Thesis (M.Sc.) -- University of Adelaide, Dept. of Organic Chemistry, 1972.

Thesis (M.S.)--Worcester Polytechnic Institute. / Keywords: synthesis, photochemistry, pyranopyrazoles. Includes bibliographical references (p.305-306).

Univ., Diss.--Rostock, 1916.

Several uninegative ligands based on a gallium core and incorporating pyrazolyl groups have been synthesized and their metathesis reactions with molybdenum, rhenium and rhodium halides have been studied. The bidentate pyrazolylgallate ligand [formula omitted] has been incorporated in the complexes [formula omitted]. The unsymmetric tridentate pyrazolylgallate ligands [formula omitted] display a variable reactivity towards molybdenum, rhenium and rhodium precursors. Although no complexes incorporating L⁴ were isolated, L₂ and L₃ were shown to co-ordinate facially in the octahedral complexes [formula omitted] and [formula omitted]. In addition, a meridional co-ordination geometry of L₂ has been structurally characterized in the square planar rhodium(I) complex, L₂Rh(CO). This co-ordinatively unsaturated rhodium(I) species was shown to undergo an interesting oxidative addition reaction with methyl iodide followed by a methyl migration reaction to give a rhodium(III) acetyl derivative. Less predictable products have also been obtained in this study; these include the dimeric species [formula omitted] formed from the reaction of NaL₃ with [formula omitted] and also an unexpected chlorine-containing complex, [formula omitted] from the reaction of [formula omitted]. [formula omitted] the product of the reaction between [formula omitted]. [Formula omitted] (the precursor of Ld) has been structurally shown to possess a novel eight-membered Ga-(N-C-S)₂-Ga ring. / Science, Faculty of / Chemistry, Department of / Graduate

Two different synthetic approaches to the synthesis of pyrano[2,3-c]pyrazoles have been investigated. In one approach, dehydroacetic acid derivatives were treated with phenylhydrazine and methylhydrazine led to the formation of the phenylhydrazones and methylhydrazones, which undergo rearrangement in refluxing acetic acid to diketo-phenylpyrazoles and diketo-methylpyrazoles. Upon treatment with a mixture of acetic and sulfuric acid these compounds isomerize to the phenylpyrano[2,3-c]pyrazol-4-one and methylpyrano[2,3-c]pyrazol-4-one derivatives. In a second approach, phenylhydrazine and methylhydrazine reacted with dimethyl(methoxymethylene)malonate (34) to give phenylpyrazole and methylpyrazole ester derivatives which were converted to phenylpyrazolone and methylpyrazolone by hydrolysis and decarboxylation. C-acylation of these compounds with trans-cinnamoyl chloride gave á,â-unsaturated-4-acetyl-5-hydroxypyrazoles. Bromination of these á,â-unsaturated-4-acetyl-5-hydroxypyrazoles with spontaneous cyclization, followed by dehydrobromination led to pyrano[2,3-c]pyrazol-4-one derivatives, respectively. Phototochemical excitation of 1-phenyl and 1-methylpyrano[2,3-c]pyrazol-4-ones in acetonitrile led to the formation of cis-head-to-tail [2+2] cycloaddition products. Irradiation in ethanol solvent led to photodimerization and to photofragmentation to yield pyrazole ethylesters.

A series of penta-aryl/alkyl-1-(toluene-4-sulfonyl)-4,5-dihydro-1H-pyrazole 5a-c was synthesized by addition of methyllithium or phenylllithium followed by trapping the nitrogen anion intermediate with tosyl-fluoride to cyclic azines 2a,b. Addition of methyllithium or phenyllithium to 5a-c generated a series of hexa-aryl/alkylsubstituted-4,5-dihydro-3H-pyrazoles 6a-c. Neat thermolysis of hexa-aryl/alkylsubstituted-4,5-dihydro-3H-pyrazoles 6a-c at 200◦C produced hexa-aryl/alkylsubstituted cyclopropanes 7a-c in high yield.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009.

Chapter 1 of thesis is a literature review of adenosine research. The central importance of the contributions of both classical pharmacology and, more recently, molecular biology to adenosine research is demonstrated. These disciplines have enabled the classification and characterisation of adenosine receptors and as well an understanding of the physiological significance of endogenous adenosine. The significant benefits of developing therapeutics for regulation of the diverse physiological functions of adenosine, by regulation of adenosine receptors, is outlined. For this therapeutic potential to be realised both high affinity and subtype selective adenosine agonists and antagonists are required. The structure-activity relationships for agonists and xanthine antagonists are discussed. The assimilation of these structure-activity relationships have guided the development of ligand based models of the adenosine receptor pharmacophore. The 'flipped', 'N6-C8' and 'three binding domain' models were described. These models aim to direct the future design of high affinity and selective ligands for adenosine receptors. The development of receptor based models by modelling of the receptor-ligand complex is also presented. The main body of this thesis presents a study of the structure-activity relationships for pyrazolo(3,4-d) pyrimidines binding to adenosine Ai and A2a receptors. Prior to this study few non-xanthine adenosine antagonists had been well defined or optimised in terms of structure-activity relationships. However, the value of such ligands is immense, facilitating further definition of structural requirements for high affinity and selective adenosine receptor binding. These ligands should complement existing agonists and xanthine antagonists in developing an understanding of adenosine receptor binding. The experimental approach to development of the lead compound of this study, a-(6-(l'-carbamoylethylthio)- l-phenylpyrazolo(3,4-d)pyrimidin-4-ylthio)propanamide (5), is outlined in Chapter 2 of this thesis. 5 is substituted at C-4, C-6 and N-i of the pyrazolo(3,4-d)pyrimidine heterocycle. The experimental approach to optiniising 5 was approached in a rational manner, requiring an iterative approach i.e. design of generation I target compounds --synthesis -- biological evaluation -- structure-activity relationships -- design of generation II target compounds, etc. Chapters 3, 4 and 5 of this thesis describe this experimental approach as it relates to optimising the lead compound, 5, for adenosine receptor affinity and subtype selectivity. The importance of receptor interactions with multiple ligand domains, to achieve both potency and selectivity, was recognised so that optimisation of the C-4, C-6 and N-i substituents of the lead compound was targeted and achieved. Previous structure-activity studies with agonists and xanthine antagonists have concentrated on modifying a single ligand domain. Chapter 3 presents twelve generation I target compounds to examine C-4 and C-6 substituent structure-activity relationships. Chapter 4 presents twelve generation II target compounds to further examine C-4 and C-6 substituent structure-activity relationships. Chapter 5 presents sixteen generation ifi target compounds to examine N-I substituent structure-activity relationships. A major outcome from the research presented in these chapters was the development of highly potent and highly selective ligands for the adenosine A1 receptor subtype. a(4-Methylamino- I -phenylpyrazolo(3,4-d)pyrimidin-6-ylthio)hexanamide (29) was the most potent ligand at the Ai receptor identified in this study, and is one of the most potent Ai selective antagonists ever reported. 29 has an A1 K1 value of 0.745±0.045 nM and is 332-fold selective for the A1 receptor over the A2a receptor. a-(1-Phenyl-4-propylthiopyrazolo(3,4-d)pyrimidin-6-ylthio)butanainide (27) was the most selective ligand of this study. It is four orders of magnitude selective for the A1 receptor (up to 16900-fold), and one of the most selective antagonists ever reported. This high selectivity has been achieved with the maintenance of good A1 affinity (A1 K1 = 29.5±6.6 nM). These results prove the value of modifying multiple substituents of adenosine receptor ligands, generating ligands which bind with high potency and selectivity to adenosine Al receptors compared to adenosine A2a receptors.

Thesis (Ph. D.)--University of North Texas, Dec., 2007. / Title from title page display. Includes bibliographical references.

The x-ray structures of several alkyl halide, alkyl dihalide, and hydrogen adducts to pyrazolyl-bridged diiridium complexes [special characters omitted] are determined. The diiridium (bis-pyrazolyl) core of these complexes enables contact between the two centers so that metal-metal bond formation may occur, exemplified by a short iridium-iridium distance of 2.78(I) A in the diiridium(II) complex [special characters omitted]. Oxidation mechanisms are postulated based on reaction kinetics. The oxidative addition of methyl iodide to [special characters omitted] is observed to occur by a two-step mechanism, where a high positive ΔS‡ term may be due to a highly ordered intermediate. This is proposed as evidence for an [special characters omitted] addition, where coordination of the alkyl halide is followed by halide dissociation and migration to a trans diaxial coordination site. Different kinetics of the reaction are observed in THF and benzene, which is also attributed to a polar [special characters omitted] intermediate. Occupation of the 3,3’ and 5,5’ positions of the pyrazolyl ligand decreases the reaction rate by an order of magnitude or greater, which indicates steric inhibition of the reaction by the bridging ligands. Experimental evidence for a competing light-induced reaction that corresponds to a radical-chain mechanism rather than the dark [special characters omitted] reaction is also presented. Oxidative isomerization of an iodo (iodomethylene) complex to the methylene-bridged isomer is determined to be an intramolecular process based on isotope labelling experiments and kinetics. Negligible isomerization to the bridging methylene complex under ambient conditions is attributed to coordinative saturation; the stability of [special characters omitted] is likewise due to coordinative saturation of the metal centers. The addition of hydrogen or hydride to [special characters omitted] is possible through a number of synthetic routes, but the stereochemistry of the iridium(II) hydrido complexes is such that the metal-hydride and iridium-iridium bonds do not occupy coordination sites trans to each other: it is proposed that the strong σ-trans effect of the hydride induces structural rearrangements in substitution reactions so that stereochemistry of parent complexes is not conserved. This is demonstrated by the x-ray structures of [special characters omitted]. The hydride ligand promotes nucleophilic attack on an electron-rich iridium center; thus water and other Lewis bases are found to react with the cationic diiridium hydride complex [special characters omitted]. / Graduate