A test system for adjusting a wireless communication device by impedance loading features includes a power supply for generating a plurality of voltages, a test fixture coupled to the power supply for generating impedances corresponding to a plurality of impedance loading areas, a test equipment coupled to a test point of the wireless communication device via the test fixture for measuring a plurality of radio frequency characteristic sets of the wireless communication device, and a decision device coupled to the test equipment for determining an optimal impedance loading area of the wireless communication device according to the plurality of radio-frequency characteristic sets.

1. Field of the Invention
The present invention relates to a test system for adjusting a wireless communication device by impedance loading features, and more particularly, to a test system for reducing time and resources for designing the wireless communication device.
2. Description of the Prior Art
RF (radio-frequency) performance of a wireless communication device determines the communication quality of the wireless communication system. If transmission power of the wireless communication device is not well designed, reception quality of a corresponding base station will be affected. On the other hand, if reception sensitivity of the wireless communication device is not well designed, reception efficiency of the wireless communication device will be affected. In other words, once a defect appears in either Uplink or Downlink, the overall communication quality will be greatly influenced, which may lead to disconnection. Therefore, when designing a wireless communication device, the designer must consider transmitting and receiving performance of an RF circuit in the wireless communication device, in order to achieve the required communication quality.
Please refer to FIG. 1. FIG. 1 is a schematic diagram of an RF circuit 10 of a wireless communication device in the prior art. The RF circuit 10 comprises an RF transmitting module 12, an RF receiving module 14, an antenna switching module 16, an antenna 18, and an antenna matching circuit 20. The RF transmitting module 12 comprises a power amplifier 120 and a matching circuit 122, and is utilized for enhancing power of signals outputted from an RF signal processing unit, so as to emit the signals via the antenna 18. The RF receiving module 14 comprises a low noise amplifier 140, a matching circuit 144, and a surface acoustic wave (SAW) filter 146, and is utilized for receiving wireless signals via the antenna 18, and transmitting the received signal to the RF signal processing unit for performing demodulation, decoding, etc. Generally, when designing the RF circuit 10, a test point TP, taken as a boundary, is connected to a test device with 50Ω impedance to adjust characteristics of the RF transmitting module 12 and the RF receiving module 14 according to a design specification. Then, the antenna 18 is installed in the RF circuit 10, and a network analyzer is utilized for measuring the antenna 18 via the test point TP, so as to adjust a shape of the antenna 18 and the characteristics of the antenna matching circuit 20 to reach an optimal standing wave ratio or reflection coefficient.
After the design of the RF circuit 10 is complete, a wireless communication device installed with the RF circuit 10 is placed in the three-dimensional microwave anechoic chamber for testing total radiation power (TRP) and total isotropic sensitivity (TIS), as shown in FIG. 2. TRP and TIS are used to evaluate the transmitting and receiving abilities of the wireless communication device, and related illustration is as follows.
TRP is the average value of outwardly radiated power of a transmitter in the wireless communication device in omni directional space, which overall estimates the transmitting ability of the transmitter in the three-dimensional space. The testing method of TRP is: set up the wireless communication device to the three-dimensional microwave anechoic chamber as shown in FIG. 2, estimate the effective isotropic radiated power (EIRP) respectively at each 15 degrees interval between the θ-axis and φ-axis on a spherical coordinate system by controlling the location of the wireless communication device, and by carrying out the integral operation on all estimated results, TRP therefore can be obtained. On the other hand, TIS is the receiving sensitivity of the receiver in the wireless communication device in omni directional space, which overall estimates the receiving ability of the receiver in the wireless communication device. The testing method of TIS is: estimate the effective isotropic sensitivity (EIS) respectively at each 30 degrees interval between the θ-axis and φ-axis on a spherical coordinate system by controlling the location of the wireless communication device, and by carrying out the integral operation on all estimated results, TIS therefore can be obtained.
Thus, after the design of the RF circuit 10 is completed, the TRP and the TIS of the wireless communication device are estimated in the three-dimensional microwave anechoic chamber to evaluate the transmitting and receiving abilities of the wireless communication device. After that, the designers may re-adjust the RF circuit 10 according to the estimated TRP and TIS in order to obtain the highest TRP and the lowest TIS conforming to the communication specification. Such designing process, however, takes too much time and resources, and the optimal TRP and TIS may not be obtained with limited time and resource.
In order to improve the above drawback, Taiwan patent application No. 096146318 provides a method and related electronic device for adjusting an RF circuit by impedance loading features, which comprises designing a plurality of test fixtures corresponding to different impedance loading areas according to a predefined operating frequency band, coupling each of the plurality of test fixtures to a test point of the RF circuit for measuring a plurality of RF characteristic sets, and determining an optimal impedance loading area of the RF circuit according to the measured RF characteristic sets in order to adjust the RF circuit. Thus, using the method and related electronic device disclosed in the above-mentioned application, the designers can initially estimate transmitting and receiving abilities of the RF circuit without estimating TRP and TIS in the three-dimensional microwave anechoic chamber, so that time and resources for designing the RF circuit can be reduced. However, as disclosed in the Taiwan patent application No. 096146318, the plurality of test fixtures corresponding to different impedance loading areas are designed in advance, and each test fixtures is coupled to a test point of the RF circuit during testing. Such test method can initially estimate transmitting and receiving abilities, but it takes a lot of time and resources for designing and replacing the test fixtures. Therefore, the prior art cannot effectively reduce time and resources for testing the RF circuit, and thus, the application range is limited.

This patent is subject to a terminal disclaimer.

Test system for adjusting a wireless communication device by impedance loading features


System and method of gas-cluster ion beam processing is realized by incorporating improved beam and workpiece neutralizing components. Larger GCIB current transport is enabled by low energy electron neutralization of space charge of the GCIB. The larger currents transport greater quantities of gas in the GCIB. A vented faraday cup beam measurement system maintains beam dosimetry accuracy despite the high gas transport load.

The present invention relates generally to the formation of and application of increased-current gas-cluster ion beams (GCIB's) for processing the surfaces of workpieces, and, more particularly to reducing space charge effects in GCIB's, reducing workpiece charging, and to improving the measurement accuracy of GCIB currents and doses.
The use of GCIB's for processing surfaces is known (see for example, U.S. Pat. No. 5,814,194, Deguchi et al.) in the art. For purposes of this discussion, gas clusters are nano-sized aggregates of materials that are gaseous under conditions of standard temperature and pressure. Such clusters typically consist of aggregates of from a few to several thousand molecules loosely bound to form the cluster. The clusters can be ionized by electron bombardment or other means, permitting them to be formed into directed beams of controllable energy. Such ions typically carry positive charges of q×e (where e is the electronic charge and q is an integer greater than or equal to one). The larger-sized clusters are often the most useful because of their ability to carry substantial energy per cluster ion, while yet having only modest energy per molecule. The clusters disintegrate on impact, with each individual molecule carrying only a small fraction of the total cluster energy. Consequently the impact effects of large clusters are substantial, but are limited to a very shallow surface region. This makes ion clusters effective for a variety of surface modification processes, without the tendency to produce deeper subsurface damage characteristic of conventional monomer ion beam processing.
Means for creation of and acceleration of such GCIBs are described in the reference (U.S. Pat. No. 5,814,194) previously cited. Presently available ion cluster sources produce clusters ions having a wide distribution of sizes, N (where N=the number of molecules in each cluster—in the case of monatomic gases like argon, an atom of the monatomic gas will be referred to as a molecule and an ionized atom of such a monatomic gas will be referred to as a molecular ion—or simply a monomer ion—throughout this discussion).
Many useful surface processing effects can be achieved by bombarding surfaces with GCIB's. These processing effects include, but are not necessarily limited to, smoothing, etching, and film growth. In many cases it is found that in order to achieve industrially practical throughputs in such processes, GCIB currents on the order of hundreds to thousands of microamps are required. Space charge effects in ion beams are expected when Poissance as defined by A. T. Forrester in Large Ion Beams, Wiley, New York (1987) approaches unity. In the case of a 400 μA beam with an N/q ratio of 5000, the Poissance varies with the GCIB acceleration voltage up to about 0.3 or so depending on exact operating conditions. Accordingly, some space charge beam expansion would be expected and is observed. Particularly at low acceleration voltages, providing a degree of space charge neutralization to the beam by providing a source of low energy electrons enhances the ability to transport larger gas-cluster ion beam currents and reduces beam spot size. In the beamline of a practical production GCIB processing tool, to minimize beam loss due to space charge expansion of the beam, it is useful to keep the beamline as short as practical (˜50 cm) and the beam size at the workpiece is nevertheless relatively large (˜6 cm). In the prior art, a simple thermionic electron emitter in the vicinity of the beam has been used to provide space charge neutralizing electrons. In order to achieve successful transport of higher beam currents (compared to the typical hundred or so microamps in practical prior art GCIB tools) it is highly desirable to achieve more effective space charge neutralization in the GCIB.
Another important consideration in extending the useful GCIB beam currents to increase processing throughput is the fact that the workpiece can be charged up by the effects of the GCIB bombardment. This is especially important when the workpieces are semiconductor substrates, magnetic memory sensors, or other charge sensitive materials. Workpiece surface charge neutralization is required for successful GCIB processing. In some applications, such as magnetic memory smoothing, the requirements are even more stringent than for semiconductor devices and a maximum surface charging of ±6 volts or even less is required for successful processing. Low energy electrons supplied to the GCIB and the workpiece surface can provide surface charging control as well as GCIB space charge control, but in order to achieve low workpiece charging potentials under varying conditions, such electrons must be low energy. In the past it has not been practical to achieve satisfactory space charge neutralization and to simultaneously control workpiece surface charging at acceptably low potentials. Simple thermionic filament electron sources act as space-charge-limited-diodes, and thus do not readily emit adequate quantities of electrons. It is possible to dramatically reduce the space-charge-limited-diode effect by using an accelerating potential to extract electrons from a thermionic filament's space charge region. This can dramatically increase electron current emission, but results in an increased electron energy problem and in unacceptable risk of workpiece negative charging by energetic electrons if the GCIB should fluctuate momentarily or be momentarily interrupted. Thus, while an accelerated electron source can provide suitably high electron currents, the risk of high energy electrons charging the workpiece make the method unacceptable in many sensitive applications.
For GCIB process control purposes, it is important to be able to measure and control the GCIB intensity. One convenient way of achieving this is by measuring the GCIB current. Faraday cups have traditionally been used as ion beam current measuring devices and are well known in the art of conventional monomer ion beams and have been used successfully for low current GCIB measurement. Inherently, a gas-cluster ion beam transports gas. For an argon beam having a beam current, IB, the gas flow, F (SCCM), in the beam is
                    F        =                  2.23          ×                      10                          -              18                                                      (                          N              q                        )                                                                                (                                          I                B                            e                        )                                              (                  Eqn          .                                                    1                )
With a beam current of 400 μA and an N/q ratio of 5000, the beam conducts a gas flow of 27 SCCM. In a typical GCIB processing tool the ionizer and the workpiece being processed are each typically contained in separate chambers. This provides for better control of the substrate processing pressure. However, a major area of difficulty with beams carrying large amounts of gas occurs in terms of beam current measurement. The entire gas load is released when the cluster beam strikes the inside of the faraday cup. Charge exchange and gas ionization by the beam within the confines of the faraday cup become extreme and significant measurement errors occur with conventional faraday cup designs.
It is therefore an object of this invention to provide a neutralizer capable of providing large neutralizing electron currents but having low electron energy.
It is also an object of this invention to provide a method of effective space charge neutralization of a high current GCIB.
It is a further object of this invention to provide an improved method of limiting the charging of the surface of a workpiece being processed by GCIB.
Another object of this invention is to provide an improved faraday cup for beam current measurement in beams having high gas transport.
A still further object of this invention is to provide a method for accurate measurement of gas-cluster ion beam current in GCIBs transporting large amounts of gas.

System for and method of gas cluster ion beam processing


Disclosed is a bias and measuring circuit that improves the ion sense measurement and ignition performance of an Ion Sense Ignition system where the ion current signal processing is implemented remote from the ignition coil. Specifically, the bias and measuring circuit of the invention reduces the effects of secondary harness capacitance on the ion current signal, minimizes the effects of harness electrical leakage and reduces the chances for xe2x80x9cspark-on-makexe2x80x9d (an ignition firing when the ignition coil primary is initially energized).

Ion sense ignition has been in limited use in automotive engines for several years, and has recently started to appear in more applications, driven in part by regulated on-board diagnostic requirements. Ion Sense systems measure the presence of ions or free electrons in the engine""s combustion chamber by electrically biasing the gap of the spark plug with a voltage. The current flow induced by the applied bias voltage is a measure of the ion or free electron density in the cylinder. The ion or free electron density is related to the chemistry of the fuel and the combustion process itself. It has been clearly demonstrated that Ion Sense Ignition systems can be used to detect and measure combustion (or misfire) and engine knock as well as the cylinder location of peak pressure, air to fuel ratio and other combustion characteristics.
Disclosed is a bias and measuring circuit that improves the ion sense measurement and ignition performance of an ion sense ignition system where the ion current signal processing is implemented remote from an ignition coil. The circuit comprises an energy storage device connected in series with a spark gap and an ignition coil secondary winding. A spark current from the ignition coil charges the energy storage device, where the energy storage device acts as an ion current generating source. A voltage control device connected in parallel with the energy storage device, limits a voltage to be charged onto the energy storage device to within a specified value. A diode in series with the voltage control device and a resistor connected in parallel with the diode direct the current flow.
A second resistor is connected in series with the first resistor, via an electrical harness wire, a voltage across which corresponds to a measured ion current. A second voltage control device is connected in parallel with the second resistor, to allow a selected magnitude of voltage to be generated across the second resistor by the ion current without voltage limiting.
The bias and measuring circuit disclosed reduces the effects of secondary harness capacitance on the ion current signal, minimizes the effects of harness electrical leakage and reduces the chances for xe2x80x9cspark-on-makexe2x80x9d (an ignition firing when the ignition coil primary is initially energized).


A component (100) for an internal combustion engine includes a plurality of as-cast features (e.g. 116) formed thereon, and a plurality of machined features (e.g. 120). The component (100) also includes at least one witness mark (128), the witness mark (128) including a cavity (202) surrounded by a first lateral surface (204), a first inclined surface (208), a second inclined surface (210), and a valley surface (212). The at least one witness mark (128) is formed during a casting operation, and is used to locate the component (100) on a fixture (300). The plurality of machined features (120) do not encroach onto an area of the at least one witness mark (128). The first inclined surface (208) and the second inclined surface (210) are at an angle (α) with respect to each other.

Internal combustion engines include crankcases having a plurality of cylinders. The cylinders contain pistons whose reciprocating motion due to combustion events may be transferred through a crankshaft to yield a torque output of the engine. Often, engine crankcases are made of cast metal, and include features that are either formed or machined therein subsequent to the casting thereof.
Known methods for machining crankcases include the casting of machining datums, or, cast features that are used to locate the casting onto a machining device. By proper placement and location of a casting onto a machining device, positional and tolerance dimensions may be accomplished in the creation of various machined features in a crankcase.
Typical machining datums are "nubs", or protrusions, that are cast into the metal of the crankcase and that fit into openings in a "table" of a machining device. These nubs typically serve no purpose other than to locate the crankcase, and are usually placed onto surfaces that will eventually be machined themselves thus obliterating the nubs. The reason for deletion of the nubs is primarily to reduce the weight of the finished and machined crankcase, and to also improve the shape, appearance, and fit of same in an engine.
One disadvantage of the existing machining datum configuration, or nubs, for cast metal crankcases is that their shape, typically a rectangular shape, does not allow for alignment of a casting for more than two degrees of freedom of motion. Moreover, existing datum configurations that are obliterated in the finished product do not allow for a dimensional check for the quality of each machining operation in the finished product.
Accordingly, there is a need for an improved machining datum design configuration that allows for location for more than two degrees of freedom of the casting for machining, and that allow for a dimensional check for the quality of each machining operation in the finished product.

Engine cast component having witness marks and method of machining same

International Engine Intellectual Property Company, LLC


This disclosure relates to a phase locked loop and a frequency locked loop.

Mobile devices (e.g. mobile telephones) typically operate using multiple frequency sources. The first frequency source is a high-frequency crystal clock (e.g., having a reference frequency of 26 MHz) used in active modes, such as when communicating with the cellular base-station or performing high frequency processing. The second frequency source is a low-frequency clock (e.g., having a reference frequency of 32 kHz) that is used for maintaining a time base during idle states. The second, low-frequency clock avoids current consumed in generating and distributing the high frequency clock source, as well as current consumed in devices connected to the high frequency clock that do not implement adequate clock gating.
According to conventional designs, separate circuits having different components are required to utilize the high frequency and low frequency sources.


A matrix display device comprising a row and column array of display elements (14), e.g. LC display elements, each of which is connected in series with a two terminal non-linear device (15), such as a MIM, between associated row and column address conductors (16,17) and drive means (20,22,25) for applying drive voltages to the picture elements comprising a scanning signal circuit (20) and a data signal circuit (22) for applying selection signals and data signals respectively to the sets of address conductors, in which a sensing circuit (40) provides a control signal (V.sub.1) indicative of current flowing in one, or more, address conductor (16) of one set during the application of selection signals to that conductor which determines the drive voltages applied to the picture elements, preferably by adjustment of the selection signal level, so as to compensate for changes over time in the threshold characteristics of the non-linear devices. Four or five level scanning signal drive schemes may be used. Such compensation may be effected periodically or continually in operation of the display device.

This invention relates to a matrix display device comprising sets of row and column address conductors, a row and column array of picture elements operable to produce a display, each of which comprises an electro-optic display element connected in series with a two terminal non-linear device exhibiting a threshold characteristic between a row conductor and a column conductor, and picture element drive means connected to the sets of address conductors for applying drive voltages to the picture elements comprising a scanning signal drive circuit for applying selection signals to the conductors of one set and a data signal drive circuit for applying data signals to the conductors of the other set. The invention relates also to a method of operating such a display device.
Display devices of this kind are suitable for displaying alpha-numeric or video information using passive electro-optical display media such as liquid crystal material, electrophoretic suspensions or electrochromic materials. Examples of such display devices, using liquid crystal material, are described in GB-A-2129182, EP-A-0185995, and GB-A-2147135. The two terminal non-linear devices can be of various forms, such as diode rings, back to back diodes, MIMs, etc., which are bidirectional. The polarity of the drive voltages applied to the picture elements can then conveniently be inverted periodically, typically in successive field periods, in order to prevent degradation of the electro-optic display material and improve display quality. The picture elements are addressed by sequentially applying a selection voltage signal to each one of the first set of address conductors, usually the row conductors, and data, for example video, signals to the other set of address conductors to set the display elements to a desired display condition which is maintained until they are again selected.
For acceptable quality of display it is important that the non-linear devices of the matrix array demonstrate substantially similar threshold and I-V characteristics in operation so that the same drive voltages applied to any picture element in the array produce substantially identical visual results, for example in the case of a liquid crystal display device, as regards picture element transmission levels. Differences in the threshold or turn-on point of the non-linear devices can appear directly across the electro-optical material producing different display effects from picture elements addressed with the same drive voltages.
Serious problems can arise if the threshold level of the non-linear devices changes over a period of time, for example through ageing effects. The consequential change in display element voltages not only leads to inferior display quality but, depending on the drive scheme employed, can cause an image storage problem and also degradation of the LC material.
In the aforementioned GB-A-2129182 a drive scheme is described which involves a four level row drive in which the scanning signal applied to a row conductor consist of first, selection, voltage level for a selection interval of fixed duration followed by a second, hold, voltage level of less value but of the same polarity as the selection level and which is maintained for at least a major portion of the time which elapses until the row conductor is next addressed with the selection voltage level. The polarity of the selection and hold levels is inverted for successive field periods. It is said that by using this method non-linear devices having a comparatively low threshold voltage would be sufficient allowing relatively low drive voltages. There is also described briefly in this specification a reference voltage setting circuit which is used to adjust the selection and hold voltages applied to the picture elements in accordance with changes in the threshold voltage level of a non-linear element caused by variations in operating temperatures in use of the display device. This circuit uses a reference non-linear element, namely a diode element, one side of which is connected to ground, and operates to compare the threshold voltage of the reference element with reference potentials comprising a predetermined threshold voltage level. This is achieved by sensing the voltage across the reference element.

Matrix display device and its method of operation


A new and distinct cultivar of Angelonia plant named ‘Balangbakin’, characterized by its lavender pink-colored flowers, medium green-colored foliage, and moderately vigorous, prostrate growth habit.

The present invention relates to a new and distinct cultivar of Angelonia plant botanically known as Angelonia angustifolia and hereinafter referred to by the cultivar name 'Balangbakin'.
The new cultivar originated in a controlled breeding program in Elburn, Ill. during June 2003. The objective of the breeding program was the development of Angelonia cultivars with unique flower coloration, continuous flowering, and a moderately vigorous, freely branching, and prostrate growth habit.
The new cultivar is the result of cross-pollination. The female (seed) parent of the new cultivar is the proprietary Angelonia angustifolia breeding selection designated 147-1,2-6-2-3, not patented, characterized by white-colored flowers, dark green-colored foliage, and semi-prostrate growth habit. The male (pollen) parent of the new cultivar is AngelMist® Basket Purple 'Balangbeke', U.S. Plant Pat. No. 15,546, characterized by purple-colored flowers, medium green-colored foliage, and semi-prostrate to trailing growth habit. The new Angelonia cultivar was discovered and selected at a single flowering plant within the progeny of the above stated cross-pollination during March 2004 in a controlled environment at Elburn, Ill.
Asexual reproduction of the new cultivar by terminal stem cuttings since March 2004 at Elburn, Ill., Arroyo Grande, Calif., and West Chicago, Ill. has demonstrated that the new cultivar reproduces true to type with all of the characteristics, as herein described, firmly fixed and retained through successive generations of such asexual propagation.


The disclosed implementations relate generally to improved workflows for color correcting digital images. In some implementations, a method of correcting images includes: presenting a user interface on a display device, the user interface including a display area; presenting a digital image in the display area; overlaying a correction interface on the digital image; and performing a correction operation on at least a portion of the digital image in response to a user interaction with the correction interface, where the correction operation is performed with real-time responsiveness.

Color correction tools are used in the film industry and other disciplines to alter the perceived color of an image. Conventional color correction tools typically allow users to perform primary and secondary color corrections. Primary color correction involves correcting the color of an entire image, such as adjusting the blacks, whites or gray tones of the image. Secondary color correction involves correcting a particular color range in an image. For example, a user may want to change the color of an object in an image from red to blue. The user would identify the range of red in the object and then shift the hue to blue. This process could also be applied to other objects in the image.
Conventional color correction tools often provide poor performance when multiple secondary corrections are applied to images due to the computations involved. Users are often forced to render an entire image before seeing the results of a color adjustment. This delay when multiplied by many adjustments can add significant delay to the overall color correction process.
Conventional color correction tools also fail to provide an intuitive workflow that allows users to make multiple fine adjustments without losing context. For example, the image to be color corrected may be displayed in a different window than the correction interface used to make the corrections, forcing the user to repeatedly take their eyes off the image while making adjustments. Additionally, a user may have to select an appropriate range for one or more color correction parameters (e.g., luminance, hue, saturation, etc.) because the default or preset ranges for the parameters are not sufficient for the task at hand.
Many color correction tasks are most easily accomplished through the use of several tools. Unfortunately, many conventional color correction tools make it difficult to accomplish even simple tasks by scattering the tools over several user interfaces, menus, layers, etc. The failure to combine, tie or link tools together based on the task can interrupt workflow.


According to the present invention, a process is provided for making paper or board comprising forming a cellulosic suspension that may or may not comprise a filler, flocculating the cellulosic suspension, draining the cellulosic suspension on a screen to form a sheet, wherein the cellulosic suspension is flocculated using a flocculation system comprising the sequential or simultaneous addition of a siliceous material and an organic, cationic or anionic, water-in-water or dispersion micropolymer in a salt solution.

This invention relates to processes for making paper and paperboard from a cellulosic stock, employing a novel flocculation system in which a new micropolymer technology is employed.
During the manufacture of paper and paperboard, a cellulosic thin stock is drained on a moving screen (often referred to as a machine wire) to form a sheet, which is then dried. It is well known to apply water-soluble polymers to the cellulosic suspension in order to effect flocculation of the cellulosic solids and enhance drainage on the moving screen.
In order to increase output of paper, many modern papermaking machines operate at higher speeds. As a consequence of increased machine speeds, a great deal of emphasis has been placed on drainage and retention systems that provide increased drainage and retention of the papermaking components. It is known that increasing the molecular weight of a polymeric retention aid (which is generally added immediately prior to drainage) will tend to increase the rate of drainage, but will also damage formation. It can be difficult to obtain the optimum balance of retention, drainage, drying and formation by adding a single polymeric retention aid, and it is therefore common practice to add two separate materials in sequence or jointly.
More recent attempts to improve drainage and retention during papermaking have used variations on this theme by using different polymers and siliceous components. These systems can consist of multiple components.
U.S. Pat. No. 4,968,435 describes a method of flocculating an aqueous dispersion of suspended solids which comprises adding to, and mixing with the dispersion, from 0.1 to 50,000 parts per million of dispersion, solids of an aqueous solution of a water-insoluble, crosslinked, cationic, polymeric flocculent having an unswollen number average particle size diameter of less than 0.5 micrometers, a solution viscosity of 1.2 to 1.8 centipoise, and a crosslinking agent content above 4 molar parts per million, based on the monomeric units present in the polymer, to flocculate the suspended solids, and separating the flocculated suspended solids from the dispersion.
U.S. Pat. No. 5,152,903 is a continuation of this patent, and describes a method of flocculating a dispersion of suspended solids that comprises adding to, and mixing with the dispersion, from 0.1 to 50,000 parts per million of dispersion solids of an aqueous solution of a water-soluble, crosslinked, cationic, polymeric flocculent having an unswollen number average particle size diameter of less than 0.5 micrometers, a solution viscosity of from 1.2 to 1.8 centipoise and a crosslinking agent content above 4 molar parts per million based on the monomeric units present in the polymer.
U.S. Pat. No. 5,167,766 further describes a method of making paper which comprises adding to an aqueous paper furnish from 0.05 to 20 pounds per ton, based on the dry weight of paper furnish solids, of an ionic, organic, crosslinked polymeric microbead, the microbead having an unswollen particle diameter of less than 750 nanometers and an ionicity of at least 1%, but at least 5%, if anionic and used alone.
U.S. Pat. No. 5,171,808 is a further example which describes a composition comprising crosslinked anionic or amphoteric polymeric micropolymers derived solely from the polymerization of an aqueous solution of at least one monomer, the micropolymers having an unswollen number average particle size diameter of less than 0.75 micrometers, a solution viscosity of at least 1.1 centipoise, a crosslinking agent content of 4 molar parts to 4000 parts per million, based on the monomeric units present in the polymer, and an ionicity of at least 5 mole percent.
U.S. Pat. No. 5,274,055 describes a papermaking process wherein improved drainage and retention are obtained when ionic, organic microbeads, of less than 1,000 nanometers in diameter if crosslinked or less than 60 nanometers in diameter if non crosslinked, are added either alone or in combination with a high molecular weight organic polymer and/or polysaccharide. Further addition of alum enhances drainage formation and retention properties in papermaking stock with and without the presence of other additives used in papermaking processes.
U.S. Pat. No. 5,340,865 describes a flocculant comprising a water-in-oil emulsion comprising an oil phase and an aqueous phase wherein the oil phase consists of fuel oil, kerosene, odorless mineral spirits or mixtures thereof, and one more surfactants at an overall HLB ranging from 8 to 11, wherein the aqueous phase is in the form of micelles and contains a crosslinked, cationic, polymer produced from 40 to 99 parts by weight of acrylamide and 1 to 60 parts by weight of a cationic monomer selected from N,N-dialkylaminoalkylacrylates and methacrylates, and their quaternary or acid salts, N,N-dialkylaminoalkylacrylamides and methacrylamides, and their quaternary or acid salts, and dialkyldimethylammonium salts. The micelles have a diameter of less than 0.1 micrometers, and the polymer has a solution viscosity of from 1.2 to 1.8 centipoise, and a content of N,N-methylenebisacrylamide of 10 molar parts to 1000 molar parts per million, based on the monomeric units present in the polymer.
U.S. Pat. No. 5,393,381 describes a process of making paper or board by adding a water-soluble branched cationic polyacrylamide and a bentonite to the fibrous suspension of pulp. The branched cationic polyacrylamide is prepared by polymerizing a mixture of acrylamide, cationic monomer, branching agent, and chain transfer agent by solution polymerization.
U.S. Pat. No. 5,431,783 describes a method for providing improved liquid-solid separation performance in liquid particulate dispersion systems. The method comprises adding to a liquid system containing a plurality of finely divided particles from 0.05 to 10 pounds per ton, based upon the dry weight of the particles, of an ionic, organic crosslinked polymeric microbead with a diameter of less than 500 nanometers, and from 0.05 to 20 pounds per ton, on the same basis, of a polymeric material selected from the group consisting of polyethylenimines, modified polyethylenimines, and mixtures thereof. In addition to the compositions described above, additives such as organic ionic polysaccharides may also be combined with the liquid system to facilitate separation of the particulate material therefrom.
U.S. Pat. No. 5,501,774 describes a process where filled paper is made by providing an aqueous feed suspension containing filler and cellulosic fiber, coagulating the fiber and filler in the suspension by adding cationic coagulating agent, making an aqueous thinstock suspension by diluting a thickstock consisting of or formed from the coagulated feed suspension, adding anionic particulate material to the thinstock or to the thickstock from which the thinstock is formed, subsequently adding polymeric retention aid to the thinstock and draining the thinstock for form a sheet and drying the sheet.
U.S. Pat. No. 5,882,525 describes a process in which a cationic branched water-soluble polymer with a solubility quotient greater than 30% is applied to a dispersion of suspended solids, e.g. a paper making stock, in order to release water. The cationic, branched, water-soluble polymer is prepared from similar ingredients to U.S. Pat. No. 5,393,381, by polymerizing a mixture of acrylamide, cationic monomer, branching agent and chain transfer agent.
U.S. Pat. No. 4,913,775 describes a process wherein paper or paperboard is made by forming an aqueous cellulosic suspension, passing the suspension through one or more shear stages selected from cleaning, mixing and pumping, draining the suspension to form a sheet, and drying the sheet. The suspension that is drained includes an organic polymeric material that is a flocculant or a retention aid, and an inorganic material comprising bentonite, which is added in an amount of at least 0.03% to the suspension after one of the shear stages. The organic polymeric retention aid or flocculant comprises a substantially linear synthetic cationic polymer having molecular weight above 500,000 and having a charge density of at least 0.2 equivalents of nitrogen per kilogram of polymer. The organic polymeric retention aid or flocculant is added to the suspension before the shear stage in an amount such that flocs are formed. The flocs are broken by the shearing to form microflocs that resist further degradation by the shearing, and that carry sufficient cationic charge to interact with the bentonite to give better retention than that which is obtainable when adding the polymer alone after the last point of high shear. This process is commercialized by Ciba Specialty Chemicals under the Hydrocol registered trademark.
U.S. Pat. No. 5,958,188 further describes a process where paper is made by a dual soluble polymer process in which a cellulosic suspension, which usually contains alum or cationic coagulant, is first flocculated with a high intrinsic viscosity (IV) cationic synthetic polymer or cationic starch and, after shearing, the suspension is reflocculated by the addition of a branched anionic water-soluble polymer having an intrinsic viscosity above 3 deciliters per gram, and a tan delta at 0.005 Hertz of at least 0.5.
U.S. Pat. No. 6,310,157 describes a dual soluble polymer process in which a cellulosic suspension which usually contains alum or cationic coagulant is first flocculated with a high IV cationic synthetic polymer or cationic starch and, after shearing, the suspension is reflocculated by the addition of a branched anionic water-soluble polymer having IV above 3 dl/g and tan delta at 0.005 Hz of at least 0.5. The process gives an improved combination of formation, retention, and drainage.
U.S. Pat. No. 6,391,156 describes a process of making paper or paper board comprising forming a cellulosic suspension, flocculating the suspension, draining the suspension on a screen to form a sheet and then drying the sheet, characterized in that the suspension is flocculated using a flocculation system comprising a clay and an anionic branched water-soluble polymer that has been formed from water-soluble ethylenically unsaturated anionic monomer or monomer blend and branching agent and wherein the polymer has an (a) intrinsic viscosity above 1.5 dl/g and/or saline Brookfield viscosity of above 2.0 mPa·s and (b) rheological oscillation value of tan delta at 0.005 Hz of above 0.7 and/or (c) deionised SLV viscosity number which is at least three times the salted SLV viscosity number of the corresponding unbranched polymer made in the absence of branching agent.
U.S. Pat. No. 6,454,902 describes a process for making paper comprising forming a cellulosic suspension, flocculating the suspension, draining the suspension on a screen to form a sheet, and then drying the sheet, wherein the cellulosic suspension is flocculated by addition of a polysaccharide or a synthetic polymer of intrinsic viscosity at least 4 deciliters per gram, and then reflocculated by a subsequent addition of a reflocculating system, wherein the reflocculation system comprises a siliceous material and a water-soluble polymer. In one embodiment, the siliceous material is added prior to or simultaneously with the water-soluble polymer. In another embodiment, the water-soluble polymer is anionic and added prior to the siliceous material.
U.S. Pat. No. 6,524,439 provides a process for making paper or paperboard comprising forming a cellulosic suspension, flocculating the suspension, draining the suspension on a screen to form a sheet and then drying the sheet. The process is characterized in that the suspension is flocculated using a flocculation system comprising a siliceous material and organic microparticles that have an unswollen particle diameter of less than 750 nanometers.
U.S. Pat. No. 6,616,806 describes a process for making paper comprising forming a cellulosic suspension, flocculating the suspension, draining the suspension on a screen to form a sheet and then drying the sheet, wherein the cellulosic suspension is flocculated by addition of a water-soluble polymer which is selected from a) a polysaccharide or b) a synthetic polymer of intrinsic viscosity at least 4 dl/g and then reflocculated by a subsequent addition of a reflocculating system, wherein the reflocculating system comprises i) a siliceous material and ii) a water-soluble polymer. In one aspect the siliceous material is added prior to or simultaneous with the water-soluble polymer. In an alternative for the water-soluble polymer is anionic and added prior to the siliceous material.
JP Publication No. 2003-246909 discloses polymer dispersions is produced by combining an amphoteric polymer having a specific cationic structural unit and an anionic structural unit and soluble in the salt solution, and a specific anionic polymer soluble in the salt solution and polymerizing them in dispersion under agitation in the salt solution.
However, there still exists a need to further enhance paper making processes by further improving drainage, retention and formation. Furthermore there also exists a need for providing a more effective flocculation system for making highly filled paper. It would be desirable if these improvements included use of polymers that require less make-down equipment, less complicated feed-systems, and environmentally friendly, e.g., polymers with low or no volatile organic chemicals (VOC).

Composition and method for paper processing


A collet chuck configured to connect to a standard milling machine spindle, wherein the collet chuck includes a centering sleeve having a tapered outer peripheral surface for contact with an inside peripheral tapered surface of the spindle and has an outer end disposed adjacent the mounting end of the spindle, a chuck body having a base with an outer end including mounting end to mount to the end of the spindle, and a biasing element operably disposed between the outer end of the centering sleeve and a portion of a back side of the base in a manner such that the biasing element exerts a force on the back side prior to a direct connection of the base to the mounting end thereby providing for variances in connection of the base to the mounting end of the spindle and assuring concentricity is maintained when so connected.

1. Field of the Invention
The present invention relates to a spindle collet chuck, and more particularly, to a spindle collet chuck with a novel mounting self centering and quick connect aspect.
2. Description of Related Art
The known conventional collet chuck for holding rotating bits installed on spindle shaft of a machine tool includes a chuck body with a collar which is flush mounted to a mounting face of a spindle using screws. The conventional collet chuck has a problem that a gap is often left between the mounting face of the spindle shaft and the mounting face of the chuck collet due to surface variations. These variances between the components are due to tolerances. Attempts to rectify the resulting variance have been made to enable the installation in which the collet chuck and in turn, tool, is positioned with respect to the spindle shaft in a concentric manner. One such way requires that the chuck body include a plurality of indexing screws which are used to align the collet chuck body, and in turn the spindle nose in concentric relation with the spindle shaft. Other concentricity techniques use the tapered center for mounting and centering via a drawbar in the spindle, however, they do not mount to the end of the spindle. While this enables good centering, upon release of the drawbar, it releases the entire holding device as opposed to just the tool needing to be changed and thus is more costly. Existing face mounts to the end of the spindle have problems with achieving concentricity and require clearance for attachment to the spindle. A further problem resides in the need for quick interchange of tool parts.
Such prior designs have yet to meet the expectations in the field. Such prior techniques are time consuming and difficult to align and or change out tool parts. There remains a need to simplify and improve collet chuck—spindle connections to quickly enable concentricity to be achieved and quick interchangeability of tool parts. The present invention meets such prior needs.


The present invention aims to perform communication between the wireless terminals by adopting the existing networks and by avoiding the congestion on the network. The terminal location databases set at various networks control the position information of the wireless terminals. According to one of the steps in the method of the present invention, a wireless terminal inquires a terminal location database for the position information of a destination wireless terminal. Then, as for the next step, the wireless terminal receives a reply from the terminal location database regarding the position information of the destination wireless terminal. As for the following step, the wireless terminal communicate to the destination wireless terminal.

1. Field of the Invention
The present invention relates to a communication method of a wireless terminal communicating to a desired wireless terminal. Both wireless terminals are situated under the same wireless communication environment.
2. Description of the Related Arts
Rapidly increasing uses of the cellular communication networks for the purposes of various data communication have been brought about from a recent advancement in their variety of types. Uses of these cellular communication networks continue to accelerate owing to the introduction of such services as cellular phone service that can have the internet connection and communication service that makes the high-speed delivery of the data possible. In addition to the ever increasing uses of these services which are provided by the operators, even the contents of these services are becoming diverse. A service which supplies the position information of a wireless terminal to a user of the network side and passes it onto another wireless terminal is one example of the diversified services. The example of such services are the service of supplying a timetable of the nearby train station to a wireless terminal based on its position information: and a service of locating the positions of the employees. Japanese unexamined patent publication HEI 10-221106 discloses a technique of informing the network user the position information of the wireless terminals using the internet. This technique is commonly being adopted for a purpose of controlling the positions of the wireless terminals.
As mentioned briefly, various types of the cellular communication networks provided and controlled by the operators are used by various wireless terminals for the purposes of various kinds of data communication. These data communication are the wireless communication from a wireless terminal to a cellular communication network, and vice versa, in other words, the wireless communication involving the operator. In the wireless communication involving the operator, it is the network who supplies the wireless communication mechanisms to the wireless terminal. Not only the wireless communication involving the operator supplying the wireless communication mechanism to the wireless terminal, but also other kinds of wireless communication which is the wireless communication not involving the operator, are becoming widespread. The wireless communication not involving the operator is the wireless communication from a wireless terminal to another wireless terminal. In this case, the wireless communication mechanisms are integrated to the wireless terminal. As an example, the communication method known as infrared data access (IrDA) interface exchanges data between one wireless terminal and another wireless terminal. The infrared data access integrates the wireless communication mechanisms to the wireless terminals. The communication method known as Bluetooth utilizes a high-speed and weak micro wave. The Bluetooth is a communication method from a wireless terminal to a well-known destination wireless terminal. The communication method known as wireless local area network is disclosed in Japanese unexamined patent publication HEI 11-163875. The wireless local area network (wireless LAN) implements the ad hoc network integrating media access control (MAC) to the wireless communication media. This publication discloses the wireless local area network system which deploys a mechanism to register position of a wireless terminal, to give a specific example, this technology is adopted in such locality as art museum, supplying an information to a user holding a wireless terminal, and the system supplies the information on any piece of artwork responding to position of the user holding the wireless terminal in the art museum.
Accordingly, various wireless communication mechanisms are beginning to be integrated to the wireless terminals making them possible to communicate from one wireless terminal to another wireless terminal without involving the operator in its way. Yet still, the mechanisms supplied by the operators allow the users to connect to the network to receive many different kind of services, however, the disadvantages in using their mechanisms are that the users are charged for using these services and also charged for the connection fee. With the increasing number of users using these services, without doubt this will cause a significant amount of communication traffics such that the operators also need more money to reinvest in the new equipment. Not to mention the fact that the wireless communication involving the operator is generally slow in speed. Thus, without doubt that the communication from one wireless terminal to another wireless terminal bypassing the operators such as in public switched telephone network is not at all practical.
On the other hand, the wireless communication not involving the operator is used in a fixed communication from one wireless terminal to another well-known destination wireless terminal using a weak radio wave in a narrow region. This can generally attain the high-speed communication rate. According to one of the aims of the present invention, not only it attempts to solve the pre-mentioned problems, but the present invention also aims to supply the data communication method between the wireless terminals integrating the data communication mechanisms by forming what is essentially a contingent and local network (ad hoc network). In precise terms, the present invention attempts to carry out a service to the wireless terminal by adopting a part of the existing network, setting up a terminal location database having various types of information, and further forming the ad hoc network consisting of wireless terminals, joining any wireless terminals to the ad hoc network formed, and allowing free communication between the joined wireless terminals. This way, even if the communication device in use such as wireless terminal which does not wish to involve the operator, the wireless terminal user can still search and inquire for a service or data provided by the operator, and in response to the inquiry of this wireless terminal, any other wireless terminal user who happens to have the service or the data being requested can send them instead. The application for which its use is limited to a business card exchanges between the wireless terminals is adopted and extended to the extent of exchanging of non-specified amount of services and data. This enables the wireless terminal to utilize the high-speed wireless communication to the unknown wireless terminal at a reasonable cost.


A method and device is provided for combining various forms of flotation techniques to achieve a very high degree of purification of waste water while energy consumption is maintained low.

Humankind is encountered with increasing problems of municipal and industrial waste waters, which must be purified and reused. Physical, chemical, and biological purification processes have been developed for these purposes. The impurities to be removed during the purification are usually particles, which are kept in aqueous phase by their colloidal nature. After a biological purification, waste waters usually contain still unfermented materials and high content of viable microbes as well as microbial cell debris. The complex microbe-colloid system can be broken by suitable chemicals, like polyvalent metal ions or polymers, which allow colloids to combine and form bigger particles or flocks. The colloidal particles remain suspended in water with extremely complex molecular mechanisms and there is no single universal method to break such ionic and hydrophobic forces in the system. Even small amounts of dissolved molecules can affect the flock formation. Alive microbes have metabolically acquired means to create electrical charges around them and thus to avoid sedimentation. It follows that destroying of the metabolisms will facilitate aggregation of the microbes. On the other hand, providing nutrients and oxygen to microbes will prevent the aggregation. If flocks can be developed, they can easily sediment in gravitational systems or be subjected to a centrifugation process. A less common manner would be to lift the flocks onto the surface of the waste water tank by exploiting the buoyance force of air or other gas bubbles with flotation techniques.
The traditional or air flotation exploits compressed air, which is pumped through nozzles into waste water as described in FIG. 1. Whilst air flotation is the simplest flotation process, it has several drawbacks. Only a part of treated water is saturated by gas and the incidence of meeting of particle and the lifting air bubbles is low. The bubble sizes are in all cases big (diameter>200 μm) and their internal pressure is therefore small (0.2-0.5 bars). This leads to a big increase of the bubble volume during the movement up in waste water with an accelerating speed. Because the bubble volume is big, it moves very fast in the solution. These facts cause that bubbles' surface will lose the particles, which may have already attached to them. That is why the air flotation machines always contain also means to remove suspended solids from the bottom of the flotation chamber.
Micro flotation (also termed as dissolved air flotation, DAF) is an advanced technique, which allows creation of smaller bubble sizes than in the traditional flotation (diameter>100 μm). Micro flotation has been shown to be an efficient process for the removal of various colloid-sized impurities from water and waste water. Laboratory studies have shown that for this purpose very small bubbles are required. The investigation showed a rapid decrease in micro flotation removal efficiencies when bubble diameters exceed 55-60 μm (Water Research, 9, 1975, pp 1017-1024 by E. Cassel et al.). In micro flotation water is saturated with pressurized air. Each gas in air gas mixture dissolves in water according to its mole fraction in the mixture. The amount of dissolved gas is dependent on its partial pressure and temperature. Such air-saturated water is mixed with incoming waste water as shown in FIG. 2. When pressure is released, very small (visibly seen as milky) air-bubbles are generated, which attach effectively to suspended particles and lift them up onto the surface of the flotation tank. This technique has the advantage that gas bubbles tend to be generated around particles and the bubbles do not need to find the particles like in the traditional flotation, i.e. particles act as bubble generation centers. Moreover, since tiny gas bubbles are generated in huge amounts (effective surface area is big) also the probability factor determining that suspended particles and small bubbles meet each other is high and therefore the purification results are definitely better than in any traditional flotation systems. Because the waste water and air-saturated water can be mixed instantaneously, gas bubbles do not need to be spread (diffuse) in the solution like in traditional flotation. The pressurized water can be, for example, circulated from the outlet of the purification system. A drawback is that a limited amount of air can be dissolved in water and hence a limited amount of bubbles can be created in a given volume. Micro flotation also suffers from the absence of a covering bubble mat over the whole waste water pathway and a part of the particles is sedimented.
Electroflotation has been mainly deployed for industrial waste water purification (especially fatty impurities) and is not so familiar in communal purification systems. FIG. 3 shows a typical electroflotation machine. Gas bubbles are generated by electrical current through water electrolysis. The bubbles are small (diameter 10-70 μm) and they are either positively or negatively charged. It is possible to regulate bubble size by changing the electric current density, pH, geometry of electrodes, added chemicals, etc. Electrolytically generated bubbles are very homogenous in size and practically they do not coalesce after leaving the electrode surface and keep their constant diameter during moving up in the liquid. Because of the very small volume (and high surface tension/volume), the internal pressure of the bubbles can be up to 103 bars. The generated oxygen and hydrogen (in statu nascendii) in the bubbles can cause significant changes in the properties of the suspended solids through the chemical reactions. Proteins may react with oxygen and hydrogen (reduce or oxidize) and also living microbes may lose their colloidal properties. Thus, the electrolysis advance flock formation or flocculation. An advantage of electroflotation is that water can be saturated by gas as much as it is required for the process by increasing the current to electrodes. Electroflotation may be performed at any temperature of water, what is impossible for other types of flotation. However, a serious drawback in adoption of electric technologies in waste water purification is the technical realization of convenient and long-life maintenance-free equipment. The primary reason for that origins from electrode corrosion and electrode passivation by deposition of materials on the electrodes. When considering the overall economy, usual low corrosion anode materials, like titanium and stainless steel may be optimal. The corroded electrodes should be easily serviced, i.e. changed and cleaned.

Combiflotation for purification and disinfection of waste water


A gas measuring device includes a dissolving unit for dissolving gas to be measured in solvent medium, a measuring unit for measuring the amount of ions generated when the gas to be measured is ionized in the liquid medium, and a calculating unit for calculating the amount of the gas to be measured from a value measured by the measuring unit.

1. Field of the Invention
The present invention relates to a gas measuring device suitable for use with the processing apparatus in which a certain process of process gas is applied to objects to be processed, and also relates to a processing apparatus provided with the gas measuring device.
2. Description of the Related Art
Most semiconductor manufacturing apparatuses including the heat treating apparatus, diffusing apparatus, etching apparatus, sputtering apparatus and others are intended to process the surface of objects to be processed such as semiconductor wafers by process gases supplied. They are exhausted after this surface process and their certain processes are then finished.
In the case of the heat treating apparatus of the batch type, for example, SiH.sub.2 Cl.sub.2 gas is supplied as reaction gas into the reaction tube through the reactive gas supply pipe, Si film is formed on the surface of each of wafers positioned at the soaking zone in the reaction tube, and gas remaining in the reaction tube is then exhausted through the exhaust pipe by the vacuum pump connected to the exhaust pipe. The process is thus finished. After the finish of this process, purge gas such as inactive N.sub.2 gas is introduced into the reaction tube through the reactive gas supply pipe to replace atmosphere in the reaction tube by N.sub.2 gas. The semiconductor wafers which have been processed are then unloaded out of the reaction tube.
However, it has been found that the remaining reaction gas still discharged, though low in density, from the reaction gas supply pipe and adheres to the inner wall of the reaction tube and the surface of each of the processed objects, even when the reaction tube is purged by the purge gas such as N.sub.2 gas. This remaining reaction gas creates harmful substances and particularly in the case of SiH.sub.2 Cl.sub.2 gas it creates poisonous and corrodible HCl on the way of its reaction. It is therefore asked that HCl is measured even if its amount is extremely small. However, a device has not yet been provided to continuously measure such gas component that is low in density and extremely small in amount.

Gas measuring device and processing apparatus provided with the gas measuring device


A dropping electrolyte electrode for use in electrochemical analysis of non-polar sample solutions, such as benzene or cyclohexane. The liquid electrode, preferably an aqueous salt solution immiscible in the sample solution, is introduced into the solution in dropwise fashion from a capillary. The electrolyte is introduced at a known rate, thus, the droplets each have the same volume and surface area. The electrode is used in making standard electrochemical measurements in order to determine properties of non-polar sample solutions.

1. Field of the Invention
The present invention relates to electrodes for electrochemical analysis. More particularly, the present invention relates to electrodes that are drops of conducting liquids for use in making electrochemical measurements of sample solutions.
2. Discussion of Background
In electrochemical analyses, electrodes are used to cause an electrical current to flow through a sample of a solution of interest so that data characteristic of the sample solution can be obtained. Most electrodes used are solid, typically made of metal or other electrically conducting material. However, during repeated use, the surfaces of electrodes tend to erode, reducing the operational accuracy of the device. Further, electrode surfaces tend to accumulate foreign matter caused by the deposit of migrating ions.
Because of these problems, mercury is often used in electrochemical analyses. Typically, mercury, which is liquid at room temperature, is introduced into the sample solution one drop at a time. Thus, a fresh electrode surface is provided by each mercury drop, avoiding the problems of the degradation of the surfaces of solid electrodes.
For example, Ladisch, in U.S. Pat. No. 2,706,710, discloses a polarographic mercury cell used for measuring diffusion currents. His cell has an upper chamber of fritted glass through which mercury drops.
However, the use of mercury in such applications presents health and disposal problems because mercury is highly toxic and therefore requires careful handling and carries with it special disposal requirements. There exists a need for alternate liquid electrodes.

The United States of America as represented by the United States Department of Energy


Disclosed herein are recombinant polypeptides comprising an elastin-like peptide (ELP) and a scFv, or a biological equivalent of the scFv. Also disclosed are compositions containing scFv-ELP polypeptides and methods of use.

Non-Hodgkin Lymphoma (NHL) accounts for 4% of all reported cancers. The most prescribed course of treatment is a regimen of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP). The CHOP regimen, developed in the 70's, is effective in 90% of the patients but is responsible for severe side effects.
NHL is characterized by increased production of malignant B-cells, which can be targeted specifically through cell-surface CD20. Antibodies against CD20 have been developed for NHL and have successfully made their way to the clinic. The most prominent example is Rituximab™, a chimeric antibody that targets malignant as well as normal B-cells. Crosslinking of Rituximab™ using a secondary antibody against the Fc region promotes cell apoptosis, which led to the observation that CD20-mediated apoptosis can be potentiated through strategies that induce multivalency. Multivalent antibodies against CD20 are potent inhibitors of the MAP Kinase pathway and upregulate Raf-1 kinase inhibitor protein (RKIP), which promotes apoptosis. In combination with chemotherapy, immunotherapeutics overcome resistance in greater than 50% of NHL patients. Particles targeting CD20 may also be effective in drug resistant NHL.
Autoimmune disorders and cancers including NHL are currently being treated by surgery, radiotherapy, chemotherapy, and more recently immunotherapy. Substantial efforts have been expended to explore these modalities, but more innovative ideas are needed to gain ground against tumor resistance. In addition, many cancer therapeutics have an associated risk of cytotoxicity to healthy tissue. Therefore, there is a need in the art for therapeutics with reduced toxicity.


The present invention relates to novel compounds which are suitable as pharmaceuticals, to processes for their preparation and to their use as pharmaceuticals, in particular as antiviral agents.

This application is a 371 of PCT/EP00/03492 filed Apr. 18, 2000.
The present invention relates to novel compounds which are suitable as pharmaceuticals, to processes for their preparation and to their use as pharmaceuticals, in particular as antiviral agents.
xcex1,xcex2-Naphthyl-linked phenylsulphonamides are mainly disclosed in photographic publications [compare in this connection JP-06 122 669-A2, EP-684 515-A1; JP-59 174 836-A2, DE-2 902 074, U.S. Pat. No. 3,925,347, U.S. Pat. No. 4,035,401, U.S. Pat. No. 3,622,603, U.S. Pat. No. 3,482,971, EP-284 130].
WO 90/09 787 dicloses sulphonamides as radio- or chemosensitizing agents and their use in the treatment of tumours.
In addition, the compound N-[4-[[[5-(dimethylamino)-1-naphthalenyl]sulphonyl]-amino]phenyl]acetamide is known (J. Inst. Chem. (India) (1976), 48, Pt 6, 280-5).
The invention relates to compounds of the general formula (I)
in which
R1 represents a group which is selected from the following formulae
xe2x80x83in which
---- represents a single or double bond,
R3 represents hydrogen, (C1-C6)alkyl or (C3-C6)cycloalkyl, each of which may be substituted by 1 to 3 substituents selected from the group consisting of hydroxyl, halogen, amino, mono- or di(C1-C6)-alkylamino, (C1-C6)alkanoylamino, (C1-C6)alkanoyloxy, (C1-C6)alkanoyl, carboxyl, (C1-C6)alkoxycarbonyl, carbamoyl, mono- or di(C1-C6)alkylaminocarbonyl and cyano, or
R3 represents (C6-C10)arylsulphonyl, (C6-C10)arylcarbonyl, the (C6-C10)aryl group of which in each case can be substituted by 1 to 3 substituents selected from the group consisting of halogen, (C1-C3)alkyl, carboxyl, (C1-C3)alkoxycarbonyl, carbamoyl, mono- or di(C1-C6)alkylaminocarbonyl, cyano, hydroxyl and (C1-C3)alkoxy, or
R3 represents (C1-C6)alkanoyl, (C1-C6)alkylsulphonyl, (C3-C6)cycloalkylcarbonyl, camphorsulphonyl or (C3-C6)cycloalkylsulphonyl, or
R3 represents R4xe2x80x94Xxe2x80x94COxe2x80x94or R4xe2x80x94Xxe2x80x94CSxe2x80x94 in which
X represents O, S, NR5 in which R5 represents hydrogen or (C1-C3)alkyl, and
R4 represents (C1-C6)alkyl, (C3-C6)cycloalkyl, (C6-C10)aryl or 5- to 10-membered heteroaryl, and
R2 represents
xe2x80x83in which
R6 is (C2-C6)alkenyl or (C1-C8)alkyl which is optionally substituted once to three times, identically or differently, by amino, protected amino, (C1-C4)alkylamino, hydroxyl, cyano, halogen, azido, nitro, trifluoromethyl, carboxyl or phenyl, where phenyl in turn can be substituted up to twice, identically or differently, by nitro, halogen, hydroxyl, (C1-C4)alkyl or (C1-C4)alkoxy, or
R6 represents radicals of the formulae
or
rxe2x80x94Lxe2x80x94Oxe2x80x94LOxe2x80x94Q,
xe2x80x83in which
L represents a straight-chain or branched alkanediyl group with up to 6 carbon atoms,
Q represents (C1-C6)alkyl which is optionally substituted by carboxyl, or
xe2x80x83represents radicals of the formulae
xe2x80x83in which
a denotes the number 1 or 2,
R8 denotes hydrogen,
R9 denotes (C3-C8)cycloalkyl, (C6-C10)aryl or hydrogen, or denotes (C1-C8)alkyl,
xe2x80x83where the (C1-C8)alkyl is optionally substituted by cyano, methylthio, hydroxyl, mercapto, guanidyl or by a group of the formula xe2x80x94NR12R13 or R14xe2x80x94OCxe2x80x94,
xe2x80x83in which
xe2x80x83R12 and R13 denote, independently of one another, hydrogen, (C1-C8)alkyl or phenyl,
xe2x80x83and
xe2x80x83R14 denotes hydroxyl, benzyloxyl, (C1-C6)alkoxy or the abovementioned group xe2x80x94NR12R13,
xe2x80x83or the (C1-C8)alkyl is optionally substituted by (C3-C8)-cycloalkyl or by (C6-C10)aryl which is in turn substituted by hydroxyl, halogen, nitro, (C1-C8)alkoxy or by the group xe2x80x94NR12R13,
xe2x80x83in which R12 and R13 have the meaning indicated above,
xe2x80x83or the (C1-C8)alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or by indolyl, in which the corresponding xe2x80x94NH functions are optionally substituted by (C1-C6)alkyl or are protected by an amino protective group,
R10 and R11 are identical or different and denote hydrogen or an amino protective group,
R7 represents hydrogen or represents a radical of the formula
xe2x80x83in which
R8xe2x80x2, R9xe2x80x2, R10xe2x80x2 and R11xe2x80x2 have the meaning indicated above for R8,
R9, R10 and R11 and are identical to or different from the latter,
and the salts thereof.
The substances according to the invention may also be in the form of salts. Physiologically acceptable salts are preferred for the purposes of the invention.
Physiologically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
Physiologically acceptable salts may likewise be metal or ammonium salts of the compounds according to the invention. Particularly preferred examples are sodium, potassium, magnesium or calcium salts, and ammonium salts derived from ammonia or organic amines such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.
The compounds in accordance with the invention of the general formula (1) may occur in various stereochemical forms which either are related as image and mirror image (enantiomers) or are not related as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms, and the mixtures of diastereomers. The racemic forms can, just like the diastereomers, be separated into the stereoisomerically homogeneous components in a known manner.
In addition, certain compounds may exist in tautomeric forms. This is known to the skilled person, and the scope of the invention likewise encompasses such compounds.
(C1-C6)Alkyl generally represents for the purposes of the invention straight-chain or branched hydrocarbon radicals with 1 to 6 carbon atoms. Correspondingly, (C1-C4)alkyl and (C1-C3)alkyl generally represent for the purposes of the invention straight-chain or branched hydrocarbon radicals with respectively 1 to 4 and 1 to 3 carbon atoms. Examples which may be mentioned are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.
(C3-C6)Cycloalkyl represents cycloalkyl group with 3 to 6 carbon atoms and includes, for example: cyclopropyl, cyclopentyl and cyclohexyl. Cyclopropyl is preferred.
The (C1-C6)alkoxy group used in the present invention and also used in the definitions of (C1-C6)alkoxycarbonyl includes, for example, straight-chain or branched alkoxy groups with 1 to 6 carbon atoms, particularly preferably alkoxy groups with 1 to 4 carbon atoms ((C1-C4)alkoxy), and more preferably alkoxy groups with 1 to 3 carbon atoms ((C1-C3)alkoxy). Examples which may be mentioned are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy, isopentoxy, hexoxy and isohexoxy. Methoxy, ethoxy and propoxy are preferred.
Mono- or di(C1-C6)alkylamino includes for the purposes of the invention those whose alkyl groups have 1 to 6 carbon atoms. The alkylamino groups in this connection may be symmetrical or nonsymmetrical, such as, for example, dimethylamino, diethylamino, methylethylamino etc. This also applies to the mono- or di(C1-C6)alkylamino moiety in the mono- or di(C1-C6)alkylaminocarbonyl group.
(C6-C10)Aryl represents for the purposes of the invention an aromatic radical with 6 to 10 carbon atoms. Preferred aryl radicals are phenyl and naphthyl.
5- to 10-membered heteroaryl represents for the purposes of the invention 5- to 10-membered heteroatom-containing rings which may contain in the ring 1 to 8 heteroatoms which are selected from O, S and N and include, for example, a pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, oxazolyl, thiazolyl, isoxazolyl, triazolyl, thiadiazolyl, pyridazinyl, pyrazinyl, pyrimidinyl, indolizinyl, indolyl, benzo[b]thienyl, benzimidazolyl, pyridoimidazolyl, indazolyl, quinolyl, isoquinolyl, naphthyridinyl, quinazolinyl, etc.
5- to 6-membered nitrogen-containing heterocycles include, for example: pyrrolidine, piperidine, piperazine, morpholine, pyridyl, furyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, etc.
Halogen includes for the purposes of the invention fluorine, chlorine, bromine and iodine. Chlorine or fluorine is preferred.
Concerning (C6-C10)arylsulphonyl and -carbonyl, reference may be made to the definitions mentioned above for (C6-C10)aryl.
(C1-C6)Alkanoyl, and (C1-C6)alkanoyl in the definition of (C1-C6)alkanoyloxy and (C1-C6)alkanoylamino, represents for the purposes of the invention straight-chain or branched alkanoyl with 1 to 6 carbon atoms. Examples which may be mentioned are: formyl, acetyl, propanoyl, butanoyl, pentanoyl, pivaloyl and hexanoyl.
The xe2x80x9calkanediyl group with up to 6 carbon atomsxe2x80x9d designates in this connection straight-chain or branched hydrocarbon groups linked at two positions to other radicals. Examples of alkanediyl groups are: xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94, xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94CH2xe2x80x94etc.
Amino protective groups for the purposes of the invention are the conventional amino protective groups used in peptide chemistry.
These preferably include: benzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyl-oxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 3,4,5-tri-methoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1,1-dimethylethoxycarbonyl, adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluoroenyl-9-methoxycarbonyl, formyl, acetyl, propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl, 2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl.
In a preferred embodiment, the invention includes compounds of the formulae
in which R1 and R2 have the meaning indicated above.
In another preferred embodiment, the invention includes compounds of the general formula (I) in which:
R1 represents a group selected from the formulae:
xe2x80x83in which
---- represents a single or double bond, and
R3 has the meaning indicated above,
and the salts thereof.
In a preferred embodiment, the invention includes compounds of the general formula (I) in which:
R3 represents hydrogen, (C1-C6)alkyl or (C1-C6)alkanoyl, and
R2 represents
xe2x80x83in which
R6 is (C1-C8)alkyl, which is optionally substituted by halogen or hydroxyl, and
R7 is hydrogen,
and the salts thereof.
In a preferred embodiment, the invention includes compounds of the general formula (I) in which R is tert-butyl which is optionally substituted by halogen or hydroxyl, and the salts thereof.
The invention furthermore relates to processes for preparing the compounds of the formula (I).
In process (A), compounds of the general formula (II)
in which R1 is as defined above, are reacted with compounds of the general formula (III)
in which R2 is as defined above, to give compounds of the general formula (I).
The reaction is preferably carried out in the presence of bases such as pyridine, triethylamine and Hxc3xcnig base etc.
The reaction is preferably carried out in a solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, etc.
The reaction is preferably carried out in a temperature range from xe2x88x9210xc2x0 C. to 70xc2x0 C.
The reaction is preferably carried out at atmospheric pressure.
In process (B), compounds of the general formula (Ia):
in which R2 is, as defined above, and
R1a represents a group selected from the following formulae:
are reacted with compounds of the formula (IV):
R3xe2x80x94Axe2x80x83xe2x80x83(IV)
in which R3 is as defined above, and A is a conventional leaving group, in a manner known per se in the presence of a base to give compounds of the general formula (Ib):
in which R2 is as defined above, and R1b represents a group selected from the following formulae:
in which R3 is as defined above.
A in this case represents a conventional leaving group used in nucleophilic substitution reactions, such as, for example, halogen (for example chlorine, bromine, iodine), OTs (Ts=tosyl) and OMes (Mes=mesyl).
Bases preferred in the reaction are tertiary amines such as pyridine, Hxc3xcnig base etc., alkali metal hydroxide and alkali metal carbonate.
The reaction is preferably carried out in an inert solvent such as tetrahydrofuran, 1,4-dioxane, dichloromethane, dimethylformamide etc.
The reaction is preferably carried out in a temperature range from xe2x88x9210xc2x0 C. to 100xc2x0 C.
The reaction is preferably carried out under atmospheric pressure.
In process (C), compounds of the general formula (Ic)
in which R2 is as defined above, and R1c represents a group selected from the following formulae:
in which R3 is as defined above, are converted by oxidation with DDQ (2,3-dichloro-5,6-dicyano-para-benzoquinone) in a manner known per se into compounds of the general formula (Id):
in which R2 is as defined above, R1d represents a group selected from the following formulae:
in which R3 is as defined above.
The reaction is preferably carried out in a solvent such as 1,4-dioxane or 1,2-dichloroethane.
The reaction is preferably carried out in a temperature range from room temperature to the boiling point of the particular solvent under atmospheric pressure.
The reaction is preferably carried out under atmospheric pressure.
In process (D), compounds of the general formula (Ie)
in which R2 is as defined above, and R1e has the following formulae:
are reacted in a manner known per se in the presence of water with alkali metal hydroxides to give compounds of the formula (Ia).
Alkali metal hydroxides include in this case, for example, lithium hydroxide, sodium hydroxide, potassium hydroxide etc., and lithium hydroxide is preferred.
The reaction is preferably carried out in homogeneous aqueous solvent systems.
The reaction is preferably carried out in a temperature range from room temperature to 70xc2x0 C.
The reaction is preferably carried out under atmospheric pressure
In process (E), compounds of the general formula (If)
in which R2 is as defined above, and R11 has the following formulae:
in which R3b represents (C1-C6)alkanoyl, are reacted in a manner known per se with complex metal hydrides to give compounds of the general formula (Ig):
in which R2 is as defined above and R1g has the following formulae:
in which R3c represents (C1-C6)alkyl.
Complex metal hydrides preferably used in the reaction are lithium aluminium hydride, diisobutylaluminium hydride, etc.
The reaction is preferably out in a solvent such as tetrahydrofuran, 1,4-dioxane etc.
The reaction is preferably carried out in a temperature range from xe2x88x9250xc2x0 C. to 40xc2x0 C.
The reaction is preferably carried out under atmospheric pressure.
The processes according to the invention can be illustrated by the following reaction diagrams.
The indole and indoline compounds can be prepared as follows:
The compounds of the general formula (I) can then be obtained as described above from the unsubstituted indole and indoline compounds (R3=hydrogen) by reaction with R3xe2x80x94A.
The isoindoline compounds can be obtained, for example, as shown in the following diagram:
The compounds of the general formula (I) can then be obtained as described above from the unsubstituted isoindoline compounds (R3=hydrogen) by reaction with R3xe2x80x94A.
The preparation of the sulphonyl chloride starting compounds of the formula (II) is illustrated by the following reaction diagram:
In this case, the sulphonyl chloride 1 is prepared, for example, as described by A. L. Borrer, E. Chinoporos, M. Filosa, S. R. Herrchen, C. R. Petersen, C. A. Stern, J. Org. Chem. 53, 2047 (1988).
The sulphonyl chloride 3 can be prepared in analogy to the above reaction.
The sulphonyl chloride 2 is prepared, for example, as described by P. R. Carlier, M. P. Lockshin, M. P. Filosa, J. Org. Chem. 59, 3232 (1994).
The compounds of the general formula (I) can then be obtained from these compounds after reaction with the amines of the formula (III), hydrolysis of the acetyl group, for example with LiOH/H2O and subsequent reaction with R3xe2x80x94A.
The preparation of the compounds of the general formula (III) is illustrated for example in the following reaction diagram:
In this Pyr. means pyridine.
The aniline 4 is prepared, for example, as described in U.S. Pat. No. 3,979,202.
The aniline 6 is prepared, for example, as described by S. Rajappa, R. Sreenivasan, A. Khalwadekar, J. Chem. Res. Miniprint 5, 1657 (1986).
The aniline 7 is prepared, for example, as described in WO 96/31462.
The aniline 8 is prepared, for example, as described by R. W. Hartmann, M. Reichert, S. Goehring, Eur. J. Med. Chem Chim. Ther. 29, 807 (1994).
The anilines 5 and 9 are prepared in an analogous manner.
Concerning the exact reaction conditions, reference may be made to the examples and starting examples.
The invention further relates to. compounds of the formula (I) for use as pharmaceuticals.
The invention further relates to a pharmaceutical composition comprising a compound of the general formula (I) mixed with at least one pharmaceutically acceptable carrier or excipient.
The invention further relates to the use of the compounds of the general formula (I) for producing a pharmaceutical.
The invention further relates to the use of a compound of the general formula (I) for producing a pharmaceutical for the treatment of viral infections, in particular infections by cytomegaloviruses.
The compounds according to the invention of the general formula (I) show a surprising range of actions which could not have been predicted. They show an antiviral action on representatives of the group of Herpesviridae, in particular on human cytomegalovirus (HCMV). They are thus suitable for the treatment and prophylaxis of disorders caused by herpes viruses, in particular disorders caused by human cytomegalovirus (HCMV).
The anti-HCMV action was determined in a screening test system in 96-well microtitre plates with the assistance of human embryonic lung fibroblasts (HELF) cell cultures. The affect of these substances on the extent of the cytopathogenic effect was determined by comparison with the reference substance ganciclovir (CymeveneR sodium), a clinically approved anti-HCMV chemotherapeutic agent (EC50, corresponding to the effective concentration at which a 50% inhibition of virus activity is achieved).
The substances dissolved (50 mM) in DMSO (dimethyl sulphoxide) are investigated on microtitre plates (96-well) in duplicate determinations (4 substances/plate). Toxic and cytostatic effects of the substances are also detected thereby (CC50, corresponding to the concentration at which half the cells are destroyed owing to administration of the substance). After the appropriate substance dilutions (1:2) on the microtitre plate, a suspension of 50-100 HCMV-infected HELF cells and 30xc3x97105 uninfected HELF cells in Eagle""s MEM with 10% fetal calf serum are put in each well, and the plates are incubated at 37xc2x0 C. in a CO2 incubator for several days.
After this time, the cell lawn in the virus controls free of substance, starting from 50-100 infectious centres, is completely destroyed by the cytopathogenic effect of the HCMV (100% CPE). After staining with Neutral Red and fixing with formalin/methanol, the plates are evaluated using a projection microscope (plaque viewer).
The results for two exemplary compounds are given below:
The compounds according to the invention thus represent valuable active substances for the treatment and prophylaxis of disorders caused by human cytomegalovirus. Examples of areas of indication which may be mentioned are:
1) Treatment and prophylaxis of HCMV infections in AIDS patients (retinitis, pneumonitis, gastrointestinal infections).
2) Treatment and prophylaxis of cytomegalovirus infections in bone marrow and organ transplant patients who often suffer life-threatening HCMV pneumonitis or encephalitis or gastrointestinal and systemic HCMV infections.
3) Treatment and prophylaxis of HCMV infections in neonates and in infants.
4) Treatment of an acute HCMV infection in pregnant women.
Animals:
5-week old male mice, strain NOD/LtSz-Prkdc(scid)/J, were purchased from a commercial breeder, (The Jackson Lab., Bar Harbor). The animals were kept under sterile conditions (including bedding and feed) in isolators.
Virus/Infection
Murine cytomegalovirus (MCMV), Smith strain, was passaged in vivo (BALB/c) and purified by fractional centrifugation. The titre was investigated using a plaque assay on primary embryonic mouse fibroblasts. The mice were infected intraperitoneally with a dose of 5xc3x97105 pfu in a total volume of 0.2 ml. This dose leads to death of 100% of the infected animals after about 11 days.
Treatment/Evaluation
24 hours after the infection, the mice were treated orally with substance twice a day (morning and evening) for a period of 8 days. The dose was 25 mg/kg of body weight, and the volume administered was 10 ml/kg of body weight. The substances were formulated as a 0.5% strength Tylose suspension. 16 hours after the last administration of substance, the animals were sacrificed painlessly and the salivary gland, liver and kidney were removed.
Genomic DNA was purified by phenol/chloroform extraction from 25 mg of the tissues. The DNA was quantified by photometry using the formula OD260xc3x9750=mg/ml.
The purity of the DNA was checked by the OD260/OD280 ratio, and the DNA was then adjusted to pH=8.0 with tris-EDTA.
The MCMV DNA was quantified by DNA dot-blot hybridization. The probe used was a digoxygenin-labelled (Boehringer-Mannheim, likewise buffers mentioned unless otherwise described) 1.2 kb fragment from the MCMV, Smith, HindIII J, region. The signals were detected by chemiluminescence. For this purpose, the membrane was washed in 1xc3x97 digoxygenin washing buffer 1 for 3 minutes. The filters were then incubated in 1xc3x97 digoxygenin blocking solution, shaking at room temperature for 30 minutes. The filters were subsequently incubated in 20 ml/100 cm2 of membrane with the anti-DIG-alkaline phosphatase conjugate solution (1:20000 in 1xc3x97 digoxygenin blocking solution) for 30 minutes. This was followed by 2 washing steps each lasting 15 minutes with 1xc3x97 digoxygenin washing buffer. The filters were then equilibrated in 1xc3x97 digoxygenin detection buffer for 5 minutes, and detection took place with 1 ml/100 cm2 area of membrane CDP-Star solution diluted 1:100. Spreading of the CDP-Star solution and incubation in a dark box for 5 minutes were followed by detection of the chemiluminescence or evaluation using an X-ray film (Kodak) or LumiImage (Boehringer Mannheim). All the results were statistically confirmed (analysis of variance using Statistica; StatSoft Inc.).
The novel active substances can be composed in a known manner into conventional formulations such as tablets, coated tablets, pills, granules, aerosols, syrups, emulsions, suspensions and solutions by use of inert, nontoxic, pharmaceutically suitable carriers or solvents. The therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the complete mixture, that is to say in amounts sufficient to reach the dosage range indicated.
The formulations are produced, for example, by extending the active substances with solvents and/or carriers, where appropriate with use of emulsifiers and/or dispersants, and it is possible for example in the case where water is used as diluent where appropriate to use organic solvents as auxiliary solvents.
Administration takes place in a conventional way, preferably orally, parenterally or topically, in particular perlingually, intravenously or intravitally, where appropriate as depot in an implant.
In the case of parenteral use, solutions of the active substances can be employed using suitable liquid carrier materials.
It has generally proved advantageous on intravenous administration to administer amounts of about 0.001 to 10 mg/kg, preferably about 0.01 to 5 mg/kg, of body weight to achieve effective results, and the dose on oral administration is about 0.01 to 25 mg/kg, preferably 0.1 to 10 mg/kg, of body weight.
It may nevertheless be necessary where appropriate to deviate from the stated amounts, in particular as a function of the body weight and the type of the administration route, of the individual behaviour in relation to the medicament, the nature of its formulation and the time or interval over which administration takes place. Thus, in some cases it may be sufficient to make do with less than the aforementioned minimum amount, whereas in other cases the upper limit mentioned must be exceeded. In the event of administration of larger quantities, it may be advisable to divide these into several individual doses over the day.
It may, where appropriate, be worthwhile to combine the compounds according to the invention with other active substances.

Substituted indole sulfonamides as anitviral agents