A method and system for removing from an aqueous system which is contaminated therewith: (1) mercury present as colloids, ions and/or organically bound compounds, and (2) hydrocarbons solubilized, dispersed, and/or emulsified in the said system. Pursuant to the invention the aqueous system to be treated (such as “produced water”) is passed successively through three filtration stages. The first filtration stage is provided with absorption media which effects reduction/removal of dispersed organically bound mercury species and of the dispersed and partially dissolved hydrocarbon phases, as well as of some colloidal mercury and other dissolved metallic species. The second filtration stage utilizes a salt modified reticulated granular filtration media for reduction/removal of slightly dissolved hydrocarbon phases, mercury in colloidal and ionic form and other dissolved metals. The third filtration stage is a polishing stage, which serves to further reduce by electroless or voltaic reduction residual elemental mercury and/or residual colloidal and ionic mercury. At this third stage metallic mercury is incorporated into a metallic matrix from which the mercury may preferably be recovered.

In the course of practicing a wide variety of commercially important industrial processes, aqueous process streams (or more generally "aqueous systems") are produced which are contaminated with pernicious quantities of mercury present as colloids, ions or organically bound compounds, and with hydrocarbons which are solubilized, dispersed, or emulsified in the aqueous system. The mercury contaminants have proved to be particularly difficult to remove or reduce to levels deemed harmless to humans. This is a problem that has reached very serious dimensions, in part because even where mercury may initially be present in low concentrations in sea water, the natural predator-prey relation in the oceanic food chain causes build up of mercury in the large fish species widely eaten by humans to a level where e.g. certain types of tuna are now considered unsafe for frequent human consumption, especially by women who are pregnant.
Generally similar concerns exist with respect to hydrocarbon contaminants. Many of these latter noxious contaminants are also among the more difficult compounds to remove from aqueous media. Most are carcinogenic, and yet such compounds must be removed or minimized before discharge of the industrial stream in which they may be present in order to environmentally protect the bodies of water which the discharges eventually reach.
One type of such hydrocarbon contaminant consists of dispersed oils, which are often present as oil-in-water emulsions. A further source of contamination arises from presence in the water of pernicious slightly soluble organic compounds such as benzene, toluene, xylene, halogenated hydrocarbons, ethoxylated glycols, etc.
In the present inventor's U.S. Pat. No. 6,180,010 it is disclosed that the compositions described in the inventor's U.S. Pat. Nos. 5,437,793; 5,698,139; 5,837,146; and 5,961,823, (all of which disclosures are hereby incorporated by reference) have extremely strong affinities for the aforementioned contaminants in water; and that when aqueous streams containing these noxious contaminants are passed through filtration media incorporating these compositions, the contaminants are immobilized at the media, as a result of which concentration levels of the contaminants in the filtrate may be reduced to very low values. The principles of these earlier inventions are also applied in the present invention, but in a synergistic combination with further contaminant removal methodology.
An important example of the type of operation to which the present invention is directed arises in the operation of oil and gas exploration and drilling facilities maintained upon platforms in natural or other bodies of water, including so-called "off shore drilling platforms". In conducting operations at these platforms industrial streams are developed (often referred to as "produced water") which by virtue of the processes conducted contain comparatively large quantities of mercury and various organic contaminants, including those mentioned above.
These contaminants must be partially or entirely removed from the industrial streams before such streams can be safely discharged. It will, of course, be understood that this is indeed merely one among very numerous examples of aqueous sources of polluting mercury and organic compounds which are of particular interest for the present invention.
Precipitating agents and flocculants have in the past been extensively used in batch operations for removal of pollutants, especially when colloidal suspensions and emulsions are involved. Precipitating agents are also often used by forming insoluble salts. In the case of semi-soluble organic compounds such as phenols and halogenated hydrocarbons, adsorbents such as activated carbon are among the most common materials used. Large amounts of such materials are often required due to desorption from the carbon because of the relative solubility of these compounds. Phenols and halogenated hydrocarbons are examples of organic materials which behave as organic acids under appropriate conditions. The present invention is in part directed at utilizing these characteristics of acidic organics, such as those mentioned, in order to remove same from the aqueous media in which they are present, and by use of a continuous process as opposed to batch processes.
Although mercury is a naturally occurring element that is present throughout the environment, direct exposure to mercury is harmful to people and wildlife. Power plants and other industrial sources release mercury pollution into the air. In the U.S., coal-fired power plants are the largest source of man-made mercury emissions to the air, accounting for approximately 40% of all mercury emissions. Once in the air, rain and snow deposit mercury into water bodies. Once in the water, mercury bioaccumulates in fish. People and wildlife are exposed to mercury primarily through consuming contaminated fish. Exposure to mercury can lead to toxicological effects in animals and humans, such as neurological and kidney disorders. The most sensitive populations are pregnant woman and their unborn children.
With respect to removal of mercury from aqueous systems such as the mentioned produced water, activated carbon is currently one of the most established mercury control technologies. Among other things different forms of mercury absorb at different rates, in consequence of which activated carbon is not very efficient at removing elemental mercury. Chemical reduction and air stripping has also been used as a low concentration mercury treatment concept for water containing Hg(II). The process consists of dosing the water with low levels of stannous chloride [Sn(II)] to convert the mercury to elemental mercury)(Hg0). Hg0 can then be removed from the water by air stripping or sparging. Also known is a process based on photochemical oxidation. This has chiefly been known for use in treating flue gas wherein ultraviolet (UV) light is introduced into the flue gas, to convert elemental mercury to an oxidized form (i.e. mercuric oxide, mercurous sulfate, and mercurous chloride). Once in the oxidized form, mercury can be collected in existing air pollution control devices such as wet SO2 scrubbers, electrostatic precipitators, and baghouses (fabric filters).
None of the foregoing techniques, however, have been fully successful in treating aqueous systems of the type with which the present invention is concerned.

System for removal of contaminants from industrial streams


A system and method for determining a position of a moving platform are provided. The method includes transmitting a carrier signal from one of the moving platform and a stationary platform, receiving a received signal at the other of the moving and stationary platforms, deriving a frequency shift between the carrier signal and the received signal, and calculating the apparent closing velocity using the frequency shift and a frequency of the carrier signal.

The invention is related to velocity estimation systems and more specifically to a system and method for estimating an apparent closing velocity of a moving platform with respect to a stationary platform.
In many applications, for example in railroad systems, advanced, radio-based control systems are used to increase operational safety. For the railroad system to perform safely and efficiently there is a need to know which of a number of possible tracks a locomotive traveling at high speeds has taken. Most often, determining the locomotive position as it travels through a track turn-out and switches to a second parallel track is a significant challenge. In the above example, the locomotive is a moving platform.
Standard global positioning systems (GPS) and differentially corrected GPS are usually deployed to provide fairly accurate locomotive position. However, such systems do not usually provide sufficient information to track a fast moving train through a turn-out and onto a parallel track. In general, the position estimates are averaged over time in order to reduce noise and obtain a sufficient level of confidence in the position estimate. Because locomotives typically travel at very high speeds, using such a method to determine which one of the parallel tracks a locomotive is traveling on is substantially difficult.
Typically, additional sensors such as accelerometers and gyros are used to augment the global positioning systems so as to provide a more robust inertial navigation solution system. One problem with adding additional sensors to the existing GPS is the significant increase in the overall cost, complexity and failure modes of the system.
It would therefore be desirable to implement a low-cost, high-performance system that can accurately determine the position of a moving platform, like a locomotive, traveling at high speeds.

Moving platform position determination system and method


An integrated color pixel (ICP) with at least one integrated metal filter is presented. Rather than utilizing a separate color filter, the wavelength responsivity of the ICP is specified and integrated at pixel level into the ICP itself using metal materials already available for standard integrated circuit design and fabrication process. The ICP of the present invention is thus distinguished from a conventional color pixel constructed in a two-stage process that combines an image sensor with a color filter array or other optical material.

1. Field of the Invention
The present invention relates generally to a color image sensor and, more particularly, to an integrated color pixel (ICP) and a method of integrating control of wavelength responsivity into the ICP itself during a standard integrated circuit (IC) design and fabrication process.
2. Description of the Related Art
A basic image sensor captures an image in gray scale. That is, the image sensor, with its monochrome pixels, generally records the image in a series of tones ranging from pure white to pure black. A color image sensor captures the image in colors with monochrome pixels and color filters. The color filters are utilized for controlling the wavelength responsivity of the individual monochrome pixels. The wavelength transmittance of the color filters, along with the other optical elements, determine the wavelength responsivity of the color channels of the color image sensor.
A conventional way to integrate the color filters and hence the wavelength responsivity into the color image sensor is to utilize a color filter process in which a color filter array (CFA) comprising a regular array of differently colored filters is overlaid or deposited onto the monochrome pixels to separate out the colors of the light reflected from an image.
Color filter process in general and the CFA technology in particular are well known in the art and thus are not further described herein. An exemplary teaching on color filter process for semiconductor array imaging devices can be found in U.S. Pat. No. 6,274,917, which is by Fan et al. and assigned to Semiconductor Manufacturing Company (TSMC), Hsin-Chu, Taiwan.
The color filter pattern or patterned CFA of each color image sensor can be specifically designed to yield sharper images, truer colors, and/or any color effects desired. Most modern semiconductor image sensors, including complementary metal-oxide semiconductor (CMOS) and charge-coupled device (CCD) image sensors, utilize red, green, or blue (RGB) filters. Some image sensors in cameras use cyan, magenta, and yellow (CMYK) filters. The color patterns also vary from company to company with the most popular pattern being the Bayer mosaic pattern, taught by Bayer in U.S. Pat. No. 3,971,065 and assigned to Eastman Kodak Company, Rochester, N.Y.
Bayer teaches a sensing array for color imaging having individual luminance- and chrominance-sensitive elements that are so intermixed that each type of element, i.e., according to sensitivity characteristics, occurs in a repeated pattern with luminance elements dominating the array. In this case, filters selectively transmissive to light in the green region of the spectrum are utilized in producing luminance-sensitive elements, and red and blue transmitting filters are used for producing a first and second chrominance-sensitive elements. In other words, in Bayer, selectively sensitized elements, i.e., individual monochrome pixels with corresponding color filters overlaid thereupon, cooperating in interlaid sampling patterns control wavelength responsivity of the color imaging array. An exemplary Bayer mosaic pattern 100 is shown in FIG. 1(a). An exemplary application of the Bayer mosaic pattern 100 utilized in a conventional color pixel array 110 is shown in FIG. 1(b) where monochrome pixels 30 are overlaid with a CFA 34. As shown in FIG. 1(b), the CFA 34 is sandwiched between layers 33 and 35. Layers 33 and 35 can be specified as an anti-reflection layer and an insulation/protection layer, respectively. Layer 32 may comprise a variety of layers including additional metal layers for a variety of application-specific purposes.
As is well known in the art, one common problem associated with the use of CFA is that pixel and therefore the sensor sensitivity varies with the specific type of color. Several implementations have been proposed to enhance the pixel sensitivity. One such example can be found in U.S. Pat. No. 6,057,586, titled "Method and apparatus for employing a light shield to modulate pixel color responsivity" by Bawolek et al. and assigned to Intel Corporation of Santa Clara, Calif.
In Bawolek et al., a light shield is utilized to modulate/modify pixel sensitivity. According Bawolet et al., a pixel cell refers to a light sensing circuit and a CFA overlaid on top of a light sensor. The light sensor, as commonly understood, can be any means that receives and converts incident light into an electrical signal representative of that light. The pixel cell having a color filter array material of a first color disposed above the light sensor has a first relative sensitivity. A modulating light shield is disposed above the light sensor to modulate the pixel sensitivity. The light shield forms an aperture whose area is substantially equal to a light receiving area of the light sensor adjusted by a reduction factor. The reduction factor is the result of an arithmetic operation between the first relative sensitivity and a second relative sensitivity, associated with a second pixel of a second color. In Bawolet et al., the light shield, constructed using one of the pixel metal layers, and the CFA overlaid thereupon control sensitivity and wavelength responsivity of the pixel, respectively. Bawolet et al. particularly note that it is important that the other metal layers do not intrude into the non-covered optical path specified by the light shield layer. FIG. 2(a) shows a conventional color pixel array 200 having monochrome pixels 201 overlaid with a CFA 210 having a typical Bayer RGB pattern. FIG. 2(b) shows a modified color pixel array 220 comprising the monochrome pixels 201 overlaid with a light shield metal layer 202 and the CFA 210. The light shield metal layer 202 has a plurality of openings 203 where the area of the openings is specifically configured based on the color responsivity, i.e., red, green, or blue, of the pixel cell. The openings employed for controlling the pixel sensitivity can range from approximately one micron by one micron to 5 microns by 5 microns.
The various pixel implementations including the aforementioned pixel sensitivity modulation layer are to improve mostly CCD technology-based or CMOS technology-based image sensors. CCD image sensors have drawbacks well known in the art including limited on-chip signal processing capability and high power consumption. CMOS image sensors have been developed to overcome these drawbacks. The advantages of CMOS image sensors over CCD image sensors are well known in the art and thus are not described herein. CMOS image sensors utilizing CFAs, however, still have the following weaknesses.
A typical CFA may include multiple layers of superimposed color filters, which often cause a color "cross-talk" problem. Also, because the height of a pixel inversely affects the pixel's efficiency, the added height of these layers may cause a decrease in pixel efficiency.
What is more, as discussed heretofore, a typical CMOS color image sensor generally comprises a basic "monochrome" image sensor with color filters overlaid thereupon. The hybrid nature of CMOS image sensors and the color filter process lead to high fabrication costs and inflexibility in color image sensor design flow. Utilizing thin film technology, Böhm et al. proposed in "High Dynamic Range Image Sensors in Thin Film on ASIC Technology for Automotive Applications" Thin-Film-on-ASIC (TFA) image sensors to overcome the weaknesses of conventional CMOS color image sensors and to further reduce color image sensor manufacturing costs.
According to Böhm et al., a TFA image sensor is a vertically integrated image sensor where the optical detector of the sensor is deposited onto an ASIC wafer by a plasma enhanced chemical vapor deposition (PECVD) process in a cluster deposition system. ASIC wafer itself is fabricated using a standard 0.7 μm CMOS process.
Thin film technology provides a possibility of retaining the entire usual design flow and fabrication steps as employed for ASICs. As shown in FIG. 3(a), a typical TFA image sensor 300 consists of an amorphous silicon (a-Si:H) based optical detector 310 being deposited on top of a crystalline silicon (x-Si) ASIC 301 in a low temperature PECVD process. a-Si:H is an excellent material for optical detectors but not for electronic circuits. On the other hand, x-Si has poor photoelectric properties but a wide range of highly developed and abundantly available technologies for fabricating powerful integrated circuits.
FIG. 3(a) also shows the layer sequence of the typical TFA image sensor 300 where an insulation layer 320 separates the optical detector 310 from the ASIC 301. The insulation layer 320 is patterned in order to provide contact holes between the optical detector 310 and the circuitry of ASIC 301. Generally, there is one hole per pixel. The ASIC 301 typically includes identical pixel circuitry underneath each detector and peripheral circuitry outside the light sensitive area. The thin film system 340 is sandwiched between a metal rear electrode 330, which is usually the third metal layer of the ASIC 301, and a transparent front electrode 350. Due to its higher absorption coefficient and its maximum spectral response for green light, an amorphous silicon detector is better qualified for an image sensor than a crystalline silicon detector. This thin film deposition sequence is adaptable to the specific requirement of an application. For example, the a-Si:H thin film system 340 may comprise multiple layers. According to Böhm et al., at a thickness of less than 1 μm, the thin film system consists of four to seven successively deposited layers.
FIG. 3(b) illustrates how the TFA image sensor 300 is developed and fabricated. As shown in FIG. 3(b), the ASIC 301 and the optical detector 310 are separately developed in TFA image sensor design and fabrication process 311 so that the photoelectric properties of the detector can be optimized independent of the ASIC process. The ASIC 301 wafer is manufactured and the optical detector 310 including the a-Si:H thin film system 340 is subsequently deposited upon the ASIC 301. TFA image sensors are suited for automotive vision systems and are in development by Silicon Vision in cooperation with the Institute for Semiconductor Electronics (IHE) at the University of Siegen, both of Germany.
According to Böhm et al., one of the major benefits of the TFA technology is the possibility to deposit thin film detectors with adjustable spectral sensitivity on top of the ASIC. For a color sensor array, this leads to a 3-colors-in-one-pixel sensor design. The spectral response can be shifted varying the voltage applied to the pixel. FIG. 4(a) shows a pixel block diagram of the TFA color sensor array 400. The detector circuit 410 keeps the rear electrode at constant potential in order to suppress lateral balance currents. The photocurrent is fed into one of the color circuits 420, 430, 440, one at a time, during the integration phase. The TFA color sensor array 400 generates and stores the complete RGB information inside each pixel without intermediate readout operation. For readout, the integrated color voltages are sequentially applied to the column output line 450.
Wavelength responsivity of a TFA color pixel is controlled by the thin film being deposited thereupon a standard ASIC wafer. That is, the essential ability of controlling wavelength responsivity of a color image sensor is still dependent upon a separate and independent thin film process applied subsequent to standard semiconductor processing steps. What is more, pixels in the vertically integrated TFA image sensor having multiple layers deposited thereon may suffer from reduced pixel efficiency because of the increased overall height of the pixels.
What is needed, is a method of integrating control of wavelength responsivity into the pixel itself, generating a complete and highly integrated color pixel for quality color imaging using entirely standard semiconductor IC design and fabrication process, thereby solving a problem of color cross-talk in image sensors utilizing superimposed color filters and eliminating a need to subsequently applying a separate color filter process such as the thin film process, hence simplifying color image sensor design flow, further reducing color image sensor manufacturing cost, and potentially increasing pixel efficiency.

The Board of Trustees of the Leland Stanford Junior University


An exhaust gas purification system includes a transition metal/zeolite first catalyst, a three-way second catalyst, and a noble metal-type third catalyst arranged in that order in the direction of exhaust gas flow in an exhaust conduit of an internal combustion engine capable of fuel combustion at lean air-fuel ratios. NOx which has not been purified by the transition metal/zeolite first catalyst is oxidized by the three-way second catalyst into NO.sub.2, which the noble metal-type third catalyst can easily decompose into N.sub.2 and O.sub.2.

1. Field of the Invention
The present invention relates to an exhaust gas purification apparatus which includes a plurality of different kinds of catalysts arranged in series with each other and which can purify nitrogen oxides (hereinafter, NOx) included in exhaust gas from an internal combustion engine at lean air-fuel ratios at a higher NOx purification rate than the total of the NOx purification rates of the individual catalysts.
2. Description of the Related Art
To improve fuel economy and to suppress exhaust of carbon dioxide gas to thereby reduce global warming, engines capable of fuel combustion at lean air-fuel ratios (lean burn engines) are being developed and are partially in actual use. Since a conventional catalyst (three-way catalyst) cannot reduce and purify NOx at lean air-fuel ratios, there is a need to develop a catalyst or system that can purify NOx even at lean air-fuel ratios.
Japanese Patent Publication HEI 1-139145 proposes a copper (Cu)/zeolite catalyst in which copper is ion-exchanged on a zeolite carrier. This catalyst is capable of purifying NOx at lean air-fuel ratios. However, the NOx purification ability of the Cu/zeolite catalyst is poor at stoichiometric and rich air-fuel ratios. Further, the Cu/zeolite catalyst has little ability to purify hydrocarbons (hereinafter, HC) included in exhaust gas.
In order to purify HC at high engine power operating conditions and to decrease the amount of NOx exhausted into the atmosphere. Publication HEI 1-139145 further proposes to install a platinum (Pt)/alumina catalyst for oxidizing HC and CO included in the exhaust gas in a portion of the exhaust conduit located downstream of the Cu/zeolite catalyst. However, in this known apparatus, the ability of the Pt/alumina catalyst to purify whatever NOx has passed through the Cu/zeolite catalyst without being completely reduced by the Cu/zeolite catalyst is small.
The reasons why the NOx purification ability of the Pt/alumina catalyst in the Cu/zeolite-Pt/alumina exhaust gas purification system is small are thought to be as follows:
One reason is that the NOx which flows from the Cu/zeolite catalyst to the Pt/alumina catalyst is mainly in the form of NO, and the Pt/alumina catalyst has little capability for decomposing NO into N.sub.2 and O.sub.2. Another reason is that, in a high power condition, a relatively large amount of HC flows to the Pt/alumina catalyst. The HC will gradually degrades the catalyst and thus shortens its life.

Exhaust gas purification apparatus for an internal combustion engine


A two part hinge for containers and boxes. The first part includes a pair parallel arms which include axially aligned opposing sockets which are configured to rotatingly receive pintle ends. The sockets are provided with radially disposed channels which extend from the sockets to exterior edges of the arms to form a slot for guiding the pintle ends into the sockets. The first hinge part also includes a dual function tab which is generally collaterally aligned with and parallel to the arms of the first part of the hinge. The tab is provided with a camming surface and a retaining surface. The camming surface engages and deflects the center portion of the pintle as it passes thereby, while the retaining surface maintains the pintle ends in the sockets by effectively blocking movement of the center portion of the pintle. The retaining surface of the tab is consistent with the arcuate surfaces of the sockets to form a smooth transition between the socket surfaces and the retaining surface of the tab. The second hinge part includes a pair parallel arms which project outwardly from the other of the container sections and which support a pintle or hinge pin, in such a fashion that the pintle ends extend beyond the lateral extent of the arms. To assemble the hinge, the pintle ends are slid into the channels toward the sockets. Assembly is essentially complete when the pintle body passes the camming portion of the tab.

The present invention relates generally to a hinge for containers, and more particularly to a two-part hinge for use in semi-conductor wafer containers and boxes.
Containers are used in many applications within the semiconductor industry to protect components from contaminants, breakage and misplacement. These containers usually incorporate existing hinges, which typically comprise living hinges or traditional hinges with removable hinge pins or pintles which are received in barrels or knuckles of hinge segments.
These hinges are not without their drawbacks. With a living hinge, there is a tendency to resist flexation due to memory in the material. Thus, a container with a living hinge will not open and close freely within its operating range. Resistance must be overcome, and frequently the hinge must be overflexed in order to avoid reversion to a prior position. Over time, such hinges lose their effectiveness and eventually may fatigue and fail. Once such failure has occurred, the entire container must be scrapped. Additionally, if one section of the container breaks, the entire container must be scrapped.
With traditional hinge construction, hinge leaves are attached to each other by a pintle. The pintle is usually fabricated out of a different, more wear resistant material than the hinge leaves. Thus, after a period of time, the barrels or knuckles of the hinge leaves wear out. This results in improper operation of the hinge and container sealing ability suffers. Additionally, when the barrels or knuckles wear out, the pintle is prone to dislodgement and/or loss, thus rendering the hinge inoperative for its intended use. Another drawback is that pintles are often made out of metal, such as steel, which is prone to oxidation. As oxidants build up, the operation of the hinge suffers and becomes less efficient. And, depending upon the particular environment, the pintles can discolor or otherwise mar the hinge leaves. Moreover, metal is a very undesirable material for wafer carriers due to potential contamination problems.
Attempts have been made to solve the above-mentioned drawbacks. For example, U.S. Pat. No. 2,527,318 issued to Magnus, Oct. 24, 1950, discloses a plastic hinge construction for boxes and the like. In this patent, the hinge parts are integral with the container segments, with one of the hinge parts including a hinge pin, and the other hinge part including semicircular grooves and a resilient tongue member. When assembled, the tongue member exerts a force against the hinge pin to maintain the hinge pin in contact against the semicircular grooves.
U.S. Pat. No. 2,734,222 issued to Kiba, Feb. 14, 1956, discloses a hinge structure for molded boxes. This patent, like Magnus, teaches integral hinge construction. Assembly differs, however, in that the pintle ends of Kiba are received in a pair of bight portions and the pintle body is engaged by a stop to permanently retain the pintle ends within the bights. With Kiba, the stop is attached to a thinned wall portion of a container section, and the thinned wall portion is deflected by the pintle as it passes thereby. Note that the hinge is preferably assembled shortly after the container halves have been removed from their molds. This is because warm plastic is still relatively pliable and has not set. After assembly, and once the plastic has set, the assembled hinge is considered permanent.
The problem with the above-mentioned hinges is that they are structurally weak and/or they are not designed to be separated after assembly.
There is a need for a hinge which may be integrally formed with sections of a container, which may be easily assembled and disassembled, and which provides a strong, long lasting pivot joint.


The invention is directed to a centrifugal clutch having centrifugal weights wherein each weight has an arc-shaped clutch shoe and is pivotally mounted with a lever foot on a carrier disc on the drive end of the clutch. After reaching a specific rpm, the clutch shoes are pressed under the action of centrifugal force against the inner wall surface of a clutch drum for providing friction-tight torque transmission. The clutch drum surrounds the clutch shoes. The centrifugal clutch includes a carrier disc on which the centrifugal weights are pivotally mounted. A cover disc is held axially tight at the sides of the centrifugal weights which lie opposite the carrier disc. This cover disc radially covers the clutch shoes so that axial guide play is provided. In this way, wear of the clutch weights caused by operation is reduced especially in the bearing regions of the centrifugal weights.

Centrifugal clutches are rpm-actuated clutches having radially movable centrifugal weights mounted on the drive end. Under the influence of the centrifugal force, the centrifugal weights transmit a specific torque friction tight to the output end of the centrifugal clutch with the required contact force. After reaching a limit rpm, an automatic coupling takes place so that a load free startup of the drive motors is possible. Centrifugal clutches are advantageous for rapidly running drive motors such as internal combustion engines and make possible a high starting torque for accelerating large masses in relationship to the drive power so that the drive motor does not have to be designed for short-term high starting power. Furthermore, the centrifugal clutches protect the drive motors from overload and decouple the load in the low rpm range, for example, in idle, for example, in the case where the centrifugal clutch is used in a work apparatus, such as a motor-driven chain saw. Here, the load would be the saw chain.
U.S. Pat. No. 4,106,605 discloses a centrifugal clutch wherein the centrifugal weights each have an arcuately-shaped clutch shoe and are pivotally held on a carrier disc at the output end of the centrifugal clutch. The pivot journalling of the centrifugal weights is achieved via respective bearing bolts which are mounted on the carrier disc at equal spacings from each other so as to be parallel to a rotational axis of the carrier disc. When the carrier disc is driven in rotation, the centrifugal weights pivot under the action of the centrifugal force about their respective pivot bolts and the arcuately-shaped pole shoes carry out a radial movement.
At the output end of the centrifugal clutch, a clutch drum is mounted coaxially to the carrier disc and surrounds the clutch shoes. The clutch shoes are radially movable by the centrifugal force against the return force of a coiled tension spring and can be pressed against the inner wall surface of the clutch drum. The centrifugal force exceeds the return force of the tension spring above a specific rpm range by an amount which corresponds to the application force of the clutch shoes required for the friction-tight entrainment of the clutch drum.
Intense wear occurs during operation of the known centrifugal clutch especially for frequent coupling operations. The material wear in the bearing area of the centrifugal weights leads to deteriorated operation of the centrifugal clutch.


Historical access information identifies which resources in a storage area network access portions of shared storage in the storage area network. Based on an analysis of the historical access information, a management report generator application analyzing such information can infer the existence of a cluster of resources that access a common portion of shared storage. When the management report generator identifies that two or more resources access the same storage resources during approximately the same timeframe, the management report generator knows that there is a high likelihood that the two or more resources are part of a cluster sharing access to common storage resources. Thus, when reporting a tally of storage resources used in the storage area network, it is possible for the management report generator to take into account the cluster and indicate that two resources share access to a common portion of storage.

The rapid expansion of information service and data processing industries has resulted in a need for computer systems to manage and store large amounts of data. As an example, financial service companies such as banks, mutual fund companies or the like often operate complex data processing systems that require access to many hundreds of gigabytes or even terabytes of data and files stored in high capacity data storage systems. Data storage system developers have responded to these types of data storage requirements by integrating computer systems, switch fabrics, and large capacity data storage systems into networks called "storage networks" or "storage area networks" (SANs.)
In general, a storage area network is a collection of data storage systems (e.g., multiple disks) that are networked via a switching fabric to a number of host computer systems that operate as servers. For example, host computers of the storage area network couple to and access the storage systems of the storage area network through a switch fabric. Consequently, the host computers access data stored in the data storage systems on behalf of client computers that request data from the host computers. Typically, storage area networks support hi-speed acquisitions of data so that the host servers are able to promptly access storage resources in the storage area network for their corresponding clients.
Conventional storage area network management applications provide conventional graphical user interfaces (GUIs) enabling network managers to graphically manage, control and configure various types of hardware and software resources associated with a corresponding managed storage area network. For example, one conventional network management storage application enables a network manager at a computer associated with the storage area network to request reports of how much data storage resources of the storage area network are used by respective resources in the storage area network. Based on this information, the network manager can decide, among other things, how to allocate storage resources and determine at what point it is necessary to increase storage capacity of the storage area network.

Methods and apparatus for detecting use of common resources


Sulfonamide derivatives having a matrix metalloprotease inhibiting effect, which are compounds represented by general formula (I), optical isomers of the same, pharmaceutically acceptable salts of both, or solvates of them:

This invention relates to sulfonamide derivatives having oxadiazole rings and metalloproteinase inhibitors containing the same.
An extracellular matrix, consisting of collagen, fibronectin, laminin, proteoglycan, etc., has a function to support tissues, and plays a role in propagation, differentiation, adhesion, or the like in cells. Metalloproteinases which are protease having a metal ion in the active center, especially matrix metalloproteinases (MMP), are concerned with the degradation of the extracellular matrix. Many types of MMP, from MMP-1 to MMP-23, have been reported as enzymes working for the growth, remodeling of tissues, etc. under usual physiological conditions. It is reported, however, that the progression of various kinds of diseases involving breakdown and fibrosis of tissues (e.g., osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontitis, metastasis and invasion of tumor, and virus infection (HIV infection)) is related with increase of the manifestation or activity of the above-mentioned enzyme. A number of MMP inhibitors tend to have a TNF-xcex1 production inhibiting effect.
MMP inhibitors having an oxadiazole ring skeltone are described in WO99/04780.
Compounds, having a similar side chain to those of the present invention and a MMP inhibiting effect, are described in WO97/27174 and the like.
The inhibiting of such activities of MMP is considered to contribute to the improvement and prevention of the above diseases caused by or related to the activity. Therefore, the development of MMP inhibitors has been desired.
In the above situation, the inventors of the present invention have found that certain sulfonamide derivatives having oxadiazole rings have a potent activity to inhibit MMP.
The present invention relates to:
I) A compound of the formula (I):
xe2x80x83wherein
R1 and R2 are each independently hydrogen atom, optionally substituted lower alkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, or optionally substituted heteroarylalkyl;
R3 is optionally substituted lower alkyl, optionally substituted cycloalkyl, lower alkyloxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted non-aromatic heterocyclic group, unsubstituted or substituted amino, or halogen;
X is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; and
Y is xe2x80x94NHOH, hydroxy, or lower alkyloxy,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
In more detail, the invention relates to the following II)-XX).
II) A compound of the formula (II):
xe2x80x83wherein
R1, R2, X and Y are as defined in I):
R4 is hydrogen atom, optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionally substituted ureide; and
Z is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
III) A compound of the formula (III):
xe2x80x83wherein
R1, R2, X, and Y are as defined in I); and
R5 is optionally substituted alkyl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, lower alkyloxy, unsubstituted or substituted amino, or halogen,
its optically active substance, its pharmaceutically acceptable salt, or its solvate.
Preferable a compound is, wherein X is xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Sxe2x80x94; R5 is optionally substituted alkyl or optionally substituted aralkyl; R1 is optionally substituted lower alkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl; R2 is hydrogen atom; Y is hydroxy.
IV) A compound of any one of I)xcx9cIII), wherein Z and X are each independently xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94Sxe2x80x94, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
V) A compound of the formula (IV):
xe2x80x83wherein
R1, R2, and Y are as defined in I), and R4 is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VI) A compound of the formula (V):
xe2x80x83wherein
R1, R2, and Y are as defined in I), and R4 is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VII) A compound of the formula (VI):
xe2x80x83wherein
R1, R2, and Y are as defined in I), and R4 is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
VIII) A compound of the formula (VII):
xe2x80x83wherein
R1, R2, and Y are as defined in I), and R4 is as defined in II), its optically active substance, its pharmaceutically acceptable salt, or its solvate.
IX) A compound of any one of I) to VIII), wherein Y is hydroxy, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
X) A compound of any one of I) to IX), wherein R2 is hydrogen atom, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XI) A compound of any one of I) to X), wherein R1 is hydrogen atom, optionally substituted lower alkyl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XII) A compound of any one of I)xcx9cXI), wherein R1 is hydrogen atom, methyl, isopropyl, isobutyl, n-butyl, 2-methylthioethyl, phenylmethyl, or indol-3-ylmethyl, its optically active substance, its pharmaceutically acceptable salt, or its solvate.
XIII) A pharmaceutical composition containing a compound of any one of I)xcx9cXII).
XIV) A composition for inhibiting metalloproteinase containing a compound of any one of I)xcx9cXII).
XV) A composition for inhibiting matrix metalloproteinase containing a compound of any one of I)xcx9cXII).
XVI) A composition for treating or preventing cancer which contains a compound of any one of I)xcx9cXII).
XVII) A composition for treating or preventing nephritis which contains a compound of any one of I)xcx9cXII)
XVIII) A composition for treating or preventing osteoarthritis which contains a compound of any one of I)xcx9cXII).
XIX) A composition for treating or preventing cardiac insufficiency which contains a compound of any one of I)xcx9cXII).
XX) A composition for treating or preventing rheumatoid arthritis which contains a compound of any one of claims I)xcx9cXII).
In the present specification, the term xe2x80x9clower alkylxe2x80x9d employed alone or in combination with other terms means a straight- or branched chain monovalent hydrocarbon group having 1 to 8 carbon atom(s). Examples of the alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like. C1 to C6 alkyl is preferred. C1 to C3 alkyl is more preferred.
The term xe2x80x9calkenylxe2x80x9d employed alone or in combination with other terms in the present specification means a straight- or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and at least one double bond. Examples of the alkenyl include vinyl, allyl, propenyl, crotonyl, isopentenyl, a variety of butenyl isomers and the like. C2 to C6 alkenyl is preferred. C2 to C4 alkenyl is more preferred.
The term xe2x80x9clower alkynylxe2x80x9d used in the present specification means a straight or branched chain monovalent hydrocarbon group having 2 to 8 carbon atoms and at least one triple bond. The alkynyl may contain (a) double bond(s). Examples of the alkynyl include ethynyl, 2-propynyl, 3-butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl and the like. C2 to C6 alkynyl is preferred. C2 to C4 alkynyl is more preferred.
The term xe2x80x9ccycloalkylxe2x80x9d used in the present specification includes cycloalkyl group having 3 to 8 carbon atoms. Examples of cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like. C3 to C6 cycloalkyl is preferred.
In the present specification, the term xe2x80x9carylxe2x80x9d employed alone or in combination with other terms includes monocyclic or condensed ring aromatic hydrocarbons. Examples include phenyl, 1-naphtyl, 2-naphtyl, anthryl, and the like.
The term xe2x80x9caralkylxe2x80x9d herein used means the above mentioned xe2x80x9clower alkylxe2x80x9d substituted with the above mentioned xe2x80x9carylxe2x80x9d at any possible position. Examples of the aralkyl are benzyl, phenylethyl (e.g., 2-phenethyl and the like), phenylpropyl (e.g., 3-phenylpropyl and the like), naphthylmethyl (e.g., 1-naphthylmethyl and 2-naphthylmethyl and the like), anthrylmethyl (e.g., 9-anthrylmethyl and the like), and the like. Benzyl and phenylethyl are preferred.
In the present specification, the term xe2x80x9cheteroarylxe2x80x9d employed alone or in combination with other terms includes a 5 to 6 membered aromatic heterocyclic group which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and may be fused with cycloalkyl, aryl, non-aromatic heterocyclic group, and other heteroaryl at any possible position. Examples of the heteroaryl are pyrrolyl (e.g., 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), furyl (e.g., 2-furyl, 3-furyl), thienyl (e.g., 2-thienyl 3-thienyl), imidazolyl (e.g., 2-imidazolyl, 4-imidazolyl), pyrazolyl (e.g., 1-pyrazolyl, 3-pyrazolyl), isothiazolyl (e.g., 3-isothiazolyl), isoxazolyl (e.g., 3-isoxazolyl), oxazolyl (e.g., 2-oxazolyl), thiazolyl (e.g., 2-thiazolyl), pyridyl (e.g., 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrazinyl (e.g., 2-pyrazinyl), pyrimidinyl (e.g., 2-pyrimidinyl, 4-pyrimidinyl), pyridazinyl (e.g., 3-pyridazinyl), tetrazolyl(e.g., 1H-tetrazolyl), oxadiazolyl (e.g., 1,3,4-oxadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), indolizinyl (e.g., 2-indolizinyl, 6-indolizinyl), isoindolyl (2-isoindolyl), indolyl (e.g., 1-indolyl, 2-indolyl, 3-indolyl), indazolyl (e.g., 3-indazolyl), puriyl (e.g., 8-puriyl), quinolizinyl (e.g., 2-quinolizinyl), isoquinolyl (e.g., 3-isoquinolyl), quinolyl (e.g., 3-quinolyl, 5-quinolyl), phthalazinyl (e.g., 1-phthalazinyl), naphthyridinyl (e.g., 2-naphthyridinyl), quinolanyl (2-quinolanyl), quinazolinyl (e.g., 2-quinazolinyl), cinnolinyl (e.g., 3-cinnolinyl), pteridinyl (e.g., 2-pteridinyl), carbazolyl (e.g., 2-carbazolyl, 3-carbazolyl), phenanthridinyl (e.g., 2-phenanthridinyl, 3-phenanthridinyl), acridinyl (e.g., 1-acridinyl, 2-acridinyl), dibenzofuranyl (e.g., 1-dibenzofuranyl, 2-dibenzofuranyl), benzimidazolyl (e.g., 2-benzimidazolyl), benzisoxazolyl (e.g., 3-benzisoxazolyl), benzoxazolyl (e.g., 2-benzoxazolyl), benzoxadiazolyl (e.g., 4-benzoxadiazolyl), benzisothiazolyl (e.g., 3-benzisothiazolyl), benzothiazolyl (e.g., 2-benzothiazolyl), benzofuryl (e.g., 3-benzofuryl), benzothienyl (e.g., 2-benzothienyl) and the like.
Preferable are indole, imidazole, and benzothiazole as xe2x80x9cheteroarylxe2x80x9d for R1.
Preferable are thienyl, furyl, and pyridyl as xe2x80x9cheteroarylxe2x80x9d for R2.
Preferable are thienyl, furyl, pyridyl and pyrrolyl as xe2x80x9cheteroarylxe2x80x9d for R3. More preferred is furyl.
The term xe2x80x9cheteroarylalkylxe2x80x9d herein used includes the above mentioned xe2x80x9clower alkylxe2x80x9d substituted with the above mentioned xe2x80x9cheteroarylxe2x80x9d at any possible position. Examples of the heteroarylalkyl are thiazolylmethyl (e.g., 4-thiazolylmethyl), thiazolylethyl (e.g., 2-(thiazol-5-yl)ethyl), benzothiazolylmethyl (e.g., (benzothiazol-2-yl)methyl), indolylmethyl (e.g., indol-3-ylmethyl), imidazolylmethyl (e.g., 4-imidazolylmethyl), indazolylmethyl (e.g., 1-indazolylmethyl), benzotriazolylmethyl (e.g., 1-benzotriazolylmethyl), benzoquinolylmethyl (e.g., 2-benzoquinolylmethyl), benzimidazolylmethyl (e.g., 2-benzimidazolylmethyl), pyridylmethyl (e.g., 4-pyridylmethyl), and the like.
Preferable are indol-3-ylmethyl and imidazol-5-ylmethyl as xe2x80x9cheteroarylalkylxe2x80x9d for R1.
Preferable are 2-thienyl, 2-furyl and 3-pyridyl as xe2x80x9cheteroarylxe2x80x9d for R2.
In the present specification, the term xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d employed alone or in combination with other terms includes a 5 to 7 membered non-aromatic ring which contains one or more hetero atoms selected from the group consisting of oxygen, sulfur, and nitrogen atoms in the ring and a condensed ring which are formed with two or more of the non-aromatic ring. Examples of the non-aromatic heterocyclic group are pyrrolidinyl (e.g., 1-pyrrolidinyl, 2-pyrrolidinyl), pyrrolinyl (e.g., 3-pyrrolinyl), imidazolidinyl (e.g., 2-imidazolidinyl), imidazolinyl (e.g., imidazolinyl), pyrazolidinyl (e.g., 1-pyrazolidinyl, 2-pyrazolidinyl), pyrazolinyl (e.g., pyrazolinyl), piperidinyl (piperidino, 2-piperidinyl), piperazinyl (e.g., 1-piperazinyl), indolynyl (e.g., 1-indolynyl), isoindolinyl (e.g., isoindolinyl), morpholinyl (e.g., morpholino, 3-morpholinyl), 1,3-benzodioxolyl (e.g., 5-(1,3-benzodioxolyl)) and the like.
Preferable are pyrazolidinyl, piperidinyl, pyrrolinyl, morpholinyl, and 1,3-benzodioxolyl as xe2x80x9cnon-aromatic heterocyclic groupxe2x80x9d for R3.
In the present specification, the term xe2x80x9cacylxe2x80x9d employed alone or in combination with other terms includes alkylcarbonyl in which alkyl group is the above-mentioned xe2x80x9clower alkylxe2x80x9d and arylcarbonyl in which aryl group is the above-mentioned xe2x80x9carylxe2x80x9d. Examples of the acyl are acetyl, propyonyl, benzoyl, and the like. xe2x80x9cLower alkylxe2x80x9d and xe2x80x9carylxe2x80x9d may be substituted respectively with substituents mentioned below.
The term xe2x80x9chalogenxe2x80x9d herein used means fluoro, chloro, bromo, and iodo. Fluoro, chloro, and bromo are preferred.
The term xe2x80x9clower alkyloxyxe2x80x9d herein used are methyloxy, ethyloxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, tert-butyloxy, and the like. Methyloxy, ethyloxy, n-propyloxy, i-propyloxy and n-butyloxy are preferred. C1 to C3 alkyloxy is more preferred.
The term xe2x80x9clower alkylthioxe2x80x9d herein used are methylthio, ethylthio, and the like. C1 to C3 alkylthio is preferred.
The term xe2x80x9clower alkyloxycarbonylxe2x80x9d herein used are methyloxycarbonyl, ethyloxycarbonyl, n-propyloxycarbonyl, isopropyloxycarbonyl, and the like.
In the present specification, the term xe2x80x9chalo(lower)alkylxe2x80x9d employed alone or in combination with other terms includes the above-mentioned xe2x80x9clower alkylxe2x80x9d which is substituted with the above mentioned xe2x80x9chalogenxe2x80x9d at 1 to 8 positions, preferably, at 1 to 5. Examples of the halo(lower)alkyl are trifluoromethyl, trichloromethyl, difluoroethyl, trifluoroethyl, dichloroethyl, trichloroethyl, and the like. Preferable is trifluoromethyl.
Examples of the term xe2x80x9chalo(lower)alkyloxyxe2x80x9d herein used are trifluoromethyloxy and the like.
Examples of the term xe2x80x9clower alkylsulfonylxe2x80x9d herein used are methylsulfonyl, ethylsulfonyl and the like. Preferable is methylsulfonyl.
Examples of the term xe2x80x9cacyloxyxe2x80x9d herein used are acetyloxy, propionyloxy, benzoyloxy and the like.
In the present specification, the term xe2x80x9csubstituted aminoxe2x80x9d employed alone or in combination with other terms includes amino substituted with one or two of the above mentioned xe2x80x9clower alkylxe2x80x9d, xe2x80x9caralkylxe2x80x9d, xe2x80x9cheteroarylalkylxe2x80x9d or xe2x80x9cacylxe2x80x9d. Examples of the optionally substituted amino are methylamino, dimethylamino, ethylmethylamino, diethylamino, benzylamino, acetylamino, benzoylamino and the like. Preferable are methylamino, dimethylamino, ethylmethylamino, diethylamino and acetylamino.
Examples of the term xe2x80x9csubstituted aminocarbonylxe2x80x9d herein used are methylaminocarbonyl, dimethylaminocarbonyl, ethylmethylaminocarbonyl, diethylaminocarbonyl and the like. Preferable is diethylaminocarbonyl.
The substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d are cycloalkyl hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, substituted or unsubstituted amino, substituted or unsubstituted aminocarbonyl, acyl, acyloxy, optionally substituted non-aromatic heterocyclic group, aryloxy (e.g., phenyloxy), aralkyloxy (e.g., benzyloxy), lower alkylsulfonyl, guanidino, azo group, optionally substituted ureide and the like. These substituents are able to locate at one or more of any possible positions.
Preferable are mercapto, lower alkylthio, hydroxy, aminocarbonyl, carboxy as substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d for R1.
Preferable are aminocarbonyl, optionally substituted non-aromatic heterocyclic group as substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d for R2.
Preferable are hydroxy, lower alkyloxy, unsubstituted or substituted amino, acyl, optionally substituted non-aromatic heterocyclic group as substituents of xe2x80x9coptionally substituted lower alkylxe2x80x9d for R5.
The substituents of xe2x80x9coptionally substituted cycloalkylxe2x80x9d, xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d, xe2x80x9coptionally substituted heteroaryl alkylxe2x80x9d, and xe2x80x9coptionally substituted ureidexe2x80x9d herein used are optionally substituted lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted non-aromatic heterocyclic group, optionally substituted aralkyl, lower alkylsulfonyl, guanidino group, azo group, or optionally substituted ureide and the like. These substituents are able to locate at one or more of any possible positions.
Preferable are optionally substituted lower alkyl, lower alkenyl, lower alkynyl, hydroxy, lower alkyloxy, mercapto, lower alkylthio, halogen, nitro, cyano, carboxy, lower alkyloxycarbonyl, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, acyl, acyloxy, aryl, heteroaryl, non-aromatic heterocyclic group, aralkyl and the like, as substituents for R1 and R2 of xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted aralkylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, and xe2x80x9coptionally substituted heteroaryl alkylxe2x80x9d.
Preferable are lower alkyl, cycloalkyl, hydroxy lower alkyl, hydroxy, acyl, lower alkyloxy, lower alkylthio, halogen, nitro, carboxy, cyano, halo(lower)alkyl, halo(lower)alkyloxy, unsubstituted or substituted amino, unsubstituted or substituted aminocarbonyl, heteroaryl, non-aromatic heterocyclic group, and the like as substituents of xe2x80x9coptionally substituted cycloalkylxe2x80x9d, xe2x80x9coptionally substituted arylxe2x80x9d, xe2x80x9coptionally substituted heteroarylxe2x80x9d, and xe2x80x9coptionally substituted non-aromatic heterocyclic groupxe2x80x9d for R3.
Compounds (I) of the invention are able to be synthesized from natural or unnatural amino acids, their esters or their salts as starting materials in accordance with the procedure described WO97/27174. And it is possible to produce the compounds as follows.
This is a process of obtaining sulfonamide derivatives (X) by the reaction of compound (VIII) having an amino group and compound (IX) having a cyano group. The process may be carried out in accordance with the same procedure as (Method A-Process 1) in WO97/27174.
(Process 2)
The present process is a process of obtaining compound (XI) by the reaction of compound (X) having cyano group and hydroxylamine. To a solution of compound (X) and a hydroxyl amine derivative such as of hydroxylamine hydrochloride in ethanol and the like is added a base (e.g., triethylamine) and the mixture is reacted under 10xc2x0 C. to reflux to obtains the target compound (XI).
(Process 3)
The present process is a process of constructing of an oxadiazole ring by the reaction of compound (XI) and compound (XII) having a carboxy group. This process may be carried out in the same manner as that described in Gui-Bai Liang, Danqing D. Feng, Tetrahedron Letters, 37, 6627 (1996). Another method for the process of construdting the oxadiazole ring by acid chloride is reported (Cuy D. Diana, et al., J. Med. Chem., 1994, 37, 2421-2436).
(Process 4)
The present step is a process of yielding the compound (XIV) by hydrolysis of the compound (XIII). This step may be carried out in accordance with a usual method as described in xe2x80x9cProtective Groups in Organic Synthesis, Theodora W Green (John Wiley and Sons)xe2x80x9d and the like.
The effect of a treating agent of heart failure can be confirmed by the procedure described in WO00/15213.
The effect of a treating agent of nephritis (glomerulopathy) can be confirmed by the procedure described in WO00/04780.
The above effects can be confirmed as follows.
(Animals)
Five to eight weeks old male Slc-Wistar rats were used in the experiment.
(Procedure for the Establishment of Nephritogenic Antibody)
Mouse monoclonal antibodies are established against rat glomeruli and the monoclonal antibodies which induce nephritis are screened as described below.
To induce glomerulonephritis by the injection of antibody, the presence of the antigen on the cell surface is required. First of all, we investigated by immunofluorescence whether or not the obtained monoclonal antibodies accumulate in the glomeruli after the intravenous injection to rats.
The distribution and molecular weight of antigen recognizing each clone of monoclonal antibodies are determined. Furthermore, nephritis-inducing activity is evaluated based on the urinary excretion of protein within a week after single injection of antibody.
During this study, a monoclonal antibody E30 was established (J.J.N., vol. 36, p106, 1994). It has been known that E30 recognizes the surface antigen of mesangial cells by the immunohistochemical study, and that single administration of E30 to rats induces complement-dependent mesangial cell injury. The pathological changes are described below.
E30 antibodies immediately bind to the surface antigens of mesangial cells in glomeruli after a intravenous injection to rats, followed by the activation of complement system within 30 min. And then, degeneration and necrosis of mesangial cells are occurred, resulting in the detachment of glomerular basement membrane from mesangial area. A series of these pathological features is known as mesangiolysis. Accumulation of platelet and infiltration of inflammatory cells such as polymorphonuclear leukocyte and macrophage are observed during mesangiolysis. Mesangiolysis is prominent 1-3 days after the injection of the antibody and mesangial expansion is frequently observed at that time. Proliferation of glomerular cells, mainly mesangial cells, is initiated 3-5 days after the injection, resulting in the morphological features of mesangial proliferative glomerulonephritis by a week. The reconstruction of the glomerular capillary network is accompanied with mitosis and proliferation of mesangial cells and irregular patterns of angiogenesis. After then, increased number of mesangial cells and overproduced extracellular matrix are resolved with time course and the pathological features recover to the normal one by a month.
Thus, since a single injection of the monoclonal antibody induces a reproducible nephritis model, the antibody-induced nephritis model is useful for grasping a basic changes in glomerular disease as a biological response.
In Asia, a half of the patients with glomerulonephritis is diagnosed as IgA nephropathy. IgA nephropathy is characterized as IgA deposition to glomerular mesangial cells. IgA nephropathy belongs to proliferative nephritis caused by immunoreaction against mesangial cell itself. Therefore, the monoclonal antibody-induced nephritis model is also useful for studying the pathogenesis of IgA nephropathy.
In addition, the monoclonal antibody, E30, is available for establishing some chronic nephritis models induced by the combination dosing with puromycin aminonucleoside (J.J.N., vol. 39, p220, 1997) or by a single injection of it to uni-nephrectomized rats (J.J.N., vol. 39, p300, 1997). The preventing or treating effects of test compounds on the development of glomerulosclerosis could be evaluated by utilizing these chronic nephritis models. Similar experiments can be examined by using following methods: 1) methods by using other monoclonal antibodies or anti-thymocyte serum instead of E30, 2) methods by using hereditary nephrosis rats or mice, 3) methods by using spontaneously diabetic rats or mice, and 4) methods by using streptozotocin- or alloxan-induced diabetic rats or mice.
(Protocol for Assay)
In order to induce glomerulonephritis, E30 of 20 to 500 xcexcg, preferably 50 to 200 xcexcg, is intravenously injected to rats of five to eight weeks old. Test compounds of 0.1 to 500 mg, preferably 1 to 200 mg, are suspended with 3 to 10%, preferably 4 to 6%, gum arabic solution and the like, and are orally given 1 to 5 hours, preferably 1.5 to 3 hours, prior to E30 injection. Constant amount of test compounds are then consecutively given 1 to 3 times a day. Evaluation of test compounds are determined by the amount of urinary protein excretion 2 days after E30 injection when proteinuria reaches to the maximum level.
As for some compounds which exhibit antiproteinuric effects in the method described above, the amount of urinary protein excretion during 5 to 8 days, changes in body weight, morphological changes in glomeruli by autopsy, inhibitory ratio of mesangial proliferation and renal function are assessed after the treatment of these compounds.
Determination of the amount of urinary protein excretion is performed by the collection of 24-hour urine samples with stainless metabolic cages followed by the measurement of the concentration of urinary protein. Blood samples obtained at the follow-up period are processed for the determination of blood urea nitrogen and plasma creatinine, which indicate renal function. As a marker of damaged renal tubules, urinary amounts of N-acetyl-D-glycosaminidase excretion is measured. Furthermore, to study the inhibitory effects of compounds on mesangial proliferation following E30 injection, the number of PCNA (proliferating cell nuclear antigen) positive cells per single glomerulus is counted. Morphological changes are observed with light and electron microscopy.
The term xe2x80x9csolvatexe2x80x9d includes, for example, solvates with organic solvents, hydrates, and the like.
The term xe2x80x9ccompound of the present inventionxe2x80x9d herein used includes a pharmaceutically acceptable salt or solvate thereof. The salt is exemplified by a salt with alkali metals (e.g., lithium, sodium, potassium, and the like), alkaline earth metals (e.g., magnesium, calcium, and the like), ammonium, organic bases, amino acids, mineral acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and the like), or organic acids (e.g., acetic acid, citric acid, mallein acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like). These salts can be formed by the usual method. These hydrates can coordinate with any water molecules.
The compound of the present invention is not restricted to any particular isomers but includes all possible isomers and racemic modifications.
The compound of the present invention has an excellent activity for inhibiting MMP-2 and inhibits matrix dissolution, as described in the following test example.
Definitely, the compounds of the present invention are useful in the prevention or treatment of diseases such as osteoarthritis, rheumatoid arthritis, corneal ulceration, periodontal disease, advanced virus infection (e.g., HIV), arteriosclerosis obliterans, arteriosclerotic aneurysm, atherosclerosis, restenosis, sepsis, septic shock, coronary thrombosis, aberrant angiogenesis, scleritis, multiple sclerosis, open angle glaucoma, retinopathies, proliferative retinopathy, neovascular glaucoma, pterygium, keratitis, epidermolysis bullosa, psoriasis, diabetes, nephritis (glomerulopathy), neurodegengerative disease, inflammation, osteoporosis, deossification, gingivitis, tumor growth, tumor angiogenesis, ocular tumor, angiofibroma, hemangioma, fever, hemorrhage, coagulation, cachexia, anorexia, acute infection, shock, autoimmune disease, malaria, Crohn disease, meningitis, heart failure, asthmatic respiatory tract disease, arteriosclerosis, and gastric ulcer. The compounds are expected especially as nephritis (glomerulopathy).
When the compound of the present invention is administered to a person for the treatment of the above diseases, it can be administered orally as powder, granules, tablets, capsules, pilulae, and liquid medicines, or parenterally as injections, suppositories, percutaneous formulations, insufflation, or the like. An effective dose of the compound is formulated by being mixed with appropriate medicinal admixtures such as excipient, binder, penetrant, disintegrators, lubricant, and the like if necessary. Parenteral injections are prepared by sterilizing the compound together with an appropriate carrier.
The dosage varies with the conditions of the patients, administration route, their age, and body weight. In the case of oral administration, the dosage can generally be between 0.01 to 100 mg/kg/day, and preferably 0.1 to 30 mg/kg/day for adult.

Sulfonamide derivatives having oxadiazole rings

Abstract: wherein R1 and R2 are each independently hydrogen atom, optionally substituted lower alkyl or the like; R3 is optionally substituted aryl, optionally substituted heteroaryl or the like; X is xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94Sxe2x80x94; Y is NHOH, hydroxy, or lower alkyloxy.


A device includes a first leg including a first connector. The first connector includes multiple electrical contacts. The device includes a second leg substantially parallel to the first leg and configured with a connector, a set of conductors, or both. The device includes a transverse portion connected to the first leg and to the second leg. Together, the transverse portion and the first and second legs form a substantially rigid or semi-rigid body. The transverse portion includes multiple conductors electrically coupling respective connectors on the first and second legs.

Mobile devices, such as tablet computers and mobile phones, conventionally include a connector to enable data transfer with an external device and/or power transfer. For example, Universal Serial Bus (USB) connectors are commonly used to enable charging of a mobile device and to enable data transfer to and from a memory internal to the mobile device. As an example, a mobile phone may include a micro-USB socket embedded within a top edge of the mobile phone to enable a micro-USB plug to be inserted downward into the socket, with a cord protruding upward from the plug.
Operators of vehicles such as automobiles often use a cradle to hold a mobile phone to enable hands-free use of the mobile phone while operating the vehicle. However, using a conventional micro-USB plug to charge a mobile phone having a top-mounted socket may cause the upwardly-protruding cord to at least partially obscure a field of view of the operator. In addition, for in-vehicle charging, the cord typically terminates with a cigarette lighter-type adaptor that is inserted into a power socket (e.g. a cigarette lighter socket) that is positioned lower than the cradle. To illustrate, the cradle may be positioned at a car dashboard near the steering wheel and the power socket may be positioned at a center console of the car. As a result, the upwardly-projecting cable from the micro-USB plug at the top of the mobile phone may bend 180 degrees to extend downward to the power socket, producing mechanical stress (e.g. torque) on both the micro-USB plug and the micro-USB socket in the mobile phone.


A sight tube for an optical temperature measuring device suitable for immersion in molten steel comprises an elongated, cylindrical body having an optical sighting bore therein extending axially from an open end of the body to a closed end. The body is a carbon bonded alumina graphite material made from a mix consisting of, in weight percent, between about 5-45% graphite; between about 20-85% alumina; 0 to 15% anti-oxidant; and between about 3-20% phenolic resin binder. The mixture is isostatically pressed in the desired body shape and fired at a temperature in excess of 1400.degree. C. in a reducing atmosphere. The graphite is preferably a high purity flake graphite, greater than 99% pure. The alumina is preferably "brown" fused alumina grain having minimum amounts of volatile elements: sodium (Na), potassium (K), boron (B), phosphorous (P), sulphur (S) and chlorine (Cl). The sodium content, present as Na.sub.2 O in the alumina source is less than 0.05% by weight, and preferably no more than 0.02% by weight.

The invention relates generally to optical temperature measuring devices for monitoring the temperature of molten metals. More particularly, the invention relates to a refractory sight tube for use with an optical temperature sensing device adapted for continuous immersion in molten steel, for example.
Heretofore, it has been common to employ disposable lance thermocouple devices to measure steel temperature. The disposable lance thermocouples have been found to be inaccurate and do not allow for continuous measurement of the molten metal. In addition, the use of such disposable lance thermocouples involves some safety hazards to the operating personnel.
More recently, a continuous temperature measuring thermocouple has been developed for use in molten steel, as disclosed in commonly owned U.S. Pat. No. 4,721,533 "Protective Structure For An Immersion Pyrometer" to Phillippi et al. and U.S. Pat. No. 5,071,258 "Thermocouple Assembly" to Usher et al. The structures disclosed in these patents include an inner thermocouple assembly housed in a molybdenum sheath and an outer protective casing of a refractory metal oxide and graphite material for immersion in molten slag and steel.
While the continuous sensing thermocouple devices of the cited patents perform well, they require periodic replacement of the expensive noble metal inner thermocouple elements which gradually degrade over time at high temperature. Of course, the outer refractory casing must also be replaced at even more frequent intervals due to the severe corrosive and erosive effects of molten slag and steel.
Needless to say, there has been a need in the metallurgical field for a continuous temperature measuring device which accurately and economically determines the temperature of liquid steel. Infrared radiation detecting optical pyrometers have been known in the art for many years. These devices are optically sighted on a hot object, such as the surface of a metal bath, and the infrared radiation emitted from the bath is converted to an electrical signal calibrated to a given temperature read out. The accuracy of the conventional optical sighting pyrometer device is affected by furnace gases and variations in the slag/metal surface which gives rise to inaccurate readings. In addition, conventional optical pyrometers cannot sight beneath the slag layer to determine the steel temperature which is usually different than the temperature at the surface of the slag layer.
In U.S. Pat. No. 4,737,038 to Dostoomian, there is disclosed a device employing an optical pyrometer and a hollow dipstick of a ceramic material for immersion in molten metal to determine the temperature of the melt at a desired depth. The composition of the ceramic dipstick is not disclosed in the subject patent and is apparently not deemed to be critical, except for its ability to maintain its integrity at temperatures on the order of 1200.degree. C.-1500.degree. C. The ceramic dipstick of this patent also requires a preheating treatment in an induction heating apparatus prior to immersion to prevent cracking of the dipstick due to thermal shock. A protective quartz window is mounted in the dipstick along with a convex lens to establish a focal point coincident with the bottom surface of the dipstick for transmitting the infrared radiation emitted at the end of the dipstick to an infrared detector means. The detector means is either mounted on the end of the dipstick or disposed at a remote location and optically connected to the dipstick by fiber optic means.
To the best of my knowledge, this prior attempt to combine an optical pyrometer with a ceramic dipstick or sight tube has not found any significant commercial success, possibly due to shortcomings in the ceramic dipstick portion of the device. Refractory elements which are continuously immersed in slag and steel must be capable of withstanding the corrosive and erosive effects of the molten media. Ideally, these elements should also be resistant to thermal shock so as to reduce or eliminate the need for costly and time consuming preheat devices and procedures. In the case of temperature measuring devices, the refractory immersion tube should also possess some degree of enhanced thermal conductivity to prevent a time lag in monitoring accurate melt temperatures. Ceramic materials heretofore commonly used in the art to protect temperature measuring devices for immersion in molten metal such as fused silica, alumina and clays do not possess relatively high thermal conductivity for these purposes.
Other refractory compositions such as alumina-graphite possess enhanced thermal conductivity and thermal shock resistance but have been found to contain certain impurities which volatilize at molten steel temperatures. Such volatile constituents in the refractory material contaminate the optical system of the temperature sensing device which adversely affects the accuracy of the system.
The present invention solves the problems of the prior art by providing a refractory sight tube for an optical temperature measuring device for continuous immersion in molten steel or other molten media. The sight tube of the invention is made from a refractory composition which provides an environment for the optical pyrometer which is substantially free of harmful vapor phase contaminants so as to improve the temperature measuring accuracy of the device.
Still further, the present invention provides a refractory sight tube which has enhanced thermal conductivity so as to improve the thermal responsiveness of the temperature sensing device while also improving the thermal shock resistance of the tube and eliminating the necessity to preheat the refractory prior to use.

Refractory sight tube for optical temperature measuring device


In the present invention, an iterative process is provided for cone-beam tomography (parallel-beam and fan-beam geometries are considered as its special cases), and applied to metal artifact reduction and local reconstruction from truncated data, as well as image noise reduction. In different embodiments, these iterative processes may be based upon the emission computerized tomography (CT) expectation maximization (EM) formula and/or the algebraic reconstruction technique (ART). In one embodiment, generation of a projection mask and computation of a 3D spatially varying relaxation factor are utilized to compensate for beam divergence, data inconsistence and incompleteness.

1. Field of the Invention
The present invention generally relates to a system and method for reconstructing cone-beam tomographic images and particularly to an iterative process for performing such functionality.
2. Description of the Prior Art
Nondestructive analysis and visualization of three-dimensional microstructures of opaque specimens are important techniques in biomedical and material sciences and engineering. Due to its penetration ability and contrast mechanism, X-ray microtomography is a powerful tool in this type of application. For example, and as described in G. Wang et al., "Cone-beam X-ray microtomography", Multi-dimensional microscopy, Springer-Verlag, New York, Chapter 9, pages 151-169 (1994), an X-ray shadow projection microscope with a microtomography capability is being developed at the State University of New York at Buffalo (SUNY/Buffalo). FIG. 1, described in further detail later, shows such a system.
Cone-beam geometry is also important for emission tomography, medical and industrial X-ray CT. Due to 3D divergency, reconstruction from cone-beam data is much more intricate than in parallel-beam or fan-beam geometry. Having been studied for many years, cone-beam tomography remains a major topic in CT.
A cone-beam reconstruction formula for an infinitely long scanning line has been developed. Additionally, a formula has been derived for reconstruction of a real function with a compact support under the condition that almost every plane through the support meets a scanning locus transversely. A cone-beam reconstruction formula for two intersecting source circles has also been established. Thorough theoretical analyses on cone-beam reconstruction have been reported by Tuy, Smith and Grangeat. As a result, the following sufficient condition for exact cone-beam reconstruction has been developed:
if on every plane through an object there exists at least one source point, exact cone-beam reconstruction can be achieved. PA1 if a source curve is connected and compact, and if its convex hull contains a planar region, the cone-beam data from the source curve is complete for exact reconstruction of the planar region.
A theoretical framework for local cone-beam reconstruction has been developed. The concept of the planar region of an object as intersection of the object support and a set of planes has been defined, proving that
An estimation formula for local reconstruction and a convergence condition for the formula have also been created.
Exact cone-beam reconstruction algorithms have been implemented in the past, including filtered backprojection algorithms. Among current exact algorithms, a direct Fourier transform method is computationally the most efficient for a sufficiently large amount of data.
Approximate cone-beam reconstruction algorithms are also important in practice. Generally speaking, approximate cone-beam reconstruction cannot be avoided in the cases of incomplete scanning geometry and partial detection coverage. Furthermore, approximate reconstruction is usually associated with higher computational efficiency, and likely less image noise and ringing. Others have adapted the equispatial fan-beam algorithm for cone-beam reconstruction with a circular scanning locus. Because this algorithm is limited by circular scanning, spherical specimen support and longitudinal image blurring, it has been extended in various ways.
Tam, U.S. Pat. No. 5,270,926, discloses an iterative algorithm for cone-beam reconstruction from incomplete data. In this algorithm, Radon data are first computed, and missing data initialized to zero. Then, an image volume is reconstructed slice-by-slice via 2D filtered backprojection. Projection data are corrected by a priori information on the object support, upper and lower bounds of projection values, and reprojected to calculate the missing data. The steps are repeated until some convergence criterion is satisfied.
However, the convergence and optimality of this iterative algorithm have not been established. Other existing cone-beam algorithms require that projections be complete at least along one direction, and therefore cone-beam reconstruction is impossible in cases where objects contain X-ray opaque components and/or are larger than the cone-beam aperture defined by effective detection area and X-ray source position.
The expectation maximization (EM) approach is well known. This iterative formula has been interpreted in a deterministic sense, and its desirable theoretical properties have been established. Based on this formula, 2-D parallel-beam CT algorithms for metal artifact reduction and local reconstruction from truncated data may be developed.

Iterative process for reconstructing cone-beam tomographic images


Novel 6-pyridyl substituted pyrimidine derivatives are disclosed for use as antiviral agents, particularly for the treatment of retroviral infections such as HIV infections and related disorders, as well as for use in anti-cancer therapies to improve the efficacy of anti-cancer therapeutics. These compounds and their pharmacologically acceptable salts operate to disrupt viral replication an exhibit lower cell toxicity, thereby providing more efficient agents for use alone or in conjunction with other chemical or biological agents to provide prolonged antiviral therapy. In addition, the compounds can be used to increase the efficacy of anti-cancer therapeutics including 5-fluropyrimidines such as 5-fluorouracil, thereby reducing the dosage requirement of the therapeutic in anti-cancer therapies so as to decrease toxic effects to the host.

The present invention relates to synthesis and pharmaceutical compositions of novel 6-pyridylthio- and 6-pyridylseleno-substituted pyrimidine derivatives, useful for the treatment of infectious viral diseases, and for improving the efficacy of of anti-cancer therapeutics such as 5-fluorouracil in cancer therapy. With particular regard to antiviral activity, the compounds of this invention are useful in the treatment of Acquired Immunodeficiency Syndrome (AIDS) and related illnesses.
Acquired Immunodeficiency Syndrome is generally accepted to be the result of infection with a type of retrovirus termed the Human Immunodeficiency Virus (HIV). A number of strains or classes of HIVs have been identified, and it appears that HIVs are part of a broader family of retroviruses having similar genomes that are responsible for a wide range of diseases having diverse clinical manifestations.
In cases of AIDS, the infections are characterized by a marked depression in the hematological profile of the host and a general loss of the host immune response to invading pathogens, leaving the afflicted individuals extremely vulnerable to opportunistic infections by other microbes. In early stages of the infection, a number of less life-threatening manifestations have been reported and are generally referred to as AIDS-related complex.
At present, management of patients with HIV infections typically involves the administration of a pyrimidine nucleoside, such as, for example, azidothymidine (3'-azido-2',3'-deoxythymidine or "AZT"). Such chemotherapeutic agents function by inhibiting the reverse transcriptase of the HIV and reducing the cytopathic effects of the virus.
For further disclosures of pyrimidine nucleosides having antiviral properties and methods of synthesizing such compounds, see U.S. Pat. No. 3,282,921 issued to Verheyden et al. on Nov. 1, 1966; U.S. Pat. No. 3,687,931 issued to Verheyden et al. on Aug. 29, 1972; U.S. Pat. No. 3,755,295 issued to Verheyden et al. on Aug. 28, 1973; U.S. Pat. No. 3,775,397 issued to Etzold et al. on Nov. 27, 1973; U.S. Pat. No. 3,817,982 issued to Verheyden et al. on Jun. 18, 1974; U.S. Pat. No. 4,071,680 issued to Cook on Jan. 31, 1978; U.S. Pat. No. 4,093,715 issued to Lin et al. on Jun. 6, 1978; U.S. Pat. No. 4,128,639 issued to Lin et al. on Dec. 5, 1978; U.S. Pat. No. 4,210,638 issued to Greer on Jul. 1, 1980; U.S. Pat. No. 4,230,698 issued to Bobek et al. on Oct. 28, 1980; U.S. Pat. No. 4,331,662 issued to Eckstein et al. on May 25, 1982; U.S. Pat. No. 4,604,382 issued to Lin et al. on Aug. 5, 1986; U.S. Pat. No. 4,681,933 issued to Chu et al. on Jul. 1, 1987; Horwitz, Vol. 29, J. Org. Chem., pp. 2076-2078 (1964); Lin et al., Vol. 21, J. Med. Chem., pp. 109-112 (1978); Lin et al., Vol. 36, Biochem. Pharmacol., pp. 311-316 (1987); and Schinazi et al., Interscience Conference on Antimicrobial Agents and Chemotherapy, Abstract #369 (1987), herein incorporated by reference.
To date no compounds for the chemotherapy of AIDS have been discovered that are completely satisfactory or even as effective as AZT. Only a few others (3'-azido-2',3'-dideoxycytidine, 2',3'-dideoxyinosine, etc.) have even reached clinical trials. In view of the epidemic spread of the disease, there is a pressing need to find compounds that will be active against HIV during the latent stage of its life cycle to facilitate complete abrogation of the virus.
The treatment of AIDS with AZT has a number of drawbacks. In the first place it is only active against the HIV virus during the part of its life cycle during which it is replicating itself. AZT does not eradicate the virus as long as it remains latent, it only slows down the progress of the disease. It must be taken daily for an indefinite period of time, perhaps years, to keep the virus more or less in check. AZT is a toxic drug. In many cases, over a long period of time AZT causes damage to bone marrow and the hematopoietic system, and may give rise to neurological disorders. It would therefor be desirable to have other drugs available which are at least as good as AZT, which could be varied to avoid long-term side effects, and that would be more effective and less toxic.
In the field of cancer chemotherapy, the use of halogenated pyrimidine bases such as 5-fluorouracil (5-FUra), and halogenated pyrimidine nucleosides such as 5-fluoro-2'-deoxyuridine (5-FdUrd) as chemotherapeutic agents is well documented in the art (Heidelberger, C., in Antineoplastic and Immune Suppressive Agents Part II, A. C. Sartorelli and D. G. Jones ed.s, pp. 193-231, (Springer-Verlag, Heidelberg, 1975)). However the halogenated pyrimidine nucleosides are rapidly degraded to their respective pyrimidine bases, thereby reducing their effectiveness against the cancer tissue they are meant to treat. Moreover, cytotoxicity is caused by 5-FUra's toxic metabolites that are produced by the catabolism process.
These factors have limited the use of 5-FUra due to a low therapeutic index, leading to studies aimed at increasing its antitumor activity and decreasing its toxic effects on host tissue by combining 5-Fura with agents such as methotrexate (Cadman et al. (1979) Science 205:1135), N-(phosphonacetyl)-L-aspartate (Martin et al. (1989) Cancer 45:1117) allopurinol (Schwartz et al. (1980) Cancer Res. 40:1885), 5-benzylacyclouridine and AZT. Susceptible normal tissue can also be selectively rescued by the subsequent administration of large doses of uridine (Klubes et al. (1983) Cancer Res. 43:3182). However, this augmentative therapy is hampered by toxicity associated with the administration of high uridine dose, such as phlebitis and pyrogenic reactions.
It is a goal of this invention to provide a compound which is an effective antiviral agent, particularly against the retrovirus HIV.
It is another goal of this invention to provide an antiviral agent which is less toxic to a subject than AZT.
It is a further goal of the invention to increase the efficacy of 5-fluorouracil treatment in cancer therapy while decreasing host toxicity due to 5-fluorouracil and its metabolites.


A filter installation and method, especially a seawater filter installation and method, includes at least one fluid line (18,20) for transporting a biological fluid, a filter device (54) mounted in the fluid line with at least one filter element (22) in a filter housing (10), and a device for biological decontamination. The device for biological decontamination contains active substances that can be introduced into the filter housing (10), such as inert gases or special metals, ensuring that toxic impurities cannot enter. The active substances used are ecofriendly unlike chemically produced fungicides and herbicides.

DE 20 2004 002 616 U1 discloses a generic water filter installation, a seawater filter installation in particular, comprising a water line as a fluid line and a filter connected between two line sections of the fluid line. Individual filter elements are provided with a filter surface located in the filter interior for filtering water. One line section forms a feed line to the filter for the water to be cleaned. The other line section forms a drain line for the filtered water. In the known solution, feeding and draining of the filter can be blocked relative to the water line with blocking means (valves). The filter interior can be heated by a heating means with the blocking means blocked to a setpoint temperature of more than 50° C., preferably approximately 60±5° C. for decontamination of the filter surface. Preferably, the filter is designed as a backflushing filter with a backflushing means for cleaning the filter surfaces in counterflow to the actual filtering direction.
Aboard ship, such as for example container ships, ballast water is pumped on board in a particular harbor or underway in certain waters to be able to equalize missing ship's ballast. Ballast equalization can be achieved while sailing for example by a decreasing amount of fuel and by taking on new seawater ballast and/or pumping seawater between the individual ballast chambers to level the ship. When a new harbor is being approached and ballast water is pumped out into the harbor basin to load the ship with new cargo, it cannot be precluded that living organisms taken aboard in the original harbor or underway will be discharged in the new port of call. Thus, in a type of biological tourism, foreign organisms become settled in the biotopes, where they in fact do not belong, with the result that they can displace native species to their complete extinction. This occurrence can lead to a serious environmental situation. In addition to viruses, fungi, algae, protozoa, and other microorganisms can also be transported at the same time in this way. However, tiny organisms can indeed also be transported at the same time, including mussels and the like.
With the known solution according to the German utility model, this biological contamination is controlled by heating all the parts located in the filter interior of the filter for a sufficient time interval to a high enough temperature, for example 60° C., to kill algae, microorganisms and other tiny organisms. With the corresponding backflushing process, the killed organisms are returned immediately to the original water and are not delivered into foreign water after a forthcoming voyage. By preference, the known solution calls for cleaning by superheated steam. As a result of the indicated high temperature and considering that salt water is heated, this decontamination is highly corrosive and leads to the corresponding corrosion damage, thus necessitating the use of expensive materials, such as duplex steels, titanium or the like. The known solution is biologically very compatible for the environment. In particular, no toxic contaminants are formed. Only temperature control for the heating means to be triggered and monitored is very complex, and requires correspondingly trained operators.
It had already been suggested in the prior art that the microorganisms in the filter fabrics of a filter be destroyed by oxidation technologies using UV radiation. Ozone, chlorine dioxide and other toxic contaminants are then formed which contraindicate industrial use. The described devices in the prior art need not be limited to seawater applications, but can fundamentally always be used wherever problems occur with respect to bacterial and organic contaminants, as can occur for example in water filtering in industrial facilities, such as power plants.

Filter installation and method for operating one such filter installation