Showing papers on "Bicyclic molecule published in 1999"

2-Amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines as a Novel Class of Inhibitors of Human Rhinovirus: Stereospecific Synthesis and Antiviral Activity

Abstract: A series of 2-amino-3-substituted-6-[(E)-1-phenyl-2-(N-methylcarbamoyl)vinyl]imidazo[1,2-a]pyridines 1a−i, structurally related to Enviroxime and its analogous benzimidazoles, was designed and prepared for testing as antirhinovirus agents. The imidazo ring in this class of compounds was constructed starting from the aminopyridine after tosylation and subsequent treatment with the appropriate acetamides. The key steps in the synthesis include the development and use of a new Horner−Emmons reagent for the direct incorporation of methyl vinylcarboxamide. The reaction was stereospecific in the substrates 5a−f leading exclusively to the desired E-isomer and avoiding the use of reverse-phase preparative HPLC for the separation of both possible isomers before antiviral activity evaluation. The isopropylsulfonyl group, known as the best substituent at the 1-position in the benzimidazole SAR in terms of activity, was introduced in this new series of imidazo[1,2-a]pyridines via halogen−metal exchange and subsequent...

Bicyclic hydroxamic acid derivatives

Abstract: A compound of formula (I), wherein Z and Q are as defined in the specification, to pharmaceutical compositions containing them and to their medicinal use.

Substituted bicyclic derivatives useful as anticancer agents

Abstract: The invention relates to compounds of formula (1) and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R?1, R3 and R4? are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals with administering the compounds of formula (1) and to pharmaceutical compositions for treating such disorders which contain the compounds of formula (1). The invention also relates to methods of preparing the compounds of formula (1).

N-aryl(thio)anthranilic acid amide derivatives, their preparation and their use as vegf receptor tyrosine kinase inhibitors

Abstract: Described are compounds of formula (I), wherein W is O or S; X is NR8; Y is CR9R10-(CH2)n wherein R9 and R10 are independently of each other hydrogen or lower alkyl, and n is an integer of from and including 0 to and including 3; or Y is SO2; R1 is aryl; R2 is a mono- or bicyclic heteroaryl group comprising one or more ring nitrogen atoms with the exception that R2 cannot represent 2-phthalimidyl, and in case of Y = SO2 cannot represent 2,1,3-benzothiadiazol-4-yl; any of R3, R4, R5 and R6, independently of the other, is H or a substituent other than hydrogen; and R7 and R8, independently of each other, are H or lower alkyl; or a N-oxide or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutical product for the treatment of a neoplastic disease which responds to an inhibition of the VEGF receptor tyrosine kinase activity. The compounds of formula (I) can be used for the treatment e.g. of a neoplastic disease, such as a tumor disease, of retinopathy and age-related macular degeneration.

Acylnitrene Route to Vicinal Amino Alcohols. Application to the Synthesis of (-)-Bestatin and Analogues.

Abstract: Bestatin, valinoctin A, and microginin are naturally occurring small peptides containing a nonproteinogenic alpha-hydroxy-beta-amino acid at the N-terminus of the peptide chain. We report here our development of a general method for the synthesis of alpha-hydroxy-beta-amino acids and exemplify this with a synthesis of (-)-bestatin and analogues. Our synthesis utilizes an intramolecular acylnitrene-mediated aziridination to generate a key bicyclic aziridine in excellent yield and stereoselectivity. This bicyclic aziridine can be opened with a number of organometallic reagents to provide a series of substituted oxazolidinones. The oxazolidinones are readily converted to bestatin and a series of bestatin analogues. As part of this approach, we have developed a new method for the synthesis of azidoformates. We have also demonstrated that oxazolidinones can be selectively hydrolyzed in the presence of peptide bonds. This acylnitrene route to bestatin should prove useful for the synthesis of a variety of analogues of bestatin as well as other alpha-hydroxy-beta-amino acids and their corresponding peptides.

Total Synthesis of the Antitumor Marine Sponge Alkaloid Agelastatin A

Abstract: The first total synthesis of the cytotoxic marine metabolite agelastatin A (1) has been achieved in about 14 steps performed in 12 operations in approximately 7% overall yield starting from cyclopentadiene. Hetero Diels−Alder cycloaddition of cyclopentadiene with N-sulfinyl methyl carbamate (7) afforded cycloadduct 8, which without purification was converted to allylic sulfoxide 9 and then by a [2,3]-sigmatropic rearrangement into bicyclic oxazolidinone 11. The C-5a nitrogen was introduced into the oxazolidinone Boc derivative 16 by a Sharpless/Kresze allylic amination with SES sulfodiimide 12c. Palladium-promoted cyclization of 2-acyl pyrroles 20 and 21 via a π-allylpalladium intermediate 22 led to ABC-tricycles 23 and 24, respectively. A hydroxyl urea D-ring model system was constructed by hydroborating 24, leading eventually to keto amide 31 and then to tetracycle 33. A modified strategy was developed for synthesis of the pivotal tricyclic ketone 58, involving as key steps a chemoselective hydrolysis o...

Enantioselective Total Syntheses of (+)-Castanospermine, (+)-6-Epicastanospermine, (+)-Australine, and (+)-3-Epiaustraline

Abstract: The total syntheses of the potent glycosidase inhibitors castanospermine ((+)-1), 6-epicastanospermine ((+)-2), australine ((+)-3), and 3-epiaustraline ((+)-4) are described. The syntheses of indolizidine alkaloids (+)-1 and (+)-2 were accomplished in eight steps and in 18% and 24% overall yields from 2,5-dihydrofuran while the pyrrolizidine alkaloids (+)-3 and (+)-4 were obtained in a nine-step sequence in 17% and 22% overall yields from the same starting material. These four natural products are derived from a single common intermediate, nitroso acetal (−)-31, which is created in the key step by the asymmetric tandem [4 + 2]/[3 + 2] cycloaddition between silaketal nitro olefin 18 and chiral vinyl ether (+)-23. The ability to access both 5,5- and 5,6-fused bicyclic systems was a result of a successful in situ N-alkylation strategy during the hydrogenolysis of four highly functionalized nitroso acetals. A novel silaketal tether provided exceptional levels of diastereocontrol and the ideal combination of p...

Synthesis, in Vitro Pharmacology, and Molecular Modeling of Very Potent Tacrine−Huperzine A Hybrids as Acetylcholinesterase Inhibitors of Potential Interest for the Treatment of Alzheimer's Disease

Abstract: Eleven new 12-amino-6,7,10,11-tetrahydro-7, 11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the 9-ethyl derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of (-)-19 and (-)-huperzine A.

Palladium-catalyzed annulation

Abstract: The palladium-catalyzed annulation of cyclic and bicyclic alkenes; unsaturated cyclopropanes and cyclobutanes; 1,2-, 1,3- and 1,4-dienes; as well as internal alkynes, by functionally substituted aryl or vinylic halides and triflates provides a very versatile route to a wide variety of heterocycles and carbocycles.

High affinity ligands for nociceptin receptor orl-1

Abstract: Compounds of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein: the dotted line represents an optional double bond; X1 is optionally substituted alkyl, cycloalkyl, aryl, heteroaryl or heterocycloalkyl; X2 is -CHO, -CN, optionally substituted amino, alkyl, or aryl; or X1 is optionally substituted benzofused heterocyclyl and X2 is hydrogen; or X?1 and X2? together form an optionally benzofused spiro heterocyclyl group; R?1, R2, R3 and R4? are independently H and alkyl, or (R?1 and R4) or (R2 and R3) or (R1 and R3) or (R2 and R4?) together can form an alkylene bridge of 1 to 3 carbon atoms; Z1 is optionally substituted alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl, or -CO?2?(alkyl or substituted amino) or CN; Z?2? is H or Z1; Z3 is H or alkyl; or Z?1, Z2 and Z3?, together with the carbon to which they are attached, form bicyclic saturated or unsaturated rings; pharmaceutical compositions therefore, and the use of said compounds as nociceptin receptor inhibitors useful in the treatment of pain, anxiety, cough, asthma, depression and alcohol abuse are disclosed.

2-(Diethylamino)thieno[1,3]oxazin-4-ones as Stable Inhibitors of Human Leukocyte Elastase

Abstract: A series of 2-(diethylamino)thieno[1,3]oxazin-4-ones was synthesized and evaluated in vitro for inhibitory activity toward human leukocyte elastase (HLE). The Gewald thiophene synthesis was utilized to obtain several ethyl 2-aminothiophene-3-carboxylates. These precursors were subjected to a five-step route to obtain thieno[2,3-d][1,3]oxazin-4-ones bearing various substituents at positions 5 and 6. Both thieno[2,3-d] and thieno[3,2-d] fused oxazin-4-ones possess extraordinary chemical stability, which was expressed as rate constants of the alkaline hydrolysis. The kinetic parameters of the HLE inhibition were determined. The most potent compound, 2-(diethylamino)-4H-[1]benzothieno[2,3-d][1,3]oxazin-4-one, exhibited a Ki value of 5.8 nM. 2-(Diethylamino)thieno[1,3]oxazin-4-ones act as acyl-enzyme inhibitors of HLE, similar to the inhibition of serine proteases by 4H-3,1-benzoxazin-4-ones. The isosteric benzene−thiophene replacement accounts for an enhanced stability of the acyl-enzyme intermediates.

Regio- and Enantioselective Cyclization of Epoxy Alcohols Catalyzed by a [CoIII(salen)] Complex.

Abstract: The intramolecular cyclization of epoxy alcohols was catalyzed with excellent regio- and enantiocontrol by a [CoIII(salen)] complex. High endo selectivity was observed for the enantioselective cyclization of terminal epoxy alcohols [Eq. (a)], while the reaction of meso substrates produced novel cyclic and bicyclic ethers in good yields and high enantiopurity. TBME=tert-butyl methyl ether.

Methods for preparing ruthenium metal films

Abstract: The present invention provides methods for the preparation of ruthenium metal films from liquid ruthenium complexes of the formula (diene)Ru(CO)3 wherein 'diene' refers to linear, branched, or cyclic dienes, bicyclic dienes, tricyclic dienes, fluorinated derivatives thereof, derivatives thereof additionally containing heteroatoms such as halide, Si, S, Se, P, As, N, or O, or combinations thereof. Preferred examples are cyclohexadine or cycloheptadine ruthenium tricarbonyl.

Total Synthesis of (−)-Coriolin

Abstract: An efficient synthetic method for (-)-coriolin has been developed on the basis of a [3+2] cycloaddition reaction of a 1-(methylthio)-2-siloxyallyl cationic species and vinylsulfides An enantiomerically pure C-ring unit was prepared through optical resolution of five-membered allyl ester 6b using a lipase The first [3+2] cycloaddition reaction of C-ring unit (S)-7 gave bicyclic ketones 8 and 9, which were easily converted into vinyl sulfide 11 Stereoselective construction of the A-ring was achieved by the second [3+2] cycloaddition reaction of the BC-ring unit New methods for introduction of the oxygen functional groups to the triquinane skeleton were also developed for the last stages of the total synthesis Thus, the C7 hydroxyl group was introduced by epoxidation of dienol silyl ether 17, and stereocontrolled construction of the spiro epoxide moiety was accomplished on the basis of a Darzens-type reaction

Total Syntheses of (−)-Herbertenediol, (−)-Mastigophorene A, and (−)-Mastigophorene B. Combined Utility of Chiral Bicyclic Lactams and Chiral Aryl Oxazolines

Abstract: A nonracemic bicyclic lactam has been used to construct a chiral cyclopentane containing vicinal quaternary carbon centers in optically pure form, which is common to all of the title compounds. An oxazoline-mediated asymmetric Ullmann coupling was then utilized to establish chirality about the biaryl axis of mastigophorenes A and B. Through the course of this synthesis, it was clearly demonstrated that smaller chiral auxiliaries lead to higher levels of atroposelection, a previously unknown phenomenon of the asymmetric Ullmann coupling.

Photomodulation of conformational states. Synthesis of cyclic peptides with backbone-azobenzene moieties.

Abstract: The search for photoresponsive conformational transitions accompanied by changes in physicochemical and biological properties led us to the design of small cyclic peptides containing azobenzene moieties in the backbone. For this purpose, (4-aminomethyl)phenylazobenzoic acid (H-AMPB-OH) and (4-amino)phenylazobenzoic acid (H-APB-OH) were synthesized and used to cyclize a bis-cysteinyl-octapeptide giving monocyclic derivatives in which additional conformational restriction could be introduced by conversion to bicyclic structures with a disulphide bridge. While synthesis with H-AMPB-OH proceeded smoothly on a chlorotrityl-resin with Fmoc/tBu chemistry, the poor nucleophilicity of the arylamino group of H-APB-OH required special chemistry for satisfactory incorporation into the peptide chain. Additional difficulties were encountered in the reductive cleavage of the S-tert-butylthio group from the cysteine residues since concomitant reduction of the azobenzene moiety took place at competing rates. This difficulty was eventually bypassed by using the S-trityl protection. Side-chain cyclization of the APB-peptide proved to be difficult, suggesting that restricted conformational freedom was already present in the monocyclic form, a fact that was fully confirmed by NMR structural analysis. Conversely, the methylene spacer in the AMPB moiety introduced sufficient flexibility for facile and quantitative side-chain cyclization to the bicyclic form. Both of the monocyclic peptides and both of the bicyclic peptides are photoresponsive molecules which undergo cis/trans isomerization reversibly.

Nucleosides having bicyclic sugar moiety

Abstract: Conformationally restricted 2′, 4′—bridged nucleoside analogues are described herein. The compounds can be prepared by cyclization at C2′ and C4′ of nucleosides through a linker or linking molecule. These novel nucleosides have a desired, locked sugar pucker and are potentially useful as pharmaceutical ingredients. Oligonucleotides composed of these novel nucleosides are useful for oligonucleotide therapeutic and diagnostic compounds.

Disubstituted bicyclic heterocycles, the preparation thereof, and their use as pharmaceutical compositions

Abstract: The present invention relates to disubstituted bicyclic heterocycles of general formula R a - Het- B- Ar - E ,(I) wherein R a, Ar, B, Het and E are defined as in claim 1, the tautomers, stereoisomers, the mixtures thereof, the salts thereof and their preparation, as well as that of the pharmaceutical com-positions containing the pharmacologically active compounds, and their use. The compounds of the above general formula I wherein E denotes a cyano group are valuable intermediates for preparing the other compounds of general formula I, and the compounds of the above general formula I wherein E denotes a R b NH-C(=NH) group have valuable pharmacological properties, particularly a throm-bin-inhibiting action and the effect of prolonging the thrombin time.

Cyclization Phenomena in the Sol−Gel Polymerization of α,ω-Bis(triethoxysilyl)alkanes and Incorporation of the Cyclic Structures into Network Silsesquioxane Polymers

Abstract: Intramolecular cyclizations during acid-catalyzed sol−gel polymerizations of α,ω-bis(triethoxysilyl)alkanes substantially lengthen gel times for monomers with ethylene (1), propylene (2), and butylene (3) bridging groups. These cyclization reactions were found, using mass spectrometry and 29Si NMR spectroscopy, to lead preferentially to monomeric and dimeric products based on six- and seven-membered disilsesquioxane rings. 1,2-Bis(triethoxysilyl)ethane (1) reacts under acidic conditions to give a bicyclic dimer (5) that is composed of two annelated seven-membered rings. Under the same conditions, 1,3-bis(triethoxysilyl)propane (2), 1,4-bis(triethoxysilyl)butane (3), and Z-1,4-bis(triethoxysilyl)but-2-ene (10) undergo an intramolecular condensation reaction to give the six- and seven-membered cyclic disilsesquioxanes 6, 7, and 11. Subsequently, these cyclic monomers slowly react to form the tricyclic dimers 8, 9, and 12. With NaOH as polymerization catalyst, these cyclic silsesquioxanes readily reacted to ...

Bicyclic pyrimidines and bicyclic 3,4-dihydropyrimidines as inhibitors of cellular proliferation

Abstract: This invention provides bicyclic heterocycles that are useful for treating cell proliferative disorders, such as cancer and restenosis, as well as angiogenesis and atherosclerosis. We have now discovered a group of bicyclic compounds that are potent inhibitors of cyclin-dependent kinases (cdks), growth factor-mediated kinases, and non-receptor kinases. The compounds are readily synthesized and can be administered by a variety of routes, including orally, and have sufficient bioavailability for clinical use. This invention provides compounds of Formula (I), where Z is N or CH; G is N or CH; W is NH, S, SO, or SO2, R1 includes phenyl and substituted phenyl, R2 includes alkyl and cycloalkyl, R3 includes alkyl and hydrogen, R?8 and R9? include hydrogen and alkyl, and the pharmaceutically acceptable salts thereof. This invention also provides pharmaceutical formulations comprising a compound of Formula (I) together with a pharmaceutically acceptable carrier, diluent, or excipient therefor.

Novel Ruthenium Complex-Catalyzed Dimerization of 2,5-Norbornadiene to Pentacyclo[6.6.0.02,6.03,13.010,14]tetradeca-4,11-diene Involving Carbon−Carbon Bond Cleavage

Abstract: Bicyclo[2.2.1]hepta-2,5-diene (2,5-norbornadiene) dimerizes in the presence of a catalytic amount of Ru(1-2:5-6-η-cyclooctadiene)(1-6-η-cyclooctatriene) (Ru(cod)(cot)) and an electron-deficient olefin such as N,N-dimethylacrylamide, dimethyl fumarate, or dimethyl maleate in toluene or tetrahydrofuran (THF) to give a new compound, pentacyclo[6.6.0.02,6.03,13.010,14]tetradeca-4,11-diene (PCTD), in high yield along with a small amount of a known endo−endo dimer, heptacyclo[6.6.0.02,6.03,13.04,11.05,9.010,14]tetradecane (HCTD), which is a major product in the reaction in DMSO. Ru(cod)(cot)-dimethyl fumarate in THF was the most efficient catalyst, and the yield of PCTD was 96% even at 40 °C. The structure of PCTD was determined by X-ray analysis of its derivative, [AgOTf(PCTD)]n. PCTD was found to be derived via endo−endo dimerization of 2,5-norbornadiene. Formation of PCTD from two molecules of 2,5-norbornadiene involves the cleavage of two carbon−carbon bonds. Dimerization of 7-tert-butoxy-2,5-norbornadiene ...