation of the magnesium enolate derived from anhydro-6,6-dibromopenicillin with acetaldehyde allows for the stereospecific introduction of a 1-R-hydroxyethyl substituent at C-6. Protection of the hydroxy group followed by reductive dehalogenation provides anhydro-6(α)-[(1-R)-(tert;-butyldimethylsilyloxy)-ethyl]-penicillin, an intermediate in the synthesis of thienamycin. A high yield conversion of this anhydro derivative to (4-R)-acetoxy-(3-S)-[(1-R)-(tert-butyldimethylsilyloxy-ethyl]-azetidin-2-one (5) is also reported.

Chemischer InformationsdienstVolume 17, Issue 3 Preparative Organic Chemistry ChemInform Abstract: Secondary Amines from the Iron(II) Ion-Catalyzed Reaction of Amine Oxides: A General Method for the Dealkylation of Tertiary Amines. I. MONKOVIC, Search for more papers by this authorH. WONG, Search for more papers by this authorC. BACHAND, Search for more papers by this author I. MONKOVIC, Search for more papers by this authorH. WONG, Search for more papers by this authorC. BACHAND, Search for more papers by this author First published: January 21, 1986 https://doi.org/10.1002/chin.198603117Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onEmailFacebookTwitterLinked InRedditWechat No abstract is available for this article. Volume17, Issue3January 21, 1986 RelatedInformation

AbstractDie Lactame (VI) bzw. (VIIIb) sind Schlüsselsubstanzen bei der Synthese von chiralen Penem‐ bzw. Carbapenemsystemen und werden wie im Formelschema angegeben ausgehend von dem Penicillansäurederivat (I) dargestellt.

AbstractDas durch Acylierung nach Standard‐Verfahren aus dem Isochinolinderivat (Ia) erhältliche Amid (Ib) wird zu einem (trennbaren) Gemisch der Epimeren (II) epoxidiert, aus dem durch säurekatalysierte Ringöffnung das Diol (III) zugänglich ist (75% Ausb., bezogen auf (Ia)).

AbstractAus den Amiden (I) entstehen mit Hypochlorit bzw. Hypobromit (IIa) und (IIb) die Salze (IIIa) und (IIIb), die mit Schwefelsäure definiert zu den N‐Monochlorverbindungen (IV) neutralisiert werden.