Unsubstituted Derivatives Research Articles

Separation of α-adrenergic and imidazoline/guanidinium receptive sites (IGRS) activity in a series of imidazoline analogues of cirazoline

To characterize the structure-activity relationship between alpha 1-adrenergic receptors and the family of imidazoline/guanidinium receptive sites (IGRS), we synthesized and characterized a series of analogues of cirazoline, an imidazoline with high affinity for alpha 1-adrenergic receptors and IGRS. Analysis of potency, affinity and efficacy of the synthesized molecules indicate different structure-activity relationships for IGRS and alpha-adrenergic receptors. Cirazoline exhibits a 25-fold higher affinity for IGRS (pKi 7.9) than for alpha 1-adrenergic receptors. Replacement of the cyclopropyl ring with an isopropoxy group resulted in a molecule that was 20-fold more selective for alpha 1-adrenergic receptors than for IGRS, i.e. a 500-fold increase in selectivity relative to cirazoline. The unsubstituted derivative 3 and the methyl and allyl substituted analogues 4 and 12 are of particular interest: compounds 3 and 4 recognize IGRS with high affinity (pKi 7.83 and 8.17) and high selectivity (398 and 123) with respect to the alpha 1-adrenergic receptor; compound 12 also recognizes IGRS with high affinity (pKi 8.08) and high selectivity (228 and 138) with respect to the alpha 2B and alpha 2C-adrenergic receptor subtypes. Thanks to their IGRS selectivity, these compounds represent novel and valuable pharmacological tools for the characterization and elucidation of the physiological role of these novel sites.

Charge-Carrier Evolution in Electrically Conducting Substituted Polymers Containing Biheterocycle/p-Phenylene Repeat Units

The effects of backbone and pendant side-chain structure on the electronic and electrochemical properties of series of poly[1,4-bis(2-heterocycle)-p-phenylenes] have been studied using a combination of optical spectroscopic, electrochemical, and EPR techniques. The selection of the heterocycle (thiophene or furan) and the nature of the pendant groups, substituted at the 2 and 5 positions of the phenyl ring, were found to impart a strong influence on the types and stability of electrochemically created charge carriers. Substitution with long-chain alkoxy substituents results in a decrease in the monomer and polymer oxidation potentials, narrowing of the electronic bandgap relative to unsubstituted or alkylsubstituted derivatives, and the creation of metallic charge carriers at the highest doping levels. Two oxidation states can be clearly resolved in the cyclic voltammograms of these alkoxy derivatives indicating the formation of stable, polaron species at intermediate doping levels. The synthesis of a new monomer, 1,4-bis(2-thienyl)-2,5-bis[(cyclohexylmethyl)oxy]benzene, and its polymer prepared using both chemically and electrochemically induced oxidative polymerization methods are reported. This monomer displays unique electropolymerization behavior with two oxidative redox processes during electrochemical polymerization. The first redox process (onset ca. +0.65 V vs Ag/Ag + ) results in exceedingly slow film growth. Polymer film growth at the second oxidation (onset ca. +0.9 V vs Ag/Ag + ) is ca. 25 times more rapid.

Tyrosine kinase inhibitors. 7. 7-Amino-4-(phenylamino)- and 7-amino-4-[(phenylmethyl)amino]pyrido[4,3-d]pyrimidines: a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor.

The synthesis of 7-aminopyrido[4,3-d]pyrimidines bearing aromatic side chains at the 4-position is reported. These compounds are shown to be a new class of inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR). Structure-activity relationships (SARs) for substitution in both 4-(phenylamino)- and 4-[(phenylmethyl)amino] side chains were determined, using a series of substituents (NO2, Br, CF3, OMe, NH2, and NMe2) selected primarily for their wide range of electronic properties. In the phenylamino series, 3-substituted derivatives were more potent than the corresponding 2- and 4-substituted analogues. For the 3-substituted compounds, activity was favored by electron withdrawal, in a relationship which could be quantified, with the 3-Br being the most potent compound (IC50 = 0.01 microM compared with IC50 = 0.34 microM for the unsubstituted side chain derivative). No such correlation was apparent for the 2- or 4-substituent, although Br was still the best substituent. In contrast, in the 4-[(phenylmethyl)amino] series, substitution of the side chain was not beneficial. For the 4-(phenylamino) series, the substituent SARs are broadly similar to that found previously for 4-(phenylamino)quinazolines. These results suggest that side chain SARs may be broadly invariant over a range of different chromophores, with the side chain of choice for optimization of EGFR inhibitory activity being 4-[(3-bromophenyl)amino].

High affinity and selectivity on 5-HT1A receptor of 1-aryl-4-[1-tetralin)alkyl]piperazines. 2.

Several 4-alkyl-1-arylpiperazines that present a tetralin moiety on the terminal part of the side chain were synthesized in order to increase the selectivity on the 5-HT1A versus D-2, alpha 1, sigma, and other 5-HT receptors. Many changes have been effected on previous structures of type 3(1-aryl-4-[3-(1,2-dihydronaphthalen-4-yl)-n-propyl]piperazines). Several synthetic procedures were followed to obtain the final products, depending on the presence or absence of a double bond, as well as of a heteroatom on the side chain. In the first case versatile use of Grignard reaction was made, whereas in the second one usual synthetic ways were applied. Final compounds were evaluated for in vitro activity on dopamine D-1 and D-2, serotonin 5-HT1A, 5-HT1B, 5-HT1C, and 5-HT2, alpha 1 adrenergic, and sigma receptors by radioreceptor binding assay. For the 2-MeO-Ph, 2-pyridyl, and unsubstituted phenyl N-piperazine derivatives, low IC50 values (0.3 nM) on 5-HT1A receptors and high selectivity values were observed.

Some pyrrolopyrimidine chemistry directed to the synthesis of tricyclic purine analogues

Chemistry directed to the synthesis of the tricyclic ring system 3, a purine analogue with degenerate hydrogen-bonding potential, has been investigated and has resulted in the synthesis of several novel pyrrolo[2,3-d]pyrimidine derivatives as potential precursors. The known analogue 2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-one (7-deazaguanine) is converted by the Vilsmeier reagent into 4-chloro-2-dimethylaminomethyleneamino-6-formyl-7H-pyrrolo[2,3-d]pyrimidine 10. Formylation at the α-position of the pyrrole ring was determined by the comparison of 13C NMR data of the corresponding alcohol and the unsubstituted derivative and is in agreement with the regiospecificity reported for the Mannich reaction of this compound. In contrast, base-catalysed hydroxymethylation of 4-chloro-2-methylsulfanyl-7H-pyrrolo[2,3-d]pyrimidine with formaldehyde in aqueous THF occurs at the desired β-position to afford the 5-hydroxymethyl product 17. 7-Methylation of the ButMe2Si-protected alcohol 17 led to several potential precursors of the desired tricyclic structure. The 5-phthalimidooxymethyl derivatives of either 2-methylsulfanyl- or 4-chloro-7-methyl-2-methylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine with ammonia gave the aminooxymethyl derivatives but these subsequently failed to cyclise. Several approaches to cyclise 4-hydroxyamino-5-hydroxymethyl-7-methyl-2-methylsulfonyl-7H-pyrrolo[2,3-d]pyrimidine 27 afforded the corresponding 4-amino compound as the major component. Both the experimental and modelling results show that considerable strain is associated with the formation of 3.

The cytotoxicity of N-pyridinyl and N-quinolinyl substituted derivatives of phthalimide and succinimide

The N-pyridinyl and N-quinolinyl substituted derivatives of phthalimides and succinimides demonstrated cytotoxicity against the growth of a number of cultured cell lines. The substituted succinimides were more effective than the unsubstituted succinimide derivative in reducing cell growth. On the other hand, phthalimide demonstrated more potent cytotoxicity than its N-substituted derivatives. Three representative examples N-[2-pyridinyl-1-oxide) methyl] phthalimide 8, 1-[N-2-phthalimidoethyl]-3,4-dihydroiso-quinoline 12, and 1-[N-(2-(1,2,3,4-tetrahydro-2-quinolinyl)] ethylphthalimide 14 were shown to inhibit L1210 leukemia DNA synthesis whereas RNA synthesis was not inhibited at 25-100 uM. All three agents inhibited the activities of DNA polymerase alpha, PRPP-amido transferase, nucleoside kinases, and dihydrofolate reductase. The cellular pool levels of d[GTP], d[CTP], and d[TTP] were reduced after 60 minutes incubation at 100 uM. The DNA molecule itself was not a target of these agents.

1,2,3-Triazole-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO) analogues: synthesis and anti-HIV-1 activity.

Several 4- or 5-monosubsituted and 4,5-disubstituted 1,2,3-triazole analogues of the anti-HIV-1 lead compound [1-[2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D- ribofuranosyl]thymine]-3'-spiro-5"-(4"-amino-1",2"-oxathiole 2",2"-dioxide) (TSAO-T) have been prepared and evaluated as inhibitors of HIV-1-induced cytopathicity. These analogues have been prepared by 1,3-diplar cycloaddition of [2,5-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]- 3-spiro-5'-(4'-amino- and 4'-(N-acetylamino)-1',2'-oxathiole 2',2'-dioxide) (TSAO) azides to various substituted acetylenes. Several 4- and 5-substituted 1,2,3-triazole-TSAO analogues proved superior to the unsubstituted derivative by 1-2 orders of magnitude. In particular the 5-substituted amido-, (methylamido)-, and (dimethylamido)-1,2,3-triazole derivatives of TSAO were endowed with potent anti-HIV-1 activity (50% effective concentration: 0.056-0.52 microM). They show a similar resistance spectrum as previously noted for TSAO-T and related derivatives.

Far infrared spectra of mono- and bisphthalocyanine derivatives

The far infrared spectra of a series of unsubstituted monophthalocyanine (Pc) and di-Pc derivatives and some of the corresponding tetra-tert-butyl substituted Pc molecules are reported. The infrared data were recorded between 100 and 4.50 cm−1. The vibrational assignment of metal-nitrogen stretching frequencies is discussed. The far infrared data for tert-butyl Pc derivatives and a group of C4ν Pc complexes are presented here for the first time.

2,2'-Di-O-acetyl-3,6;3',6'-dianhydro-4,4'-dideoxy-α,α-trehalose

The structure of 2,2'-di-O-acetyl-3,6;3',6'-dianhydro-4,4'-dideoxy-α,α-trehalose (2-O-acetyl-3,6-anhydro-4-deoxy-α-D-xylo-hexopyranosyl 2-O-acetyl-3,6-anhydro-4-deoxy-α-D-xylo-hexopyranoside), C 16 H 22 O 9 is described. The molecule has approximate twofold symmetry through O(1). Both pyranoid rings have distorted 1 C 4 chair conformations and the five-membered anhydro rings have distorted 4 E conformations. The structure of the compound appears to show the absence of a sweet AH,B glucophore, which would explain the absence of sweetness in the unsubstituted derivative

Thermal ring opening of diphosphiranes: experimental and theoretical approaches

Thermal ring opening of diphosphiranes 1a-g leading to 1,3-diphosphapropenes 2 by preferential P-P bond rupture is investigated. The experimental approach indicates that the regio- and stereoselectivity of the reaction depend on the nature of the ring substituents. For the unsymmetrical functionalized diphosphiranes 1a,b only the trans-syn diphosphapropenes 2a,b are quantitatively obtained whereas for 1c-f the resulting trans-gauche diphosphapropenes are the major products. In addition to the trans diphosphapropenes, the corresponding cis isomers are formed for 1e,f. The theoretical calculations (MNDO and ab initio) performed on unsubstituted derivatives reveal two preferred mechanisms involving exo-exo biradical or exo-endo radical intermediates

Synthesis of water soluble sulfur-bridged molybdenum dimers with substituted cyclopentadienyl ligands

The ester substituted cyclopentadienyl ligand C[sub 5]H[sub 6]CO[sub 2]CH[sub 3][sup [minus]] was used in the synthesis of dinuclear molybdenum complexes with bridging sulfur ligands. New derivatives include [MeO[sub 2]C-CpMoSC[sub 2]H[sub 4]S][sub 2], 3, [MeO[sub 2]C-CpMoSCHCPhS][sub 2], 4, and [MeO[sub 2]C-CpMo)[sub 2](S[sub 2]CH[sub 2])(SC[sub 2]H[sub 4]S)], 7. Analogous dinuclear complexes with one ester substituted and one unsubstituted Cp ligand have also been isolated and characterized. The base hydrolysis reaction of 7 leads to the formation of the water soluble derivative (NaO[sub 2]C-CpMo([mu]-S))[sub 2]S[sub 2]CH[sub 2], 9. A second water soluble derivative containing three carboxylate substituents, (NaO[sub 2]C-CpMo([mu]-S))[sub 2]S[sub 2]C(H)CO[sub 2]Na, 11, was also synthesized and characterized. The formyl substituted cyclopentadienyl ligand was used in the preparation of new dinuclear molybdenum derivatives, including (OHC-CpMoSC[sub 2]H[sub 4]S[sub 2], 13, and [OHC-CpMoSC[sub 2]H[sub 2]S][sub 2], 14. Spectroscopic data for the new complexes are presented. The reactivity of the new series of complexes has been surveyed and found to be qualitatively similar to that of the unsubstituted cyclopentadienyl derivatives. The new products will permit a more detailed study of solvent and substituent effects on sulfur ligand reactivity. 16 refs., 2 tabs.

Indoles XI. Syntheses and Stereochemistry of 5,6,7,8,13,13b-Hexahydrobenz[a]indolo[2,3-h]quinolizines and of 5,6,7,8,13,13b-Hexahydro-14H-bisindolo[3,2-a][2,3-h]quinolizine

A new and efficient synthesis of substituted 5,6,7,8,13,13b-hexahydrobenz[a]indolo[2,3-h]quinolizines (5b,d) via lactamisation of dihydropyrano[3,4-b]indol-1-one (3), cyclisation with phosphorus oxychloride and reduction with sodium borohydride is described. The unsubstituted 5,6,7,8,13,13b-hexahydrobenz[a]indolo[2,3-h]quinolizine (5) is prepared by analogy starting with the lactamisation of isochromanone with tryptamine. The unsubstituted 5,6,7,8,13,13b-hexahydro-14H-bisindolo[3,2-a][2,3-h]quinolizine (9) is synthesized by lactamisation of 3 with tryptamine, cyclisation and again reduction of the intermediate immonium salt. The stereochemistry of the unsubstituted quinolizine derivatives is investigated by 1 H-, 13 C-nmr-, NOE spectroscopy and by X-ray analysis

Relationships between nitro group reduction potentials and torsion angles in di-ortho-substituted nitrobenzenes; a crystallographic and oxygen-17 NMR study

A series of 3-nitro-4-alkylbenzamides has been prepared, and the effects of nitro group torsion angle on reduction potential studied. Nitro and carboxamide group torsion angles have been determined by 17O NMR spectroscopy and X-ray crystallography, and one-electron reduction potentials by pulse radiolysis. 17O Chemical shifts indicated similar amide torsion angles (from 35° to 45°) as the alkyl group varied from hydrogen to tert-butyl, but widely differing nitro group torsion angles; from 36°(hydrogen) to 92°(tert-butyl). Crystal structures of the isopropyl and tert-butyl derivatives indicate amide group torsion angles (50° and 64°) somewhat larger than those predicted by 17O NMR, and nitro group torsion angles (59° and 65° respectively) considerably smaller than those predicted by 17O NMR (75° and 92° respectively). These results support earlier data that 17O chemical shifts predict for erroneously large nitro group torsion angles in non-rigid but sterically crowded molecules, because of additional contributions to the shift from van der Waals repulsions. The drop in reduction potential of 90 mV between the unsubstituted and tert-butyl derivatives is too large to be accounted for by the electronic effects of the alkyl groups, and indicates that increasing the nitro group torsion angle significantly lowers reduction potential.

Novel thieno[2,3- b]- and [3,4- b]pyrans as potassium channel openers. Thiophene systems—XVII

The syntheses and antihypertensive activity of the thieno[3,4- b]pyran and thieno[2,3- b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (± 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2- b] series increased potency. Similar substitution on the thieno[3,4- b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (± 1).

ChemInform Abstract: Structurally Simplified Squalestatins: A Convenient Route to a 6,7‐ Unsubstituted Derivative.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Studies on Specific Inhibition of Benzodiazepine Receptor Binding by Some C-Benzoyl-1,2,3-triazole Derivatives

Certain new (1–15) or previously described (16-25) 1,2,3-triazole derivatives, characterized by a C-benzoyl substituent, were synthesized and tested for their ability to displace [3H]flunitrazepam from bovine brain membrane. Compounds 11a and 9a, bearing neutral and lipophilic substituents (phenethyl and cyclohexyl, respectively) showed the higher activity. The 5-benzoyl isomer 11b presented a lower activity, equivalent to that of the triazole acetic derivative 23, which is 4-benzyl substituted. Generally, the carboxymethyl radical in the 1-position of the triazole ring decreased the activity, probably because of intramolecular hydrogen bonding with the carbonyl function of the benzoyl substituent. The N-1 unsubstituted triazole derivatives 24 and 25 were ineffective; this result is in disagreement with our previous observations. Probably these molecules interact with the receptor site by a hydrogen bonding acceptor group and by a bulky and lipophilic portion or a hydrogen bonding donor function that is appropriately arranged.

6-Unsubstituierte 2H-Pyran-2-one Synthese und Reaktivität

Although the 2H-pyran-2-ones have been known for more than 100 years, their importance as versatile intermediates was not widely recognized before the sixties of this century. Until then, the C(6)-unsubstituted derivatives represented only a small minority due to their difficult accessibility. This review is dealing in the first part with the syntheses as well as, in the second part, with the reactivities of most of the C(6)-unsubstituted 2H-pyran-2-ones known so far. Of all reactions of the 2H-pyran-2-ones, the Diels-Alder cycloaddition is the most studied. Depending on conditions, the 2H-pyran-2-one ring can react as dienophile or as enophile. Furthermore, the subsequent elimination of CO2 from the formed bicyclolactone can frequently be influenced. This opens the opportunity of stereoselective syntheses. Recently, there were also reports on [4+3] and [3+2] cycloadditions. The photochemistry of the 2H-pyran-2-ones was studied intensely in the seventies of this century. Again, the enormous versatility of this ring system was demonstrated. Depending on conditions and substituent patterns, some ring contraction, ring opening, or dimerization by [4+4], [2+2], or [4+2] cycloaddition occurs. However, the highest variability in the reactivity of the C(6)-unsubstituted 2H-pyran-2-ones is demonstrated in their reactions with nucleophiles. These reactions, mostly accompanied by ring opening, give different, often otherwise difficultly accessible products depending on the conditions. The reactions with N-nucleophiles were the most productive so far, but also H-, O-, and C-nucleophiles gave interesting products. In recent years, much more became known about the synthesis and reactivity of C(6)-unsubstituted 2H-pyran-2-ones. This opened further possibilities of their applications in all fields of modern organic synthesis.

An improved synthesis of 3-(1,1-dimethylallyl)coumarins

The syntheses of several 3-(1,1-dimethylallyl)coumarins, simple or bearing additional furan or pyran rings is achieved starting from the corresponding C-3 unsubstituted derivatives. The key step involves Ireland-Claisen rearrangements of allyl esters.

Spectroscopic properties and photopolymerization activities of water soluble 1-substituted derivatives of 2-hydroxy-3-(9-oxo-9 H-thioxanthene-4-yloxy)- N, N, N-trimethyl-1-propanaminium chloride salt

The spectroscopic, photochemical and photopolymerization properties of four novel 1-substituted water soluble 2-hydroxy-3-(9-oxo-9 H-thioxanthene-4-yloxy)- N, N, N-trimethyl-1-propanaminium chloride salts are examined. From absorption and fluorescence and phosphorescence analysis substitution in the 1-position by halogen groups induces more charge-transfer character than aliphatic alkyl groups. The photoreduction quantum yields of all the 1-substituted derivatives in the presence of a tertiary amine are lower than that for the unsubstituted derivative which is again indicative of the higher degree of charge-transfer content of the lowest excited states. The reduced activity of the 1-substituted derivatives is also reflected in the microsecond flash photolysis data on radical and radical anion formation. The addition of a tertiary amine, however, enhances the formation of both species probably due to triplet exciplex formation. Photopolymerization and photoinitiation rates for acrylamide are also reduced by 1-substitution. The data are discussed in terms of the nature of 1-substitution increasing the degree of charge-transfer character of the lowest excited singlet and triplet states.

Brominated short-chain basket-handle porphyrins and their copper(II) derivatives: spectral and electrochemical studies on the effect of β-substitution versus distortion

Pyrrole-brominated short-chain basket-handle porphyrins and their copper(II) derivatives have been synthesized and characterized. These porphyrins are significantly distorted and the β-substitution by bromines further enhances the degree of distortion. Optical absorption and electrochemical sudies reveal considerable shifts in the energies of absorption maxima and electrode potentials. An analysis of these shifts indicates significant changes in the energies of the highest-occupied (HOMO)[a1u(π) and a2u(π)] and lowest-unoccupied molecular orbitals (LUMOs)[eg(π*)] of the porphyrin ring upon β-substitution and distortion. Specifically: (a) both distortion and β-substitution decreases the energy gap between the HOMO and LUMO due to different stabilization/destabilization mechanisms and (b) the magnitude of separation between a1u(π) and a2u(π) is large for β-substitution while it is small for distortion relative to the corresponding planar unsubstituted derivative. The absorption and redox potential shifts show a non-linear behaviour with the number of bromine substituents and this is ascribed to the combined effect of antagonistic inductive interactions and steric hindrance. ESR spectral studies indicate weakening of the Cu–N σ bond without much change in the electronic structure of Cu2+.