A highlighting system for use with electronic circuit design tools is provided for displaying signal waveforms and Register Transfer Logic (RTL) source code portions corresponding to a selected signal in the same window. The user selects a time and signal to be explored. Based on the selected time and signal, the values of all related signals are identified from a database generated by simulation of RTL source code. Nodes corresponding to the related signals are identified from a gate-level netlist corresponding to the RTL source code and the nodes responsible for the particular value of the selected signal at selected time are identified. The nodes are then mapped on to the RTL source code portions by a process of Instrumentation. The RTL source code portions so identified are then displayed. In particular, the portions of the RTL source code responsible for the particular value or transition in particular value of the signal at the selected time are highlighted.

This invention relates to electronic circuit design tools and methodology (expressed as software) that are typically used to capture the design intent and the specific circuit behavior during the design of a circuit. These tools are also used to communicate the design intent and the circuit behavior between a circuit designer and other technical personnel such as design team member. To make the process easier, textual and graphical tools are embedded in these circuit design tools so as to enhance the understanding and visualization of various aspects of the circuit design. These textual and graphical tools provide an interface in order to display waveforms of various signals and in order to highlight various characteristics that are associated with the circuit design. To display waveforms these tools make use of various kinds of timing waveform diagrams, finite state machine transition diagrams, process flowcharts, etc. Indeed, such graphical representations are standard methods that are currently being used in the circuit design industry. Computer Aided Design (CAD) environments combine the design tools with the graphical tools for this purpose. CAD tools typically provide software-automated environments in order to enable communication between a designer and various kinds of computer-related tools, and by doing so, the designer is able to capture, analyze, and manipulate the design data more effectively and efficiently.
As the complexity in circuit design has increased over the last 30 years, there has been a corresponding improvement in various kinds of verification and debugging techniques (for circuit design). In fact, these verification and debugging techniques have evolved from relatively simple transistor circuit-level simulation (in the early 1970s) to logic gate-level simulation (in the late 1980s) to the current art that uses Register Transfer Language (RTL)-level simulation. RTL is a hardware description language (HDL) used in describing the registers of a computer or digital electronic system, and the way in which data is transferred between them.
Contemporary verification and debugging tools use various levels of abstraction for defining design specification. These abstractions are written using high-level description languages. High-level description languages provide a number of functionalities for analyzing and verifying the design while performing simulation. For example, a designer can navigate the design hierarchy, view the RTL source code, and set breakpoints on a statement of the RTL source code to stop the simulation. Also, line numbers are provided in the RTL source code to identify different lines and statements. Further, the verification and debugging tools often support viewing and tracing variables and some times even signal values. These RTL simulation tools typically also offer these and other types of RTL debugging functionalities.
Recent system chip designs exceed a million or more gates. This kind of complexity requires even more abstract design definition (at the RTL-level) than was available in the past, and such a definition may be difficult to manage. Hence, this has led to the development of a behavior-level modeling, which in turn, allows a designer to define system functionality at a higher level of behavior abstraction.
The abovementioned verification and debugging tools (also referred to as RTL Simulators) operate on a digital representation (or a Simulation Model) of a circuit, a list of inputs, and data regarding the performance characteristics of the circuit elements. These tools generate a numerical representation of the circuit response, which can be viewed on a display screen in graphical form.
The verification and debugging tools as mentioned above typically follow a design flow. This design flow comprises creation of a circuit design at the RTL level followed by its verification using the RTL Simulator. This verification results in the generation of a database, which includes the verification results. This database can be then used for providing information regarding the behavior of the designed circuit. Simulation can be performed at greater speeds using gate-level simulators, hardware Accelerators or software simulators called Emulators. Gate-level simulation involves synthesizing the RTL source code into a gate-level "netlist". A netlist is a list of components such as gates, flip-flops, etc. and describes the properties of the components and the connections between them. The gate-level netlist can be then verified using a software gate-level simulator or by converting the gate-level netlist into a format suitable for programming an Emulator, a hardware Accelerator, or a rapid-prototyping system so that the circuit specification can take an actual operating hardware form. Accelerators are hardware elements designed for performing special purpose computation required in circuit simulation. Accelerators perform computation that is much faster than software simulators. However, the ability of Accelerators to debug the design at the gate level is severely limited in comparison with software simulators.
As mentioned above, design flow begins with creation of circuit design at the RTL level. Circuit design is created using the RTL level source code. The RTL source code is specified according to Hardware Description Language (HDL) such as Verilog HDL or VHDL. Circuit designers use high-level hardware description languages because of the size and complexity of modern integrated circuits. Circuit design in high-level language is implemented using computer-implemented software applications. These applications enable a user to dynamically review various design facets. Also, these applications enable a user to utilize text-editing and graphical design tools to create HDL-based design.
In the design flow, creation of the RTL source code is followed by verification so as to check if the RTL source code meets the design specifications. This is done using a "Test Bench" or constraints and requirements. The verification method involving the use of RTL source code and Test Bench is referred to as Simulation process. The Test Bench contains a subset of all possible inputs to the circuit/logic. For an 'n' input circuit, there are 2n possible inputs at any given time. For large n, e.g., for a complex design, the number of possible input sequences becomes prohibitively large. To simplify this, only a subset of all possible inputs is described in any given test bench. The verification method involving RTL source code and constraints is referred to as Model Checking method. Constraints refer to design constraints, i.e. specifications to be satisfied by the circuits. Intensive mathematical properties are used to define circuit specifications in pure mathematical terms. This results in the generation of all possible valid inputs for a given circuit and it is akin to exhaustive simulation, i.e. testing the circuit for all possible inputs.
The simulation process is simple but doesn't verify the circuit behavior for all possible combinations of inputs. Hence, simulation is not very reliable especially for complex design (wherein large combinations of inputs are possible). The Model Checking method is more exhaustive but utilizes intensive mathematical calculations to verify the circuits.
Results of the verification using the method of either Model Checking or Simulation are stored in a database. This database includes simulation results and design data such as component instances, component pins, routing wire connections, information regarding the buses, etc. The database can be used by a graphical interface to generate timing waveforms for various signals defined in the circuit. The waveforms can also be used to visually highlight various design aspects. This graphical interface is also referred to as the waveform viewer.
Three major categories of tools are currently available in the market to facilitate the RTL-level simulation and testing of circuit designs. These comprise Model Checking tools, Simulation tools and Waveform viewing tools. A typical example of the RTL Simulation tool is ModelSim™ from Model Technology Inc, VCS from Synopsys. A typical example of the Model checking tool is RuleBase from IBM. A typical example of the Waveform viewing tool is Debussy from Novas Software.
Software RTL Simulators provide a high level of verification and debugging environment but have relatively slow speed and verify only a small fraction of the possible input sequences. They provide good flexibility in terms of design verification and also provide a high-level of abstraction environment for verification and debugging. It is easier to change design parameters and observe the changes in the RTL Simulators. However, for complex designs, the verification requires a large number of test vectors. Test vectors comprise a legal input sequence to a given circuit. This can take a considerable amount of time using software RTL Simulation as contrasted with hardware Acceleration or Emulation starting from a gate-level representation. Furthermore, it may be useful to perform in-situ verification. This comprises validating the design under test by connecting the Emulator or hardware Accelerator to the target system environment (where the design is to be inserted after the design is completed). One disadvantage of the gate-level simulation, however, is that most of the high-level information from the RTL source code is lost. Without the high-level information, many of the debugging functionalities are unavailable.
Currently, effort has been directed towards improving the visualization of the circuits and the various parameters guiding the circuit design. This involves display of various waveforms and expressions corresponding to the characteristic waveform of the signal. The existing waveform viewers such as Debussy and Signalscan have the ability to display the waveform of the signals and also display corresponding expressions in separate windows. Further, these waveform viewers provide an added functionality of adding or dropping an icon representing a collection of signals on the waveform-displaying window. Additionally, it is also possible to display a portion of the source code corresponding to a waveform by clicking on the waveform and vice-versa.
The existing waveform viewers display portions of source code and waveforms in different windows. However, there is a need for a system and method that displays the portions of the RTL source code and the waveform in the same window. This is required to enhance the readability and visualization of the circuit parameters. Further, there is a need for a system and method that provides the reason for a characteristic waveform to a designer. This facility will help the designer to better understand the circuit design (as embodied in the RTL source code) and behavior. Also, there is a need for a system and method that isolates and displays only the portion of the RTL source code (and possibly some surrounding source code to provide context) that correspond to a waveform that the designer desires to see. Also, there is a need to have a means of interactively browsing the RTL source code and debugging problems in the RTL source code in the context of a simulation value database.

Trace based method for design navigation


Conversion of an RF signal amplifier from an unbalanced signal configuration to a balanced signal configuration is provided while including an image trap for both sides of the balanced circuit. The grounded side of the secondary of a double tuned circuit is lifted from ground to provide a balanced circuit configuration. A trap filter is provided in the balanced circuit configuration by a pair of small capacitors coupled between the balanced secondary leads to appropriate signal nodes.

The present invention concerns RF tuning circuits for a television receiver, and more particularly a double tuned circuit with a balanced output having an image trap.
It is sometimes desirable to process RF signals in a balanced circuit configuration. In particular, a tuner integrated circuit (IC), the CXA1594L of the Sony Corporation, is designed for a balanced input signal to the UHF mixer. The data sheet for this IC shows the deriving of a balanced signal from a balun transformer. Balun transformers have the disadvantage of being larger and more expensive than RF transformers.
Additionally, it is often desirable that certain traps or filters be included in RF tuning circuits in order to prevent unwanted harmonics, beat frequencies, and images which are produced by extraneous signals and can have a detrimental effect on the processing of the desired signal. Some such traps are for a strong channel 7 signal which can interfere with a channel 6 signal, a 27 MHz trap against strong citizens band transmitters in the United States, and a trap for 890 MHz image signals produced by the transmissions of cellular telephones in the United States. It is herein recognized that when a trap or other filter is used to prevent detrimental effects of such extraneous signals in a balanced circuit, that it is necessary that such traps be used on both sides of the balanced configuration.

Double tuned circuit with balanced output and image trap


A spirobifluorene compound and a perovskite solar cell including the spirobifluorene compound are disclosed. More particularly, a spirobifluorene compound which can be used as a hole transport material of a perovskite solar cell is disclosed. A perovskite solar cell including the spirobifluorene compound as a hole transport material is further disclosed.

In order to solve the problems of depletion of fossil energy and global environmental issues due to the use thereof, research on a recyclable and clean alternative source of energy such as solar energy, wind power, and water power, has been actively conducted.
Among them, interest on a solar cell which directly changes energy from sunlight to electric energy is significantly growing. Here, the solar cell refers to a battery producing current-voltage using a photovoltaic effect which absorbs light energy from sunlight to generate electrons and holes.
Currently, it is possible to manufacture an n-p diode-type silicon (Si) single crystal-based solar cell having light energy conversion efficiency over 20%, which is actually used for solar power generation, and there is a solar cell using a compound semiconductor such as gallium arsenide (GaAs) which has better conversion efficiency than the solar cell based on an n-p diode-type silicon single crystal.
However, since the inorganic semiconductor-based solar cell needs a very highly purified material for higher efficiency, much energy is consumed in purification of raw materials, and expensive process equipment is required for a process of producing a single crystal or thin film using the raw materials, and thus, there is a limitation on lowering the manufacturing cost of the solar cell, which becomes an obstacle to large-scale utilization.
Accordingly, in order to manufacture the solar cell at low cost, costs of the materials used as a core in a solar cell or a manufacturing process need to be greatly reduced, and as an alternative to the inorganic semiconductor-based solar cell, a dye-sensitized solar cell and an organic solar cell which may be manufactured by low cost materials and processes are actively studied.
The organic solar cell allows a simple manufacturing process of elements as compared with the conventional solar cells due to easy processability, versatility, and low unit price of the organic materials, thereby realizing lower manufacturing unit price than that of the conventional solar cells. However, in the case of the organic solar cell, the structure of BHJ is deteriorated by moisture or oxygen in the air to rapidly lower the efficiency, that is, there is a big problem in stability of the solar cell, and when a complete sealing technique is introduced as a method for solving the problem, stability is increased but the price rises.
Meanwhile, a perovskite solar cell, specifically a lead halide perovskite solar cell, has been significantly developed for several years, due to a photoactive layer made of perovskite materials having excellent characteristics, and as a result, currently has efficiency up to 21%, and in order to solve the problems of the organic solar cell as mentioned above, a study to apply Spiro-OMeTAD to the perovskite solar cell also to achieve high efficiency (J. Burschka, N. Pellet, S.-J. Moon, R. Humphry-Baker, P. Gao, M. K. Nazeeruddin and M. Gratzel, Nature, 2013, 499, 316-319) has been conducted.
However, satisfactory efficiency to be commercialized has yet to be obtained, and a high-efficiency solar cell is still required.

Spirobifluorene compound and perovskite solar cell comprising same

KOREA RESEARCH INSTITUTE OF CHECMICAL TECHNOLOGY


Multiple fluid nozzles are mounted in a machine tool such that the cutting tool in the spindle is targeted with liquid or gas cutting fluid from multiple directions, providing better coverage and thereby more effectiveness. This provides more efficient and safer use of a machine tool by automating the aiming of fluids at a desired location. Multiple nozzles at respective multiple physical locations are preferably controlled by a single control unit, so they can be synchronized to maintain a common target point on a cutting tool, even if the nozzles are located asymmetrically or non-uniformly with respect to the spindle axis or target point. Preferably, modular nozzle assemblies can be configured for flexibility in mounting on the machine tool.

The present invention relates to the cooling of machine tools, and in particular to the cooling of the cutting tool with a fluid (i.e., gas or liquid or combination). The fluid typically cools and lubricates the "cut" which can be considered as the interface of the cutter and work piece. It also serves to push the chips that are created away from the cutting area. In some cases only compressed air is used, which has minimal cooling properties and no lubrication properties, but only serves to blow the chips out of the way. As used herein, "fluid", "cooling fluid", and "cutting fluid" should be considered synonymous and applicable to any of cooling, lubricating, or chip removal with liquid and/or gas.

Multi-nozzle machine tool cooling system


A method for preparation of alcohols by catalytic hydrogenation of carbonyl compounds with hydrogen or hydrogen-containing gases in the presence of a hydrogenation catalyst of Raney type, where the catalyst is used in the form of hollow bodies, Preferred as catalytically active components are nickel, cobalt, copper, iron, platinum, palladium or ruthenium.

The invention is directed toward an improved method for producing alcohols from carbonyl compounds that includes catalytic hydrogenation of carbonyl compounds with hydrogen or hydrogen-containing gases in the presence of a molded hydrogenation catalyst of Raney type. The invention especially concerns the production of sugar alcohols. The method allows the use of distinctly lower amounts of catalyst in the production of alcohols while having the same or higher yields than with the methods known up to now.
In accordance with this invention all organic compounds that contain a Cxe2x95x90O group, including those compounds that contain an Oxe2x95x90Cxe2x80x94O group, are seen as carbonyl compounds. Thus, ketones, aldehydes, carboxylic acids, carboxylates, carboxylic anhydrides, carboxylic acid esters, carboxylic acid amides and carboxylic acid halides are meant by the term carbonyl compounds.
Alcohols are a decidedly important class of substances in organic chemistry. They serve, for example, as starting materials for the production of solvents, surfactants, perfumes, flavorings, additives, drugs and other organic substances. Moreover, they are very important as monomers for various plastics. Sugar alcohols are widely used, for example, as sugar substitutes.
In the production of alcohols by hydrogenation [of] carbonyl compounds Raney catalysts are frequently preferred because of their good catalytic properties and because they are significantly easier to make than supported catalysts. Raney catalysts, which are also called activated metal catalysts, consist of an alloy of at least one catalytically active metal and at least one metal that can be leached out by alkalis. Chiefly aluminum is used as the alkali-soluble alloy component, but other metals like zinc and silicon can also be used. By adding alkalis to the alloy the leachable component is dissolved out, due to which the catalyst becomes activated.
Numerous inventions for producing alcohols from carbonyl compounds by catalytic hydrogenation with Raney catalysts are known. In each case according to the process, various Raney catalysts, more precisely catalysts with different active metals or combinations of metals, are used.
EP 0 724 908 describes a method for producing alcohols from carbonyl compounds in which Raney catalysts whose catalytically active component is a noble metal are used as hydrogenation catalysts. The catalysts are used in powder form.
Raney catalysts in powder form have the disadvantage that they can only be used in batch processes, and have to be separated from the reaction medium after the catalytic conversion, at high cost. Because of this, among other things, it is preferable to carry out the production of alcohols by hydrogenation of carbonyl compounds using molded Raney catalysts and as far as possible in a continuous process. Fixed bed catalysts, which also have to have sufficient strength for continuous operation, in addition to having good catalytic activity, are necessary for this purpose.
JP 07206737 A2 describes another method for producing alcohols by catalytic hydrogenation of carbonyl compounds. The catalysts used in this method are spherical Raney catalysts based on copper, which preferably also contain iron and, as leachable component, aluminum. The method can be run using a fixed catalyst bed.
EP 0 773 063 describes a method for producing sugar alcohols using a fixed catalyst bed in which a Raney nickel catalyst is used. The use of a nodular Raney catalyst produced by dripping the liquid alloy into a liquid, preferably water, is important in accordance with this invention.
Sugars are hydrogenated by the method described in EP 0 854 149, likewise continuously and using a fixed catalyst bed. The catalysts used with this method are produced by mixing a catalyst alloy and a metal that serves as binder and then pressure molding this mixture to form molded pieces. After drying and calcination, these molded pieces are activated by treatment with aqueous alkalis. This produces a catalyst that consists of a catalytically active shell and a largely catalytically inactive core. It is necessary to use the binder in order to give the catalyst the necessary mechanical stability.
A serious disadvantage of the methods noted in the documents JP 07206737 A2, EP 0 773 063 and EP 0 854 149 for producing various alcohols by hydrogenation of carbonyl compounds lies in the high bulk density of the Raney catalysts. Because of this, these catalysts have relatively low activity with respect to the weight of catalytically active metal that is used.
Another disadvantage is that the reactors that are used have to have high stability. This requires additional investments in the construction and operation of a hydrogenation plant.
Metal catalysts in the form of hollow bodies, preferably in the form of hollow spheres, are described in DE 199 33 450.1. These catalysts have a low bulk density, from 0.3 to 1.3 g/mL. Besides the catalysts, the use of these catalysts in hydrogenation reactions is also claimed. The examples [in this document] give activity tests for hydrogenation of nitrobenzene to aniline, in which the hydrogen uptake and thus the activity of the catalyst per gram of catalyst is clearly higher when the hollow spherical catalysts are used than when a comparison catalyst is used. However, the use of the described catalysts for production of alcohols by hydrogenation of carbonyl compounds is not mentioned.
For this reason the task of this invention is to develop a method for producing alcohols from carbonyl compounds by catalytic hydrogenation in which the disadvantages of the said methods do not arise. Another goal of the invention is to achieve the same or better starting material conversion rates by comparison with the known methods while using less catalyst material.
The task underlying the invention is solved by the fact that alcohols can be produced by hydrogenation of carbonyl compounds with distinctly higher conversion rates per unit of weight of catalyst if hollow Raney catalysts are used than with the known catalysts. This observation is surprising in that one cannot necessarily assume that the hollow Raney catalysts achieve the necessary activities in the particular case of the hydrogenation of carbonyl compounds.
The object of the invention is a method for producing alcohols by catalytic hydrogenation of carbonyl compounds with hydrogen or hydrogen-containing gases in the presence of a molded hydrogenation catalyst of the Raney type, which is characterized by the fact that the Raney catalyst is in the form of hollow bodies. This method has the advantage that alcohols can be produced with the same or higher yields while using clearly lesser amounts of catalyst than was possible up to now according to the prior art.
The advantage underlying this invention is achieved through the use of Raney catalysts in the form of hollow bodies. The production of the catalysts used in the method in accordance with the invention can be carried out in correspondence with the method described in DE 199 33 450.1. According to this method, a mixture of an alloy powder of a catalytically active metal and a leachable metal, preferably aluminum, an organic binder and optionally an inorganic binder, water and promoters is deposited onto spheres that consist of a thermally removable material. Preferably, polystyrene foam spheres can be used. The deposition of the mixture containing the metal alloy onto the polymer spheres can preferably be carried out in a fluidized bed. Preferably, 0-10 wt % polyvinyl alcohol and/or 0-3 wt % glycerol can be used as organic binders. The coated polymer foam spheres are then calcined at a temperature above 300xc2x0 C., preferably in a range from 450 to 1300xc2x0 C., in order to remove the polymer foam thermally and to sinter the metal. In this way the hollow spheres obtain a stable shape. After calcination the hollow spherical catalysts are activated by treatment with basic solutions, preferably alkali or alkaline earth hydroxides in water, more preferably aqueous sodium hydroxide. The resulting catalysts have bulk densitys between 0.3 and 1.3 kg/L.
For the method in accordance with the invention it is preferred that the hollow spherical Raney catalysts contain nickel, cobalt, copper, iron, platinum, palladium, ruthenium or mixtures of these metals as catalytically active components.
Preferably, Raney nickel catalysts that have been activated by leaching out of aluminum, silicon and/or zinc, especially aluminum, by means of alkalis, are used in the production of alcohols in accordance with the invention.
The method is carried out in accordance with the invention with catalysts in the form of hollow bodies. It is preferred that the Raney catalyst be in the form of hollow spheres. Hollow spheres are usually easy to produce and have high resistance to breakage.
Another advantage of the method in accordance with the invention lies in the fact that the Raney catalysts that are used have lower bulk density than the Raney catalysts for hydrogenation of carbonyl compounds known from the prior art. It is advantageous for the bulk density of the Raney catalysts that are used to lie in the range from 0.3 g/mL to 1.3 g/mL.
If molded catalyst bodies that are too large are used, it is possible that the educt to be hydrogenated will not sufficiently come into contact with the catalyst. A catalyst particle size that is too small will lead to a very large, possibly too great, pressure loss occurring in a continuous process.
For this reason it is preferred that the catalyst molded bodies that are used have a diameter in the range from 0.05 to 20 mm.
So that the catalysts that are used in the method in accordance with the invention will have, on the one hand, sufficient strength and, on the other, low bulk density, it is preferred that the catalyst molded bodies that are used have a shell thickness in the range from 0.05 to 7 mm, preferably 0.1 mm to 5 mm.
The catalyst shells can be impermeable or can have a porosity from 0 up to 80% and higher.
Hollow catalysts that consist of one or more layers can be used in the method in accordance with the invention. If the catalyst molded bodies have more than one layer, the molded bodies are dried between the individual coating steps in producing them. This is preferably carried out in a fluidized bed at temperatures from 60 to 150xc2x0 C.
It is possible for the catalyst molded bodies used in the method to contain an inorganic binder. The binder allows the catalyst molded bodies to have higher strength, which is necessary because of their hollow shape. Preferably, powders of the metals that are also contained in the catalyst alloy as catalytically active components are added as binders in producing the catalyst hollow bodies. However, it is also possible to add other binders, especially other metals, as binders.
Frequently it is also advantageous for the catalyst molded bodies used in the method not to contain any binders. If cobalt catalysts are used in accordance with the invention to produce the alcohols, these catalysts are preferably used without binders. Hollow cobalt catalysts have sufficient strength even without added binders.
The catalyst alloy of the catalysts used in accordance with the invention is preferably composed of up to 20-80 wt % of one or more catalytically active metals and up to 20-80 wt % of one or more alkali-leachable metals, preferably aluminum. A fast or slowly cooled alloy can be used as the catalyst alloy. Fast cooling is understood to mean, for example, cooling at a rate from 10 to 105 K/sec. Cooling media can be various gases or liquids such as water. Slow cooling is understood to mean methods with slower cooling rates.
In the method in accordance with the invention it is possible to use hollow Raney catalysts doped with other metals. The doping metals are frequently also called promoters. The doping of Raney catalysts is described, for example, in U.S. Pat. No. 4,153,578, DE 21 01 856, DE 21 00 373 or DE 20 53 799. The cobalt catalyst that is used can preferably be doped with one or more of the elements from groups 3B through 7B, 8 and 1B of the periodic system, especially chromium, manganese, iron, vanadium, tantalum, titanium, tungsten, molybdenum, rhenium and/or metals of the platinum group. It is also possible for the cobalt catalyst that is used to be doped with one or more elements from groups 1A, 2A, 2B and/or 3A of the periodic system and/or germanium, tin, lead, antimony or bismuth. The amount of promoters in the catalyst can preferably be 0-20 wt %. The promoters can already be contained as an alloy in component or can be added only later, especially after activation.
During the method in accordance with the invention the hollow Raney catalysts are used in the activated form. The leachable metal present in the unactivated catalyst particle can in the activated state have been leached out with alkalis entirely or only partially.
The method in accordance with the invention can be carried out with hydrogen as the hydrogenation gas or with gas mixtures that contain hydrogen, for example, a mixture of hydrogen and carbon monoxide and/or carbon dioxide. In order to avoid possible poisoning of the catalyst, it is preferable to carry out the method in accordance with the invention with a gas or gas mixture that contains at least 95%, preferably at least 99% hydrogen.
The method enables the production of more or less pure individual substances and also the production of mixtures of different alcohols. Especially in the production of chiral alcohols, for example, by hydrogenation of asymmetric ketones, product mixtures of different enantiomers or diastereomers can be obtained.
It is preferred that the hydrogenation be carried out in a fixed bed or suspension reactor in continuous operation. However, the invention also provides for hydrogenation to be carried out in a batch process. In a continuous process the reactor can be operated in a soaking bed or trickle bed process, with the trickle bed process being preferred.
The method in accordance with the invention can be carried out with ketones, aldehydes, carboxylic acids, carboxylates, carboxylic acid anhydrides, carboxylic acid esters, carboxylic acid amides and/or carboxylic acid halides. The choice of appropriate starting compound is dependent, among other things, on the desired product. The starting compound must be chosen so that the desired product can be obtained by the hydrogenation of one or more carbonyl groups and possibly the hydrogenation of other groups that are subject to hydrogenation. The choice of suitable starting compound is also dependent, among other things, on what starting product is more readily available. For instance, in one case it may be preferable to produce an alcohol by hydrogenation of an aldehyde, since the aldehyde is more readily available than a corresponding carboxylic acid amide. In contrast, in other cases it may be better to start from the corresponding carboxylic acid amide. However, independent of the desired alcohol, the preparation is basically possible starting with all of the listed carbonyl compounds. The desired, especially the preferred alcohols listed further below, can thus in principle be produced from a ketone, aldehyde, carboxylic acid, carboxylate, carboxylic acid anhydride, open-chain and cyclic carboxylic acid esters, open-chain and cyclic carboxylic acid amides and/or carboxylic acid halide that leads to the desired alcohol. The relevant compounds can be aliphatic, aromatic, alicyclic and aromatic-aliphatic compounds with one, two, three or more Cxe2x95x90O groups.
Some examples of starting materials for the method for producing alcohols in accordance with the invention, which however do not limit the method in accordance with the invention to the starting materials, are: acetic acid, propionic acid, butyric acid, pentanoic acid, hexanoic acid, heptanoic acid, octanoic acid, nonanoic acid, stearic acid, lauric acid, pivalic acid, isobutyric acid, oxalic acid, malonic acid, maleic acid, succinic acid, glutaric acid, adipic acid, crotonic acid, benzoic acid, o-chlorobenzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid, m-fluorobenzoic acid, p-fluorobenzoic acid, methylbenzoic acid, o-hydroxybenzoic acid, m-hydroxybenzoic acid, p-hydroxybenzoic acid, phthalic acid, terephthalic acid, isophthalic acid, naphthalenedicarboxylic acid, phenoxybenzoic acid, cyclohexanecarboxylic acid, the methyl and ethyl esters and amides of the said acids, benzaldehyde, propionaldehyde, acetaldehyde, propionaldehyde, acetone, benzophenone, xcex3-butyrolactone, xcex5-caprolactone, maleic anhydride, phthalic anhydride, glucose, xylose, lactose, fructose, 3-hydroxypropionaldehyde.
Aliphatic and aromatic alcohols and alcohols with aromatic and aliphatic groups can be prepared from the underlying carbonyl compounds using the method in accordance with the invention. The alcohols can be primary and secondary alcohols. The products can be alcohols with the general formula
R1R2CHxe2x80x94OH
where R1 and R2, independent of one another, are aliphatic and/or aromatic, unbranched and/or branched, substituted and/or unsubstituted, saturated and/or unsaturated residues or hydrogen. The alcohols produced in accordance with the invention can be open-chain or alicyclic alcohols or alcohols containing aromatic groups.
It is preferred that one obtain as product alcohols with the general formula R1R2CHxe2x80x94OH, where R1 and R2, independent of one another, are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, n-heptyl, n-octyl, isooctyl, n-nonyl, n-decyl, n-undecyl and/or n-dodecyl residues and/or residues of the general formula H3Cxe2x80x94(CH2)n, where n is a whole number from 11 to 30, or hydrogen. Preferred as starting material are the aldehydes, ketones, carboxylic acids, carboxylates, open-chain esters, especially methyl and ethyl esters, and not or [sic] N-alkylated carboxylic acid amides.
It is further possible for the residues R1 and/or R2 to be substituted with one or more residues from the series F, Cl, Br, I, NO2, NH2, OH, CN, alkyl, aryl, alkenyl, alkynyl, Oxe2x95x90C, HOOC, H2NOC, ROOC, RO with R=alkyl, aryl, alkenyl or alkynyl.
It is possible for one to obtain as products alcohols that contain two or more hydroxyl groups. These alcohols can be obtained by hydrogenation of carbonyl compounds that have two or more Cxe2x95x90O groups and optionally already have hydroxyl groups or by hydrogenation of carbonyl groups that have only one Cxe2x95x90O group and at least one hydroxyl group.
Likewise preferred is the preparation of alcohols with the general formula Arxe2x80x94(CH2)CR3Hxe2x80x94OH, where Ar is a mononuclear aromatic residue substituted zero, one, two, three, four or five times, or a polynuclear aromatic residue substituted any number of times, m is a whole number between 0 and 20 and R3 is a substituted or unsubstituted alkyl, cycloalkyl, aryl, alkenyl or alkynyl residue. Possible substituents for the aromatic residue Ar and/or the residue R3 are F, Cl, Br, I, NO2, NH2, HO, CN, alkyl, especially methyl and ethyl, aryl, alkenyl, alkynyl, Oxe2x95x90C, HOOC, H2NOC, R3OOC and/or RO residues.
Diols of the general formula HOxe2x80x94(CH2)pxe2x80x94OH, where p is a whole number between 2 and 30, especially such diols with p=2, 3, 4, 5, 6, 7 and 8, are preferred. Preferably these alcohols are prepared from the underlying hydroxy aldehydes, hydroxycarboxylic acids, hydroxycarboxylates, hydroxycarboxylic acid amides, hydroxycarboxylic acid esters, dialdehydes, dicarboxylic acids, dicarboxylates, dicarboxylic acid amides and/or dicarboxylic acid esters or cyclic esters (lactones) that have the same number of carbon atoms. For example, 1,4-butanediol can be produced by hydrogenation of xcex3-butyrolactone, 4-hydroxybutyraldehyde or succinic anhydride.
A likewise preferred embodiment of the method in accordance with the invention is the production of substituted and unsubstituted diols, sugar alcohols and polyalcohols of the general formula R4H(OH)Cxe2x80x94(C(OR5)R6)qxe2x80x94C(OR9)R7R8, where R4, R6, R7 and R8, independent of one another, can be F, Cl, Br, I, NO2, NH2, HO, CN, alkyl, aryl, alkenyl, alkynyl, Oxe2x95x90C, HOOC, H2NOC, R3OOC and/or RO residues and R5 and R9 can be substituted or unsubstituted alkyl, cycloalkyl, aryl, alkenyl, alkynyl, polyhydroxyalkyl or sugar residues, and q is a whole number between 1 and 5. Especially preferably, the residues R4, R5, R6, R7, R8 and R9 can be hydrogen, a methyl or ethyl group, a polyhydroxyalkyl residue or a sugar residue. Likewise preferred is the production of diols, sugar alcohols and polyalcohols that, in a departure from the general formula R4H(OH)Cxe2x80x94(C(OR5)R6)qxe2x80x94C(OR9)R7R8, have various residues OR10 and R11 at nonterminal carbon atoms, independently of one another and in all combinations with each other, where R10 can have the same meaning as R5 and R11 the meaning of R6.
In a likewise preferred embodiment it is possible for sugar alcohols to be obtained as product. Sugar alcohols is the group name for the polyhydroxy compounds that result from saccharides by reduction or hydrogenation of the carbonyl group. In their open chain form sugars have a Cxe2x95x90O group. Thus certain sugars can be seen as aldehydes or ketones and thus in principle can be used as starting material for the method in accordance with the invention. The preferred embodiment includes the sugars in unsubstituted and in substituted form, especially in the form in which other organic residues are bonded to the sugar via one, two, three, four or five hydroxyl groups in the form of an ether, acetal or ester bond.
Particularly preferred embodiments of the method in accordance with the invention are the methods for producing sorbitol from dextrose, a mixture of sorbitol and mannitol from fructose, xylitol from xylose, maltitol from maltose, isomaltitol from isomaltose, dulcitol from galactose and lactitol from lactose, in each case by catalytic hydrogenation of the sugar. However, other sugars can also be hydrogenated to the corresponding sugar alcohols, for example, lactulose, trehalulose, maltulose, isomaltulose, leucrose or starch hydrolyzates. The starting compounds can be highly pure products or components of a mixture that preferably contain at least 80, especially at least 95 wt % of the relevant sugar.
Examples of polyols that can be produced by the method in accordance with the invention and that carry other organic residues via an oxygen, are 1-O-xcex1-D-glucopyrabosyl-D-mannitol, 6-O-xcex1-D-glucopyranosyl-D-sorbitol, which can be prepared in each case from 6-O-xcex1-D-glucopyranosyl-D-fructose, or 3-O-xcex2-D-galactopyranosyl-D-sorbitol, which can be prepared from lactulose.
Regardless of which types of alcohols are supposed to be produced, it is possible in accordance with the invention to produce just one alcohol in a reaction. However, it is also possible by the method in accordance with the invention to produce mixtures of different alcohols. These mixtures can be obtained, for example, by nonselective hydrogenation of starting substances that contain more than one hydrogenatable carbonyl group or through the formation of diastereomers during the reaction or by hydrogenation of mixtures that contain two or more carbonyl compounds.
In each case according to the starting compound it is possible to carry out the method in accordance with the invention in the liquid phase or in the gas phase. The method can be carried out in the liquid phase only if the compound to be hydrogenated is liquid under the reaction conditions. However, in many cases it is preferable to carry out the process in the presence of a solvent. Basically all common solvents can be used, provided they are not degraded during the hydrogenation reaction. Examples of ordinary solvents are water, dioxane, tetrahydrofuran, cyclohexane, methanol, ethanol, n-propanol, isopropanol, n-butanol, cyclohexanol, ethylene glycol, 1,4-butanediol, 1,6-hexanediol, ethylene glycol methyl ether, ethylene glycol ethyl ether, ethylene glycol dimethyl ether or triethylene glycol methyl ether. Mixtures of different solvents are also possible. The presence of one or more solvents can on the one hand result in the operating parameters like pressure and temperature lying in more moderate regions than with a solvent-free process conduct, or to it being possible to conduct the reaction at all. On the other hand, the selectivity of the hydrogenation reaction can be increased through the skilled selection of solvents. In many cases, especially in the production of sugar alcohols, water or water-containing mixtures are preferred.
Because of the great breadth of variation of the possible starting compounds and synthesizable compounds the reaction parameters lie in relatively broad ranges.
The usual pressures at which the method in accordance with the invention is conducted lie in the range from 1 to 450 bar, preferably between 5 and 300 bar. The usual reaction temperatures lie in the range between room temperature and 300xc2x0 C., preferably between 30xc2x0 C. and 250xc2x0 C., especially in the range between 40xc2x0 C. and 1 80xc2x0 C. The catalyst load can preferably lie in the range from 0.05 kg to 5 kg of the compound being hydrogenated per kg of catalyst per hour. If the method in accordance with the invention is carried out in a batch process, the weight ratio between the catalyst and the carbonyl compound that is to be hydrogenated preferably lies in the range between 0.01 and 1.
In accordance with the invention the starting compounds are preferably hydrogenated by the following method for the production of polyols, especially sugar alcohols: a 10-70 wt %, preferably 15-50 wt %, especially 40-50 wt % solution of a hydroxyaldehyde or hydroxyketone, preferably a sugar, is prepared in demineralized water. The pH is preferably in the range between 3.0 and 12.0. The pH can be adjusted to the desired value, for example, through the addition of water-soluble basic compounds like alkali carbonates or ammonia in an aqueous solution or acid compounds like sugar acids, sorbic acid or citric acid. This solution is then hydrogenated.
The production of polyalcohols can be carried out in an especially preferred way continuously in a fixed bed process or semicontinuously. The solution to be hydrogenated can be passed through the catalyst bed from above or from below. A cocurrent or countercurrent process can be used, as is known. The catalyst loads, [LHSV, WHSV] can usually lie in the range between 0.05 and 5 kg carbonyl compound per kg of catalyst per hour.
However, the invention also provides for the hydrogenation to be carried out in a suspension process or in a batch process so that the catalyst is fixed in position in a catalyst basket. Suitable reactors for the said types of processes are known from the prior art.
Preferably, hydrogenation is carried out with pure hydrogen at a pressure from 30 to 450 bar, preferably between 30 and 300 bar, and at a temperature in the range between 60 and 150xc2x0 C., preferably in the range between 70 and 120xc2x0 C. At higher temperatures there is the danger, particularly when sugars are used as starting compounds, that the sugars will caramelize and deactivate the catalyst. If polyalcohols are produced in a batch process, usually lower pressures are needed, in the range from 30 to 150 bar. With a continuous process, in contrast, higher pressures are used as a rule, because of the lower residence times, which are chiefly in the range from 100 to 300 bar.
The hydrogen is usually added in an at least threefold molar excess. Especially preferred is a mol ratio of hydroxyaldehyde or hydroxyketone to hydrogen from 1:5 to 1:10 with respect to dry substances. By precise adjustment of the ratio of carbonyl compound to hydrogen it is possible to control the product ratios when different stereoisomers can result in a process.
In a continuous process it is also possible to conduct the hydrogenation in two or more steps. For example, the hydrogenation can be carried out in a first step at a temperature in the range between 60 and 90xc2x0 C. and can be completed in a second step at a temperature from 90 to 140xc2x0 C. In this way one can prevent, for example, the deactivation of the catalyst through caramelization of the educts, for example, or one can reduce the formation of by products.
The method for producing alcohols by catalytic hydrogenation of carbonyl compounds in accordance with the invention using hollow Raney nickel catalysts has the following advantages:
The hollow Raney catalyst used in accordance with the invention has a distinctly lower bulk density than the previously used Raney catalysts. In this way one needs considerably less catalyst material than in the previously known processes.
In spite of the distinctly lower amount of catalyst material the production of alcohols can be carried out with high conversion rates, very good yields and very good space-time yields.
The catalyst used in the method in accordance with the invention has very good strength. Very good hydrogenation activity that lasts a long time results from this.
The catalyst activities of the catalysts from Examples 1-6 in the hydrogenation of glucose to sorbitol were compared. For this purpose 20 mL catalyst were put into a tubular reactor and tested in a trickle phase. The reaction temperature was 140xc2x0 C., the concentration of glucose in the water was 40 wt % and the reaction pressure was 50 bar. The hydrogen throughput was 22.5 L/h and the LHSV was 3 hxe2x88x921. The product mixture was analyzed by HPLC.

Method for producing alcohols by hydrogenation of carbonyl compounds


2-(2-Hydroxy-3-perfluoroalkylthiomethyl-5-alkylphenyl)-2H-benzotriazoles are prepared by reacting the Mannich base hydrohalide or quaternary salt of a 2-(2-hydroxy-5-alkylphenyl)-2H-benzotriazole with a perfluoroalkyl mercaptan. The products exhibit outstanding efficacy in protecting organic substrates from light induced deterioration as well as good resistance to loss by volatilization or exudation during the processing of stabilized compositions at elevated temperatures.

Fluorochemical additives have demonstrated the unique ability to modify the surface properties of polymers by adsorption at the polymer/air interface even when used at very low levels. Fluorochemicals can inherently retain these unique migrating properties while maintaining the high molecular weight necessary to minimize volatility.
The UV-absorbers of the o-hydroxyphenyl-2H-benzotriazole class have long been known as effective light stabilizers for organic materials and have enjoyed considerable commercial success.
The description, preparation and uses of these valuable 2-aryl-2H-benzotriazoles are further taught in U.S. Pat. Nos. 4,383,863; 4,853,471; 4,681,905; 3,004,896; 3,055,896; 3,072,585; 4,226,763; 4,278,589; 4,675,352; 3,189,615; 3,230,194; 4,127,586 and 3,074,910.
The hitherto known 2-aryl-2H-benzotriazoles of this group have in some circumstances exhibited limited compatibility in certain substrates, and excessive tendency to exude, sublime and and/or volatilize during processing of stabilized compositions into sheets, films, fibers or other pellicles when such processing must be done at elevated temperatures. Likewise such benzotriazoles may also suffer undue loss by volatilization or sublimation from thin films or coatings, especially when subjected to elevated temperatures during use.
Attempts have been made to increase compatibility and to reduce volatilization loss by modifying the structure of the benzotriazoles. In U.S. Pat. No. 3,230,194, a higher alkyl group was substituted for methyl, and the latter compound 2-(2-hydroxy-5-tert-octylphenyl)-2H-benzotriazole exhibited superior compatibility and performance in polyethylene.
In U.S. Pat. Nos. 4,283,327; 4,278,590 and 4,383,863 there is described 2-(2-hydroxy-3,5-di-tert-octylphenyl)-2H-benzotriazole which exhibits an excellent combination of compatibility with and/or solubility in numerous polymeric substrates along with superior resistance to loss from stabilized compositions during high temperature processing, in end-use applications where coatings or films of the stabilized compositions are exposed to ambient weathering and light exposures, and in photographic applications.
In U.S. Pat. No. 4,675,352 liquid benzotriazoles of low volatility are prepared by alkylation of 2-(2-hydroxy-5-methylphenyl)-2H-benzotriazoles.
The foregoing non-fluorine containing 2-aryl-2H-benzotriazoles have not had the ability to migrate to and to protect a polymer/air interface.
In Kobunshi Ronbunshu 47, (5), 361-70 (1990) data are reported on an improvement in U.V. stabilization by the incorporation of vinylic benzotriazoles as comonomers with perfluoroalkyl monomers. The resultant polymeric U.V. stabilizers are effective in polystyrene possibly due to the surface accumulation of surface-active segments.
U.S. Pat. No. 4,788,292 describes perfluoroalkyl substituted 1-H- and 2H-benzotriazoles which do not contain the 2-(2-hydroxyphenyl) moiety.
Certain perfluoroalkyl-phenolic benzotriazoles are reported in JP 72/011074; 72/015210; 72/043949 and 73/026012. These substituted benzotriazoles are prepared from fluorinated triazole precursors which makes them inherently expensive and not commercialy viable. They are suggested for the improvement in stability of the polymer matrix surrounding encapsulated liquid crystals.
The instant 2-(2-hydroxy-3-perfluoroalkylthiomethyl-5-alkylphenyl)-2H-benzotriazoles are easily prepared from commercially available 2-(2-hydroxy-5-alkylphenyl)-2H-benzotriazoles. Further, in the instant benzotriazoles the pendant perfluoroalkyl chains are connected by a flexible sulfur atom to the remainder of the molecule, thus providing a more mobile perfluoroalkyl function, with improved solubility.
The subject benzotriazoles exhibit excellent absorption characteristics in the ultraviolet range, low volatility, and the ability to migrate to and protect a polymer/air interface. Their photographic inertness is particularly useful in photographic compositions, especially in protecting color dye images against the harmful effects of ultraviolet light.

2-(2-hydroxy-3-perflu oroalkylthiomethyl-5-alkylphenyl)-2H-benzotriazoles, processes for preparing them and stabilized compositions thereof


A method and a mobile device of providing an electronic book (e-book) service are provided. The method can independently create processed data, without altering the original contents, and share it with other mobile devices. The method includes displaying original contents, overlaying and displaying processed data according to a user's input on the original contents, and mapping the processed data to the original contents, and independently storing them, according to a user's selection.

1. Field of the Invention
The present invention relates to system and method for providing electronic book services in a mobile device. More particularly, the present invention relates to an apparatus and method that does not alter the original contents according to an e-book service, creates independently processed data according to a user's operation, and shares it with other mobile devices.
2. Description of the Related Art
With the rapid development of information and communication technology and semiconductor technology, the use of various types of mobile devices has also increased. The mobile devices utilize mobile convergence to provide additional service functions provided by other types of mobile systems, as well as their traditional service functions. For example, a mobile communication device can include additional functions as well as its usual communication functions such as a voice call, and message transmission and reception. Examples of the additional functions are a TV viewing function (e.g., mobile broadcasting, such as Digital Multimedia Broadcasting (DMB), Digital Video Broadcasting (DVB), etc.), an audio playback function (e.g., MPEG Audio Layer 3 (MP3)), a photographing function, an Internet access function, a dictionary browsing, etc.
Conventional mobile devices are developing that support an electronic book (e-book) function. The users buy e-book contents and store them in their mobile devices. Electronic books (e-books) refer to a general term representing digital books that contain information such as text, images, etc. and are stored in electronic media, which can be used as paper books. Electronic books are created from digital data that is converted from contents in paper books or publications. Electronic books are stored in electronic media. Users can view the contents in an e-book, via computers or mobile devices, via wired or wireless communication.
More particularly, tablet personal computers or tablet PCs are developed that have a relatively large display, allowing users to easily view contents therethrough. This encourages the development of technology related to an e-book function. The e-book function provides user convenience when displaying contents of an e-book.

Method and apparatus for providing an electronic book service in a mobile device


A lottery ticket includes an upper edge, a lower edge, opposite side edges, and a first area located adjacent the upper edge, the first area having a first set of gaming indicia disposed thereon that form lower portions of prize symbols. A second area is located adjacent the lower edge, the second area having a second set of gaming indicia disposed thereon that form upper portions of prize symbols. The arrangement is such that upon folding the ticket about a horizontal axis and aligning the second set of gaming indicia above the first set of gaming indicia, the winning status of the lottery ticket is determined if the upper portions of prize symbols register with the lower portions of prize symbols to create at least one complete prize symbol. Other lottery ticket constructions are further contemplated. A method of playing a lottery game is further disclosed.

This invention relates generally to lottery tickets and methods of playing a lottery game, and more particularly to a new type of lottery ticket that allows players of lottery paper-based games to determine whether the lottery ticket is a winning ticket by decrypting information contained on the ticket which is achieved by manipulating the ticket a certain way.
Players of paper-based games of chance can usually determine whether they have won by either waiting for the results of a drawing (e.g., as with a typical "numbers"-type lottery ticket) or by examining the ticket for information (e.g., as with an instant ticket). Instant tickets that require the player to scratch off an opaque layer (e.g., "scratch"-type instant tickets) are also well known in the art.
There is presently a need for another paper-based game that enables a player to decrypt information on the ticket so as to add to the suspense of whether the player owns a winning ticket. Scratch-type tickets, although suitable for their intended purpose, are somewhat expensive to manufacture primarily due to their heavy stock substrate and to the process of applying the opaque layer. Specifically, there is a need for an on-line lottery ticket that requires the player to manipulate the ticket (as with a scratch-type ticket) to determine whether the ticket is a winner. Presently, on-line tickets are used primarily for numbers-type games, and the like. Such games are not particularly exciting since the player must wait for a drawing to occur, unlike an instant ticket where the status of a winning ticket is immediately, or nearly immediately, identified.

Lottery ticket and method of playing a lottery game


A reclosable bag-like container which is constituted of a flexible semi-rigid plastic material and which is adapted to store pourable contents, preferably, such as dry cereals, snacks, sugar, salt, cake mixes and similar types of foodstuffs or comestibles. The container includes a resealable corner dispensing spout which can be closed by interengaging slide fastener elements.

1. Field of the Invention
The present invention relates to a reclosable bag-like container which is constituted of a flexible material and which is adapted to store pourable food products; for instance, such as dry cereals, or semi-moist products.
Currently, in the packaging technology, and particularly the facets thereof which concern themselves with the packaging and storage of dry cereals, among similar foodstuffs which are in granular form, it is generally the custom to employ an inner bag which is normally constituted of a moisture-impervious flexible plastic or wax-coated material and which receives and stores the contents or foodstuffs until such time as it is desired to dispense the dry cereal contents or portions thereof as may be desired by a consumer. In that connection, an upper sealed edge of the flexible plastic container, which is in the form of the inner bag, is ripped open by the consumer, normally along a previously formed heat seal, and the contents of the bag dispensed to the extent desired. Inasmuch as flexible bags or containers of that type are generally not self-supporting, they are normally placed within the outer container, which is ordinarily constituted of a substantially rigid paperboard or similar laminated material, and wherein the outer container is of a primarily rectangular parallelipiped configuration internally dimensioned to easily receive the inner bag, and wherein the outer container is adapted to be reclosed by means of overlapping flaps with interengageable tab and slit fastener structures. This, in essence necessitates the production and positioning two containers one within the other; namely an inner flexible bag-like container storing the contents, which is essentially not resealable in nature but is merely closed by folding over the previously ripped open upper edge portion, and the outer cardboard container which is only reclosed by means of the interengaging tab and slit structure formed on upper flaps thereof. This type of container arrangement, besides being expensive inasmuch as it necessitates the separate manufacture of product-receiving flexible plastic/waxed paper bags and of the rigid paperboard containers, and the assembling thereof, requires a relatively large storage and store display shelf spaces, while failing to preserve the desired integrity of the stored contents inasmuch as the containers are not hermetically resealed, thereby adversely effecting the shelflife and freshness of the comestible contents over any extended periods of time.
More recently, in order to improve upon the foregoing packaging technology, and, in particular, eliminate the necessity in providing for an outer rigid container, generally such as a rectangular paperboard container housing an inner flexible waxed paper or plastic bag storing dry pourable foodstuff contents therein, there have been developed essentially semi-rigid self-supporting flexible containers for dry foodstuffs, such as dry cereals, in an attempt to eliminate the need for an outer rigid container. This, not only provides for a simpler and less expensive package construction, but also avoids the need for outer paperboard or cardboard containers which, under some storage conditions, may attract insects or rodents, and which may also be readily susceptible to environmental damage encountered during long-term storage, possibly due to external moisture and humidity conditions or the like. Pursuant to the technology, consideration has also been given to the development of reclosable packages, in which cooperating closure elements, such as male and female profile members, enable the sealed reclosing of the package or bag, thereby protecting the contents from external and environmental influences.
2. Discussion of the Prior Art
Gordon et al, U.S. Pat. No. 5,716,473 discloses a semi-rigid cereal carton which is constituted of paperboard having the interior surface thereof coated with a thermoplastic polymer barrier layer, and possibly covered with a further moisture-imperious outer layer. The semi-rigid construction of the carton which in cross-section is vertically essentially of a trapezoidal configuration, having a wide self-supporting bottom of rectangular configuration, includes an upper edge with an openable sealed corner structure, in which the corner of the upper edge is adapted to form a pouring spout for the dispensing of the dry cereal contents. Thereafter, subsequent to the dispensing of predetermined quantities of the container contents, the latter may be reclosed by simply pressing the spout portions together and in which adhesive contact surfaces will reclose the spout. This structure is rather complex and necessitates the use of an adhesive which frequently has the dry granular or flaked contents of the container adhering thereto during and after pouring, thereby inhibiting the hermetically sealed reclosing of the container corner pouring spout structure. This potential adverse influence over the integrity of the seal prevents the remaining dry cereal or foodstuff in the container to be stored in a condition of freshness over any extended period of time.
Warr, U.S. Pat. No. 5,611,626 discloses a flexible plastic bag incorporating structure adapted to contain dry comestibles and other types of contents in a sealed condition, and wherein an upper corner portion of the essentially rectangular bag is provided with a tear line adapted to enable tearing of a corner patch thereof so as to produce a chamfered or tapered corner pouring spout. A strip which contains an adhesive on one surface thereof is adapted to be peeled from its position on an upper outer surface portion of the bag, and adhesively placed over the pouring spout subsequent to the dispensing of portions of the bag contents, so as to form a closure sealing in the remaining bag contents. This patent provides for a complex structure wherein the separate strip must be manually detached from the bag and placed over the corner portion of the bag which has the pouring spout, so as to provide the reclosable seal of the bag. Repetitive removal of the strip containing the adhesive and opening of the pouring spout therewith may cause the seal to loose its effectiveness, thereby adversely affecting the freshness and quality of the contents of the bag over any longterm storage periods.
More recently, reclosable flexible or semi-rigid plastic containers or bags have been developed in the packaging technology wherein the bags may be reclosed through the intermediary of so-called slide fasteners; in essence, interengageable profiled male and female members or tongue-and-groove elements, generally of plastic material. These fasteners are formed along openable edge portions of the bags, and upon being separated to allow for the dispensing of portions of the contents as may be required by a consumer, are thereafter resealed by simply reengaging the profiled male and female fastener members and applying pressure thereto along the length thereof.
Various types of such slide fasteners are well known in the packaging art and have been developed in the technology so as to be either integrally formed with the material of the bag walls, or formed as strips which are suitably sealed or fastened to the interior surfaces of facing or opposing sidewalls of the bags or containers, and are adapted to be separated to form a bag opening by being pulled apart and reclosed by a simple physical application of pressure by a consumer, and wherein the pressure is adapted to be applied along the length of the interengageable profile male and female fastener members so as to form a generally hermetic seal along the full length of the opening formed in the bag or container.
Thus, Branson, U.S. Pat. No. 4,787,755 discloses a flexible bag-like container wherein reclosable fastener elements include cooperable zipper-like structure consisting of male and female profiled elements adapted to form a pouring spout. In one embodiment, the fasteners are attached to external surfaces of the container in an angled corner configuration to provide a corner pouring spout which can be reclosed by folding over of the container material and joining the profiled fasteners together. This necessitates a complex folding-over and fastener aligning procedure which cannot be always easily implemented by a user.
Among other disclosures of flexible bag structures incorporating interengageable profiled male and female or tongue-and-groove type slide fasteners are Schmidt, U.S. Pat. No. 4,290,467; Van Erden, et al., U.S. Reissue Pat. No. Re 34,347; Bruno, U.S. Pat. No. 4,846,586; Johnson, U.S. Pat. No. 5,577,305; and Talbott U.S. Pat. No. 4,745,731, also setting forth apparatus and methods for producing packaging and container flexible structures employing differing types of interengagable profiled male and female fastener arrangements.
Although, in general, the foregoing patent publications provide for an adequate resealing of flexible plastic bags or containers so as to again form essentially hermetically sealed packaging structures protective of the remaining contents which are stored therein, ordinarily the reclosable seals are formed so as to extend along the entire length of an edge of the usually rectangularly shaped plastic container. Thus, the separation of the profiled male and female fasteners elements may produce an inordinately large bag opening, causing the rapid and frequently excessive dispensing of the bag contents, often by children of tender age. Also, the reclosing of such relatively large openings formed by the separation of the bag fastener elements may be implemented by children or others who are either not concerned with the complete reclosing of the bag or container, or improperly realigning the elements so as cause the bag to remain open or to be improperly reclosed.


A distribution switchboard cubicle has upper and lower ring channels; left and right corner posts attached to the ring channels for forming a support skeleton for a front face of the cubicle; and left and right intermediate posts attached to the ring channels for forming in conjunction with a corresponding corner post and the ring channels a support skeleton for left and right sides of the cubicle. First and second vertically aligned, selectively reconfigurable cubicle sections are defined within the cubicle. The first cubicle section includes at least one generally horizontally oriented mounting member for connecting each pair of corner and intermediate posts on the left and right sides of the cubicle. Left and right breaker mounting angles are connected to each respective horizontally oriented mounting member for mounting a first electrical apparatus thereto. The second cubicle section includes a draw-out cradle for mounting a second electrical apparatus therein in a reciprocable fashion, left and right generally elongated rear cradle mounting angles connected generally parallel to a corresponding intermediate post and to a rear face of the draw-out cradle, and left and right front cradle mounting plates connected to a front portion of the draw-out cradle and a corresponding corner post.

The present invention relates to electrical power distribution switchboard cubicles and in particular, the cubicle structural members which support electrical apparatus housed within the cubicles.
Electrical power distribution and circuit protection apparatus are often housed within cubicles. A cubicle cabinet is often configured in vertically stacked sections, wherein separate apparatus are stacked one on top of the other. Each cabinet section is generally separated by a horizontal barrier, often constructed of sheet metal. Power is distributed to each apparatus in the vertical section by way of vertically aligned section busses. In many field installations, cubicle cabinet sections are aligned next to each other to make a row of cabinets. Power is distributed from one cubicle to the next by way of so-called through busses that are generally horizontally aligned and connected to the vertical bus. In this way, a row of separate cubicle cabinets has a network of vertically aligned section busses and horizontally aligned through busses which form a grid-like pattern. Electrical apparatus cubicles are sold by the Electrical Apparatus Division of Siemens Energy & Automation, Inc. as well as by other manufacturers.
Individual cubicle cabinets, such as those sold by the Electrical Apparatus Division of Siemens Energy & Automation, Inc., are often constructed with supporting frame skeletons which distribute horizontal and vertical loads. Exposed surfaces of the cubicle are often sheathed with protective side panels to inhibit entry of contaminants therein and inadvertent contact of live electrical components by maintenance personnel.
Distribution switchboard cubicles often mount and support electrical apparatus, such as insulated case circuit breakers for motor control equipment and relays, in two common configurations. One commonly employed and known configuration is the so-called fixed mount, wherein the electrical apparatus is rigidly attached to the cubicle, such as by way of nuts and bolts or other known fasteners.
Another known and commonly employed electrical apparatus mounting system within cubicles is by way of draw-out cradles. The cradle is often constructed as a generally box-like sheet metal structure with reciprocable slides built into the side walls of the cradle structure. An electrical apparatus, such as an insulated case circuit breaker, is affixed to the slidable rails, so that the apparatus can be moved in and out of the cabinet on the rails. When the electrical apparatus is inserted fully into the cubicle, a hinge-mounted door is closed to prevent inadvertent entry into the front of the cubicle.
A need exists for flexible cubicle construction which allows ready conversion by qualified service technicians from fixed-type apparatus mount to draw-out-type cradle apparatus mount in a cubicle and vice versa with a minimum of parts and labor effort.
A need also exists for cubicles which allow simultaneous use of the draw-out cradle attachment and fixed attachment apparatus in a stacked array within the same vertical cubicle section. Up to now, cubicles have only been offered with all electrical apparatus held by fixed mounts or all apparatus held within draw-out mounts. Some applications would benefit from a flexible, reconfigurable cubicle which would allow simultaneous use of fixed and draw-out apparatus mounts.
These needs for flexible, distribution switchboard system reconfigurable cubicles which allow simultaneous use of fixed and draw-out apparatus mounts with a minimum of conversion parts have been attained by the present invention.

Modular construction distribution switchboard system cubicles with draw-out and fixed apparatus mounting flexibility


Dipeptide compounds have therapeutic utility, inter alia, as metalloproteinase and TNF inhibitors.

Metalloproteinases, (human fibroblast) collagenase, gelatinase and tumour necrosis factor (TNF) and their modes of action, and also inhibitors thereof and their clinical effects, are disclosed in WO-A-9611209(6/95), the content of which is incorporated by reference.
In normal tissues, cellular connective tissue synthesis is offset by extracellular matrix degradation, the two opposing effects existing in dynamic equilibrium. Degradation of the matrix is brought about by the action of proteinases released from resident connective tissue cells and invading inflammatory cells, and is due, in part, to the activity of at least four groups of metalloproteinases. These are the collagenases (interstitial collagenase, MMP-1; PMN collagenase, MMP-8, collagenase-3, MMP-13), the gelatinases (getatinase A, MMP-2, 72 kDa-gelatinase, Type IV collagenase; gelatinase B, MMP-9, 92 kDa-gelatinase, Type IV collagenase) the stromelysins (poteoglycanase, MMP-3, stromelysin-1, transin; stromelysin-2, MMP-10; stromelysin 3, MMP-11) and the membrane type matrix metalloproteinases (MT-1, MMP-14; MT-2, MMP-15; MT-3, MMP-16 and MT4, MMP-17). Normally this catabolic enzymes are tightly regulated at the level of their synthesis and secretion and also at the level of their extracellular activity, the latter through the action of specific inhibitors, such as TIMP (tissue inhibitors of metalloproteinase), which form inactive complexes with metalloproteinases, and more general proteinase inhibitors such as .alpha..sub.2 -macroglobulins.
The accelerated, uncontrolled breakdown of connective tissues by metalloproteinase catalyzed resorption of the extracellular matrix is a feature of many pathological conditions such as rheumatoid arthritis, osteoarthritis, septic arthritis, corneal, epidermal or gastric ulceration; tumour metastasis or invasion; periodontal disease, proteinuria, coronary thrombosis associated with atherosclerotic plaque rupture and bone disease. The inhibitors claimed herein may also be useful in preventing the pathological squaelae following a traumatic injury that could lead to a permanent disability. These compounds may also have utility as a means for birth control by preventing ovulation or implantation. It can be expected that the pathogenesis of such diseases is likely to be modified in a beneficial manner by the administration of metalloproteinase inhibitors and numerous compounds have been suggested for this purpose [for a general review see R C Wahl, et al Ann. Rep, Med, Chem. 25: 175-184, Academic Press Inc., San Diego (1990)].
A number of small peptide like compounds which inhibit metalloproteinaes have been described. Perhaps the most notable of these are those relating to angiotensin converting enzyme (ACE) where such agents act to block the conversion of the decapeptide angiotcnsin I to angiotensin II, a potent pressor substance. Compounds of this type are described in EP-A-0012401. Also, related mercaptoaraide peptidyl derivatives have shown ACE inhibitor activity in vitro and in vivo (H N Weller et al (1984), Biochem Biophys. Res. Comm., 125 (1):82-89).
TNF is a cytoldne which is produced initially as a cell-associated 28 kD precursor. It is released as an active, 17 kd) form (D-M Jue et al, (1990) Biochenistry, 29:8371-8377), which can mediate a large number of deleterious effects in vivo. When administered to animals or humans it causes inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase responses, similar to those seen during acute infections and shock states. Chronic administration can also cause cachexia and anorexia. Accumulation of excessive TNF can be lethal.
There is considerable evidence from animal model studies that blocking the effects of TNF with specific antibodies can be beneficial in acute infections, shock states, graft versus host reactions and autoimmune disease. TNF is also an autocrine growth factor for some myelomas and lymphomas and can act to inhibit normal heamatopoiesis in patients with these tumors.
Preventing the production or action of TNF is, therefore, predicted to be a potent therapeutic strategy for many inflammatory, infectious, immunological or malignant diseases. These include, but are not restricted to, septic shock, haemodynamic shock and sepsis syndrome (Mathison et al (1988) J. Clin. Invest, 81:1925-1937; Miethke et al (1992), J. Exp. Med. 175:91-98), post ischarmic reperfusion injury, malaria (Grau et al (1989), Immunol, Rev. 112:49-70); mycobacterial infection (Barnes et al (1992) Infect. Imm. 60:1441-6), meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, rheumatoid arthritis, multiple sclerosis, radiation damage, toxicity following administration of immunosuppressive monoclonal antibodies such as OKT3 or CAMPATH-1 and hyperoxic alveolar injury.
Current clinical ant-TNF strategies involve the use of cortirosteroids such as dexamethasone, and the use of cyclosporin-A or FK506, which are non-specific inhibitors of cytokine gene transcription. Phosphodiesterase inhibitors such as pentoxyfilline have been shown to be more specific inhibitors of TNF gene transcription (Endres S. (1991) Immunol. 72:56-60, Schandene et al (1992), Immunol. 76:30-34, Alegre M L, et al (1991); Transplantation 52:674-679, Bianco et al (1991) Blood 78:1205-1221). Thalidomide has also been shown to inhibit TNF production by leucocytes (Sampajo et al (1991), J. Exp. Med. 173:699-703). In experimental settings, anti-TNF monoclonal antibodies, soluble TNF receptors and soluble TNF receptor/immunoadhesins have been shown to specifically inhibit the effects of TNF action (Bagby et al (1991) J. Infect. Dis. 163:83-88, Charpentier et al. (1991) Presse-med. 20:2009-2011, Silva et al (1990) J. Infect. Dis. 162:421-427; Franks et al (1991) Infect. Immun. 59:2609-2614, Tracey et al (1987) Nature 330:662-664; Fischer et al (1992) PNAS USA in press, Lesslauer et al (1991) Eur. J. Immunol. 21;2883-2886, Ashkenazi et al (1991) PNAS USA 88:10535-10539).
It has recently been shown that the effects of TNF are mediated by two peptides, TNF.alpha. and TNF.beta.. Although these peptides have only 30% homology with each other, they activate the same receptors and are encoded by immediately adjacent genes. As used herein, the term tumour necrosis factor or TNF therefore means tumour necrosis factor .alpha. and peptides having a high degrees of sequence homology with, or substantially similar physiological effects to, TNF.alpha., for example TNF.beta..
One of the objectives of the present invention is to provide compounds which substantially inhibit the release of TNF from cells, and therefore may be used in the treatment of conditions mediated by TNF. Such uses include, but are not limited to, the treatment of inflammation, fever, cardiovascular effects, hemorrhage, coagulation and acute phase response, cachexia and anorexia, acute infections, shock states, graft versus host reactions and autoimmune disease.
Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase have been shown to inhibit the release of TNF both in vitro and in vivo (AJH Gearing et al (1994), Nature, 370:555-557; G M McGeehan et al (1994), Nature, 370:558-561; WO 93/20047). All of these reported inhibitors contain a hydroxamic acid zinc binding group.
As appreciated by those of skill in the art the significant proportion of homology between human fibroblast collagenase, stromelysin and gelatinase leads to the possibility that a compound that inhibits one enzyme may to some degree inhibit all of them.
Compounds that inhibit collagenase include those encompassed by U.S. Pat. No. 4,511,504 issued Apr. 16, 1985 and U.S. Pat. No. 4,568,666, issued Feb. 4, 1986. Compounds of related structure that are claimed to inhibit stromelysin (proteoglycanase) are encompassed by U.S. Pat. No. 4,771,037, issued Sep. 13, 1988.
It is believed that stromelysin and collagenase inhibitors may have utility in preventing articular cartilage damage associated with septic arthritis. Bacterial infections of the joints can elicit an inflammatory response that may then be perpetuated beyond what is needed for removal of the infective agent resulting in permanent damage to structural components. Bacterial agents have been used in animal models to elicit an arthritic response with the appearance of proteolytic activities. See J. P. Case et al (1989), J. Clin. Invest., 84:1731-40; R. J. Williams et al (1990), Arth. Rheum. 33: 533-41.
It is believed that inhibitors of stromelysin, collagenase and gelatinase may be useful to control tumour metastasis, optionally in combination with current chemotherapy and/or radiation. See L. M. Matrisian et al (1986), Proc. Natl. Acad. Sci., USA, 83;9413-7; S. M. Wilhelm et al (1987), Ibid. 84:6725-29; Werb et al (1989), J. Cell Biol., 109:872-889; L. A. Liotta et al (1983), Lab. Invest., 49:636-649; Reich et al in Metatasis, Ciba Foundation Symposium, Wiley, Chicester, 1988, pp. 193-210.
Secreted proteinases such as stromelysin, collagenase and gelatiase play an important role in processes involved in the movement of cells during metastasic tumour invasion. Indeed, there is also evidence that the matrix metalloproteinases are overexpressed in certain metastatic tumour cell lines. In this context, the enzyme functions to penetrate underlying basement membranes and allow the tumour cell to escape from the site of primary tumour formation and enter the circulation. After adhering to blood vessel walls, the tumour cells use these same metaloprotinases to pierce underlying basement membranes and penetrate other tissues, thereby leading to tumour metastasis. Inhibition of this process would prevent metastasis and improve the efficacy of current treatments with chemotherapeutics and/or radiation.
These inhibitors should also be useful for controlling periodontal diseases, such as gingivitis. Both collagenase and stromelysin activities have been isolated from fibroblasts derived from inflamed gingiva (Uitto et al (1981), J. Periodontal Res., 16:417-424). Enzyme levels have been correlated to the severity of gum disease; C. M. Overall et al (1987), J. Periodontal Res., 22:81-88.
Proteolytic processes have also been observed in the ulceration of the cornea following alkali burns (S. I. Brown et al (1969), Arch. Opthalmol., 81:370-373). Mercapto-containing peptides do inhibit the collagenase isolated from alkali-burned rabbit cornea (F. R. Burns et al (1989), Invest. Opthalmol, 30:1569-1575). Treatment of alkali-burned eyes or eyes exhibiting corneal ulceration as a result of infection with inhibitors of these metalloendoproteinases in combination with sodium nitrate or sodium ascorbate and/or antimicrobials may be effective in preventing developing corneal degradation.
Stromelysin has been implicated in the degradation of structural components of the glomerular basement membrane (GBM) of the kidney, the major function of which is to restrict passage of plasma proteins into the urine (W. H. Baricos et al (1989), Biochem. J., 254:609-612). Proteinuria, a result of glomerular disease, is excess protein in the urine caused by increased permeability of the GBM to plasma proteins. The underlying causes of the increased GBM permeability are unknown, but proteinases including stromelysin may play an important rote in glomerular diseases. Inhibition of this enzyme may alleviate the proteinura associated with kidney malfunction.
It is suggested that inhibition of matrix metalloproinase activity may prevent the rupturing of atherosclerotic plaques leading to coronary thrombosis. The tearing or rupture of atherosclerotic plaques is the most common event initiating coronary thrombosis. Destabilisation and degradation of the connective tissue matrix surrounding these plaques by proteolytic enzymes or cytolines released by infiltrating inflammatory cells has been proposed as a cause of plaque fissuring. Such tearing of these plaques can cause an acute thrombolytic event as blood rapidly flows out of the blood vessel. High levels of stromelysin RNA message have been found to be localized to individual cells in atherosclerotic plaques removed from heart transplant patients at the time of surgery (A. M. Henney et al (1991), Proc. Nat'l, Acad. Sci. USA, 88:8154-8158). Inhibition of stromelysin by these compounds may aid in preventing or delaying the degradation of the connective tissue matrix that stabilizes the atherosclerotic plaques, thereby preventing events leading to acute coronary thrombosis.
It has been recently shown in a model of congestive heart failure (CHF) in the pig, that during CHF there are marked changes in the morphological structure of the heart. Ventricular dilation and wall thinning caused by changes to the extracellular matrix results in fewer collagen connections between cardiomyocytes and less total collagen, In such an instance a weaker force of contraction leads to an inefficient ventricular operation. It is believed that specific inhibitors of matrix metalloproteinases will play a key role in stabilizing the extracellular matrix and therefore be important in the treatment and/or prevention of CHF.
It has recently been shown (WO 96/0240) that inhibitors of the matrix metalloproteinases, such as collagenase and stromelysin also inhibit the formation of human soluble CD23. CD23 is a 45 kDa type II integral protein expressed on the surface of a variety of mature cells, including B and T lymphocytes, macrophages, NK cells, Langerhans cells, monocytes, eosinophils and platelets (Delespesse et al (1991), Adv. Immunology, 49:149; Grangette et al (1989), J., Immunol, 143:3580). Several activities have been ascribed to soluble CD23 in man, all of which involve IgE regulation. Particular activities include:
i) antigen presentation PA1 ii) IgE mediated eosinophil cytotoxicity PA1 iii) B cell homing to lymph nodes and the spleen PA1 iv) downreguladon of IgE synthesis PA1 R.sup.2 is hydrogen or a C.sub.1-6 alkyl group; PA1 R.sup.3 is a [Alk].sub.n R.sup.6 group where Alk is a C.sub.1-6 alkyl or C.sub.2-6 alkenyl group and n is zero or 1; PA1 X is heteroaryl or a group CONR.sup.4 R.sup.5 where R.sup.4 is hydrogen or an C.sub.1-6 alkyl, aryl, heteroaryl, C.sub.1-6 alkyl-heteroaryl, cyclo(C.sub.3-6)alkyl, C.sub.1-6 alkyl-cyclo(C.sub.3-6)alkyl, heterocyclo(C.sub.4-6)alkyl or C.sub.1-6 alky-heterocyclo(C.sub.4-6)alkyl group and R.sup.5 is hydrogen or a C.sub.1-6 alkyl group; NR.sup.4 R.sup.5 may also form a ring such as pyrrolidino, piperidino or morpholino; PA1 R.sup.7 is hydrogen or the group R.sup.10 CO where R.sup.10 is C.sub.1-4, alkyl, (C.sub.1-4 alkyl)aryl, (C.sub.1-4 alkyl)hoteroaryl, cyclo(C.sub.3-6) alkyl, cyclo(C.sub.3-6) alkyl C.sub.1-4 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkenylaryl, aryl or heteroaryl as defined above; PA1 R.sup.8 and R.sup.16 are the same or different and are each C.sub.1-4 alkyl R.sup.11, R.sup.16 may also be H; PA1 R.sup.6 represents AR.sup.9 or cyclo(C.sub.3-6)alkyl, cyclo(C.sub.3-6)alkenyl, C.sub.1-6 alkyl, C.sub.1-6 alkoxyaryl, benzyloxyaryl, aryl, heteroaryl, (C.sub.1-3 alkyl)heteroaryl, (C.sub.1-3 alkyl)aryl, C.sub.1-6 alkyl-COOR.sup.9, C.sub.1-6 alkyl-NHR.sup.10, CONHR.sup.10, NRCO.sub.2 R.sup.10, NHSO.sub.2 R.sup.10, NHCOR.sup.10, amidine or guanidine; PA1 R.sup.11 is COR.sup.13 or NHCOR.sup.13 or the groups ##STR2## where p and q are each 0 or 1 and are the same or different but when p=q=1, Y cannot be H; PA1 R.sup.12 is hydrogen, C.sub.1-4 alkyl, COR.sup.9, CO.sub.2 R.sup.9 (where R.sup.9 is not H), CONHR.sup.9, or SO.sub.2 R.sup.9 (where R.sup.9 is not H); PA1 R.sup.13 is (C.sub.1-4 alkyl) R.sup.15 ; PA1 R.sup.15 is N(R.sup.2).sub.2 (where each R.sup.9 may be the same or different), CO.sub.2 R.sup.9, CONHR.sup.9, CON(R.sup.9).sub.2 (where each R.sup.9 may be the same or different) or SO.sub.2 R.sup.9 (where R.sup.9 is not H), phthalimido or the groups ##STR3## and the salts, solvates and hydrates thereof. PA1 a method of management (by which is meant treatment or prophylaxis) of disease or conditions mediated by TNF.alpha. and/or MMPs in mammals, in particular in humans, which method comprises administering to the mammal an effective, amount of a compound of formula (I) above, or a pharmaceutically acceptable salt thereof; and PA1 a compound of formula (I) for use in human or veterinary medicine, particularly in the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF.alpha. and/or MMPs; and PA1 the use of a compound of formula (I) in the preparation of an agent for the management (by which is meant treatment or prophylaxis) of diseases or conditions mediated by TNF.alpha. and/or MMPs.
Thus, over the excessive production of soluble CD23 has been implicated in the overproduction of IgE, the hallmark of allergic diseases such a3 extrinsic asthma, rhinitis, allergic conjunctivitis, eczema, a topic dermatitis and anaphylaxis (Sutton et al (1993), Nature, 366:421). Elevated levels of soluble CD23 have also been observed in the serum of patients with chronic B lymphocytic leukemia (Safat et al (1988), Blood, 71:94), and in the synovial fluid of patients with rheumatoid arthritis (Chomarat et al (1993), Arthritis and Rheumatism, 36:234).
Recent reports suggest that new enzymes of the MMP family also mediate the shedding of adhesion molecules such as the selections, such as L-selectin, These soluble adhesion molecules are implicated in a number of diseases including cancer, autoimmunity and in the inflammatory response. It has been proposed that once cleaved, the selectin bind to particular ligands and this accounts for their biological activity. Thus, drugs that interfere with or prevent binding of the ligands to the selections will be useful medicaments for treating a variety of the diseases described above. Therefore, it is a yet further objective of the present invention to provide compounds which inhibit the shedding of certain adhesion molecules and thus provide the production of a medicament for the treatment or prophylaxis of disorders such as cancer, autoimmune diseases or inflammatory diseases (such as inflammatory bowel disease and multiple sclerosis).
It is also believed that specific inhibitors of stromelysin and collagenase should be useful as birth control agents. There is evidence that expression of metalloproteinases, including stromelysin and coflagenase, is observed in unfertilized eggs and zygotes and at further cleavage stages and increased at the blastocyst stage of fetal development and with endoderm differentiation (C. A. Brenner et al (1989), Genes & Develop., 3:848-59). By analogy to tumour invasion, a blastocyst may express metalloproteinases in order to penetrate the extracellular matrix of the uterine wall during implantation. Inhibition of stromelysin and collagenase during these early development processes should presumably prevent normal embryonic development and/or implantation in the uterus. Such intervention would constitute a novel method of birth control. In addition there is evidence that coliagenase is important in ovulation processes. In this example, a covering of collagen over the apical region of the follicle must be penetrated in order for the ovum to escape. Collagenase has been detected during this process and an inhibitor has been shown to be effective in preventing ovulation (J. F. Wocssner et al (1989), Steroids, 54:491-499). There may also be a role for stromelysin activity during ovulation (C. K. L. Too et al (1984), Endocrin., 115:1043-1050).
Collagenolytic and stromelysin activity have also been observed in dystrophic epidermolysis bullosa (A. Icronberger et al (1982), J. Invest. Dermatol., 79:208-211; D. Sawamura et al (1991), Biochem. Biophys. Res. Commun., 184:1003-8). Inhibition of metalloendoproteinases should limit the rapid destruction of connective components of the skin.
In addition to extracellular matrix comprising structural components, stromelysin can degrade other in vivo substrates including the inhibitors .alpha..sub.1 -proteinase inhibitor and may therefore influence the activities of other proteinases such as clastase (P. G. Winyard et al (1991), FEBS Letts., 279,1:91-94). Inhibition of the matrix metalloendoproteinases may potentiate the antiproteinase activity of these endogenous inhibitors.
From recent publications it is evident that several new enzymes of the MMP family have been identified, some of which may be important in disease. Collagenase 3, an enzyme unique to breast carcinoma cells may have utility in breast cancer (JMP Freije et al (1994), J. Biol. Chem., 269 (24): 16766-16773), whilst MT-MMPs, other members of the MMP family have been shown to be a key enzymes in the activation of gelatinase A (H Sato et al (1994), Nature, 370:61-65). Gelatinase A is an important enzyme in the growth and metastasis of tumors (such as defined above).
The degradation of b-Amytoid Pressor Protein (APP) has been shown to generate amyloid plaques, a major constituent of the senile plaques, found in patients with Alzheimers Disease (AD). Two recent publications have identified metalloproteinase enzymes that cleave APP to the amyloid plaque (C R Abraham et al (1994), Biochemistry, 33:192-199; G Huber et al (1994), Biochem. Biophys Res. Comm., 201 (1): 45-53).
As appreciated by those of skill in the art, the significant proportion of homology between these new enzymes and other MMPs leads to the possibility that a compound that inhibits one enzyme may to some degree inhibit these now enzymes. Therefore, inhibitors encompassed in this invention may be useful in the diseases in which these new enzymes are implicated.
It is, therefore, a further objective of this invention to provide compounds which, in addition to inhibiting TNP release, also inhibit the action of MMPs, and hence may be used in the treatment of patients who suffer from conditions mediated by TNF and/or MMPs.
It is therefore, a further objective of the present invention to provide compounds which inhibit the formation of human soluble CD23 for the production of a medicament for the treatment or prophylaxis of disorders such as allergy and autoimmune disease in which the overproduction of soluble CD23 is implicated, such as those described above.