A process control instrument for coupling to a process is attachable to a metal flange. The flange has a first passageway adapted to be filled with process fluid. The process control instrument includes a body having an opening adjacent to the first passageway for receiving process fluid from the first passageway when the process control instrument is attached to the flange. A diaphragm is disposed across the opening for fluid communication with the process fluid. A seal is positionable against the flange to prevent process fluid from leaking past the flange and diaphragm. The seal includes a ring positioned in the opening and coupled to the body, the ring being substantially in contact with the diaphragm along an inner annular shoulder when the body is not attached to the flange (unloaded).

The present invention relates to a process control transmitter. In particular, it relates to a process seal for a process control transmitter.
Transmitters which sense pressure typically have a pressure sensor coupled to at least one isolation diaphragm. The isolation diaphragm isolates the pressure sensor from corrosive process fluids being sensed. Pressure is transferred from the isolation diaphragm to the sensor having a sensing diaphragm through a substantially incompressible isolation fluid carried in a passageway. U.S. Pat. No. 4,833,922 entitled MODULAR PRESSURE TRANSMITTER and U.S. Pat. No. 5,094,109 entitled PRESSURE TRANSMITTER WITH STRESS ISOLATION DEPRESSION show pressure transmitters of this type.
The process fluid sealing mechanism for a transmitter should be operable in a wide range of chemical environments, temperature ranges and stress conditions and work well over a broad range of pressures. Teflon® and other fluorocarbons are among the preferred sealing compounds. Hastelloy®, 316 stainless steel and other corrosion resistant materials are preferred as construction materials for wetted surfaces. While these materials have very good corrosion resistance properties, their mechanical properties, such as yield strength of the corrosion resistant alloys and the resistance to extrusion of the sealing materials, are marginal at best. Sealing material tends to extrude when subjected to high pressures and temperatures. For this reason, the sealing material must be treated as a gasket. To form effective seals with gaskets, it is usually necessary to have a sealing material with a large surface area under significant compression. The stress from compression is mechanically coupled to the isolation diaphragm and ultimately to the sensing diaphragm of the pressure transmitter. The amount of stress can vary over time as mounting bolts loosen or are re-torqued, and as the gasket sealing material extrudes. These changes result in instabilities in the pressure sensor output.
To minimize the stress coupled to the process isolation diaphragm, it is preferred to separate the diaphragm from the sealing mechanism to provide stress isolation. However, practical considerations make stress isolation of the diaphragm difficult. Industry standards and the requirement of backward compatibility with existing products dictate the size, location and pattern of the bolts and pressure ports of the assembly. The overall geometry of the transmitter limits the space that must be shared by the process sealing gaskets and the isolating diaphragms. The process isolation diaphragms must fit within the boundaries defined by the bolt pattern. Space within the bolt boundary used for sealing is generally unavailable for isolation diaphragms. It is frequently undesirable to reduce the size of the isolation diaphragms because smaller isolation diaphragms are more sensitive to stress coupling and therefore instabilities result.
Tradeoffs must typically be made among the several competing needs of the pressure transmitter design: 1) the need for large compliant diaphragms; 2) the need for diaphragms that are well isolated from the stresses of the sealing mechanism; 3) the need for a sealing mechanism that has sufficient surface area; 4) the need for a sealing mechanism held together with sufficient force to be reliable; and 5) the constraint that all structures fit within the boundary defined by the bolt pattern.
One technique which addresses some of these concerns is shown and described in U.S. Pat. No. 5,955,675, which issued Sep. 21, 1999 to Peterson entitled SELF ENERGIZING PROCESS SEAL FOR PROCESS CONTROL TRANSMITTER which is commonly assigned with the present application. This reference describes a technique in which process pressure is used to assist in sealing a process seal to a flange. The process seal has a ring shape and sealing material is coupled to the ring along its inner diameter. The ring is adapted to force the sealing material into contact with the flange to prevent process fluid from leaking past the seal. U.S. Pat. Nos. 5,922,965 and 6,055,863, entitled PRESSURE SENSOR AND TRANSMITTER HAVING A WELD RING WITH AROLLING HINGE POINT, and PRESSURE SENSOR AND TRANSMITTER HAVING A WELD RING WITH A ROLLING HINGE POINT, issued Jul. 13, 1999 and May 2, 2000, respectively, also describe process seals.

Process seal for process control transmitter


The visual display of the invention consists of a holographic display projected through the playfield. The display projects an image that is related to the playfield and is mounted on a flexible plate that is flexed by a rotating cam wheel. As the cam wheel flexes the plate mounted image appears to the player to move.

The invention relates, generally, to pinball games and, more particularly, to a holographic display for such games.
Pinball games typically consist of an inclined play field supporting a plurality of play features such as bumpers, targets, ramps and the like and a rolling ball. The game player controls flippers mounted on the playfield to propel the ball at selected play features in an attempt to score points and control game play.
Pinball games are provided with a wide variety of art work and lighted displays on the playfield to attract game players and enhance the play of the game. Moreover, some modern pinball games are provided with video displays located remote from the playfield. The video displays consist of LED, liquid crystal displays or video screens and typically show visual images that relate to the play of the game.
While such video displays have proven to have player appeal, it is necessary for game manufacturers to continuously modify and update their games to maintain player interest. Thus, a new visual display for a pinball game is desired.


Conventional network quality monitoring systems require high monitoring cost, because: physical maintenance cost is high, since monitors are required to install on many portion of the network; the number of monitoring flows is apt to increase; the cost for information synchronization between monitors is required; and the network cost to collect information from apparatuses is required. In the present invention, based on a network whose route is definable by an external controller and changing the monitoring flow route appropriately, it is possible to perform monitoring of the communication quality under a small number of monitoring terminals and flows. Further, the role of the monitoring flow is divided into the monitoring flows to monitor the quality degradation occurrence and to specify the quality degradation point. The former is used for normal time, and the latter is for the quality degradation time. Consequently, the network monitoring system reducing the cost is proposed.

In the non-patent literature 1 and the patent literature 1, an example of a conventional communication quality monitoring system is described.
The non-patent literature 1 describes a method of the technique that is referred to as the network tomography. In this method, a plurality of communication quality measuring apparatuses, each of which is referred to as a probe terminal, are installed on a network system for inferring a degradation point of a communication quality.
Further, in the patent literature 1, in order to enable monitoring of a large scale network system, a means is prepared, in which a tree-type network is assumed, and a delay cause portion is narrowed down for collecting the operational information of network apparatus in the cause portion.
Other than the above techniques, the non-patent literature 2 describes the OpenFlow framework as a new network framework.
The OpenFlow framework consists of OpenFlow switches and OpenFlow Controller. An OpenFlow switch inquires forwarding rules (rule and action) of a packet to an OpenFlow controller. An OpenFlow controller senses a network state, calculates communication paths of packets, determines forwarding rules of the packets, and then sets their forwarding rules into OpenFlow switches. An OpenFlow Controller and OpenFlow Switches are connected through a Secure Channel so that the OpenFlow Controller controls the OpenFlow Switch by using a control message based on an OpenFlow protocol. This enables a control algorithm, new ideas and the like are mounted thereon, to be easily applied to a network environment.
The OpenFlow Switches are edge switches and core switches, which are controlled by an OpenFlow controller in OpenFlow network. Flow shows a communication in specified path, which is a transfer from incoming a packet to the input side edge switch to sending it from the output side edge switch.
The forwarding rule is defined by various combinations of one or all of a destination address (Destination Address), a transmission source address (Source Address), a destination port (Destination Port) and a transmission source port (Source Port) that are included in the header region of each protocol hierarchy level in the packet and can be distinguish from other forwarding rules. In the above addresses, it is assumed that a MAC address (Media Access Control Address) and an IP address (Internet Protocol Address) are included. Further, in addition to the above, the information of an ingress port (Ingress Port) can be used as the transfer rule.
The action of the transfer rule indicates the operations such as "outputting to a particular port", "discarding" and "rewriting of a header". For example, if the identification information of an output port (the number of the output port or the like) is indicated in the action of a flow entry, the OpenFlow Switch outputs the packet to the port corresponding to the indication information, and if the identification information of the output port is not indicated, the OpenFlow Switch discards the packet. Or, if header information is indicated in the action of a flow entry, the OpenFlow switch rewrites the header of the packet on the basis of the header information.
The OpenFlow switch executes the action of the flow entry, for a packet group (a packet series) complying with the rule of the flow entry.
The details of the OpenFlow technique are described in the non-patent literature 3.
In the non-patent literature 4, a network tomography technique that uses this OpenFlow Framework is described. In the non-patent literature 4, since a monitoring route can be set, a route for comprehensively monitoring the network from a small number of probe terminals is determined, set, and monitored, and consequently, the communication quality can be monitored by the small number of probe terminals.
A problem of conventional monitoring systems is the high monitoring cost. This is caused by the fact that in many monitoring systems, a monitoring function must be installed for all of the terminals and all of the edge terminals in the network. Further, many monitoring routes are required to be set for the respective monitoring functions. For example, though the technique described in the non-patent literature 4 has a merit that the monitoring function can be reduced, in order to enable the network to be comprehensively observed, many monitoring routes are required to be set, which leads to a result that many monitoring packets flow.
Moreover, because many monitoring routes are set, the network load for information synchronization and information collection is required.

Communication quality monitoring system, communication quality monitoring method and recording medium


A diameter expansion drill bit used for inserting in a prepared hole perforated in a framework to expand a diameter of a portion of the prepared hole by grinding has a plurality of blade sections that grind the portion of the prepared hole, a blade holding section that holds the plurality of blade sections movably in a radial direction respectively, and a shank section that supports the blade holding section, and the plurality of blade sections move to spread outwardly in the radial direction with respect to the blade holding section by centrifugal force due to rotation.

An undercut drill apparatus has been known as this kind of diameter expansion drill bit which is used to be inserted into a straight-shaped prepared hole perforated in a framework such as concrete and expands an innermost of the prepared hole (see Patent Document 1).
The undercut drill apparatus has a hollow cylindrically-shaped cylindrical body inserted into the prepared hole, an abutting member which abuts on an opening edge portion of the prepared hole and rotatably supports the cylindrical body via a bearing, a shaft which slidably engages with the cylindrical body coaxially and rotates with the cylindrical body integrally, a frustum-shaped corn section which is provided at a tip side of the cylindrical body and has four guide grooves on an outer circumferential surface, four arms which are attached on a tip portion of the shaft and engages with each guide groove, and two blades and two guide sections which are provided on an outer surface of a tip portion of the four arms alternately.
The blades and the guide sections locate inside the cylindrical body with a state that the shaft is pulled up when the cylindrical body inserted in the prepared hole and the shaft are rotated integrally and the shaft is moved downwardly, the four arms move downwardly and open outwardly along the guide grooves of the corn section. Thus, the blades grind an inner circumferential surface of the prepared hole to form a diameter expansion portion at a bottom (the innermost) of the prepared hole.
[Patent Document 1] JP-A-2005-280243


Heterocyclic-substituted tricyclics of the formula

The present invention relates to substituted tricyclic thrombin receptor antagonists, pharmaceutical compositions containing them and their use in the treatment of diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, cerebral ischemia, stroke, inflammatory disorders, neurodegenerative diseases and cancer. The invention also relates to the combination of novel compounds of the invention and other cardiovascular agents.
Thrombin is known to have a variety of activities in different cell types and thrombin receptors are known to be present in such cell types as human platelets, vascular smooth muscle cells, endothelial cells and fibroblasts. It is therefore possible that thrombin receptor antagonists, also known as protease activated receptor (PAR) antagonists will be useful in the treatment of thrombotic, inflammatory, atherosclerotic and fibroproliferative disorders, as well as other disorders in which thrombin and its receptor play a pathological role.
Thrombin receptor antagonists peptides have been identified based on structure-activity studies involving substitutions of amino acids on thrombin receptors. In Bernatowicz et at, J. Med. Chem., vol. 39, pp. 4879-4887 (1996), tetra- and pentapeptides are disclosed as being potent thrombin receptor antagonists, for example N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-NH2 and N-trans-cinnamoyl-p-fluoroPhe-p-guanidinoPhe-Leu-Arg-Arg-NH2. Peptide thrombin receptor antagonists are also disclosed in WO 94/03479, published Feb. 17, 1994.
Substituted tricyclic thrombin receptor antagonists are disclosed in U.S. Pat. No. 6,063,847, U.S. Pat. No. 6,326,380 and U.S. Ser. Nos. 09/880,222 (WO 01/96330) and 10/271715.

This patent is subject to a terminal disclaimer.

Abstract: or a pharmaceutically acceptable salt thereof, wherein:                the dotted line represents an optional single bond;         represents an optional double bond,        n is 0-2;        Q is cycloalkyl, optionally substituted by R13 and R14;        R13 and R14 are independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, —OH, (C1-C6)alkoxy, R27-aryl(C1-C6)alkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, halogen and haloalkyl; or        R13 and R14 together form a spirocyclic or a heterospirocyclic ring of 3-6 atoms,        Het is a mono- or bi-cyclic optionally substituted heteroaryl group; and        B is a bond, alkylene, or optionally substituted alkenylene or alkynylene,wherein the remaining substituents are as defined in the specification, are disclosed, as well as pharmaceutical compositions containing them and a method of treating diseases associated with thrombosis, atherosclerosis, restenosis, hypertension, angina pectoris, arrhythmia, heart failure, and cancer by administering said compounds. Combination therapy with other cardiovascular agents is also claimed.


A method for secure loading, integrity checking of the runtime image and control over the runtime execution of applications which ensures that a software application loads only code it was authorized to load, and that the software application is monitored for unauthorized modifications of the runtime image. The method proposed can be used as a basis for further enforcing of authorization rules during the execution of an application, e.g. for Digital Rights Management.

Over the last two decades, the functionality and convenience of computers has improved steadily. An ever growing number of interconnected computers and mobile devices are used to perform important tasks in many areas of society and in the daily lives of a growing number of people. This development, however beneficial, brings with it new vulnerabilities and concerns for security. A central problem is to allow a user to establish trust in the integrity of a computer system, or more particularly, in the integrity of a software application used for an important or sensitive purpose.
The integrity of a computer system depends not only on the integrity of the data in the non-volatile memory such as ROM or disks but also on the integrity of the runtime image in volatile memory such as RAM. The integrity of the runtime image can be corrupted due to intentional or non-intentional modifications of this image even if the static integrity of the executables before loading is guaranteed. Relevant vulnerabilities include loading of unauthorized code, buffer overflow, insufficient input validation, or, on Microsoft Windows platforms, security attacks based on a technique known as "DLL injection" where a remote process can write to the address space of a running application. Even with genuine code such as some system tools the runtime image of an application can be modified in an unauthorized manner. Since modifications can occur at any time, it is impossible to ensure a dynamic integrity of the runtime image of a software application with a single authentication before execution.
One prior art method for "secure software registration and integrity assessment in a computer system" is described in U.S. Pat. No. 5,944,821. A loader compares hash values of software applications before execution to previously prepared hash values in secure storage. Since no integrity checks during execution are performed, a dynamic integrity of the runtime image cannot be achieved.
The 2003 Microsoft Professional Developers Conference release of Microsoft Corporation's Next-Generation Secure Computing Base technologies for the Microsoft Windows family of operating systems is described in a white paper available at the Microsoft Developer Network library (http://msdn.microsoft.com/library/en-us/dnsecure/html/nca_considerations.asp). The computing environment is divided into two separate and distinct operating modes. Users can perform routine tasks in Standard mode using their existing applications, services, and devices. For their high-security tasks, those same users can run trusted, authenticated Nexus computing agents that execute in a separate and protected operating environment called Nexus mode. While Nexus mode protects Nexus computing agents from any harmful programs that may be running in Standard mode, within Nexus mode a Nexus security kernel uses standard virtual memory protections to isolate itself from Nexus computing agents and to isolate Nexus Computing agents from one another.

Computer security method and computer system

Hewlett-Packard Development Company, L.P.


After a liquid chemical treatment is finished, in parallel with a washing away treatment and/or a drying treatment, by spraying from a nozzle for a cleaning liquid supplied by a cleaning line to an outer surface of a nozzle for a liquid chemical, crystals and the like of components of the liquid chemical adhered on the outer surface of the nozzle are removed. In the cleaning treatment, a spraying time of the cleaning liquid is five seconds to ten seconds. In addition, the components of the cleaning liquid is not specifically limited, however, since ammonium phosphate tends to be solved in purified water, if a liquid chemical containing ammonium phosphate is used, it is preferable to use purified water as the cleaning liquid. Depending on the components and the like of the liquid chemical, a solution that can solve the crystals and the like may be used in stead.

1. Field of the Invention
The present invention relates to a cleaning apparatus of a semiconductor substrate and a method of manufacturing a semiconductor device which are suitable for manufacturing a semiconductor device using a large diameter substrate.
2. Description of the Related Art
Recently, as a semiconductor device is more highly integrated, a gate width of the semiconductor device has been narrower, while maintaining the height of a gate electrode. As a result, the aspect ratio of the gate electrode has been larger. Moreover, a gap of metal wirings has also been narrower. Further, in order to reduce a capacitance between the wirings, a low dielectric constant film is often used as an interlayer insulating film. Moreover, in order to suppress wiring resistance to a low value, a copper wiring is employed, and the semiconductor device is designed to have a higher height by an amount corresponding to the width decrease. Thus the aspect ratio of the copper wiring has also been larger.
When the copper wiring is formed, a damascene method is employed. In the damascene method, after formed wiring grooves by using a dry etching process in an interlayer insulating film such as a low dielectric constant film, the copper wiring is buried in the wiring grooves. In addition, after the dry etching process is finished, in order to remove adhered matters such as copper oxide, fluorine compound, organic polymer, and inorganic polymer, a wet post-treatment is implemented as cleaning. In the cleaning, an ammonium fluoride-based liquid chemical, or an ammonium phosphate-based liquid chemical is used. The above-mentioned liquid chemicals are preferable for working environment and for safety, because they do not contain deleterious and poisonous substances, thereby, do not belong to dangerous articles. Moreover, since their organic contents are relatively small, the treatment of their waste liquids is also easy.
Moreover, recently, in order to improve yields, enlargement of the diameter of a semiconductor substrate (wafer) has been advanced. Accordingly, although in cleaning (wet post-treatment) of a semiconductor substrate with a diameter of about 8 inch, a batch-type post-treating apparatus is used, in cleaning of a large diameter semiconductor substrate, a single-wafer-type post-treating apparatus has been used. FIG. 12 is a schematic view showing a conventional single-wafer-type post-treating apparatus. In the conventional single-wafer-type post-treating apparatus, a stage 106 on which a substrate 109 is placed is arranged in a treating bath 105. Moreover, a tank 104 storing a liquid chemical, a pump 103 sucking the liquid chemical from the tank 104, a heater 102 heating the liquid chemical sucked by the pump 103, and a nozzle 101 for the liquid chemical spraying the liquid chemical warmed by the heater 102 to the substrate 109 are also provided. Further, nozzle for water cleaning and the like (not shown) are also provided.
The cleaning using such a single-wafer-type post-treating apparatus, suppresses the increase of the contact resistance of the semiconductor device.
However, with increasing the diameter of the semiconductor substrate and the like, defective products tend to occur.
Related arts are disclosed in Patent document 1 (Japanese Patent Application Laid-open No. 2004-337858), Patent document 2 (Japanese Patent Application Laid-open No. 2001-232250), and Patent document 3 (Japanese Patent Application Laid-open No. Hei 11-74179).

Cleaning apparatus of semiconductor substrate and method of manufacturing semiconductor device


An AC type plasma display panel includes a plurality of pairs of display electrodes, a dielectric layer, a data electrode and a float electrode. A pair of the plurality of pairs of display electrodes are disposed parallel to each other on a front substrate and form a discharge gap for emitting light for display. The dielectric layer is formed on the front substrate and covers the plurality of pairs of display electrodes excluding at least a part of the discharge gap. The data electrode is disposed on a rear substrate, which is placed facing the front substrate across a discharge space, in a manner to cross under the display electrodes. The float electrode is disposed at the discharge gap on the front substrate.

A plasma display panel is a display device having superior visibility and characterized by its thinness, lightness and large display. The plasma display panels are classified into two driving systems, i.e., an AC type and a DC type, and classified into two electric discharge systems, i.e., a surface discharge type and an opposed discharge type. The AC and surface discharge type plasma display panel is becoming a mainstream, because it is suitable for high resolution and is easy to manufacture.
However, brightness and luminous efficiency of plasma display panels remain low, so that current plasma display panels have only approximately ⅓ the luminous efficiency of a CRT, which is popular as a display apparatus. Accordingly, various plasma display panels have been developed for the purpose of high brightness and high efficiency.
In general, the luminous efficiency of the plasma display panel is known to increase as the space (i.e., a discharge gap) between electrodes for generating discharge increases. For example, Japanese Patent Unexamined Publication No. 2000-305516 discloses an example of a plasma display panel having two times higher luminous efficiency by forming a three to five times larger discharge gap than usual. FIG. 8 is a sectional view of a plasma display panel having high luminous efficiency by forming a large discharge gap. The discharge gap between display electrodes 62 (i.e., a pair of bus electrodes 62a and 62b), which are disposed parallel to each other on front substrate 60, is formed larger (e.g., 400 μm to 500 μm). Dielectric layer 65 and protective layer 66 are formed in a manner to cover display electrodes 62. A plurality of parallel data electrodes 74 are disposed on rear substrate 70, and dielectric layer 75 covers both of them. A plurality of barrier ribs are disposed thereon parallel to data electrodes 74, and phosphor layer 77 is formed on a surface of dielectric layer 75 and sides of the barrier rib. Front substrate 60 and rear substrate 70 are faced and stuck to each other in a manner that display electrodes 62 cross over data electrodes 74, and discharge gas is sealed into discharge space therebetween. In the plasma display panel discussed above, when a voltage is applied to display electrodes 62, plasma discharge with high luminous efficiency is generated through the large discharge gap.
However, a size of a pixel is determined by the necessary number of pixels and a screen size of the display device, so that the size of the discharge gap is restricted by the size of the pixel and can not be freely enlarged. For example, in a 42 inch plasma display used for a standard television image receptor, the size of one pixel becomes approximately 1 mm, whereby the size of the discharge gap is restricted to at most approximately 500 μm. In the future, according to high resolution of the plasma display panel, the size of the pixel tends to be smaller, so that the method of increasing luminous efficiency by enlarging the discharge gap will reach the limits. In addition, according to the high resolution, a luminous area of the plasma display panel is reduced, so that deterioration of brightness is anticipated. Therefore, higher brightness and higher efficiency are necessary for high resolution.
The present invention is directed to solve the problems discussed above, and an object of the present invention is to provide a plasma display panel with high brightness and high luminous efficiency.

Plasma display panel including dielectric layer that does not cover part of a discharge gap

Matsushita Electric Industrial Co., Ltd.


An apparatus for cleaning hydraulic fluid includes a centrifugal fluid-spinning disk arranged in a housing, of which an upper portion forms a vapor chamber and a lower portion forms a fluid collecting basin. A vacuum pump is connected to the housing through an oil mist separator, such that water vapor is vacuumed away and hydraulic fluid collects in the oil mist separator to then be pumped away. The apparatus further includes preferably a single container that contains both the contaminated hydraulic fluid that is to be cleaned and the cleaned hydraulic fluid. A flexible inlet line and a flexible outlet line with respective hydraulic quick connectors are provided to connect the apparatus and particularly the oil container to a hydraulic system of an aircraft, for example. A high pressure pump connected to the outlet line pumps the cleaned hydraulic fluid into the aircraft hydraulic system and a pressure maintaining valve in the inlet line maintains the system pressure. The apparatus is embodied as a self-contained and self-sufficient mobile unit mounted on wheels. With this apparatus, the hydraulic fluid in the hydraulic system of an aircraft can be cleaned directly plane-side, and it is unnecessary to provide an exchange quantity of hydraulic fluid.

Hydraulic fluids used in the hydraulic systems of aircraft, for example, have the tendency to collect and become contaminated with various pollutants and damaging impurities, especially including water and corrosive substances dissolved therein. Such pollutants or contaminants can lead to damage, and particularly corrosion damage, within the respective corresponding hydraulic system in which the hydraulic fluid is used. Therefore, it is necessary that the hydraulic fluid used in such hydraulic systems must be replaced or cleaned to remove these contaminants at certain maintenance time intervals. For convenience, such hydraulic fluid is sometimes referred to simply as hydraulic oil herein.
In order to carry out such a cleaning of the hydraulic oil, stationary apparatus or equipment is typically used. As a consequence, it is necessary to remove from the respective hydraulic system the dirty or contaminated oil that is to be cleaned, carry the dirty oil to the cleaning apparatus located away from the respective hydraulic system, and then after the cleaning operation it is necessary to return the cleaned oil into the hydraulic system.
An apparatus of this known type is described in U.S. Pat. No. 4,604,109, the disclosure of which is incorporated herein by reference. An essential element in the known apparatus is a centrifugal disk arrangement that centrifugally spins the oil so that the water dissolved within the oil can again be extracted therefrom, while damaging particles are simultaneously removed from the oil by means of suitable filters. In the known apparatus, the dirty hydraulic fluid or oil that is to be cleaned is supplied to the centrifugal disk through a central supply arrangement. A vacuum pump is connected to the upper portion of the housing of the centrifugal disk arrangement, so as to evaporate, extract and suck-away water vapor out of the oil, while the bottom portion of the centrifugal disk housing forms a collecting basin for collecting the cleaned hydraulic fluid. Furthermore, the known apparatus includes one container for the contaminated or dirty hydraulic fluid that is to be cleaned, and one container for the cleaned hydraulic fluid.
In using the above described known apparatus for cleaning the hydraulic oil of an aircraft hydraulic system, it is necessary to constantly maintain or store a corresponding quantity of intact oil for carrying out an exchange of the oil, in order to avoid an undesirably long ground time of the aircraft while carrying out the oil cleaning operation. However, in carrying out such a process, a portion of the contaminated or dirty oil will always remain in the hydraulic cylinders of the corresponding hydraulic system, and can thus not be processed for cleaning. As a result, a certain quantity of contaminated oil, and the corresponding contaminants, remain in the hydraulic system of the aircraft even after the oil cleaning procedure has been completed. Moreover, as a further disadvantage, the known apparatus and the method of operating it are inconvenient because the necessary cleaning step cannot be carried out directly at or adjacent to the aircraft.

Apparatus for cleaning a hydraulic fluid


An absorption spectroscopy instrument with a light source for providing a beam of light, a modulator to produce a modulated beam of light, a high finesse optical cavity, means for injecting the modulated beam of light off-axis into the high finesse optical cavity and a detector positioned to receive and measure light exiting through said optical cavity. The detector may be a highly sensitive and high bandwidth detector. The modulator may be a one or two-tone modulator having means, such as a plurality of RF synthesizers, for modulating the light source by one or two tones. If one tone of applied modulation is used, the frequency is larger than the absorption bandwidth of the target chemical. In the case where two tones are used, the first frequency is larger than the absorption bandwidth of the target chemical and the second frequency is small relative to the first frequency.

1. Field of the Invention
The present invention relates to high sensitivity spectroscopy.
2. Brief Description of the Related Art
Sensitivity of spectroscopic detection is a crucial issue for applications where trace gas chemicals are to be measured. Atmospheric chemistry, environmental monitoring, biomedical diagnostics and molecular astrophysics are just a few examples of areas of research demanding for ultra-sensitive and rugged setups, capable of field measurements. See, for example, R. M. Mihalcea, M. E. Webber, D. S. Baer, R. K. Hanson, G. S. Feller, W. B. Chapman, "Diode-laser absorption measurements of CO2, H2O, N2O, and NH3 near 2.0 μm," Appl. Phys. B 67, 283-288 (1998); E. C. Richard, K. K. Kelly, R. H. Winkler, R. Wilson, T. L. Thompson, R. J. Mclaughlin, A. L. Schmeltekopf, A. F. Tuck, "A fast-response near-infrared tunable diode laser absorption spectrometer for in situ measurements of CH4 in the upper troposphere and lower stratosphere," Appl. Phys. B 75, 183-194 (2002); G. Gagliardi, R. Restieri, G. De Biasio, P. De Natale, F. Cotrufo, and L. Gianfrani, "Quantitative diode laser absorption spectroscopy near 2 μm with high precision measurements of CO2 concentration," Rev. Sci. Instrum. 72, 4228-4233 (2001); H. Dahnke, D. Kleine, W. Urban, P. Hering, M. Mürtz, "Isotopic ratio measurement of methane in ambient air using mid-infrared cavity leak-out spectroscopy," Appl. Phys. B 72, 121-125 (2001); L. Menzel, A. A. Kosterev, R. F. Curl, F. K. Tittel, C. Gmachl, F. Capasso, D. L. Sivco, J. N. Baillargeon, A. L. Hutchinson, A. Y. Cho, W. Urban, "Spectroscopic detection of biological NO with a quantum cascade laser," Appl. Phys. B 72, 1-5 (2001); H. Dahnke, D. Kleine, P. Hering, M. Mürtz, "Real-time monitoring of ethane in human breath using mid-infrared cavity leak-out spectroscopy," Appl. Phys. B 72, 971-975 (2001); and G. J. German, and D. J. Rokestraw, "Multiplex spectroscopy: determining the transition moments and absolute concentrations of molecular species," Science 264, 1750-1753 (1994); C. R. Webster, "measuring methane and its isotopes 12CH4, 13CH4 and CH3D on the surface of Mars with in situ laser spectroscopy," Appl. Opt. 44, 1226-1234 (2005).
In general, for most of spectroscopic methods, the Beer-Lambert law that underpins much of molecular absorption spectroscopy leaves two clear paths to improve the detection sensitivity: increasing the radiation/sample interaction pathlength and reducing the noise that affects the absorption signal.
With regard to the first, there are a number of well-established methods for absorption length enhancement, the most effective of which exploit the several-kilometers paths attainable in high finesse optical cavities. Techniques such as cavity ring-down spectroscopy (CRDS), cavity-enhanced absorption spectroscopy (CEAS) and integrated cavity output spectroscopy (ICOS), demonstrated minimum detectable absorption coefficients ranging from 10−8 cm−1 Hz−1/2 to 10−11 cm−1 Hz−1/2. See, D. Romanini, A. A. Kachanov, N. Sadeghi, and F. Stockel, "CW cavity ring down spectroscopy," Chem. Phys. Lett. 264, 316-322 (1997) and K. Nakagawa, T. Katsuda, A. S. Shelkovnikov, M. de Labachelerie, and M. Ohtsu, "Highly sensitive detection of molecular absorption using a high finesse optical cavity," Opt. Commun. 107, 369-372 (1994).
As for noise suppression, different strategies are usually adopted for the various optical and electronic noise components. For example, high speed ensemble averaging can reduce white noise of a detector and its associated electronics while antireflection coatings can suppress the optical noise that often limits the sensitivity of laser-based spectrometers.
Since the 1980's heterodyne detection schemes have been employed to suppress the technical 1/f (flicker) noise associated with all laser sources and most photodetectors. See, J. M Supplee, E. A. Whittaker, W. Lenth, Appl. Opt. 33, 6294 (1994); D. E. Cooper, J. P. Watjen, Opt. Lett. 11, 606 (1986); and G. C. Bjorklund, Opt. Lett. 5, 15 (1980). The general principle underlying these methods consists of modulating the laser current to produce a pair of sidebands on the laser carrier and, after interaction with the sample, detecting and demodulating their beat frequency by means of phase-sensitive electronics. In this way, a sample's absorption depth and linewidth are encoded at the modulation frequency, which can be set in the radiofrequency (RF) domain, where the flicker noise is reduced by a few orders of magnitude. Many variations of this basic heterodyne detection scheme have been successfully applied, providing in some cases sensitivity enhancements up to two orders of magnitude with respect to traditional laser spectroscopy. See, P. Werle, F. Slemr, M. Gehrtz, and C. Bräuchle: Appl. Phys. B 49, 99 (1989); J. A. Silver: Appl. Opt. 31, 707 (1992); and P. Werle: Spectrochim. Acta Part A 54, 197 (1998).
Additionally, in U.S. Pat. No. 6,795,190, a method and apparatus was disclosed in which a continuous wave light beam was introduced into a cavity using off-axis cavity alignment to systematically eliminate optical resonant noise commonly associated with optical cavities while preserving the absorption signal amplifying properties of such cavities.
The realization of a technique that combines the signal enhancement of cavity-based techniques with the noise suppression of a heterodyne detection scheme has proven non-trivial. It was addressed only in 1998 by Ye et al., with a technique called noise-immune cavity-enhanced optical-heterodyne molecular spectroscopy (NICE-OHMS). See, J. Ye, Long-Sheng Ma, and J. L. Hall, "Ultrasensitive detections in atomic and molecular physics: demonstration in molecular overtone spectroscopy" J. Opt. Soc. Am B 15, 6-15 (1998). In NICE-OHMS, the radiation injected in the optical resonator is modulated at a frequency that is a multiple of the cavity mode spacing (FSR), thus creating a couple of sidebands available at the cavity output. Then, the transmitted signal is heterodyned to retrieve information on the intracavity absorption. In this way, an unprecedented shot-noise limited detection sensitivity, as low as 10−14 cm−1 Hz−1/2 was demonstrated in the near infrared. However, in order to be transmitted by the cavity, both carrier and modulation sidebands must be constantly in resonance with three cavity modes. To achieve this condition, the cavity mode spacing or free spectral range (FSR) and the laser frequency need to be stabilized independently by means of tight, fast, and low-noise frequency-locking schemes. As a consequence, the setup is technically extremely demanding and particularly sensitive to mechanical shocks and vibrations. This makes the extraordinary high sensitivity reachable by NICE-OHMS only attainable in laboratory environments.

Heterodyne off-axis integrated cavity output spectroscopy

President and Fellows of Harvard College


A method and a base station for calibrating data transmitted by coordinated APs are disclosed. The method includes: a base station obtaining an uplink channel frequency-domain response and a downlink channel frequency-domain response between a first AP and a second AP which participate in coordination; the base station dividing the uplink channel frequency-domain response by the downlink channel frequency-domain response to obtain an uplink and downlink channel response difference between the first AP and the second AP; and the base station calibrating the data transmitted by the first AP and the second AP in coordination according to the uplink and downlink channel response difference. The method and base station in the embodiments of the present document are applied to calibrate the data transmitted by coordinated APs.

With the continuous improvements of people's requirements on future communications, more attention is paid to the spectrum efficiency of the cell edge, and how to improve the transmission quality and throughput of the cell edge become a research topic. The CoMP technique uses antennas of multiple APs for collaboration of transmission and reception, and one or more APs are set under one base station (cell). The coordinated multiple points in the CoMP may be multiple APs from one cell, or multiple APs from multiple cells, wherein, the cell includes a primary cell and coordinated cells of a terminal. The CoMP can effectively solve the problem of interference at the cell edge, so as to improve the capacity and reliability of the wireless link. Therefore, the CoMP technology, as a key technology, has been introduced into a Long Term Evolution-Advanced (LTE-A) system.
Under a Time Division duplex (TDD) mode of the CoMP system, a problem of antenna calibration between APs needs to be considered. After the antenna calibration is performed independently by the APs themselves, a reciprocity error may exist in an uplink-downlink radio frequency channel of the antenna of the AP, i.e., HDL=C*HUL, wherein, HDL and HUL are frequency-domain responses of a downlink channel and an uplink channel of the antenna of the AP respectively, and C is a complex scalar of an uplink-downlink channel reciprocity error. When Joint Transmission is performed on data between multiple coordinated APs, due to uplink-downlink channel reciprocity errors C of different APs are different, it will cause a phase difference and/or amplitude difference in the data transmitted by the coordinated APs, influence coherent transmission between the coordinated APs, and also influence the system performance. In order to reduce the phase difference and/or amplitude difference in the data transmitted by the coordinated APs, those skilled in the art propose a solution of calibrating transmission of data transmitted by coordinated APs in conjunction using an uplink-downlink channel response difference between the coordinated APs, but has not proposed a method for effectively calculating the uplink-downlink channel response difference between the coordinated APs.

Method for calibrating data sent by coordinated APs and base station


An information processing apparatus includes a plurality of controller modules capable of performing communications with each other, and a memory included in each controller module to be stored with status information reflecting a status of an error occurring during the communications with other controller modules with respect to the controller module of a communication partner apparatus and/or the controller module of the self-apparatus, wherein, when determining whether or not a fault occurs in a certain controller module in the plurality of controller modules, the controller module different from a determination target controller module determines, based on status information of the determination target controller module that is stored on the memories of two or more controller modules different from the determination target controller module, whether the fault occurs in the determination target controller module.

In the information processing apparatuses, there exist some apparatuses each including the plurality of controller modules capable of performing the communications with each other, in which if a certain controller module gets into a fault, the operation continues by detaching this controller module from other portions. This type of information processing apparatus is configured so that normally one module (the controller module or a status monitoring module) determines (decides) which component (a controller module, a circuit in the controller module, etc) gets into the fault. In the apparatus in which one module determines whether each component gets into fault or not, however, if this module falls into the fault, such situations occur that "the actually normal component is erroneously determined to have the fault and is then detached" and "the apparatus does not normally function because the failure component is not detached". Therefore, such an information processing apparatus (which will hereinafter be referred to as a conventional apparatus) has been developed that each of the plurality of controller modules monitors a status of each component, and a specified controller module determines, based on the monitoring results of the whole controller modules, which component is the failure component.

Information processing apparatus and operation status monitoring method


An apparatus for use in total knee arthroplasty includes a tibia engaging plate which is coupled to an upstanding rack member, a drill bushing bracket coupled to the rack member by a lockable pinion member, and a femoral positioning jig which is rotatably coupled to the drill bushing bracket. The drill bushing bracket has a pair of spaced apart drill bushings which are dimensionally located to correspond in position to medial and lateral condyles of the femur. The centers of the drill bushings lie in a plane which is parallel to the plane in which the tibia engaging plate lies. The femoral positioning jig is provided with a pair of posterior skids, one for the lateral posterior condyle and one for the medial posterior condyle, a pair of holes for attaching the jig to the resected distal femur with spikes, and a pair of holes for receiving the two drill bushings. Two different femoral positioning jigs are provided, one for the right knee and one for the left knee. In both jigs, the hole for receiving the medial drill bushing is circular and the hole for receiving the lateral drill bushing is oblong or kidney shaped. This allows the positioning jig (and the femur) to rotate about the axis of the medial drill bushing. The positioning jigs are also each provided with angular indicia adjacent the lateral oblong hole and the drill bushing bracket is provided with left and right indicia indicating the axial center of each drill bushing.

1. Field of the Invention
The invention relates to surgical apparatus. More particularly, the invention relates to an apparatus for determining the degree of femoral rotation in flexion and for accurately locating a cutting block for resection of the medial and lateral posterior femoral condyles as well as a method for using the apparatus.
2. Description of the Related Art
Total knee arthroplasty involves the replacement of portions of the patellar, femur and tibia with artificial components. In particular, a proximal portion of the tibia and a distal portion of the femur are cut away (resected) and replaced with artificial components. In order to properly place the artificial components, the femur and tibia must be resected in a relatively precise manner so that the artificial knee is balanced throughout its range of motion. Modern knee prostheses are now designed to ensure that so long as the prosthetic knee is balanced in the flexion (90 degrees) and extension (0 degrees) positions, it will function properly throughout its full range of motion.
It is normal for a natural knee to exhibit irregular alignment due to soft tissue differences in the medial and lateral compartments. Differences in the soft tissue, e.g. collateral ligaments, will allow a certain degree of outward (valgus) rotation of the femur relative to the tibia when the knee is in flexion and will allow a certain degree of inward (varus) bending of the tibia and valgus bending of the femur when the knee is in extension. If the artificial knee is not balanced to compensate for these variations in collateral ligaments, it will wear excessively on one condyle, the components may loosen, and most importantly, the patient will experience discomfort.
The traditional methods used to balance the knee relied primarily on x-rays and the surgeon's own senses. Imbalance in the knee when the knee is in extension may be accurately ascertained by x-ray examination. However, imbalance during flexion cannot be ascertained by x-ray examination because the collateral ligaments are contracted during flexion. Traditionally, imbalance during flexion was estimated by visual inspection and palpation of the ligaments during surgery. More recently, various tools referencing bony landmarks have been made available to aid the surgeon in determining the amount of imbalance when the knee is in flexion.
According to an exemplary state of the art procedure, the natural knee is first examined in extension. The potential varus/valgus conditions are assessed with the aid of an x-ray prior to performing the distal femoral and proximal tibial resection. Cutting blocks are attached to the femur and the tibia with drill pins and the proximal tibia and distal femur are resected using either classical or anatomic alignment methods.
The difference in the two alignment approaches is due to a difference in opinion among specialists. The objective of classical alignment is to create a prosthetic joint line which is perpendicular to the reconstructed mechanical axis of the joint. Classical alignment specifies a neutral tibial cut of 0 degrees varus and a valgus femoral cut of 5 degrees-7 degrees. The objective of anatomic alignment is to reproduce a joint line which is parallel to the ground with a normal gait pattern. Anatomic alignment specifies a tibial cut which is made in a plane having a varus angle of 2 degrees-3 degrees and a valgus femoral cut of 7 degrees-9 degrees. Resecting at these respective angles assures that the resected distal femoral condyles lie in a plane which is parallel to the resected proximal tibial surface when the knee is in extension.
The procedures used to balance the knee in the flexion position are more difficult and less accurate than the procedures for balancing in the extension position. In order to balance the knee in flexion, the posterior femoral condyles must be resected so that they lie in a plane which is parallel to the resected proximal tibial surface when the knee is in flexion and the surrounding soft tissues are in balance. Some presently used procedures include referencing the angle of the posterior condylar resection to the classical or anatomic alignment modes used in extension balancing, resecting the condyles parallel to the epicondylar axis, or parallel to the posterior condylar axis.
The angle of resection is measured relative to the center of the two condyles using a jig which has two posterior skids which are placed under the posterior condyles and which orients the jig at 0 degrees rotation relative to the coronal plane of the femur. Drill holes in the jig (or drill bushings attached to the jig) reference an angle of rotation of the femur. The drill holes are used to drill into the resected distal end of the femur so that a cutting block may be attached at a selected angle for resecting the posterior condyles.
None of these procedures accounts for the presence of soft tissues and ligamentous structures. The presence of these tissues and structures tends to negate the assumed correlation between extension balancing and flexion balancing. In particular, the posterior capsule and surrounding soft tissues, which are taut when the knee is in extension, collapse or become laxed when the knee is in flexion and therefore have more significant impact on flexion balance. While the amount of error in flexion balancing due to the presence of these tissues and structures may only amount to a few degrees, it is enough to result in a significant imbalance in the prosthetic knee.
In order to accurately assess the impact of soft tissues on the balance of the knee in flexion, it is necessary to tension the tissues. Several tensioning devices are known in the art which allow the surgeon to spread the femur and tibia apart so that the collateral ligaments may be inspected when the knee is in flexion. Generally, it is found that the medial ligaments are either shorter or have greater tensile strength than the lateral ligaments which results in a valgus rotation of the femur. Most of the known tensioning devices do not provide any means for measuring the degree of rotation and this determination is made with the surgeon's own senses. If it appears that there is a valgus rotation of more than 3 degrees, the surgeon may elect to partially release the medial ligaments which tends to lessen the amount of rotation. If it appears that the amount of rotation is less equal to or less than three degrees, the ligaments are generally left untouched. If it appears that the amount of rotation, according to the indicia, is in a negative range (less than 0 degrees) the surgeon may elect to release the lateral soft tissues until the femur is in an acceptable range of internal rotation (0 to 3 degrees) In any case, the posterior condyles are then resected using a drill jig and cutting block as described above.
U.S. Pat. No. 5,468,244 to Attfield et al. discloses a tensioning device which includes a means for measuring the amount of femoral rotation when the knee is in flexion with the ligaments tensioned. Generally, the device has a tibial engaging plate and a pivoting femoral engaging plate. The plates are arranged between the tibial plateau and the posterior condyles of the femur. The plates are displaced relative to each other and the femoral engaging plate rotates about a central axis in response to femoral rotation. A scale is provided to indicate the angle of rotation of the femoral engaging plate.
The Attfield et al. device is useful in assessing the amount of femoral rotation, but it is not entirely accurate. In particular, the instrument is imprecise because it measures femoral rotation about an axis which lies between the medial and lateral condyles. In reality, the internal (valgus) rotation of the femur is not about a centrally located axis, but is about an axis closer to the medial condylar compartment. In addition, the device provides no assistance in mounting or choosing a cutting block for posterior condyle resection.

Surgical apparatus for use in total knee arthroplasty and surgical methods for using said apparatus


Novel compounds having the Formulas 1 through 8, wherein the symbols have the meaning defined in the specification, and certain previously known compounds have been discovered to act as inhibitors of the cytochrome P450RAI (retinoic acid inducible) enzyme, and are used for treating diseases responsive to treatment by retinoids. The compound can also be used in co-treatment with retinoids.

1. Field of the Invention
The present invention is directed to providing, preparing and using compounds which inhibit the enzyme cytochrome P450RAI. More particularly, the present invention is directed to selecting and preparing compounds which inhibit the enzyme cytochrome P450RAI, many of which are derivatives of phenylacetic or heteroarylacetic acid, and using said compounds for treatment of diseases and conditions which are normally treated by retinoids.
2. Background Art
Compounds which have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. In other words, it is generally accepted in the art that pharmaceutical compositions having a retinoid-like compound or compounds as the active ingredient are useful as regulators of cell proliferation and differentiation, and particularly as agents for treating skin-related diseases, including, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. Retinoid compounds are also useful for the prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. In addition, retinoid compounds can be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoid compounds include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis. Retinoid compounds have relatively recently been also discovered to be useful for treating type II non-insulin dependent diabetes mellitus (NIDDM).
Several compounds having retinoid-like activity are actually marketed under appropriate regulatory approvals in the United States of America and elsewhere as medicaments for the treatment of several diseases responsive to treatment with retinoids. Retinoic acid (RA) itself is a natural product, biosynthesized and present in a multitude of human and mammalian tissues and is known to play an important rule in the regulation of gene expression, tissue differentiation and other important biological processes in mammals including humans. Relatively recently it has been discovered that a catabolic pathway in mammals, including humans, of natural retinoic acid includes a step of hydroxylation of RA catalyzed by the enzyme Cytochrome P450RAI (retinoic acid inducible).
Several inhibitors of CP450RAI have been synthesized or discovered in the prior art, among the most important ones ketoconazole, liarozole and R116010 are mentioned. The chemical structures of these prior art compounds are provided below. It has also been noted in the prior art, that administration to mammals, including humans, of certain inhibitors of CP-450RAI results in significant increase in endogeneous RA levels, and further that treatment with CP450RAI inhibitors, for example with liarozole, gives rise to effects similar to treatment by retinoids, for example amelioration of psoriasis.
The following publications describe or relate to the above-summarized role of CP450RAI in the natural catabolism of RA, to inhibitors of CP-450RAI and to in vitro and in vivo experiments which demonstrate that inhibition of CP450RAI activity results in a increases endogeneous RA levels and potential therapeutic benefits:
Kuijpers, et al., xe2x80x9cThe effects of oral liarozole on epidermal proliferation and differentiation in severe plaque psoriasis are comparable with those of acitretinxe2x80x9d, British Journal of Dermatology, (1998) 139: pp 380-389.
Kang, et al., xe2x80x9cLiarozole Inhibits Human Epidermal Retinoid Acid 4-Hydroxylase Activity and Differentially Augments Human Skin Responses to Retinoic Acid and Retinol In Vivoxe2x80x9d, The Journal of Investigative Dermatology, (August 1996) Vol. 107, No. 2: pp 183-187.
Van Wauwe, et al., xe2x80x9cLiarozole, an Inhibitor of Retinoic Acid Metabolism, Exerts Retinoid-Mimetic Effects in Vivoxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1992) Vol. 261, No 2: pp 773-779.
De Porre, et al., xe2x80x9cSecond Generation Retinoic Acid Metabolism Blocking Agent (Ramba) R116010: Dose Finding in Healthy Male Volunteersxe2x80x9d, University of Leuven, Belgium, pp 30.
Wauwe, et al., xe2x80x9cKetoconazole Inhibits the in Vitro and in Vivo Metabolism of All-Trans-Retinoic Acidxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, (1988) Vol. 245, No. 2: pp 718-722.
White, et al., xe2x80x9ccDNA Cloning of Human Retinoic Acid-metabolizing Enzyme (hP450RAI) Identifies a Novel Family of Cytochromes P450 (CYP26)*xe2x80x9d, The Journal of Biological Chemistry, (1997) Vol. 272, No. 30, Issue of July 25 pp 18538-18541.
Hanzlik, et al., xe2x80x9cCyclopropylamines as Suicide Substrates for Cytochromes P450RAIxe2x80x9d, Journal of Medicinal Chemistry (1979), Vol. 22, No. 7, pp 759-761.
Ortiz de Montellano, xe2x80x9cTopics in Biologyxe2x80x94The Inactivation of Cytochrome P450RAIxe2x80x9d, Annual Reports in Medicinal Chemistry, (1984), Chapter 20, pp 201-210.
Hanzlik, et al. xe2x80x9cSuicidal Inactivation of Cytochrome P450RAI by Cyclopropylamines greater than  Evidence for Cation-Radical Intermediatesxe2x80x9d, J. Am. Chem. Soc., (1982), Vol. 104, No. 107, pp. 2048-2052.
In accordance with the present invention several previously known and several new compounds are utilized as inhibitors of CP450RAI to provide therapeutic benefit in the treatment or prevention of the diseases and conditions which respond to treatment by retinoids and or which in healthy mammals, including humans, are controlled by natural retinoic acid. The perceived mode of action of these compounds is that by inhibiting the enzyme CP450RAI that catabolyzes natural RA, endogenous RA level is elevated to a level where desired therapeutic benefits are attained. The chemical structures of certain previously known compounds which have been discovered to be inhibitors of the enzyme CP450RAI are provided in the descriptive portion of this application for patent. The chemical structures of the novel compounds which are used in the methods of treatment in accordance with the invention are summarized by Formulas 1 through 8 in the Summary Section of this application for patent. Based on these chemical structures the following art is of interest as background to the novel structures.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,089,509; 5,616,712; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,015,658; 5,130,335; 4,740,519; 4,826,984; 5,037,825; 5,466,861; WO 85/00806; EP0 130,795; DE 3316932; DE 3708060; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 1.
U.S. Pat. Nos. 5,965,606; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 4,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP 0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press Inc., 1990, pages 324-356; are of interest to compounds of Formula 2.
Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; is of interest to compounds of Formula 3.
U.S. Pat. Nos. 5,965,606; 5,773,594; 5,675,024; 5,663,347; 5,023,341; 5,264,578; 5,089,509; 5,149,705; 5,130,335; 4,740,519; 4,826,969; 4,833,240; 5,037,825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP0 098 591; EP0 170 105; EP0 176 034; EP0 253,302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP0 661 259; DE 3316932; DE 3602473; DE 3715955; UK application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37, 1508-1517; Graupner et al. Biochem. and Biophysical Research Communications, (1991), 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 4.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwent JP6072866; Dawson, et al xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 5.
U.S. Pat. Nos. 5,965,606; 6,025,388; 5,534,641; 5,663,357; 5,013,744; 5,326,898; 5,202,471; 5,391,753; 5,434,173; 5,498,795; 4,992,468; 5,723,028; 4,855,320; 5,563,292; WO 85/04652; WO 91/16051; WO 92/06948; EP0 170 105; EP0 286 364; EP0 514 269; EP0 617 020; EP0 619 116; DE 3524199; Derwert JP6072866; Dawson, et al xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 6.
U.S. Pat. Nos. 6,048,873; 5,663,347; 5,045,551; 5,023,341; 5,739,338; 5,264,578; 5,089,509; 5,616,712; 5,399,561; 4,826,984; 5,037,825; EP0 130 795; DE 3316932; Dawson, et al. xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 7.
U.S. Pat. Nos. 5,965,606; 5,998,471; 5,773,594; 5,675,024; 5,663,347; 5,045,551; 5,023,341; 5,264,578; 5,134,159; 5,346,895; 5,346,915; 5,149,705; 5,399,561; 4,980,369; 5,130,335; 4,326,055; 4,539,154; 4,740,519; 4,826,969; 4,826,984; 4,833,240; 5,037,825; 5,466,861; 5,559,248; WO 85/00806; WO 92/06948; WO 95/04036; WO 96/05165; EP0 098 591; EP0 130 795; EP0 176 034; EP0 253 302; EP0 303 915; EP0 514 269; EP0 617 020; EP0 619 116; EP0 661 259; DE 3316932; DE 3602473; DE 3708060; DE 3715955; U.K. application GB 2190378; Eyrolles et al., J. Med. Chem., (1994), 37 1508, 1517; Graupner et al., Biochem. and Biophysical Research Communications, (1991) 1554-1561; Kagechika, et al., J. Med. Chem., (1988), 31, 2182-2192; Dawson, et aL xe2x80x9cChemistry and Biology of Synthetic Retinoidsxe2x80x9d, published by CRC Press, Inc., (1990), pages 324-356; are of interest to compounds of Formula 8.
Prior art which is of interest as background to the previously known compounds that have been discovered in accordance with the present invention to be inhibitors of cytochrome P450RAI, is identified together with the identification of these known compounds.
In accordance with the present invention novel compounds of Formulas 1 through 8 are used as inhibitors of the enzyme cytochrome P450RAI to treat diseases and conditions which are normally responsible to treatment by retinoids, or which are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism""s naturally occurring retinoic acid. These novel compounds are shown by Formulas 1
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94;
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 2;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 2
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons or benzyl;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 4;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 4;
R5 is H, alkyl of 1 to 6 carbons, fluorosubstituted alkyl of 1 to 6 carbons, benzyl, or lower alkyl or halogen substituted benzyl;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 1 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 4
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X1 is 1-imidazolyl, or lower alkyl or halogen substituted 1-imidazolyl, OR, SR, NRR6 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
R6 is H, lower alkyl, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, with the proviso that when Y is H, A is phenyl and X1 is OH then n is 1 to 4.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 5
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X is O, S or NR where R is H, alkyl of 1 to 6 carbons, C1-6-trialkylsilyl or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons or lower alkyl substituted cycloalkyl of 1 to 6 carbons;
n is an integer having the values of 1 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 6
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X2 is 1-imidazolyl, lower alkyl or halogen substituted 1-imidazolyl, OR7, SR7 or NRR7 where R is H, alkyl of 1 to 6 carbons or benzyl;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 3;
R7 is H, alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons or C1-6-trialkylsilyl.
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 7
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
Y is H, alkyl of 1 to 10 carbons, benzyl, lower alkyl or halogen substituted benzyl, fluoro-substituted alkyl of 1 to 10 carbons, cycloalkyl of 3 to 6 carbons, lower alkyl substituted cycloalkyl of 3 to 6 carbons, F, Cl, Br, or I;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
p is an integer having the values of 0 to 5;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base.
The novel compounds used in the method of treatment of the present invention are also shown in Formula 8
wherein
A is a phenyl or naphthyl group, or heteroaryl selected from a group consisting of pyridyl, thienyl, furyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, imidazolyl and pyrrazolyl, said phenyl and heteroaryl groups being optionally substituted with one or two R2 groups;
X3 is S, or O, C(R1)2, or CO;
Y1 is H, lower alkyl of 1 to 6 carbons, cycloalkyl of 3 to 6 carbons, benzyl, lower alkyl substituted cycloalkyl of 3 to 6 carbons;
Z is
xe2x80x94Cxe2x89xa1Cxe2x80x94,
xe2x80x94(CR1xe2x95x90CR1)nxe2x80x2
where nxe2x80x2 is an integer having the value 1-5,
xe2x80x94COxe2x80x94NR1xe2x80x94,
NR1xe2x80x94COxe2x80x94,
xe2x80x94COxe2x80x94Oxe2x80x94,
xe2x80x94Oxe2x80x94COxe2x80x94,
xe2x80x94CSxe2x80x94NR1xe2x80x94,
NR1xe2x80x94CSxe2x80x94,
xe2x80x94COxe2x80x94Sxe2x80x94,
xe2x80x94Sxe2x80x94COxe2x80x94,
xe2x80x94Nxe2x95x90Nxe2x80x94;
R1 is independently H or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, alkoxy of 1 to 6 carbons, or alkylthio of 1 to 6 carbons;
R3 is independently alkyl of 1 to 6 carbons, F, Cl, Br, I, CF3, fluoro substituted alkyl of 1 to 6 carbons, OH, SH, alkoxy of 1 to 6 carbons, alkylthio of 1 to 6 carbons or benzyl;
m is an integer having the values 0 to 2;
R4 is independently H, alkyl of 1 to 6 carbons, or F; fluorosubstituted alkyl of 1 to 6 carbons, or halogen;
o is an integer having the values of 0 to 4;
n is an integer having the values of 0 to 4, and
R8 is H, alkyl of 1 to 6 carbons, xe2x80x94CH2O(C1-6-alkyl), or a cation of a pharmaceutically acceptable base, the compound meeting at least one of the provisos selected from the group consisting of:
Y1 is cycloalkyl,
when Y1 is not cycloalkyl then X3 is O or S and n is 1,
when Y1 is not cycloalkyl then X3 is CO, and n is 1,
when Y1 is not cycloalkyl then X3 is CO and the moiety A is substituted with at least one F group.
In accordance with the invention the novel compounds of Formula 1 through Formula 8 as well as the previously known compounds disclosed below in the specification are used for the prevention or treatment of diseases and conditions in mammals, including humans, those diseases or conditions that are prevented, treated, ameliorated, or the onset of which is delayed by administration of retinoid compounds or by the mammalian organism""s naturally occurring retinoic acid. Because the compounds act as inhibitors of the breakdown of retinoic acid, the invention also relates to the use of the compounds of Formula 1 through Formula 8 in conjunction with retinoic acid or other retinoids. In this regard it is noted that retionoids are useful for the treatment of skin-related diseases, including, without limitation, actinic keratoses, arsenic keratoses, inflammatory and non-inflammatory acne, psoriasis, ichthyoses and other keratinization and hyperproliferative disorders of the skin, eczema, atopic dermatitis, Darriers disease, lichen planus, prevention and reversal of glucocorticoid damage (steroid atrophy), as a topical anti-microbial, as skin anti-pigmentation agents and to treat and reverse the effects of age and photo damage to the skin. The retinoids are also useful for the prevention and treatment of metabolic diseases such as type II non-insulin dependent diabetes mellitus (NIDDM) and for prevention and treatment of cancerous and precancerous conditions, including, premalignant and malignant hyperproliferative diseases such as cancers of the breast, skin, prostate, cervix, uterus, colon, bladder, esophagus, stomach, lung, larynx, oral cavity, blood and lymphatic system, metaplasias, dysplasias, neoplasias, leukoplakias and papillomas of the mucous membranes and in the treatment of Kaposi""s sarcoma. Retinoids can also be used as agents to treat diseases of the eye, including, without limitation, proliferative vitreoretinopathy (PVR), retinal detachment, dry eye and other corneopathies, as well as in the treatment and prevention of various cardiovascular diseases, including, without limitation, diseases associated with lipid metabolism such as dyslipidemias, prevention of post-angioplasty restenosis and as an agent to increase the level of circulating tissue plasminogen activator (TPA). Other uses for retinoids include the prevention and treatment of conditions and diseases associated with human papilloma virus (HPV), including warts and genital warts, various inflammatory diseases such as pulmonary fibrosis, ileitis, colitis and Krohn""s disease, neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and stroke, improper pituitary function, including insufficient production of growth hormone, modulation of apoptosis, including both the induction of apoptosis and inhibition of T-Cell activated apoptosis, restoration of hair growth, including combination therapies with the present compounds and other agents such as MinoxidilR, diseases associated with the immune system, including use of the present compounds as immunosuppressants and immunostimulants, modulation of organ transplant rejection and facilitation of wound healing, including modulation of chelosis.
This invention also relates to a pharmaceutical formulation comprising one or more compounds of Formula 1 through Formula 8 or one or more of the previously known compounds disclosed below in the specification, in admixture with a pharmaceutically acceptable excipient, said formulation being adapted for administration to a mammal , including a human being, to treat or alleviate the conditions which were described above as treatable by retinoids, or which are controlled by or responsive to the organism""s native retinoic acid. These formulations can also be co-administered with retinoids to enhance or prolong the effects of medications containing retinoids or of the organism""s native retinoic acid.
The present invention also relates to a method of providing a compound which is an inhibitor of the enzyme cytochrome P450RAI, wherein the method of providing the cytochrome P450RAI inhibitory compound comprises:
identifying a compound that has activity as a retinoid in any of the art recognized assays which demonstrate retinoid-like activity, the retinoid compound having a formula such that it includes a benzoic acid, benzoic acid ester, naphthoic acid, naphthoic acid ester or heteroaryl carboxylic acid or ester moiety, with a partial structure of xe2x80x94A(R2)xe2x80x94(CH2)nxe2x80x94COOR8 where the symbols are defined as in Formulas 1 through 8, and where n is 0, and
selecting a compound that is a homolog of the previously identified retinoid compound where in the formula of the homolog n is 1 or 2, preferably 1. Said homolog, if it is not a previously known compound can be prepared by homologation procedures well known to the synthetic organic chemist, such as for example the well known Arndt-Eistert synthesis. Alternatively, said homologs can be prepared by any of the applicable synthetic processes illustrated below for the preparation of the novel compounds of Formulas 1 through 8 wherein the symbol n represents the integral 1 (one).

Methods of providing and using compounds having activity as inhibitors of cytochrome P450RAI


Real time correction to ground generated satellite ephemeris implements a reference trajectory management module (334), an error estimation module (336), an parameter calculation module (338) and a position information management module (340). The reference trajectory management module (334) accesses reference trajectory data such as ground generated ephemeris data which is uplinked to a spacecraft through a communications unit (312). The position information management module (340) accesses and interprets position information such as Global Positioning System (GPS) measurement data to provide measured spacecraft positions. The parameter calculation module (338) calculates spacecraft position and velocity from the reference trajectory data. The error estimation module (336) compares the measured and calculated positions to provide a position difference, smoothes the position difference to filter anomalous data, and provides a correction term for the determination of corrected spacecraft orbital parameters such as position and velocity. The time rate of change of the correction term may be used to provide additional correction to the orbital parameters.

The competing needs for accuracy and reduced computational overhead have presented problems in orbital parameter determination. Traditionally, either ephemeris data or information supplied by position measuring satellites have been independently used to determine orbital parameters such as spacecraft position and velocity.
Ephemeris data may be a tabulation of estimated orbital object positions at discrete instants in time which are used as a reference trajectory for predicting orbital parameters such as position and velocity. A large number of measurements and very sophisticated models can gene rate an extremely accurate ephemeris, but the computational overhead required for such accuracy makes it impractical to store it aboard orbital objects such as spacecraft. Additionally, even the most accurate ephemeris progressively loses accuracy with time because the forces influencing orbital motion are not precisely known. Specifically, unpredicted changes in the orbital perriod due to factors including atmospheric drag fluctuation tend to significantly affect the in-track component of reference trajectories.
Position information may also be used to determine orbital parameters. For example, a Global Positioning System ("GPS") receiver may be used to determine spacecraft position from signals transmitted from GPS satellites to the GPS receiver. Accuracy is adversely affected by factors such as the position and orientation of the spacecraft relative to the GPS constellation of satellites, GPS constellation position and timing errors, signal propagation errors, and internal receiver noise and timing errors. Additionally, GPS receivers are subject to Selective Availability ("S/A") which intentionally degrades signals and adds GPS satellite position and constellation timing errors. Each of these factors can cause positional error spikes in the position information.
Spacecraft position determination based solely upon GPS receiver outputs is also deficient because data output rates (typically 1 per second) are often too slow for spacecraft maneuvering. Additionally, GPS position estimates may not be available during maneuvers since GPS availability depends upon the antenna location and orientation of the spacecraft.
Sophisticated processes for GPS error correction such as those using full orbital state and Kalman filtering may be impractical because the extent of data collection, complex software and high precision arithmetic operations require high computational overhead and may prevent real-time processing. Additionally, such processes remain adversely affected by S/A errors since such errors are very difficult to predict.
Thus, there remains a need for real time orbital parameter determination with low computational overhead, high accuracy and S/A error mitigation.

Real time position correction to ground generated spacecraft ephemeris


A spindle which can be used by using the two-channel minimal quantity lubrication. The feeding of the lubricating oil is done by way of a central oil tube which is rotationally fixedly joined to a fixed base piece and which is radially supported on the revolving spindle in the radial direction by way of at least one pivot bearing.

Two channel minimal quantity lubrication (MQL) devices are known, in which in the vicinity of the point of contact between a tool such as a drill bit and a workpiece a mixture of air and lubricant is produced, which contains a very low proportion of lubricant. Such an MQL device may be inferred for example from DE 196 55 334 B4.
In this known MQL device the lance unit rotates with the spindle, thereby necessitating a high-precision and costly rotary coupling at the rear end of the lance unit because spindles in modern machining centres rotate at up to 20,000 rpm and fluids are to be handled at pressures of 8 bar and more.
The present invention is directed to providing a device that addresses these and other matters.

Lance unit and spindle comprising the same


A process for reducing the pressure buildup in an automobile radiator which contains a bottom section, a radiator header, a multiplicity of tubes extending between the bottom section and the radiator header, and a heat expansion chamber disposed at least about 0.5 inches above the radiator header and connected to the radiator header by a conduit. In this process, hot fluid containing antifreeze at a temperature of at least about 200 degrees Fahrenheit is flowed through the radiator tube; but hot fluid flow into the heat expansion chamber is prevented. The heat expansion chamber is made from a material with a resistivity at 20 degrees Centigrade greater than about 6 microhoms-centimeters; and the material within the heat expansion chamber has a resistivity at 20 degrees Centigrade of from about 6 to about 40 microhms-centimeters.

Automobile radiators are well known to those skilled in the art. By way of illustration, reference may be had to U.S. Pat. Nos. 5,329,982, 5,279,157, 5,186,246, 5,181,554, 4,896,718, 4,343,353, 4,036,288, and the like. The disclosure of each of these United States patents is hereby incorporated by reference into this specification.
The normal automobile radiator, in use, experiences a substantial amount of pressure buildup and contact with hot liquid under pressure. Because of this exposure to high-temperature and pressure conditions, such radiators, and their components (such as, e.g., radiator hoses, gaskets), often fail.
It is an object of this invention to provide an improved radiator system with increased durability for both the radiator and its component parts. It is another object of this invention to provide a process for using this improved radiator system.

Process for reducing pressure within a liquid filled container


A tracking control method includes obtaining a tracking parameter of a target object. The tracking control method also includes determining a characteristic part of the target object based on the tracking parameter. The tracking control method further includes tracking the target object based on the characteristic part.

In tracking strategies of currently available aircrafts, in order to track a target object having prominent characteristics, typically, during the process of tracking a characteristic part (e.g., human face) of the target object, because the distance between the aircraft and the target object is changing, the dimensional proportion of the tracking frame of the target object in the captured image may also change. As a result, the tracking effect may be affected. For example, when tracking a same characteristic part of the target object, and when the distance between the aircraft and the target object becomes closer, the dimensional proportion of the tracking frame of the target object in the captured image is relatively large (e.g., 10%), which may reduce the tracking speed, which in turn tends to cause the loss of tracking of the target object. In the meantime, the robustness of the tracking control is reduced. When the distance between the aircraft and the target object becomes farther, the dimensional proportion of the tracking frame of the target object in the captured image is relatively small (e.g., 5%), which may cause the characteristics of the tracked target object to become blurry, and reduce the robustness of the tracking control.
Therefore, using the currently available tracking strategies to track the target object tends to cause loss of tracking of the target object. In addition, the robustness of the tracking control is poor.

Tracking control method, device, and aircraft