Synthesis of Anellated Pyranose Derivatives on the Basis of Levoglucosenone

ABSTRACT

1,6-Anhydro-2-(dicyanomethylene)-2,3-dideoxy-4-S-ethyl-4-thio-β-D-erythro-hexopyranose (1) reacted with tosyl azide or sulfur and triethylamine to furnish the 5-aza-10, 11-dioxatricyclo[6.2.1.0^2,6]undeca-2(6),3-diene-3-carbonitrile 2 and the 10,11-dioxa-5-thiatricyclo[6.2.1.0^2,6]undeca-2(6),3-diene-3-carbonitrile 3, respectively. The reactions of 1 with arylisothiocyanates furnished the 11,12-dioxa-5-thiatricyclo[7.2.1.0^2,7]dodeca-2(7),3-diene-3-carbonitriles 4 and 5. 3 underwent cyclization with triethyl orthoformate and ammonia or hydrazine hydrate to afford the 5,7-diaza-14,15-dioxa-9-thiatetracyclo[10.2.1.0^2,10.0^3.8]pentadecatetra(tri)enes 7 and 8, respectively.     

Synthesis and in vitro evaluation of iodinated derivatives of piperazine as a new ligand for sigma receptor imaging by single photon emission computed tomography

A new series of radioiodinated analogues of 1-[2-(3,4-dimethoxyphenyl)ethyl]-4-(3-phenylpropyl)piperazine (SA4503) was synthesized and evaluated as a potential brain sigma-1 receptor imaging ligands by single photon emission computed tomography (SPECT). Iodinated analogues of SA4503 (4a-c) were prepared from piperazine in a high yield. The in vitro competition binding studies using [3H] DTG (sigma-1, 2), [3H] (+)-pentazocine (sigma-1), and [3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC50: 4a=7.1, 4b=31.0, and 4c=77.3 nM). In particular, the affinity of 4a, bearing iodine at ortho position on the phenyl ring, was 4.4 times greater than SA4503, and 3 times greater than that of haloperidol. The meta-iodo analogue 4b was the same to SA4503, the lead compound. The radioiodinated derivatives, [125I] 4a, 4b were synthesized no-carrier-added from the corresponding tributyltin precursors by the iododestannylation reaction with high yields. The binding of [125I] 4a, 4b have been characterized in the rat brain membranes. These compounds were indicated single population binding to sigma receptor with high affinity (4a: Kd=1.86+/-0.34 nM, Bmax=205+/-28.9 fmol/mg protein, 4b: Kd=3.30+/-0.51 nM, Bmax=231.5+/-13.8 fmol/mg protein). In vitro blocking studies were confirmed that the high specificity of 4a, 4b. These results suggest that radioiodinated 4a and 4b are promising sigma receptors imaging ligand for pursuing further in vivo studies.     

Photochemische reaktionen von übergansmetall-olefinkomplexen: III. [4 + 6]-cycloaddition konjugierter diene an hexacarbonyl-μ-η6:6(-1,1′-bi(2,4,6-cycloheptatrien-1-yl)dichrom(O)

UV irradiation of hexacarbonyl-μ-η^6:6-1,1′-bi(2,4,6-cycloheptatrien-1-yl)dichromium(O) (I) in THF in the presence of 1,3-butadiene (A), E-1,3-pentadiene (B) and EE-2,4-hexadiene (C) causes preferentially a twofold [4 + 6]-cycloaddition and formation of the hexacarbonyl-μ-2–5 : 8.9-η-2′–5′ : 8′,9′-η-11,11′-bi(bicyclo-[4.4.1]undeca-2,4,8-trien-11-yl)dichromium(O) complexes (IVA–IVC). Partial decomplexation after the first [4 + 6]-cycloaddition yields isomeric tricarbonyl-2–5:8,9-η- (IIA–IIC) and tricarbonyl-2′–7′-η-{11-(2′,4′,6′-cycloheptatrien-1′-yl)bicyclo[4.4.1]undeca-2,4,8-triene}chromium(O) complexes (IIIA–IIIC). With 2,3-dimethyl-1,3-butadiene (D) mainly dicarbonyl-2–6 : 2′–4′-η-{1-(2′,3′-dimethyl-3′-buten-1′,2′-diyl)-7-(8″,9″-dimethylbicyclo[4.4.1]undeca-2″, 4″,8″-trien-11″-yl)cyclohepta-3,5-dien-2-yl}chromium(O) (VD) besides small amounts of pentacarbonyl-μ-2–6 : 2′–4′-η-2″–7″-η-{1-(2′,3′-dimethyl-3′-buten-1′,2′-diyl)-7-(2″, 4″,6″-cycloheptatrien-1″-yl)cyclohepta-3,5-dien-2-yl}dichromium(O) (VID) and tricarbonyl-2′-7′-η-{11-(2′,4′,6′-cycloheptatrien-1′-yl)-8,9-dimethyl-bicyclo[4.4.1]undeca-2,4,8-triene}-chromium(O) (IIID) is obtained. VD adds readily CO to yield tricarbonyl-2–5 : 8,9-η-11,11′-bi(8,9-dimethyl-bicyclo[4.4.1]undeca-2,4,8-trien-11-yl)chromium(O) (VIID). Finally D adds to VID under formation of pentacarbonyl-μ-2–6 : 2′–4′-η-2″–5″ : 8″,9″-η-{1-(2′,3′-dimethyl-3′-buten-1′,2′-diyl)-7-(8″,9″-dimethyl-bicyclo[4.4.1]- undeca-2″,4″,8″-trien-11″-yl)cyclohepta-3,5-dien-2-yl}dichromium(O) (VIIID). From IVA–IVC the hydrocarbon ligands (IXA–IXC) can be liberated by P(OCH₃)₃ in good yields. The structures of the compounds IIA–IXC were determined by IR     

N-heterocyclic phosphenium cations: syntheses and cycloaddition reactions

A series of trifluoromethanesulfonate (OTf) salts of N-heterocyclic phospheniums (NHP) bearing phenyl (1a), para-methoxyphenyl (1b), 2,6-diisopropylphenyl (1c) and mesityl (1d) substituents is reported. The compounds are made by a modification to a literature procedure that improves the overall yields for and by 15 and 23%, respectively. Two unwanted side-products in the synthesis of , the diammonium salt, [(2,6-iPr-C6H3)N(H)2CH2CH2N(H)2(2,6-iPr-C6H3)]Cl2 (4) and the bisphosphine (2,6-iPr-C6H3)N(PCl2)CH2CH2N(PCl2)(2,6-iPr-C6H3) (5), are crystallographically characterized, as is the intermediate cyclic chlorophosphine, C1PN(4-OMe-C6H4)CH2CH2N(4-OMe-C6H4) (3b). The phenyl-substituted NHP is fully characterized, including by X-ray crystallography, for the first time; this compound contains a short P-O contact of 2.1850(14) A. Cycloaddition reactions of with 2,3-dimethyl-1,3-butadiene give the expected spirocyclic phospholeniums, 7,8-dimethyl-1,4-diaryl-1,4-diaza-5-phopshoniaspiro[4.4]non-7-ene, as their OTf salts (6a-d), while reactions with N,N'-dimesityl-1,4-diaza-1,3-butadiene give, except in the case of , which is too bulky to react, the aza analogues, 1,4-dimesityl-6,9-diaryl-1,4,6,9-tetraaza-5-phosphoniaspiro[4.4]non-2-ene (7a, 7b and 7d). The sterically congested is in thermal equilibrium with and free diazadiene, and undergoes a substitution reaction with 2,3-dimethyl-1,3-butadiene to give .     

Photochemical Experiments with 2,3-Bis(Tert-Butylsulfonyl)Bicyclo[2.2.2]Octa-2,5-Diene and Related Systems

The irradiation of 2,3-bis(tert-butylsulfonyl)norbornadiene (5) and 2-(tert-butylsulfonyl)norbornadiene (6) yielded the expected quadricyclane derivatives as stable molecules. The irradiation of 2,3-bis(tert-butylsulfonyl)bicyclo[2.2.2]octa-2,5-diene(7) 2,3-bis(tert-butylsulfonyl)-exo-7,8-epoxybicyclo[2.2.2]-octa-2,5-diene (8) and 8,9-bis(tert-butylsulfonyl)-4-anti-phenyl-3,5-dioxa-exo-tricyclo[5.2.2.0^2,6] undeca-8,10-diene 9a and its syn-isomer 9b yielded the corresponding tetracyclic and pentacyclic systems, respectively. The photoproducts of 8 and 9 reverted to the starting products slowly at room temperature. The half-life of the photoproduct of 7 was determined to be 34 min at 50 °C. Compound 9a reacted with n-BuLi to yield the unexpected desulfonylation product 27a.     

Synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane, and 2-(pyridin-3-yl)-1-azabicyclo[3.2.1]octane, a class of potent nicotinic acetylcholine receptor-ligands

In an attempt to generate nicotinic acetylcholine receptor (nAChR) ligands selective for the alpha4beta2 and alpha7 subtype receptors we designed and synthesized constrained versions of anabasine, a naturally occurring nAChR ligand. 2-(Pyridin-3-yl)-1-azabicyclo[2.2.2]octane, 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane, and several of their derivatives have been synthesized in both an enantioselective and a racemic manner utilizing the same basic synthetic approach. For the racemic synthesis, alkylation of N-(diphenylmethylene)-1-(pyridin-3-yl)methanamine with the appropriate bromoalkyltetrahydropyran gave intermediates which were readily elaborated into 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane and 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via a ring opening/aminocyclization sequence. An alternate synthesis of 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane via the alkylation of N-(1-(pyridin-3-ylethylidene)propan-2-amine has also been achieved. The enantioselective syntheses followed the same general scheme, but utilized imines derived from (+)- and (-)-2-hydroxy-3-pinanone. Chiral HPLC shows that the desired compounds were synthesized in >99.5% ee. X-ray crystallography was subsequently used to unambiguously characterize these stereochemically pure nAChR ligands. All compounds synthesized exhibited high affinity for the alpha4beta2 nAChR subtype ( K i < or = 0.5-15 nM), a subset bound with high affinity for the alpha7 receptor subtype ( K i < or = 110 nM), selectivity over the alpha3beta4 (ganglion) receptor subtype was seen within the 2-(pyridin-3-yl)-1-azabicyclo[2.2.2]octane series and for the muscle (alpha1betagammadelta) subtype in the 2-(pyridin-3-yl)-1-azabicyclo[3.2.2]nonane series.     

Vanadium complexes of the N(CH2CH2S)3(3-) and O(CH2CH2S)2(2-) ligands with coligands relevant to nitrogen fixation processes

Vanadium(III) and vanadium(V) complexes derived from the tris(2-thiolatoethyl)amine ligand [(NS3)3-] and the bis(2-thiolatoethyl)ether ligand [(OS2)2-] have been synthesized with the aim of investigating the potential of these vanadium sites to bind dinitrogen and activate its reduction. Evidence is presented for the transient existence of (V(NS3)(N2)V(NS3), and a series of mononuclear complexes containing hydrazine, hydrazide, imide, ammine, organic cyanide, and isocyanide ligands has been prepared and the chemistry of these complexes investigated. [V(NS3)O] (1) reacts with an excess of N2H4 to give, probably via the intermediates (V(NS3)(NNH2) (2a) and (V(NS3)(N2)V(NS3) (3), the V(III) adduct [V(NS3)(N2H4)] (4). If 1 is treated with 0.5 mol of N2H4, 0.5 mol of N2 is evolved and green, insoluble [(V(NS3))n] (5) results. Compound 4 is converted by disproportionation to [V(NS3)(NH3)] (6), but 4 does not act as a catalyst for disproportionation of N2H4 nor does it act as a catalyst for its reduction by Zn/HOC6H3Pri2-2,6. Compound 1 reacts with NR1(2)NR2(2) (R1 = H or SiMe3; R2(2) = Me2, MePh, or HPh) to give the hydrazide complexes [V(NS3)(NNR2(2)] (R2(2) = Me2, 2b; R2(2) = MePh, 2c; R2(2) = HPh, 2d), which are not protonated by anhydrous HBr nor are they reduced by Zn/HOC6H3Pri2-2,6. Compound 2b can also be prepared by reaction of [V(NNMe2)(dipp)3] (dipp = OC6H3Pri2-2,6) with NS3H3. N2H4 is displaced quantitatively from 4 by anions to give the salts [NR3(4)][V(NS3)X] (X = Cl, R3 = Et, 7a; X = Cl, R3 = Ph, 7b; X = Br, R3 = Et, 7c; X = N3, R3 = Bu(n), 7d; X = N3, R3 = Et, 7e; X = CN, R3 = Et, 7f). Compound 6 loses NH3 thermally to give 5, which can also be prepared from [VCl3(THF)3] and NS3H3/LiBun. Displacement of NH3 from 6 by ligands L gives the adducts [V(NS3)(L)] (L = MeCN, nu CN 2264 cm-1, 8a; L = ButNC, nu NC 2173 cm-1, 8b; L = C6H11NC, nu NC 2173 cm-1, 8c). Reaction of 4 with N3SiMe3 gives [V(NS3)(NSiMe3)] (9), which is converted to [V(NS3)(NH)] (10) by hydrolysis and to [V(NS3)(NCPh3)] (11) by reaction with ClCPh3. Compound 10 is converted into 1 by [NMe4]OH and to [V(NS3)NLi(THF)2] (12) by LiNPri in THF. A further range of imido complexes [V(NS3)(NR4)] (R4 = C6H4Y-4 where Y = H (13a), OMe (13b), Me (13c), Cl (13d), Br (13e), NO2 (13f); R4 = C6H4Y-3, where Y = OMe (13g); Cl (13h); R4 = C6H3Y2-3,4, where Y = Me (13i); Cl (13j); R4 = C6H11 (13k)) has been prepared by reaction of 1 with R4NCO. The precursor complex [V(OS2)O(dipp)] (14) [OS2(2-) = O(CH2CH2S)2(2-)] has been prepared from [VO(OPri)3], Hdipp, and OS2H2. It reacts with NH2NMe2 to give [V(OS2)(NNMe2)(dipp)] (15) and with N3SiMe3 to give [V(OS2)(NSiMe3)(dipp)] (16). A second oxide precursor, formulated as [V(OS2)1.5O] (17), has also been obtained, and it reacts with SiMe3NHNMe2 to give [V(OS2)(NNMe2)(OSiMe3)] (18). The X-ray crystal structures of the complexes 2b, 2c, 4, 6, 7a, 8a, 9, 10, 13d, 14, 15, 16, and 18 have been determined, and the 51V NMR and other spectroscopic parameters of the complexes are discussed in terms of electronic effects.     

Reactive species from aromatics and oxa-di-π-methane rearrangement: a stereoselective synthesis of (±)-hirsutene from salicyl alcohol

A total synthesis of hirsutene, a triquinane sesquiterpene, from salicyl alcohol is reported. Oxidation of salicyl alcohol in the presence of cyclopentadiene gave 9-spiroepoxy-endo-tricyclo[5.2.2.0^2,6]undeca-4,10-dien-8-one which was elaborated to the 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one containing major structural and functional features of hirsutene. Photochemical sigmatropic 1,2-acyl shift in 3-hydroxy-2-methyl-endo-tricyclo[5.2.2.0^2,6]undeca-10-en-8-one followed by radical induced cleavage of peripheral cyclopropane bond, olefination and Simmon-Smith reaction furnished 11-hydroxy-1-methyl-4-spirocyclopropanetricyclo[6.3.0.0^2,6]undecane that upon treatment with hydrogen on PtO₂ and PCC oxidation gave 1,4,4-trimethyltricyclo[6.3.0.0^2,6]undecan-11-one, a known precursor. Wittig methylenation on this precursor gave hirsutene.     

Biological properties of opioid peptides replacing Tyr at position 1 by 2,6-dimethyl-Tyr.

To understand the effect of the replacement of Tyr residue at position 1 in opioid peptides by 2,6-dimethyl-Tyr (Dmt) on the biological property, chiral (D or L) Dmt1 analogs of Leu-enkephalin (Enk) and Tyr-D-Arg-Phe-beta Ala-NH2 (YRFB) were synthesized and their enzymatic stabilities, in vitro bioactivities and receptor binding affinities compared with those of parent peptides. [L-Dmt1]Enk (1) exhibited 4-fold higher stability against aminopeptidase-M and possessed dramatically increased activities in guinea pig ilium (GPI) (187-fold) and mouse vas deferens (MVD) (131-fold) assays, and in rat brain receptor binding assays (356-fold at mu receptor and 46-fold at delta receptor) as compared to Enk. [L-Dmt1]YRFB (3) also exhibited increased activities in GPI (46-fold) and MVD (177-fold) assays, and in the binding assays (69-fold at mu receptro and 341-fold at delta receptor) as compared to the parent peptide. [D-Dmt1]Enk (2) and [D-Dmt1]YRFB (4) exhibited activities with diminished or lesser potency than the parent peptide in all assays. These results indicate that there is a tendency for mu affinity to be enhanced more than delta affinity with introduction of L-Dmt into delta ligand peptide (Enk), and for delta affinity to be enhanced more than mu affinity in case of mu ligand peptide (YRFB), resulting in reduced receptor selectivities at the receptors.     

Efficient synthesis of cyclophanes containing sulfur and nitrogen atoms by cycloaminomethylation of benzenedithiols in the presence of samarium-based catalysts

An efficient procedure has been developed for the synthesis of 3-aryl-3,4-dihydro-2H-1,5,3-benzodithiazepines, 4-aryl-2,6-dithia-4-azabicyclo[5.3.1]undeca-1(11),7,9-trienes, and 4,10,16-triaryl-2,6,8,12,14,18-hexathia-4,10,16-triaza-1,7,13(1,4)-tribenzenacyclooctadecaphanes by samarium-catalyzed cycloaminomethylation of benzenedithiols with N,N-bis(methoxymethyl)anilines.     

Triplet photochemistry of medium ring trienes

The photochemistry of the triplets of 10- and 11-membered ring 1,3,5-trienes has been studied. At ?70° cis,trans,cis-cyclodeca-1,3,5-triene goes only to the cis,cis,cis-isomer. At 25°, this latter compound is converted into cis-bicyclo[4.4.0]deca-2,4-diene via the thermally labile trans,cis,trans-cyclodeca-1,3,5-triene. At ?70° cis,trans,cis-cycloundeca-1,3,5-triene is converted to the cis,cis,cis-isomer. At 25°, this primary ptotochemical product undergoes a thermal 1,7-sigmatropic hydrogen migration to yield the trans,cis,cis, isomer. This latter triene upon sensitized irradiation yields cis-bicyclo[5.4.0]undeca-8,10-diene and trans-bicyclo[7.2.0]undeca-2,10-diene. The ratio of these latter two products changes with the temperature of the sensitized reaction. The possible mechanisims of these transformations are discussed.     

Reaction of perfluoro-2-methylpent-2-ene with ethylenediamine and hexamethylenediamine

Reaction of perfluoro-2-methylpent-2-ene with ethylenediamine and hexamethylenediamine results in 9-fluoro-5,9-bis(pentafluoroethyl)-6,8,8-tris(trifluoromethyl)-1,4-diazabicyclo[5.2.0]nona-4,6-diene, whose structure was confirmed by X-ray analysis, and 11-pentafluoroethyl-10-trifluoromethyl-1,8-diazabicyclo[7.2.0]undeca-8,10-diene, respectively. The reaction pathways are discussed. Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1578–1582, August, 1999.     

Synthesis and cytotoxic activity of some new 2,6-substituted purines

A seriesof twenty four acyclic unsaturated 2,6-substututed purines 5a-20b were synthesized. These compounds were evaluated for cytotoxic activity against NCI-60 DTP human tumor cell line screen at 10μMconcentration. N?-[(Z)-4'-chloro-2'-butenyl-1'-yl]-2,6-dichloropurine(5a), N?-[4'-chloro-2'-butynyl-1'-yl]-2,6-dichloropurine(10a), N?-[(E)-2',3'-dibromo-4'-chloro-2'-butenyl-1'-yl]-6-methoxypurine(14)and N?-[4'-chloro-2'-butynyl-1'-yl]-6-(4-methoxyphenyl)-purine(19)exhibited highly potent cytotoxic activity with GI?? values in the 1-5 μM range for most human tumor cell lines. Other compounds exhibited moderate activity.     

Synthesis,anticancer evaluation,and docking studies of some novel azo chromene derivatives

We have described a simple, convenient, and high-yielding one-pot synthesis of novel azo chromene derivatives via a three-component reaction of various azo aldehydes with dimedone and malononitrile using 10 mol% of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as catalyst and ethanol as solvent at reflux condition. All the synthesized compounds have been characterized using Fourier-transform infrared spectroscopy (FT-IR), ¹H NMR, ¹³C NMR, and HR-MS spectra and molecular docking was performed to explore new inhibitors of human placental aromatase cytochrome P450 and cyclooxygenase-2 enzymes. Of all the compounds docked, compound (E)-2-amino-4-(4,4-dimethyl-2,6-dioxocyclohexyl)-6-((3-methoxyphenyl)diazenyl-4H-chromene-3-carbonitrile ( 4o ) showed good binding affinity with the active site of human placental aromatase cytochrome P450 enzyme (PDB: 3EQM) with inhibition constant (Ki) 1.66 nM and compound 4o also showed good binding affinity with the active site of cyclooxygenase-2 enzyme (PDB: 6COX) with inhibition constant (Ki) 367.17 pM. In vitro anti-cancer activity studies against MCF-7 cells were also performed for compounds 4o , anastrozole and celecoxib. Compound 4o showed an effective cytotoxicity at 19.8 μg/ml compared to anastrozole and celecoxib (24.7 and 26.2 μg/ml).     

A novel, versatile synthetic approach to linearly fused tricyclopentanoids via photo-thermal olefin metathesis

Fifteen examples of a new, speedy and general approach to linearly fused tricyclopentanoids bearing the tricyclo[6.3.0.0^2,6]undecane (triquinane) frame of high contemporary interest is delineated. The key concept in our synthetic sequence to triquinanes is the novel photo-thermal olefin metathesis of cheap, abundantly available Diels-Alder adducts of 1,3 cyclopentadienes and p-benzoquinones. Thus photolysis of endo-tricyclo[6.2.1.0^2,7] undeca-4,9-dien-3,6-diones (9a–9j, 13a,b) furnished pentacyclo [5.4.0.0^2,6.0^3,10.0^5,9]undecan-8,11-diones (10a–10j, 14a,b), which on thermal fragmentation of the cyclobutane ring gave cis, syn, cis-tricyclo [6.3.0.0^2,6]undeca-4,9-dien-3,11-diones (11a–11j, 15a,b in just three steps and in exceptionally good yields. A few interesting transformations of the readily available parent bis-enone 11a which indicates its wider uses in syntheses, are described. Finally, a smooth thermal isomerisation of cis, syn, cis-bis-enones to cis, anti, cis-bis-enones is reported, which further enhances the scope and versatility of our synthetic theme.     

Rearrangement of O,O’-bis(2-benzylideneaminophenyl) phenylphosphonite into 1,6,7-triphenyl-3,4:9,10-dibenzo-2,11-dioxa-5,8-diaza-1-phosphatricyclo[6.3.0.01,5]undeca-3,9-diene

Keeping of O,O’-bis(2-benzylideneaminophenyl) phenylphosphonite in a CCl4 solution for 50 days resulted in its spontaneous rearrangement into 1,6,7-triphenyl-3,4:9,10-dibenzo-2,11-dioxa-5,8-diaza-1-phosphatricyclo[6.3.0.01,5]undeca-3,9-diene, a representative of spirophosphoranes with P–N bonds.     

Synthesis of some dibenzodiazepinone derivatives as potent and m2-selective antimuscarinic compounds

Two series of 5-[[4-[4-(dialkylamino)butyl]-l-cyclohexyl]acetyl], and 5-[(dialkylamino)acyl]-10,11-dihydro-5H- dibenzo[b,e][1,4]diazepin-11-ones were synthesized as potential m2-selective ligands 1,2. Their affinity and selectivity for the muscarinic cholinergic receptor m-AChR subtypes were determined. Replacing a nitrogen with CH in the piperidine ring of 5-[[4-[4-(dialkylamino)butyl]-l-piperidinyl]acetyl]-10,11-dihydro-5H-dibenzo-[b,e][1,4]diazepin-11-ones 3 significantly altered the affinity and selectivity to the muscarinic receptor subtypes.     

A new series of antiallergic agents. I. Synthesis and activity of 11-(2-aminoethyl)thio-6,11-dihydrodibenz[b,e]oxepin derivatives.

A new series of 11-substituted 6,11-dihydrodibenz[b,e]oxepin derivatives was synthesized and evaluated for antiallergic activity. Convenient methods for the preparation of sulfides from alcohols were developed. Structure-activity relationships are described. Compound 7, 11-[2-(dimethylamin)ethyl]thio-6,11-dihydrodibenz[b,e] oxepin-2-carboxylic acid hydrochloride, was the most potent in the rat passive cutaneous anaphylaxis test (ED50 = 0.92 mg/kg p.o.). It had a potent inhibitory effect on anaphylactic bronchoconstriction in guinea pigs (ED50 = 0.029 mg/kg p.o.) and H1 receptor antagonistic effect (Ki = 14 nM) with few central nervous system side effects. Additionally, an antagonistic effect against prostaglandin D2-induced contraction of isolated guinea pig trachea (pA2 = 5.73) was an attractive mechanism of action of the new antiallergic agent. Compound 7 was selected for further evaluation as KW-4994.     

Triphenylantimony(v) catecholates and o-amidophenolates: reversible binding of molecular oxygen

Novel neutral antimony(V) complexes were isolated as crystalline materials and characterized by IR and NMR spectroscopy: o-amidophenolate complexes [4,6-di-tert-butyl-N-(2,6-dimethylphenyl)-o-amidophenolato]triphenylantimony(V) (Ph3Sb[AP-Me], 1) and [4,6-di-tert-butyl-N-(2,6-diisopropylphenyl)-o-amidophenolato]triphenylantimony(v) (Ph3Sb[AP-iPr], 2); catecholate complexes (3,6-di-tert-butyl-4-methoxycatecholato)triphenylantimony(V) (Ph3Sb[(MeO)Cat], 3), its methanol solvate 3CH3OH (4); (3,6-di-tert-butyl-4,5-di-methoxycatecholato)triphenylantimony(V) (Ph3Sb[(MeO)2Cat], 5) and its acetonitrile solvate 5CH3CN (6). Complexes 1-7 were synthesized by oxidative addition of the corresponding o-iminobenzoquinones or o-benzoquinones to Ph3Sb. In the case of the phenanthrene-9,10-diolate (PhenCat) ligand, two different complexes were isolated: Ph3Sb[PhenCat] (7) and [Ph4Sb]+[Ph2Sb(PhenCat)2]- (8). Complexes 7 and 8 were found to be in equilibrium in solution. Molecular structures of 2, 4, 6, and 8 were determined by X-ray crystallography. Complexes 1-7 reversibly bind molecular oxygen to yield Ph3Sb[L-Me]O2 (9), Ph3Sb[L-iPr]O2 (10), Ph3Sb[(MeO)L']O2 (11), Ph3Sb[(MeO)2L']O2 (12) and Ph3Sb[PhenL']O2 (13), which contain five-membered trioxastibolane species (where L is the O,O',N-coordinated derivative of a 1-hydroperoxy-6-(N-aryl)-iminocyclohexa-2,4-dienol, and L' the O,O',O'-coordinated derivative of 6-hydroperoxy-6-hydroxycyclohexa-2,4-dienone). Complexes 9-13 were characterized by IR and 1H NMR spectroscopy and X-ray crystallography.     

Synthesis, NMR conformational analysis and pharmacological evaluation of 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole analogues as melatonin receptor ligands

A structure for the self-condensation product of 2-(1H-indol-2-yl)ethyl tosylate 2a, previously proposed as 6,7,14,15-tetrahydro-15aH-azocino[1,2-a:6,5-b]diindole 3a, was revised based on the (13)C-2D-INADEQUATE experiment, and proved to be 7,7a,13,14-tetrahydro-6H-cyclobuta[b]pyrimido[1,2-a:3,4-a']diindole 4a. A mechanism for the unexpected formation of this novel hexacyclic heterocycle was proposed and its NMR solution structure was elucidated. Five derivatives of the title ring skeleton 12-16 designed as melatonin receptor ligands were synthesized and their affinities for the human MT(1) and MT(2) receptors were determined. Both butyramides 13 and 15, as well as the non-methoxy acetamide 12 exhibited micromolar binding affinities for both receptors being slightly MT(2) selective. The methoxy acetamide 14 showed the best pharmacological profile exhibiting a five times higher affinity for MT(1) (K(i) = 49 nM) than for MT(2) (K(i) = 246 nM) receptor.