Showing papers on "Bicyclic molecule published in 2000"

Synthesis and biological evaluation of certain α, β-unsaturated ketones and their corresponding fused pyridines as antiviral and cytotoxic agents

Abstract: A new series of 3,5-bis(arylidene)-4-piperidones, as chalcone analogues carrying variety of aryl and heteroaryl groups, pyrazolo[4,3-c]pyridines, pyrido[4,3-d]pyrimidines, and pyrido[3,2-c]pyridines, carrying an arylidene moiety, and a series of pyrano[3,2-c]pyridines, as flavone and coumarin isosteres, were synthesized and screened for their in vitro antiviral and antitumor activities at the National Cancer Institute (NCI). Compounds 9 and 18 proved to be active against herpes simplex virus-1 (HSV-1), while compound 13 showed moderate activity against human immunodeficiency virus-1 (HIV-1). Compounds 14, 26, 28, 33, and 35 exhibited a broad spectrum antitumor activity. In addition, compounds 26, 33, and 35 proved to be of moderate selectivity toward leukemia cell lines. The pyrano[3,2-c]pyridines heterocyclic system proved to be the most active antitumors among the investigated heterocycles.

Quinazoline derivatives as angiogenesis inhibitors

Abstract: The invention relates to the use of compounds of formula (I), wherein ring C is an 8, 9, 10, 12 or 13-membered bicyclic or tricyclic moiety which optionally may contain 1-3 heteroatoms selected independently from O, N and S; Z is -O-, -NH-, -S-, -CH2- or a direct bond; n is 0-5; m is 0-3; R2 represents hydrogen, hydroxy, halogeno, cyano, nitro, trifluoromethyl, C?1-3?alkyl, C1-3alkoxy, C1-3alkylsulphanyl, -NR?3R4? (wherein R?3 and R4?, which may be the same or different, each represents hydrogen or C?1-3?alkyl), or R?5X1?- (wherein X?1 and R5? are as defined herein; R1 represents hydrogen, oxo, halogeno, hydroxy, C?1-4?alkoxy, C1-4alkyl, C1-4alkoxymethyl, C1-4alkanoyl, C1-4haloalkyl, cyano, amino, C2-5alkenyl, C2-5alkynyl, C1-3alkanoyloxy, nitro, C1-4alkanoylamino, C1-4alkoxycarbonyl, C1-4alkylsulphanyl, C1-4alkylsulphinyl, C1-4alkylsulphonyl, carbamoyl, N-C1-4alkylcarbamoyl, N,N-di(C1-4alkyl)carbamoyl, aminosulphonyl, N-C1-4alkylaminosulphonyl, N,N-di(C1-4alkyl)aminosulphonyl, N-(C1-4alkylsulphonyl)amino, N-(C1-4alkylsulphonyl)-N-(C1-4alkyl)amino, N,N-di(C1-4alkylsulphonyl)amino, a C3-7alkylene chain joined to two ring C carbon atoms, C1-4alkanoylaminoC1-4alkyl, carboxy or a group R?56X10? (wherein X?10 and R56? are as defined herein); and salts thereof, in the manufacture of a medicament for use in the production of an antiangiogenic and/or vascular permeability reducing effect in warm-blooded animals, processes for the preparation of such compounds, pharmaceutical compositions containing a compound of formula (I) or a pharmaceutically acceptable salt thereof as active ingredient and compounds of formula (I). The compounds of formula (I) and the pharmaceutically acceptable salts thereof inhibit the effects of VEGF, a property of value in the treatment of a number of disease states including cancer and rheumatoid arthritis.

4-Anilino-6,7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor kinase and their bioisosteric relationship to the 4-anilino-6,7-dialkoxyquinazoline inhibitors.

Abstract: The synthesis and SAR of a series of 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of epidermal growth factor receptor (EGF-R) kinase are described. Condensation of 3, 4-dialkoxyanilines with ethyl (ethoxymethylene)cyanoacetate followed by thermal cyclization gave, regiospecifically, 6,7-dialkoxy-4-oxo-1, 4-dihydroquinoline-3-carbonitriles. Chlorination (POCl(3)) followed by the reaction with substituted anilines furnished the 4-anilino-6, 7-dialkoxyquinoline-3-carbonitrile inhibitors of EGF-R kinase. An alternate synthesis of these compounds starts with a methyl 3, 4-dialkoxybenzoate. Nitration followed by reduction (Fe, NH(4)Cl, MeOH-H(2)O) gave a methyl 2-amino-4,5-dialkoxybenzoate. Amidine formation using DMF-acetal followed by cyclization using LiCH(2)CN furnished a 6,7-dialkoxy-4-oxo-1,4-dihydroquinoline-3-carbonitrile, which was transformed as before. Compounds containing acid, ester, amide, carbinol, and aldehyde groups at the 3-position of the quinoline ring were also prepared for comparison, as were several 1-anilino-6,7-dimethoxyisoquinoline-4-carbonitriles. The compounds were evaluated for their ability to inhibit the autophosphorylation of the catalytic domain of EGF-R. The SAR of these inhibitors with respect to the nature of the 6,7-alkoxy groups, the aniline substituents, and the substituent at the 3-position was studied. The compounds were further evaluated for their ability to inhibit the growth of cell lines that overexpress EGF-R or HER-2. It was found that 4-anilinoquinoline-3-carbonitriles are effective inhibitors of EGF-R kinase with activity comparable to the 4-anilinoquinazoline-based inhibitors. A new homology model of EGF-R kinase was constructed based on the X-ray structures of Hck and FGF receptor-1 kinase. The model suggests that with the quinazoline-based inhibitors, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 830. It is proposed that the quinoline-3-carbonitriles bind in a similar manner where the water molecule is displaced by the cyano group which interacts with the same Thr residue.

Highly potent and selective inhibition of varicella-zoster virus by bicyclic furopyrimidine nucleosides bearing an aryl side chain

Abstract: In addition to our recent report on the potent anti-varicella-zoster virus (VZV) activity of some unusual bicyclic furopyrimidine nucleosides bearing long alkyl side chains, we herein report the further significant enhancement of the antiviral potency by inclusion of a phenyl group in the side chain of these compounds. The target structures were prepared by the Pd-catalyzed coupling of a series of para-substituted arylacetylenes with 5-iodo-2‘-deoxyuridine, to give intermediate 5-alkynyl nucleosides which were cyclized in the presence of Cu to give the desired bicyclic systems. The compounds display extraordinary potency and selectivity for VZV; the most active are ca. 10 000 times more potent than the reference compound acyclovir and ca. 100 times more potent than the alkyl analogues earlier reported by us. The current compounds show little cytotoxicity, leading to selectivity index values 1 000 000. From a range of DNA and RNA viruses tested, only VZV was inhibited by these compounds indicating their extreme selectivity for this target virus. The novelty of the molecules, coupled with their extreme potency and selectivity, their desirable physicochemical properties, and their relative ease of synthesis, makes them of considerable interest for potential drug development for VZV infections.

Discovery of Novel, Potent, and Selective Small-Molecule CCR5 Antagonists as Anti-HIV-1 Agents: Synthesis and Biological Evaluation of Anilide Derivatives with a Quaternary Ammonium Moiety

Abstract: The search for new small-molecule CCR5 antagonists by high-throughput screening (HTS) of the Takeda chemical library using [125I]RANTES and CHO/CCR5 cells led to the discovery of lead compounds (A, B) with a quaternary ammonium or phosphonium moiety, which were synthesized to investigate new MCP-1 receptor antagonists. A series of novel anilide derivatives 1 with a quaternary ammonium moiety were designed, synthesized, and tested for their CCR5 antagonistic activity. Through the optimization of lead compounds, we have found N,N-dimethyl-N-[4-[[[2-(4-methylphenyl)-6,7-dihydro-5H-benzocyclohepten-8-yl]carbonyl]amino]benzyl]tetrahydro-2H-pyran-4-aminium chloride (1r, TAK-779) as a highly potent and selective nonpeptide CCR5 antagonist with a IC50 value of 1.4 nM in the binding assay. Compound 1r also inhibited the replication of macrophage (M)-tropic HIV-1 (Ba-L strain) in both MAGI-CCR5 cells and PBMCs with EC50 values of 1.2 and 3.7 nM, respectively. The synthesis and structure−activity relationships of 1r...

A Macrobicyclic Receptor with Versatile Recognition Properties: Simultaneous Binding of an Ion Pair and Selective Complexation of Dimethylsulfoxide

Abstract: A bicyclic receptor was synthesized and evaluated for its ability to bind alkali halide salts and polar neutral molecules in organic solvents. The receptor design is relatively straightforward in the sense that it is a combination of a dibenzo-18-crown-6 and a bridging 1,3-phenyldicarboxamide. In the presence of 1 mol equiv of metal cation, chloride affinities are enhanced in the order: K+ (9-fold enhancement) > Na+ (8-fold enhancement) ≫ Cs+ (no enhancement). An X-ray crystal structure shows that the receptor binds sodium chloride as a solvent-shared ion pair. The receptor has very weak affinity for acetonitrile, nitromethane, or acetone in chloroform solvent, whereas the association constant for dimethylsulfoxide is 160 M-1 at 295 K. An X-ray crystal structure shows that the dimethylsulfoxide is bound deeply in the receptor cavity and forms hydrogens bonds to the receptor via a bridging water molecule. There is also evidence for CH−O interactions. Solid−liquid extraction studies show that the receptor ...

Synthesis of Enantiopure trans-3,4-Disubstituted Piperidines. An Enantiodivergent Synthesis of (+)- and (−)-Paroxetine

Abstract: Reaction of (R)-phenylglycinol with methyl 5-oxopentanoate gave either bicyclic lactam cis-1 (the kinetic product) or its isomer trans-1 (under equilibrating conditions) as the major products, which were converted to the corresponding (cis or trans) unsaturated lactams 4 and 5 On treatment with lithium alkyl (or aryl) cyanocuprates, these chiral building blocks undergo conjugate addition to give enantiopure trans-3,4-substituted 2-piperidone derivatives in high yield and stereoselectivity The synthetic potential of this transformation is illustrated by the synthesis of (+)-femoxetine and the two enantiomers of the known antidepressant paroxetine

1,3-Diaryl-4,5,6,7-tetrahydro-2H-isoindole derivatives: a new series of potent and selective COX-2 inhibitors in which a sulfonyl group is not a structural requisite.

Abstract: Novel tetrahydro-2H-isoindoles have been prepared and evaluated as inhibitors of the COX-2 isoenzyme. A 1,3-diaryl substitution on the central polycyclic ring system and absence of a sulfonyl moiety are the two structural features of this chemical series. A short and easy synthetic pathway produced several derivatives which were shown to be potent and selective COX-2 vs COX-1 inhibitors (IC50 = 0.6−100 nM for COX-2, 100−>1000 nM for COX-1). Structural modifications established that a bicyclic ring appended to the pyrrole nucleus and 4,4‘-difluoro substitution on the phenyl rings were optimal for high inhibitory potency. Activity was confirmed in the human whole blood assay and subsequently in the murine air-pouch model in which in vivo PGE2 inhibitory activity was evaluated with respect to gastric tolerance (ED50 for inhibition of exudate PGE2 of 3 mg/kg and gastric PGE2 of 20 mg/kg). Gastric tolerance was further assessed after administration to mice of high doses (up to 400 mg/kg) of the inhibitors by m...

Ru(II)-Catalyzed Cycloadditions of 1,6-Heptadiynes with Alkenes: New Synthetic Potential of Ruthenacyclopentatrienes as Biscarbenoids in Tandem Cyclopropanation of Bicycloalkenes and Heteroatom-Assisted Cyclocotrimerization of 1,6-Heptadiynes with Heterocyclic Alkenes

Abstract: The ruthenium(II)-catalyzed tandem cycloaddition of 1,6-heptadiynes with bicyclic alkenes, such as bicyclo[3.2.1]heptenones and norbornene derivatives, furnishes the 1:2 adducts between the diynes and two molecules of the bicycloalkenes together with common [2 + 2 + 2] cyclocotrimerization products. The structure of a representative tandem 1:2 adduct between dimethyl dipropargylmalonate and 2,4-dimethylbicyclo[3.2.1]oct-6-en-3-one was unequivocally determined by X-ray analysis and was concluded to involve an unusual 1,2-dicyclopropylcyclopentene skeleton. On the basis of the spectroscopic analogy, the previously communicated structures of the tandem cycloadducts between the diynes and norbornene derivatives were corrected. The formation of the tandem double-cyclopropanation products from the diynes is chemical evidence of a bis-carbenoid hybrid structure, 1,3,5-metallacyclopentatriene, of the corresponding 2,4-metallacyclopentadiene intermediates. The selectivity for the formation of the tandem cyclopropa...

A stable bicyclic compound with two Si=Si double bonds.

Abstract: In contrast to carbon, silicon does not readily form double bonds, and compounds containing silicon-silicon double bonds can usually be stabilized only by protection with bulky substituents. We have isolated a silicon analog of spiropentadiene 1, a carbon double-ring compound that has not been isolated to date. In the crystal structure of tetrakis[tri(t-butyldimethylsilyl)silyl]spiropentasiladiene 2, a substantial deviation from the perpendicular arrangement of the two rings is observed, and the silicon-silicon double bonds are shown to be distorted. Spectroscopic data indicate pronounced interaction between two remote silicon-silicon double bonds in the molecule. Silicon-silicon bonds may be more accessible to synthesis than previously assumed.

4-amino- quinazoline and quinoline derivatives having an inhibitory effect on signal transduction mediated by tyrosine kinases

Abstract: The present invention relates to bicyclic heterocycles of general formula (I), wherein Ra to Rd, A to G and X are defined as in claim 1, the tautomers, the stereoisomers and the salts thereof, particularly the physiologically acceptable salts thereof particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibiting effect on signal transduction mediated by tyrosine kinases, their use for treating diseases, particularly tumoral diseases, diseases of the lungs and respiratory tract, and the preparation thereof.

An Efficient, Redox-Enhanced Pair of Hydrogen-Bond Tweezers for Chloride Anion Recognition, a Key Synthon in the Construction of a Novel Type of Organic Metal based on the Secondary Amide-Functionalized Ethylenedithiotetrathiafulvalene, β‘ ‘-(EDT-TTF-CONHMe)2[Cl·H2O]

Abstract: Electrocrystallization of 1,1,2-trichloroethane solutions of the redox-active secondary amide, 3-methylamido-3‘,4‘-ethylenedithiotetrathiafulvalene (EDT-TTF-CONHMe 1) in the presence of n-Bu4NF supported on silica gel afforded a mixed-valence chloride salt, formulated (1)2[Cl·H2O] from elemental analysis and X-ray crystal structure resolution. The chloride anion and water molecule are disordered on the same site, and coordinated to the π-donor molecule by two strong hydrogen bonds involving the amidic N−H and the aromatic C−H group ortho to the amide, thereby qualifying a robust pair of tweezers-like cyclic motif. This efficient anion recognition effect is also observed in solution, as demonstrated by 1H NMR downfield shifts of both the N−H and C−H hydrogen atom resonances, as well as by a cathodic shift of the oxidation potential of 1 upon Cl- complexation, establishing that the actual electrocrystallized species is a solvated anionic chloride complex [(1·Cl-)(H2O)n] rather than the free amide. (1)2[Cl·H...

Bicyclic heterocycles, pharmaceutical compositions containing these compounds, and processes for preparing them

Abstract: The present invention relates to bicyclic heterocyclic compounds of general formula (I), wherein Ra to Rd, A to D and X are defined as in claims 1 to 8, the tautomers, stereoisomers and salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, their use in treating diseases, particularly tumour diseases, diseases of the lung and airways and the preparation thereof.

Pyridine and pyrimidine derivatives and their use as inhibitors of cytokine mediated disease

Abstract: This invention concerns a bicyclic compound of Formula (I), wherein: G is N, CH or C(CN); ring X is a 5- or 6-membered fused heteroaryl ring which contains 1, 2, or 3 heteroatoms selected from oxygen, sulphur and nitrogen; m is 0 - 2; R1 is a group such as hydroxy, halo, trifluoromethyl, cyano, mercapto, nitro, amino, carboxy and carbamoyl; each of R?2 and R3? is hydrogen, halo, C?1-6?alkyl, C2-6alkenyl or C2-6alkynyl; R?4? is a group such as hydrogen, hydroxy, C?1-6?alkyl, C1-6alkoxy, amino and N-C1-6alkylamino; R?5? is a group such as hydrogen, halo, trifluoromethyl, cyano, nitro, amino and hydroxy, and q is 0 - 4; or a pharmaceutically acceptable salt or an in vivo cleavable ester thereof; processes for its preparation, a pharmaceutical composition containing it and its use in the treatment of diseases or medical conditions mediated by cytokines.

Modified guanidines as potential chiral superbases. 1. Preparation Of 1,3-disubstituted 2-iminoimidazolidines and the related guanidines through chloroamidine derivatives

Abstract: Modified guanidines were explored as potential chiral superbases. Thus, chiral 1,3-dimethyl-2-iminoimidazolidines with or without 4,5-diphenyl groups, their guanidinium salts, and the 2-iminoimidazolidines with (S)-1-phenylethyl groups on the ring nitrogens were prepared by treatment of 2-chloroimidazolinium chlorides with appropriate amines. Bicyclic guanidines were also prepared from a prolinamide using a similar procedure.

Photomodulation of conformational states. I. Mono‐ and bicyclic peptides with (4‐amino)phenylazobenzoic acid as backbone constituent

Abstract: The thioredoxin reductase active-site fragment H–Ala–Cys–Ala–Thr–Cys–Asp–Gly–Phe–OH [134–141], which is known for its high tendency to assume an almost identical conformation as in the intact enzyme, was backbone cyclized with the photoresponsive (4-amino)phenylazobenzoic acid (APB) to produce a monocyclic and disulfide-bridged bicyclic APB-peptide. Light-induced reversible cis/trans isomerization occurs at identical extents in both the linear and the two cyclic forms. Nuclear magnetic resonance conformational analysis clearly revealed that in the bicyclic APB-peptide both as a trans- and cis-azo-isomer the constraints imparted by the bicyclic structure do not allow the molecule to relax into a defined low energy conformation, thus making the molecule a frustrated system that flip-flops between multiple conformational states. Conversely, the monocyclic APB peptide folds into a well-defined lowest energy structure as a trans-azo-isomer, which upon photoisomerization to the cis-azo configuration relaxes into a less restricted conformational space. First femtosecond spectroscopic analysis of the dynamics of the photoreaction confirm a fast first phase on the femtosecond time scale related to the cis/trans isomerization of the azobenzene moiety followed by a slower phase in the picosecond time scale that involves an adjustment of the peptide backbone. Due to the well- defined photoresponsive two-state transition of this monocyclic peptide molecule, it represents a model system well suited for studying the ultrafast dynamics of conformational transitions by time-resolved spectroscopy. © 2000 John Wiley & Sons, Inc. Biopoly 54: 489–500, 2000

Generalized anomeric effect in action: synthesis and evaluation of stable reducing indolizidine glycomimetics as glycosidase inhibitors.

Abstract: A series of aminoketalic castanospermine analogues incorporating a stereoelectronically anchored axial hydroxy group at the pseudoanomeric stereocenter (C-5) have been synthesized to satisfy the need for glucosidase inhibitors that are highly selective for alpha-glucosidases. The polyhydroxylated bicyclic system was built from readily available hexofuranose derivatives through a synthetic scheme that involved (i) the construction of a five-membered cyclic (thio)carbamate or (thio)urea moiety at the nonreducing end and (ii) the intramolecular nucleophilic addition of the heterocyclic thiocarbamic nitrogen atom to the masked aldehyde group of the monosaccharide. A biological screening of the resulting reducing 2-oxa- and 2-azaindolizidines against several glycosidase enzymes is reported.

Studies on aminopyrazoles: antibacterial activity of some novel pyrazolo[1,5-a]pyrimidines containing sulfonamido moieties

Abstract: Hydrazones 2a-d were prepared from diazotiazation of sulfanilamide or its derivatives followed by coupling with ethyl cyanoacetate. 3-Aminopyrazoles 3a-d were obtained by refluxing of 2a-d with hydrazine hydrate in ethanol. [Bis(-methylthio)methylene]malononitrile (4) was reacted with aminopyrazoles 3a-d in refluxing DMF containing triethylamine to yield the novel pyrazolo[1,5-a]pyrimidines 6a-d. The anilino derivatives 8a-h were obtained by fusion of compounds 6a-d with aromatic amines. When compounds 6a,c,d were subjected to the reaction with hydrazine hydrate, the hydrazino derivatives 9a-c were isolated. Also, the aminopyrazoles 3 were reacted with some electrophiles such as arylidenemalononitriles, ethoxymethylene malononitrile and ethyl ethoxymethylene cyanoacetate to yield the novel substituted pyrazolo[1,5-a]pyrimidines 13, 17 and 19, respectively. Structures of the new compounds were established by their elemental analyses and spectral data. Most of these compounds were also tested in vitro for their antibacterial activity against some gram positive and gram negative bacteria.

Substance library containing bicyclic imidazo-5-yl-amines and/or bicyclic imidazo-3-yl-amines

Abstract: The invention relates to a substance library containing bicyclic imidazo-5-yl-amines and/or bicyclic imidazo-3-yl-amines of general formula (I) or (II), to a method for producing this substance library, and to the use of substances from this substance library for producing a medicament used to treat pain.