Molecular structures of quinuclidinic neurokinin antagonists: 2-(2-Phenylbenzylidene)-3-(2-X-benzylamino) derivatives

The solid-state molecular conformations and crystal structures of three analogues of the CP-96,345 molecule, an important nonpeptidic SP antagonist, namely the (±)-2-(3-phenylbenzilidene)-3-(2-benzylamino) quinuclidine, theo-chloro- and theo-methoxy-derivatives, have been determined by X-ray diffusion analyses and refined to finalR values of 0.055, 0.045, and 0.056, respectively. All three molecules in the solid state show the same disposition of the substituents of the double bond and differences in the conformation mainly caused by the need of releasing intramolecular strains and/or nonbonded interactions. The observed molecular structures are compared to the reported solid-state structure of the CP-96,345 and correlated to the biological activity as NK antagonists.     

3-(Acylamino)-3-amino-2-nitroacrylonitriles from N-Acyl-S-methyl-3,3-diamino-2-nitroacrylthioimidates

Reaction of N-acyl-3,3-diamino-2-nitroacrylthioamides 1 with MeI at room temperature leads to N-acyl-S-methyl-3,3-diamino-2-nitroacrylthioimidates 2 in moderate yields. The latter react with Hg(OAc)₂ in DMF yielding 3-(acylamino)-3-amino-2-nitroacrylonitriles 8 . The structures of 2a and 8a were established by X-ray crystallography.     

Synthesis of 2-(p-R-benzoylmethylene)-3-(p-R-phenyl)-1H-quinoxalines

The reaction of 1,2-diaminobenzenes with substituted 1,2-dibenzoyl-1,2-dibromoethanes constitutes a convenient synthetic route to the hitherto 2-(p-R-benzoylmethylene)-3-(p-R-phenyl)-1H-quinoxalines. Structures of all products were elucidated by ir, ¹H and ¹³C-nmr, mass spectra data. X-Ray crystallography data confirm assigned structures.     

3-Substituted Sydnone Derivatives. Structures of 3-Cyclohexylsydnone and of Two Forms of 3-(3-Pyridyl)sydnone

The crystal and molecular structures of three sydnone derivatives are reported. The compound 3-cyclohexylsydnone crystallizes in space group C2/c of the monoclinic system with sixteen molecules in a cell of dimensions a = 19.326 (3), b = 9.471 (2), c = 20.005 (4)Å, β = 106.85(1)°. The structure has been refined to a final value of 0.0581 for the conventional R-factor based on 2222 independent observed intensities. Form I of 3-(3-pyridyl)sydnone crystallizes in space group P2/n of the monoclinic system with eight molecules in a cell of dimensions a = 7.317(2), b = 9.283 (2), c = 20.891 (6) Å, β = 99.61(2)°. The structure has been refined to a final value of 0.0514 for the conventional R-factor based on 1208 independent observed intensities. Form II of 3-(3-pyridyl)sydnone crystallizes in space group P2₁/c of the monoclinic system with eight molecules in a cell of dimensions a=9.073 (2), b = 22.267 (5). c = 7.494(2)Å, β = 112.15 (2)°. The structure has been refined to a final value of 0.0462 for the conventional R-factor based on 1330 independent observed intensities. Each of the three structures contains two crystallographically independent molecules in the cell. In the case of 3-cyclohexylsydnone, one of the independent molecules exhibits disorder around the exocyclic bond at N(3). A comparison of bond lengths indicates that the (electron donating) cyclohexyl group brings about enhanced electron density in the N(3)-C(4) bond, and possibly in the N(3)-N(2) bond. All three structures studied here exhibit intermolecular hydrogen bonding involving C(4)-H(4)…O(6) interactions. Although there are no stacking interactions in the cyclohexyl derivative, there is evidence for such interactions in the 3-pyridyl derivatives.     

Darzens synthesis of 2,2-dichloro-3-(2-furyl)-3-hydroxypropionic acid derivatives

Esters and amides of 2,2-dichloro-3-(2-furyl)-3-hydroxypropionic acid were prepared by the reaction of furfural with dichloroacetic acid derivatives under the conditions of the Darzens condensation. The structures of the reaction products were confirmed by their¹H NMR and IR spectra and chemical transformations.Translated fromIzvestiya Akademii Nauk. Seriya Khimicheskaya, No. 8, pp. 1444–1448, August, 1994.     

Synthesis of some isomeric 4-ethoxycarbonyl-3-and 5-(1- and 2-hydroxyalkyl)-1,3- and 1,5-dimethylpyrazoles from 3-(2H)furanones and 2,3-dihydro-4-pyrones

The title compounds were prepared by reaction of 3-(2H)furanones and 2,3-dihydro-4-pyrones with methylhydrazine or alternatively by methylation of the corresponding N-unsubstituted pyrazoles. ¹³C and ¹H nmr were used to assign the isomeric 3-methyl or 5-methyl structures.     

Three‐Residue Turns in α/β‐Peptides and Their Application in the Design of Tertiary Structures

A new three‐residue turn was serendipitously discovered in α/β hybrid peptides derived from alternating C‐linked carbo‐β‐amino acids (β‐Caa) and L ‐Ala residues. The three‐residue β‐α‐β turn at the C termini, nucleated by a helix at the N termini, resulted in helix‐turn (HT) supersecondary structures in these peptides. The turn in the HT motif is stabilized by two H bonds—CO(i?2)–NH(i), with a seven‐membered pseudoring (γ turn) in the backward direction, and NH(i?2)–CO(i), with a 13‐membered pseudoring in the forward direction (i being the last residue)—at the C termini. The study was extended to generalize the new three‐residue turn (β‐α‐β) by using different α‐ and β‐amino acids. Furthermore, the HT motifs were efficiently converted, by an extension with helical oligomers at the C termini, into peptides with novel helix‐turn‐helix (HTH) tertiary structures. However, this resulted in the destabilization of the β‐α‐β turn with the concomitant nucleation of another three‐residue turn, α‐β‐β, which is stabilized by 11‐ and 15‐membered bifurcated H bonds. Extensive NMR spectroscopic studies were carried out to delineate the secondary and tertiary structures in these peptides, which are further supported by molecular dynamics (MD) investigations.     

SYNTHESIS OF 1- AND 3-C-(AMINOMETHYL)-1,2,3,4,5-CYCLOHEXANEPENTOLS FROM (+)-epi-QUERCITOL[1]

Oxidation of three di-O-isopropylidene derivatives 2a—4a, newly derived from (+)-epi-quercitol (1), with acetic anhydride in DMSO gave the corresponding ketones 5—7, which underwent aldol-type condensation with nitromethane under basic conditions to give selectively the protected derivatives 8a—10a of C-nitromethyl-1,2,3,4,5-cyclohexanepentols, respectively. On treatment with diazomethane in DMSO, the ketones 6 and 7 gave single spiro epoxides 11 and 12, the structures of which were confirmed by converting them into new C-(azidomethyl)cyclohexanepentols 16 and 17. The nitro compounds were hydrogenated in the presence of Raney nickel to give the amines isolated as the N-acetyl derivatives. Deprotection gave three new 1- and 3-C-aminomethyldeoxyinositols 15c—17c. The aminocyclitols obtained and their N-acetyl derivatives were assayed for inhibitory activity against examples of glycosidases.     

Synthesis of 3-(6-alkylaminopurin-9-yl)-2,3-dideoxy-D-thero-pentopyranoses and their reduction to 3-(6-alkylaminopurin-9-yl)-2,3-dideoxy-D-thero-pentitols

3-(6-Alkylaminopurin-9-yl)-2,3-dideoxy-D-threo-pentopyranoses 3 were prepared by condensation of unprotected 2-deoxy-D-ribose (2) with N⁶-alkyladenines 1 in a phosphorus pentoxide reagent mixture. Reduction of the pentoses 3 gave the corresponding 3-(6-alkylaminopurin-9-yl)-2,3-dideoxy-D-threo-pentitols 4. The structures of 3 and 4 were determined by ¹³C nmr, ¹H nmr and 2D ¹H nmr (COSY).     

超声法合成新型3-(5-氯/苯氧基-3-甲基-1-苯基-4-吡唑基)异噁唑N-取代苯基去甲去氢斑蝥酰亚胺衍生物

去甲去氢斑蝥素与取代芳胺反应得到了一系列N-取代苯基去甲去氢斑蝥酰亚胺, 再与5-氯/苯氧基-4-(α-氯-α-肟基甲基)-3-甲基-1-苯基吡唑甲酰基氯代肟发生1,3-偶极环加成反应生成一系列未见报道的3-(5-氯/苯氧基-3-甲基-1-苯基-4-吡唑基)异噁唑N-取代苯基去甲去氢斑蝥酰亚胺衍生物. 所合成化合物经元素分析, IR, ¹H NMR, ¹H-¹HCOSY, NOESY确证结构.     

Molecular and crystal structures of stereoisomeric2R,3R,6S-2-(1′S-hydroxy-1′-biphenylyl)- and2R,3R,6S-2-(1′R-hydroxy-1′-biphenylyl)methyl-3-methyl-6-isopropylcyclohexanones

It was established by X-ray diffraction analysis that 2-(1′-hydroxy-1′-biphenylyl)methyl-3-methyl-6-isopropylcyclohexanone, one of the minor products of the directed aldol reaction of (−)-menthone bromomagnesium enolate with 4-phenylbenzaldehyde, has the2R,3R,6S, 1′R configuration. The characteristic features of the spatial structure of this β-hydroxyketone were compared with those of the major stereoisomeric product of the above-mentioned reaction. The latter has the2R,3R,6S,1′S configuration. In the crystals, both stereoisomers have the cyclohexanone ring in a chair-like conformation with the three substituents in equatorial positions and are characterized by the presence of the annelated (cis-fused) pseudoring with an −OH…O=C< intramolecular hydrogen bond. The structures of the stereoisomers differ in the orientation of the aryl group and the hydrogen atom at the C(1′) chiral center with respect to the cyclohexanone ring. The results of X-ray diffraction analysis were compared with the data of molecular mechanics calculation for the energetically most favorable conformations of the isolated molecules of β-hydroxyketones under study. Translated fromIzvestiya Akademii Nauk, Seriya Khimicheskaya, No. 11, pp. 2251–2257, November, 1998.     

Totalsynthese von Decarboxybetalainen durch photochemische Ringöffnung von 3-(4-Pyridyl)alanin

Total Synthesis of Decarboxybetalaines by Photochemical Ring Opening of 3-(4-Pyridyl)alanine A photochemical approach is presented for the total synthesis of the decarboxybetalaines, which were previously known from the mild decarboxylation of the natural plant colorants, the betalaines: Irradiation of rac-3-(4-pyridyl)alanine ( 1 ) yielded the rac-2-decarboxybetalamic-acid-imine ( 4 , 86%), presumably via a Dewar pyridine 2 , a cyclic aminal 3 and an electrocyclic ring opening. The imine-zwitterion 4 was treated with three amines, namely (S)-cyclodopa ( 6 ), (S)-proline ( 7 ), and indoline ( 8 ), to afford three decarboxybetalaines, namely (2S)-17-decarboxybetanidine ( 9 , red, 34%), (2S)-13-decarboxyindicaxanthine ( 10 , yellow, 56%), and rac-16-decarboxyindobetalaine ( 11 , orange, 78%), respectively. The structures of these coloring matters were confirmed by their electrophoretic behavior and their spectroscopic properties. 17-Decarboxybetanidine 9 was shown to be a ca. 1:1 mixture of two C(15)-epimers 9a and 9b , separable by chromatography. The configuration of 9a was determined as (2S, 15S) and that of 9b as (2S, 15R), by correlating their optical rotations with those of betanidine ( 12a ) and isobetanidine ( 12b ), respectively. The decarboxybetalaines 9 , 10 , and 11 did not show the double-bond isomerism at C(β), (Cγ) of the chromophore which had been found characteristic for the corresponding betalaines 12 , 13 , and 14 .     

Azole. 47. Über 3-Thiomorpholino- und 3-(4-Methylpiperazino)-5-nitroindazole

The structures of 5-nitro-3-thio­morpholino-1H-indazole, C₁₁H₁₂N₄O₂S, (IIa), and 3-(4-methyl­piperazino)-5-nitro-1H-indazole–methanol–water (2/1/1), 2C₁₂H₁₅N₅O₂·CH₃OH·H₂O, (IIIa), are described. In the crystal lattice of (IIa), the mol­ecules are linked into dimers by N—H⃛N hydrogen bonds. The asymmetric unit of (IIIa) contains two independent mol­ecules of the indazole moiety, one mol­ecule of methanol and one of water. The three components of (IIIa) are linked by hydrogen bonds to form double chains running along the x axis. π-Stacking involving the indazole moieties occurs in both compounds.     

Synthesis and 1H-NMR spectra of halogenated spiro[isobenzofuran-1(3H),9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-ones

Reaction of spiro[isobenzofuran-1(3H).9′(9H)-6′-(methylcyclohexylamino)-3′-methyl-2′-anilinoxanthene]-3-one ( 1 ), which is typical leuco fluoran dye, with N-bromosuccinimide and N-chlorosuccinimide leads to halogenated derivatives 2a–2c and 3 , respectively. Their structures were established by two-dimensional proton-proton (COSY) experiment and their thermal properties examined by means of DSC and compared with commercially available 1 .     

Synthesis,spectroscopic, biological,and theoretical studies of new complexes from (E)-3-(2-(5, 6- diphenyl-1,2,4- triazin-3- yl)hydrazono)butan-2- one oxime

New mononuclear Fe (III), Cu (II), Ag (I), ZrO ( IV) and UO₂(VI) complexes were synthesized by the reaction of metal ions with (E)-3-(2-(5, 6- diphenyl-1,2,4- triazin-3- yl)hydrazono)butan-2- one oxime. The structures of the metal complexes were characterized using analytical, spectral (infrared, electronic, ¹H NMR, electron spin resonance (ESR), and mass), magnetic moment, molar conductance, thermal gravimetric analysis, and powder X-ray diffraction (XRD) measurements. All complexes have octahedral geometries except the Cu (II) complex, which has square planar geometry, and the UO₂(VI) complex, in which the coordination number is seven. The ligand acts as a (neutral, monoanionic or dianionic) tridentate with N₂O coordinating sites: N-azomethine, N-triazine, and O-oxime. Fluorescence spectral studies were carried out in solid state and in dimethylformamide (DMF). The kinetic parameters of the thermal decomposition stages were calculated using Coats–Redfern equations. The morphological structures of the ligand and some complexes were determined using XRD. The molecular orbital calculations were carried out for the ligand and metal complexes using the Hyperchem 7.52 program on the basis of the PM3 level. The antimicrobial activities of the ligand and its complexes were investigated towards the microorganisms S. aureus and B. subtilis as Gram-positive bacteria, S. typhimurium and E. coli as Gram-negative bacteria, C. albicans, and A. fumigatus. The ligand and its complexes showed antitumor activity against Hep G-2 cell lines, where Cu (II) and Ag (I) complexes seem to be promising as they showed IC₅₀ values that are lower than and comparable to that of the antitumor drug doxorubicin.     

Synthesis of poly-α,α-diphenylglycine. I. Thermal polymerization of 4,4-diphenyl-Δ2-1,2,3-triazolin-5-one

The thermal decomposition of 4,4-diphenyl-Δ²-1,2,3-triazolin-5-one (I) was reinvestigated and shown to yield poly-α,α-diphenylglycine (III) instead of the previously reported 3,3,6,6-tetraphenylpiperazine-2,5-dione (II). Differentiation between the two structures was made by molecular weight determinations and spectroscopic analyses. The infrared spectra were studied in detail and compared with model compounds. They showed that the absorption peak at 1470 cm^?1 must be attributed to the trans-amide II absorption of the polymer. Furthermore, the polymers were found to contain terminal CONH₂ as well as triazolinone or ether functions (from alcohol). Fractionation was performed in three solvents based on solubility differences: dichloroethane (or chloroform), methanol, and n-hexane. All the fractions were characterized by physical methods. A mechanistic investigation revealed that the polymerization process cannot be rationalized by a radical or cationic mechanism, but is compatible with a molecular mechanism involving triazolinone functions at the growing chain ends.     

微波促进下3-(2-苯并呋喃基)-4-氨基-5-巯基-1,2,4-三唑

微波辐射条件下, 首先由2-苯并呋喃甲酰肼依次与二硫化碳和水合肼反应合成3-(2-苯并呋喃基)-4-氨基-5-巯基- 1,2,4-三唑, 进一步在微波辐射条件下由4-氨基-5-巯基-1,2,4-三唑分别与芳甲酸/芳氧基乙酸、α-溴代苯乙酮及芳醛反应以较高产率制得了相应的1,2,4-三唑并[3,4-b]-1,3,4-噻二唑、1,2,4-三唑并[3,4-b]-1,3,4-噻二嗪及4-芳亚甲基亚胺基-5-巯基-1,2,4-三唑. 产物结构经IR, ¹H NMR, MS及元素分析进行了表征.     

3-芳基-1,2,3,4-噁三唑-5-亚胺与阿司匹林偶联物的合成和抗血栓活性研究

取代苯胺经重氮化、还原得苯肼盐酸盐, 与硫氰酸钾作用得苯基取代的氨基硫脲, 再在亚硝酸异戊酯、盐酸的作用下环合、成盐, 加碱中和后生成3-芳基-1,2,3,4-噁三唑-5-亚胺, 最后与乙酰水杨酰氯反应得目标物6a～6l, 其结构经MS, IR, ¹H NMR和元素分析确证. 体外血小板聚集试验和小鼠肺血栓生成试验结果表明, 部分目标物在体内、外均显示出较好的抗血栓活性, 值得深入进行研究.     

Synthesis and Stereostructure of 3-Amino-5- and -6-hydroxybicyclo[2.2.1]heptane-2-carboxylic Acid Diastereomers

All-endo-3-amino-5-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid and two epimers of 3-amino-6-hydroxybicyclo[2.2.1]heptane-2-carboxylic acid were prepared via 1,3-oxazine or γ-lactone intermediates by the stereoselective functionalization of endo-3-aminobicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. Their structures were proved by IR and NMR spectroscopy, with the use of HMQC, HMBC, DEPT, and DIFFNOE techniques.     

4-(色酮-3-基)-3-乙氧羰基-1,4,5,6,7,8-六氢-5-氧代-2,7,7-三甲基喹啉的一步合成

报道了用3-甲酰基色酮、5,5-二甲基-1,3-环己二酮、乙酰乙酸乙酯与醋酸铵一步法合成4-(色酮-3-基)-3-乙氧羰基-1,4,5,6,7,8-六氢-5-氧代-2,7,7-三甲基喹啉类化合物, 对其结构进行了表征, 并分析了代表性化合物2f的晶体结构. 2f晶体属于单斜晶系, P2/c空间群, 所得晶胞参数为: a＝2.0255(4) nm, b＝0.9132(2) nm, c＝1.4066(3) nm, β＝121.60(3)°, V＝2.2159(8) nm³, Z＝4, D_c＝1.335 g/cm³, μ＝0.209 mm^－1, F(000)＝736, R₁＝0.0556, wR₂＝0.1248.