Structure activity relationships of 1,8-disubstituted thioxanthenones.

Lucanthone, a thioxanthenone bearing a diethylaminoethylamino substituent, is orally active against Schistosoma mansoni infections in man. The structure-activity relationships of lucanthone and related compounds have been extensively investigated and the need for a 1-dialkylaminoalkylamino substituent and 4-methyl group established. The symmetrical nature of the thioxanthenone ring presents an opportunity for producing 1,8-disubstituted compounds which may possess enhanced biological activity. To investigate this situation a series of 1,8-di(dialkylamino-alkylamino)-4-methylthioxanthen-9-ones and 1,8-dipiperazinyl-4-methylthioxanthen-9-ones have been prepared from l,8-dichloro-4- methylthioxanthen-9-one. The latter compound has been synthesised from 2-chloro-6-nitrotoluene and from 2-amino-4-chlorotoluene. In the course of this work it was established that selective dehalogenation of 1,8-dichloro-4-methylthioxanthen-9-one occurred and this resulted in the isolation of a series of 1-substituted alkylamino-alkylamino- and piperazinyl-5-methylthioxanthen-9-ones. The structures of these compounds were elucidated by their n.m.r. and mass spectral properties. In addition an unambiguous synthesis of the parent l-[[2- (diethylamino)ethyl]amino]-5-methylthioxanthen-9-one from l-chloro-5-methylthioxanthen-9-one confirmed the site of dehalogenation at C-8. The biological activity of these compounds has been examined by means of the heat denaturation profile of native DNA and by assessment of their schistosomicidal activity in experimental S.mansoni infections in mice. The results obtained show that 1,8-di(diethylaminoethylamino)- and 1,8-di(dimethylaminoethylamino)-substitution leads to an increased DNA interaction compared with lucanthone. A mechanism of interaction with DNA consistent with a proposed intercalation model is discussed for the 1,8- and 1-substituted methylthioxanthenones. Enhanced schistosomicidal activity was found for l,8-di[[2- (diethylamino)ethyl]amino]-4-methylthioxanthen-9-one against S.mansoni infection in mice compared with lucanthone. The occurrence of activity with l-[[2-(diethylamino)ethyl]amino]-5-methylthioxanthen-9-one has demonstrated that the presence of a methyl group para to the basic side chain in lucanthone and related compounds is not an absolute requirement for schistosomicidal activity

Helical flow of non-Newtonian fluids, with reference to drilling fluid flow.

This thesis Is motivated by a desire to understand better the complex flow of drilling fluids in oil wells. After an initial discussion of the flow and its complexities, mathematical models are considered, and a 'helical flow' model adopted as being a reasonable approximation to the flow which may be solved in practice. Rheological models for the fluids are discussed, and it is shown that, with helical flow, a shear rate dependent viscosity model is of considerable generality. Numerical methods for obtaining velocity profiles from these models are explored and it is suggested that an iterative finite difference procedure is the most suitable to the purpose of understanding better the flow of drilling fluids. The iterative finite difference procedure is implemented in a computer program 'MUDFLO' which can be operated using either a consistent dimensioned system of units, or using the dimensionless variables defined in the text. It is shown that three dimensionless parameter groups are sufficient to describe completely the helical flow of a power law fluid. A set of velocity profile graphs is presented, covering typical values of these three parameter groups. From this set of graphs, the velocity profiles for most practically occurring flows of power law fluids may be interpolated. Some computational difficulties are however reported in calculations using the Bingham plastic fluid model, and using the power law fluid model with very low fluid index. The results of the computer program withe the power law fluid model are supported by comparison with existing experimental data, and by discussion of the general characteristics of the set of dimensionless velocity profile graphs

The thermal degradation of polystyrene.

A review is made of the thermal degradation of polystyrene. In a theoretical study the importance of intramolecular transfer during degradation is emphasized in the formation of oligomeric volatiles. To account for past experimental results a mechanism is proposed involving biradical cage combination. The presence of weak links in thermally-initiated polystyrenes cannot be accounted for in terms of peroxidic links incorporated into the polymer chains. However such links do reduce the thermal stability of the polymer. The degradation pattern of polystyrenes containing initiator fragments at the chain-ends is different from that of thermally-initiated or anionic samples. The results are explained in terms of the relative strengths of the chain-end and internal chain bonds. The presence in the polymer of the inhibitor diaminoanthraquinone supports the explanations for the behaviour of thermally- and benzoyl peroxide-initiated polystyrenes. A significant degree of recombinations is shown to take place after chain scission. The volatilisation behaviours of a thermal polystyrene and low RMM benzoyl peroxide-initiated polymer are studied. The loss of carbonyl-containing structures from the polymer residue is correlated with the gain of these structures in the volatiles. Comparisons are made throughout of the thermal stabilities of the various groups of polystyrenes used. Also the assumptions of the theory used to relate intrinsic viscosity to degree of degradation are shown to be essentially correct. Finally some suggestions are made for further work

The syntheses and reactivity of 6- and 8-azaindolizines.

Synthetic routes leading to indolitine and its mono-aza derivatives, and the reactivity of these systems have been briefly reviewed. A number of simple alkyl, aryl, methoxy and chloro substituted 6- and 8- azaindolizines have been synthesised via the Chichibabin reaction between suitably-substituted 2- or 4- methylpyrimidines and alpha-bromo ketones. The structures of the products obtained have been confirmed spectroscopically, principally by 'H NMR spectroscopy, and by formylation procedures. The reaction between 2,4,6-trimethylpyrimidine and phenacyl bromide has been showm to yield a 6-azaindolizine structure rather than an 8-azaindolizine structure as previously reported. The reaction between 2-methylpyrimidine and ethyl bromopyruvate gave 2-carbethoxy-8-azaindolizine, which gave the parent 8-azaindolizine system on hydrolysis and decarboxylation. Formylation of 6-azaindolizines bearing a C-5 methyl group gave - along with their formyl derivatives - 5-azacycl[3,2,2]azine structures, which were also synthesised by 1,3-dipolar addition reactions betvieen dimethyl acetylenedicarboxylate and 6- or 8- azaindolizines. An examination of the 'H NMR spectra of 6- and 8- azaindolizines in trifluoroacetic acid showed both systems to have a preference for protonation at their non-bridgehead nitrogen atoms, although partial carbon protonation at C-3 was observed in a number of alkyl derivatives. The protonation of 6- and 8- azaindolizinones and 5-azacycl[3,2,2]azines was also investigated. Formylation of 6- and 8- azaindolizines occurred preferentially at C-3 and then at C-1. A number of other electrophilic substitution reactions on 2,7-dimethyl-8-azaindolizine also occurred at C-3. Nucleophilic replacement of chlorine by methoxide from a 5-chloro-6-azaindolizine and a 7-chloro-8-azaindolizine occurred readily. Ammonolysis and hydrolysis were, however, only successful in the case of the former compound. These experimentally-determined sites of reactivity in 6- and 8- azaindolizines are in accord with those predicted from reported pi-electron density calculations. Formylation of 5-amino-7-methyl-2-phenyl-6-azaindolizine gave a 4,5-diazacycl[3,2,2]azine structure, and refluxing a solution of 7-methyl-2-phenyl-6-azaindolizin-5(6H)-one in phosphoryl chloride gave a peri-condensed di(6-azaindolizino)pyrazine

Growth of a silicon-gallium phosphide heterojunction by liquid and vapour phase epitaxial techniques.

As the innovation of the semiconductor industry proceeds the semiconductor heterojunction is playing an increasingly important part. One such heterojunction, the silicon/gallium phosphide crystal, however, is still in early stages of investigation. If gallium phosphide epitaxial layers can he grown on to silicon substrates then, due to the small cost of the silicon substrates and the electroluminescent properties of the gallium phosphide layer, low cost L E D's could be produced. The gallium phosphide display and the silicon display driver could also be incorporated on the one chip. With the reduction in mechanical bonds and the elimination of seperate packaging, resulting, the reliability of these devices would be improved, while the cost would drop. This project therefore sets out to investigate the growth of the silicon/gallium phosphide heterojunction. The fabrication methods chosen are liquid and vapour phase epitaxy. These methods are executed using a vertical furnace system and the advantages and disadvantages encountered are discussed

Computer aided analysis of electric circuits using state-variable techniques.

There are three main tasks that a computer program based on state-variable analysis must perform: 1) formulation of a degenerate system of equations; 2) processing of these equations until they eventually become the state equations; 3) the solution of the state equations. The first task requires the computation of a topological tree and its associated tie-set matrix. This can be done using either matrix or search methods. Degenerate variables can then be eliminated using Pottle's method or the Auxiliary Trees method, which is based on Bashkow's work. The solution of the state equations can be accomplished using: 1) an Adams-Bashforth-Moulton predictor corrector method; 2) a Runge-Kutta method (e.g. England's method); 3) Certaine's method of transition matrices; 4) methods suitable for use with systems containing equations with widely separated time constants, known as Stiff equations (e.g. Gear's method). It was found that the formulation of the degenerate system of equations was relatively easy to program, but the elimination of degenerate variables from the main system of equations proved more difficult to program. Additionally, the solution of the state equations gave rise to problems that were sometimes difficult to diagnose. Apart from one problem that could not be resolved using Certaine's method, all test networks containing capacitors, resistors, inductors and independent sources were solved. However, test circuits containing linearly-controlled sources failed without exception when a row of the augmented matrix contained all negative elements - this gave rise to transient responses of the right shape, but grossly distorted in magnitude. Program FOFSVM5 was based on Bashkow's topological formulation of the state equations and uses the Auxiliary Tree method of eliminating the degenerate variables from the main system of equations. It is hoped that FOFSVM5 can be used to investigate integrated circuits in future, subject to various improvements

System simulation using digital stochastic computing structures.

This thesis is a detailed study of the potential applications of digital stochastic computers. In particular, this work has considered the simulation of stochastic networks using digital computer software written in FORTRAN. The study of these networks was aided by hybrid computer simulations which were used to check on the stability of stochastic networks. The introduction to the thesis compares and contrasts analogue, digital, hybrid and stochastic computers. A close comparison is made between digital stochastic computers and other forms of parallel digital computers such as the Digital Differential Analyser and the phase computer. In chapter 1 the single line, symmetric, bipolar representation was chosen as the most economical method of representing problem variables in terms of hardware. Thus, the stochastic operators presented in this chapter are based on the bipolar mapping. The mathematics used is uncomplicated and the behaviour of digital circuits containing counters has been approximated by linear and non-linear differential equations in the main text. More precise analyses of digital circuits are to be found in the appendices but it was found that these studies yielded no more information than the approximate methods and were much more awkward to manipulate. Chapter 2 is concerned with developing software written in FORTRAN to simulate the operation of the basic stochastic operators. The random number generator used in these simulations is based on the Lehmer Congruence method and a detailed account of its properties is given with particular reference to the ELLIOT 4120 digital computer for which the software was written. The stochastic operators simulated include the negator, summer, multiplier, squarer, integrator and output interface. Some simple circuits involving the basic operators were investigated in chapter 3. These circuits included networks for square-root extraction, the solution of a linear equation, examining the transient behaviour of a second order stochastic system and sine/cosine generation. The second order system highlighted a problem which was not taken into account in the original definition of stochastic computation. Simple mathematical models are used to explain the transient behaviour of each circuit simulated. In chapter 4 two simple circuits for solving sets of linear equations were investigated. The first is based on an error criterion and the second circuit uses the method of steepest descent. Each circuit is analysed as a continuous system in the main text, but a discrete time analysis of each network is given in the appendices. Close attention is paid to the stability and convergence of each method. A well known linear programming algorith is adapted for use on a stochastic computer in chapter 5. This study also demonstrates the way in which threshold switching is obtained in the stochastic computer. The problem examined in this chapter is a maximisation problem but the mathematics can be easily altered to cope with a minimisation problem. Circuits for determining the parameters of first and second order systems were investigated in chapter 6. The circuit for identifying the parameters of a first order system revealed a difficulty in scaling when the method of steepest descent is used to identify system parameters but a procedure is adopted which overcomes this problem. An alternative algorithm for identifying a first order system was successfully demonstrated. The second order system was used to demonstrate the kind of difficulty which might be encountered when using a stochastic computer for parameter identification, namely induced oscillation arising from the random variance inherent in the stochastic computation method. These studies were extensively aided by hybrid computer simulations of the steepest descent algorithm. As a result of the simulation work carried out on the first order system identification a new output interface, the non-linear adaptive digital element, is proposed and this circuit is analysed in detailed in appendix 6.C. Chapter 7 is a review of the work discussed in the previous chapters and presents suggestions for further work with particular reference to Markov chains and systems which are inherently stochastic

The construction of an ellipsometer to measure the refractive index and thickness of thin films.

The ellipsometer, like all precision optical instruments, is a delicate piece of equipment requiring care in its construction, maintenance and operation. Since multiple reflections and birefringence in the optical components introduce large instrumental errors, a correct choice of component parts must be made so as to minimise these effects. This thesis is an account of the construction of an ellipsometer for use in measuring the thickness and refractive index of thin dielectric films. An attempt has been made to rationalise the mathematical approach and to present a valid method for the evaluation of results. The first Chapter is a general introduction to methods for measuring the thickness and/or refractive index of thin films and surfaces. Chapter 2 develops the fundamental equation of ellipsometry from the problem of reflection and refraction of light at a boundary between two homogeneous, isotropic media, and reflection from a film-covered surface. The construction and choice of components for the ellipsometer is outlined in Chapter 3 while in Chapter 4 the alignment of the instrument and the various components, is discussed. Chapter 5 introduces the relationship between the parameters of ellipsometry and presents various data handling methods as well as the computer program used in this thesis. An evaluation of the instrument is given in Chapter 6 with actual results taken using the instrument and the order of accuracy found

Automatic transcription of keyboard music.

The aim of this system is to produce an automatic transcription of music played on any keyboard instrument. Work undertaken is divided into 2 sections. Firstly, the keyboard is monitored and information is stored in a memory device. Hardware is developed in order to perform this task. The latter section involves processing the information using software computer programs. Two types of output are obtained, i.e. an alphanumeric printout from a teletype and a staff notation printout from a graph plotter

Some aspects of the design construction and applications of a digital stochastic computer.

The object of this project has been the construction and some aspects of design of a digital stochastic computer, in particular the patching system, initial conditions of integrators and a study of a stochastic to analogue output interface. In the latter stages of the project attention was turned to focus on the design and construction of a special purpose stochastic simulator, namely the Markov Chain and Random Walk simulator. Within the field of computer control there exists an increasing number of problems which cannot easily be solved using conventional computing systems. These problems arise for example in the real time control of large multivariable systems such as chemical processes, aircraft control systems, etc. Attempts to overcome these problems have led to the development of various arrangements of hybrid computers in an effort to obtain the advantages of the analogue and digital computers in one machine. Unfortunately the majority of these hybrid systems also incorporate the disadvantages of the two conventional computers. The digital computer although very fast and accurate, performs all computations sequentially and in applications involving, for example, the solution of differential equations where numerical iterative techniques must be employed, the time taken to obtain a solution can be in the order of minutes or even longer. This may be acceptable in a process which requires correction in this time scale but in fast processes where correction is essential within seconds, this is unacceptable. One advantage of the use of a digital computer in control is that the size of the computer required does not increase significantly as the size of the process to be controlled. Conversely the analogue computer, because of its parallel operation, can provide a solution to a differential equation almost instantaneously. However the complexity of an analogue computer increases greatly as the size of the process increases. The ideal hybrid computer should combine the advantages of the analogue and digital computers without incorporating any of their disadvantages. A stochastic computer, although not a hybrid computer, does combine the advantages of analogue and digital computers. The stochastic computer has been defined as 'an analogue computer using digital techniques.' It is defined in this way because it operates in a parallel mode, which makes it very fast, and uses conventional digital circuitry which makes it very competitive as regards cost. One disadvantage of the stochastic computer is that, as in the case of the analogue computer, the complexity increases significantly as the problem size. However because of the nature of the circuitry of the stochastic computer this disadvantage can be eliminated by using LSI techniques for constructing the computer thus making it small and inexpensive. The stochastic computer uses probability as its analogue quantity in the same way as the analogue computer uses voltage. Because probability cannot be estimated instantaneously there is a delay in obtaining a solution to any problem. The delay is proportional to the accuracy required, ie, the more accurate a solution is to be then the longer will be the time taken to obtain this solution. Therefore a balance between accuracy and speed must be struck. Nevertheless in applications involving complex problems where speed and accuracy are not critical, the stochastic computer is the ideal solution