A pipeline leak detection and location range determination system includes a set of monitoring devices installed at ends of segments of a pipeline, and server computer system communicating with the set of monitoring devices over the Internet. The server computer system is also adapted to communicate with client computer systems over the Internet. Each monitoring device within the set includes a set of sensors for reading time-varying signals, including pressure, of the pipeline, and communicates the time-varying signals and corresponding timestamps to the server computer system. The server computer system analyzes such data using regression to derive a range of possible locations of a leak in the pipeline. A probability distribution corresponding to subranges within the range is also determined. The server computer system communicates the range and probability distribution to client computer systems for being presented to pipeline maintenance professionals.

Pipelines are used to transport materials, such as gas, oil and water. A pipeline includes a plurality of connected pipe segments. Valves are oftentimes deployed along a pipeline to manage the flow of the materials running through the pipeline. Damage to a pipe segment, can cause a leak, which may be very detrimental to the environment, surrounding properties, and human beings since the flowing mass can be flammable or toxic. A leak also leads to significant economic loss.
To improve the transmission efficiency, compressor stations are oftentimes deployed along a pipeline. The compressor/pump stations pressurize the liquid (such as oil, water, liquid chemicals, etc.) or gas materials (collectively referred to herein as flowing materials) to increase the flow. The increased pressure imparts considerable kinetic energy to the moving mass within the pipeline. With even a small leak in the pipeline, the high pressure would make the leak significantly more detrimental to the environment, surrounding properties, and human beings. The high pressure would also cause significantly more economic loss.
The transmission pipelines are usually buried underground and exposed to corrosion by water and other materials. When installed above the ground, the pipelines are still exposed to the risk of damages by the natural events, human activities, corrosion by rainwater and moisture, and other factors. Pipelines are thus coated with external insulation. However, the insulation layer sometimes is compromised for various reasons. A breach to the insulation layer exposes a metal pipe segment to metallic corrosion. In addition, pipe segments are also gradually weakened by internal corrosion from active electrolytes in the flowing mass.
It is desirable to reduce the impact of any leak by prompt detection of the leak, determine the characteristics of the leak, such as the time of the leak, the location of the leak, etc. Certain methods have been proposed for detecting pipeline leaks. However, the conventional methods are not desirable for different reasons. For example, they rely upon pressure differential tests using Supervisory Control and Data Acquisition ("SCADA") or Highway Addressable Remote Transducer ("HART") industrial communication protocol-based pressure and velocity monitors that provide limited data obtained at slow time intervals. Though the conventional method provides a limited solution to situations with slowly changing pressure, they are not adequate to process, or even detect faster transient pressure waves generated by abrupt leaks to pipelines. Typically, the pressure drop due to a leak lasts less than 0.1 second. A data acquisition system with a sampling rate less than 60 Hz, or 60 samples per second, would not provide sufficient information to characterize the changing pressure.
The conventional methods can also rely on wavelet transformation. These conventional methods endeavored to identify a specific location of the leak. However, due to inaccuracy in the signal detection and the leak location estimation methods, the identified leak location is oftentimes not accurate. The wrong localization of the leak in a pipeline further delays any remedies to the leak.
A prompt and accurate determination of the location of the actual leak is thus highly desirable. Accordingly, there is a need for new and improved system and method for detecting remote pipeline leaks. It is desirable for the system and method to identify a range of possible locations of the leak and associate a probability with each subrange within the range. In addition, the new system and method needs to capture pipeline pressure data at high sampling rate to detect leaks in pipelines with fast changing pressure. Dynamic and static leak detection methods are further desired. The new system and the new methods are also desired to detect leaks on other types of metallic structures.

System and method for determining range of possible locations of pipeline leak


The present disclosure provides systems and methods for in-line thermal flattening and enameling of steel sheets. The systems and methods include an in-line thermal flattening of a feed stock steel sheet and a subsequent enamel coating of the steel sheet. The resulting enamel coated steel sheet has improved flatness compared with other coated steel sheets that are enamel coated but do not undergo the in-line thermal flattening. The systems and methods allow the use of less expensive source materials without sacrificing quality in the finished enameled product.

Certain steel vitreous enameling procedures require highly stress-relieved and extremely flat starting material in order to achieve a final coated product that has minimal deviation from flatness. One such enameling procedure is a two-step, two-fire porcelain enameling process. It is difficult to determine prior to the enameling whether a starting material has sufficient stress relief and flatness to achieve the desired minimal deviation. Historically, cold rolled commercial steel that has been batch annealed has produced coated products with deviations from flatness that have exceeded needs. The solution to this problem has historically been to source continuously-annealed steel, which comes at a significantly increased cost.
Typical methods for correcting a lack of flatness in batch-annealed steel include temper rolling, roller leveling, tension leveling, and stretch leveling.
Temper rolling is primarily aimed at hardening annealed steel and removing yield-point elongation (kinking), but it has the secondary benefit of correcting flatness. Temper rolling is not to be confused with tempering, which is an unrelated heat treatment process in hot forging that has a similar name. Temper rolling involves a 0.5-1.5% reduction in thickness using a single or double series of rolls to provide a small amount of cold work to the steel.
Roller leveling is the most inexpensive way to correct imperfections in flatness on batch annealed material. Roller leveling is typically installed at the start of the processing line. (i.e., the coating line). Roller leveling involves about 0.25-0.5% cold reduction through a series of small rolls in a cassette.
Tension leveling is another common approach to shape correction. Tension leveling is essentially roller leveling with an added tension applied. Tension leveling is typically installed as a stand-alone operation or part of a continuous annealing line. Tension leveling can achieve up to 1.5% cold reduction with fewer rolls by the addition of strip tension to the roller leveler configuration.
Stretch levelling is the least common but most effective method of shape correction. It is typically installed as a stand-alone operation and used in specialty steel and alloys. It can achieve up to 3% cold reduction with no rolls by using extremely high strip tension.
These means of correcting flatness are mentioned as potential solutions to the problem of lack of flatness in batch-annealed steel that is required for certain enameling processes. However, when attempted, these means of correcting flatness are insufficient to overcome the lack of flatness in batch-annealed steel. Conventional flattening processes are unpredictable in their ability to convert batch-annealed steel into a state suitable for certain enameled steels.
Accordingly, a need exists for systems and methods that allow cold-rolled, batch-annealed steel to be received at a manufacturing facility and coated with a two-step, two-fire enameling process to provide a product that has sufficient flatness.

Systems and methods for in-line thermal flattening and enameling of steel sheets


A pressure relief device is disclosed for a system containing a pressurized fluid. The device includes a main valve body having inlet and outlet flow ports and a valve plug positioned to seal the flowpath of the pressurized fluid between the inlet port and the outlet port of main valve body. A force transmission component is connected to the valve plug and an activation component is installed between the force transmission component and a mounting surface. The activation component is configured to prevent axial movement of the valve plug until a predetermined pressure is exerted on the valve plug. The force transmission component more efficiently transfers the output force acting on the valve plug to the activation component.

There are many types of systems that process, transport, or use a pressurized fluid. To ensure the safety of these types of systems, each such system typically includes a safety device designed to prevent the over-pressurization of the system. In an emergency situation, where the fluid in the system reaches an unsafe level, the pressure of the fluid acts on the safety device to create an opening to release fluid from the system. Venting fluid to the environment or a safety reservoir through the opening reduces the pressure in the system and prevents another portion of the system from failing due to the high pressure of the fluid.
Examples of commonly used safety devices include rupture disks and explosion panels. These safety devices can be attached to a pressurized system to expose a certain portion of the device to the pressurized fluid in the system. The portion of the device exposed to the fluid is configured to rupture or tear when the fluid reaches a predetermined pressure. The tearing or rupture of the disk or panel creates an opening through which the pressurized fluid flows to reduce the pressure in the system. This type of safety device is, therefore, self-destructing and must be replaced after each use. Typically, to replace one of these safety devices, some disassembly of the system is needed so that the disk or panel can be properly engaged with the system.
Another type of safety device for a pressurized system is a pressure relief valve, which may be a reclosing valve or a non-reclosing valve. Typically, a spring, a pin, or a combination of a spring and pin, is used to hold a moving plug in sealing engagement with the housing of the device while connected to the pressurized system. When the pressure of the fluid reaches the predetermined safety level in such systems, the force exerted on the plug by the pressurized fluid overcomes the bias of the spring or exceeds the resistance of the pin that holds the plug in place. When either of these events occurs, the pressurized fluid moves the plug to expose an opening through which fluid may escape to relieve the pressure in the system. Reclosing valves will automatically reset once the pressurized fluid at the inlet of the device has reduced sufficiently for the spring or other mechanism to reseat the plug. Non-reclosing valves require that the device be manually reset so that the valve plug is re-engaged with the seal and, if necessary, the pin or other expendable component replaced.
As noted above, relief valves are known that use buckling pins, or breaking pins, to hold a sealing plug in sealing engagement to block the flow of a pressurized fluid. The pin release device prevents the plug from venting pressurized fluid until the output force exceeds a predetermined limit. Prior release devices have included a pin that is subject to a compressive force and that buckles according to Euler's Law when the output force reaches the predetermined limit or a shearing or tensile force that causes the breaking of the pin when the output force reaches the predetermined limit. Such a device is typically termed a "Buckling Pin Non Reclosing Pressure Relief Device."
Buckling pins are carefully manufactured components configured to buckle at a particular predetermined compressive force. Breaking pins are carefully manufactured components configured to fail at a particular predetermined tensile or shear force. Such pins used for a pressure relief valve require considerable care and control during installation. Maintenance personnel must ensure that the pin is properly secured and tightened to properly bear the pressure exerted on the pressure relief valve. Failure to do so may result in untimely opening of the valve. A premature opening below the predetermined safety level leads to an unwanted downtime for the system, while a delayed opening above the predetermined safety level jeopardizes the physical integrity of the system. Another problem with a bare pin is that there is a risk of pin damage stemming from maintenance personnel having to contact the bare pin during installation or maintenance. This risk of pin damage is especially high for a fragile, low pressure bare pin.
As noted above, it order to properly function as a safety pressure relief device, it is important that the relief device vents at, or close to, the set pressure. Since buckling pins are designed to buckle at a predetermined compressive force, a pressure relief system must assure that force from the pressurized system is efficiently transferred to the buckling pin. In prior devices, forces from the pressurized system are often improperly transferred through the pressure relief device's structural system such that the compressive force experienced by the buckling pin is not an accurate representation of the actual force transmitted by the pressurized system. For example, forces transferred to the buckling pin from the pressurized system are often lost due to bending, friction between moving parts, and moments generated along the path of transmitted force.
In some pressure relief devices, and particularly those having a low set pressure, mishandling and improper installation of the underlying buckling pin can interfere with the accuracy of the set pressure of the device. For example, buckling pins can be dangerously overloaded during the pre-assembly and installation process such that the pin activates at a much lower pressure than desired during use.
In light of the foregoing, there is a need for a pressure relief apparatus that (1) efficiently and accurately transfers force between the pressurized fluid and the buckling pin, (2) assures that pins are not overloaded during the pre-assembly and installation process, and (3) can provide for resistance to back pressure while maintaining proper positive pressure venting as a pressure relief device.

Force transferring pressure relief device


Method of operating a pressure swing adsorption system having a plurality of parallel adsorber vessels and a plurality of valves and gas manifolds adapted to introduce gas into each adsorber vessel and withdraw gas from each adsorber vessel in a cyclic series of sequential process steps. A leaking valve may be identified by (1) determining a value of an operating parameter that is a function of the mass of gas provided to a receiving adsorber vessel or withdrawn from an adsorber vessel during a selected process step, portion of a process step, or series of process steps; (2) determining the deviation of the value of the operating parameter from a predetermined reference value; and (3) using the magnitude and direction of the deviation to determine whether any valves are leaking.

Pressure swing adsorption is a well-known method for the separation of bulk gas mixtures and for the purification of gas streams containing undesirable impurities. The method has been developed and adapted for a wide range of feed gases, operating conditions, product recovery, and product purity. Most large pressure swing adsorption (PSA) systems utilize multiple parallel adsorber beds operated in staggered sequential cycles using typical process steps of feed/adsorption, pressure equalization, depressurization, provide purge, purge, and repressurization. These PSA systems are widely used in the chemical process industries for the recovery and purification of valuable gaseous products such as hydrogen, carbon oxides, synthesis gas, light hydrocarbons, and atmospheric gases.
The design of these PSA systems can present complex operating challenges because of the large number of switching valves required for the cyclic operation of multiple adsorber beds. For example, a relatively simple four-bed PSA system has at least 24 valves while a large ten-bed PSA system may have up to 67 valves. The operation of PSA systems to meet design specifications for product recovery and purity requires that these valves operate reliably of over long periods of time. All valves eventually will experience some type of malfunction, however, and replacement will be necessary. Valve testing and replacement may be carried out during scheduled maintenance outages, but it is likely that some valve malfunctions will occur between scheduled outages.
Valve malfunctions may include, for example, failure of a valve to open or close completely, slow valve response to control signals, no valve response to control signals, and leakage to the atmosphere due to faulty stem seals. These types of malfunctions can be detected relatively easily by skilled plant operators. Another type of valve malfunction is the leakage of gas across a closed valve due to seal degradation. This type of malfunction is much more difficult to detect than the other type of malfunctions because it generally occurs slowly and therefore is not immediately obvious to the plant operators. When the operators finally realize that a valve is leaking, which could take weeks or even months, it is a difficult and time-consuming task to determine which valve is leaking from analysis of available process information. This type of leak can cause a drop in performance of the PSA plant due to unbalanced operation of the adsorbers or due to a direct loss of product gas. In addition, such a leak eventually can progress to a point at which the PSA plant trips off-line, for example, because the concentration of impurities in the product gas exceeds specified limits. This results in unplanned downtime and an economic penalty for the plant owner.
In order to identify the valves that have a sealing defect in the closed position, seal tests are conventionally employed during periodic maintenance shutdowns. However, this type of inspection is time-consuming, laborious, and extends downtime, thereby resulting in lost production. In addition, the time between maintenance shutdowns may be several months to two or more years.
There is a need in the field of PSA gas separation technology for improved operating methods to detect and identify leaking valves while the plant is in operation between regular maintenance shutdowns. This need is addressed by the embodiments of the present invention described below and defined by the claims that follow.

Valve operation diagnostic method for pressure swing adsorption systems


A tangible, non-transitory machine-readable medium includes machine-readable instructions that, when executed, cause processing circuitry to receive a signal indicative of high dynamic range content. The signal includes 1) a first portion that forms a first percentage of the signal and is associated with a first brightness range and 2) a second portion that forms a second percentage of the signal associated with a second brightness range. The instructions, when executed, are also configured to cause the processing circuitry to produce an adjusted signal to represent the signal such that a graphical representation of the adjusted signal includes an area corresponding to the first portion of the signal that is expanded relative to a graphical representation of the first portion of the signal. Furthermore, the instructions, when executed, are configured to cause the processing circuitry to cause display of a graphical representation of the adjusted signal.

The present disclosure relates generally to high-dynamic range (HDR) content. More particularly, the present disclosure relates to normalizing HDR content for display and analysis via electronic devices such as waveform monitors.
This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present techniques, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.
Various electronic devices may be utilized to monitor and review video content. For example, waveform monitors may measure the voltage of a video signal over time and display an indication of the measured voltage. In essence, a traditional waveform monitor is a oscilloscope that is triggered synchronously with one or more scan lines of the video raster that represent a frame or field of the video signal. For example, optical data (e.g., image data) may be represented using electrical units, such as volts, by converting the optical data using an optical transfer function. The measured voltage may be indicative of a brightness (e.g., luminance) of an image or frame of video content. Additionally, for a color difference signal (e.g., Cr or Cb component signals), the measured voltage may be indicative of the color saturation on. Data presented on waveform monitors may also be used for production purposes, such as to adjust lighting on a set or to set camera iris and exposure.
Traditionally, video content, such as television and films, was standard-dynamic range (SDR) video content having a dynamic range based on cathode ray tube (CRT) display technology. For example, brightness of SDR video content may range from approximately 0 to 100 nits, where nits are units of luminance (1 nit is defined as 1 candela/square meter). When reviewing video signals of SDR video content, a graphical representation of the signal may be presented on a display of a waveform monitor, and the graphical representation can often occupy large amounts of the display. In other words, the distribution of video data in a typical scene (or a test pattern) may be spread out across the display and readily visible and interpretable. However, with the advent of other forms of video content, such as HDR video content, the range in brightness can be many times greater, though much of the content may be concentrated within a relatively small portion of the range. Due to the larger range, when video signals for HDR video content are presented on a waveform monitor, graphical representations of the signals may occupy only a small portion of the display when the display is designed to facilitate the interpretation of video signals from SDR content.

Normalized high-dynamic range visualization


In a p-type flash memory array, separate programming and read bit lines are provided. The programming bit line is used only to program the floating gate transistors in the memory cells connected to that bit line. The read bit line is used only to read the state of a floating gate transistor in a selected memory cell connected to that bit line during the operation of the memory circuit. The resulting structure allows the use of low voltages during both programming and operation of the memory array. This makes possible the use of transistors in the memory array with feature sizes less than, for example, 0.18 microns. At the same time variable, unpredictable capacitances associated with each bit line in prior art p-type flash memory structures using comparable low programming voltages are eliminated when a particular memory cell attached to that bit line is being read out.

A certain type of flash memory array uses a p-channel MOS transistor as the storage element and a p-channel MOS transistor as the control element in each memory cell. This type of flash memory can have a large number of memory cells, for example, 2 million or 4 million such cells arranged typically in a 1K by 2K or 1K by 4K configuration. Each memory cell will contain a control transistor and a floating gate transistor. The floating gate of the floating gate transistor will be programmed to either contain a charge (which typically will turn on the floating gate transistor) or no charge (which typically will leave off the floating gate transistor). Thus binary information (i.e. a one ("1") or a zero ("0") can be stored in the floating gate transistor.
Small portions of two typical prior art flash memory arrays are illustrated in FIGS. 1c and 1d. FIGS. 1c and 1d each show an array of memory cells with control transistors Q11 through QRC (where R equals the number of rows in the array, C equals the number of columns in the array and RC equals the number of memory cells in the array) and floating gate transistors F11 through FRC. Each control transistor Qrc (where 1≦r≦R and 1≦c≦C) is associated with a corresponding floating gate transistor Frc in a memory cell rc. Floating gate transistors F11 through FRC are shown in the arrays of FIGS. 1c and 1d. Each floating gate transistor Frc contains a floating gate (139 in FIG. 1c and 149 in FIG. 1d) which will store or not store charge depending upon the information to be stored in each memory cell.
FIG. 1a shows in cross section the structure of a typical P-type transistor Q11. In FIG. 1a, P-type regions 102a and 102b are formed, typically by ion implantation, in an N-type substrate or N well 101. P-type regions 102a and 102b are separated from each other by a channel region 103 the conductivity type of which can be changed by a voltage applied to control gate 106 through conductive lead 107 in ohmic contact with gate 106. Gate insulation 105 is formed between control gate 106 and the underlying channel region 103.
The source of a P-type transistor is that one of the P-type regions 102a and 102b which is at a higher voltage than the other P-type region 102 when the P-type transistor is being used. Thus, during one operation, a given p-type region 102 might be the source of the p-type transistor. During another operation this same p-type region might be the drain of the p-type transistor. Typically, during programming, the control transistor Qrc and the floating gate transistor Frc will each have one p-type region be the source and the other p-type region be the drain whereas during readout of information stored on the floating gate transistor, the source and drain of each of these transistors can, in some embodiments, be reversed.
FIG. 1b shows a cross section of a typical MOS P-channel floating gate transistor 100b. The regions within floating gate transistor 100b which are identical in structure to the regions within control transistor 100a are identically numbered. Floating gate transistor 100b includes a floating gate 116 which is insulated from the underlying channel region 103 by gate insulation 105 and to which no other conductor is attached. During the charging of floating gate 116, current will flow from the source region of the floating gate transistor into the channel region 103 and electrons will be diverted through the gate insulation 105 onto the floating gate 116 as a result of a phenomenon known as hot electron injection or Fowler-Nordheim tunneling or both. As a result, electrons are placed on floating gate 116. Should the charge created by these electrons be sufficiently high, these electrons will cause inversion of the underlying channel region 103 from N-type to P-type thus providing a conductive path between the P-type regions 102a and 102b. When this conductive path exists in a given floating gate transistor Frc in a memory cell rc (see FIGS. 1c and 1d), and the control transistor Qrc in that memory cell rc is turned on, a current will flow through memory cell rc if a voltage drop is created across memory cell rc. The current will indicate the nature of the information stored in the memory cell rc. If no charge has been placed on the floating gate 116 of floating gate transistor Frc (100b in FIG. 1b), then no current will flow through memory cell rc when a voltage is placed across memory cell rc and control transistor Qrc is turned on. Thus a binary one ("1") or zero ("0") is stored in each memory cell rc and the state of the memory cell is detected by the presence or absence of current when a voltage is placed across the memory cell and the control transistor Qrc is turned on.
Typically, to program a floating gate transistor such as F11 (FIG. 1c), a minus eight (−8) volts programming voltage is applied to the gate 133-11 of control transistor Q11 from X-decoder 132 by means of lead 137-1. Simultaneously, minus five (−5) volts is applied from Y-line decoder 131 by means of lead 136-1 to P-type region "b" of P-type transistor Q11. Row interconnect 137-1 connects and thus applies the same voltage to the gates of all control transistors in row 137-1 which is minus eight (−8) volts during programming of one or more memory cells connected to the row. However, if only F11 is being programmed, only the column line 136-1 will be placed at minus five (−5) volts. Thus, P-type transistor Q11 turns on and conducts current and causes P-type region "b" of floating gate transistor F11 to be slightly above approximately minus five (−5) volts due to the voltage drop across channel 103 of Q11. Because interconnect 138-1 is at ground potential, during programming P-type region "a" of floating gate transistor F11 acts as a source as does P-type region "a" of control transistor Q11. The P-type regions denoted "b" of control transistor Q11 and of floating gate transistor F11 will act as drains. With the voltages as described, current will flow from grounded lead 138-1 to lead 136-1 at minus five (−5) volts. This current will cause electrons to flow onto floating gate 139-11 of F11 thus creating a negative charge on this gate. This negative charge will cause the channel region 103 of floating gate transistor F11 to invert. Inverted channel 103 will allow current to flow between P region "a" and P region "b" of F11 should control transistor Q11 subsequently be turned on during subsequent readout of memory cell 11.
The minus eight (−8) volts required to turn on control transistor Q11 during the programming of floating gate transistor F11 is larger in absolute magnitude than the control transistor can sustain if the control transistor is manufactured using feature sizes under 0.18 microns. Accordingly, it is necessary to provide a structure which will allow the programming of floating gate transistors (such as F11) in the array of FIG. 1c using a gate voltage on the control transistors (such as gate 133-11 on Q11) smaller in absolute magnitude than eight (8) volts.
Note that when minus eight (−8) volts is applied to interconnect 137-1 and all the other control gates 133-12 (not shown) through 133-1C connected to interconnect 137-1 are at minus eight (−8) volts, the control transistors Q12 (not shown) through Q1C turn on but do not conduct current because the voltages on their column lines 136-2 (not shown) through 136-C are kept at zero (0) volts, the same as the voltage on grounded lead 138-1.
To read out the signal stored on floating gate transistor F11 during normal operation of the memory array, a voltage of minus three (−3) volts is applied to the control gate 133-11 of control transistor Q11 while a voltage of minus one point five (−1.5) volts is applied to column interconnect 136-1. Transistor Q11 turns on and current then flows from grounded interconnect 138-1 through floating gate transistor F11 because floating gate transistor F11 has had its channel region 103 inverted as a result of the electrons stored on floating gate 139-11. This current then passes through turned-on control transistor Q11 and is detected by the sense amp 130-1 (not shown) in sense amp block 130 connected to column line 136-1. The other transistors in row 137-1 which have their gates also held at minus three (−3) volts will not have a current flowing through them because their corresponding column lines 136-2 (not shown) through 136-C are held at zero (0) volts, the same as the voltage on grounded interconnect 138-1.
In one embodiment, all the memory cells connected to a given row can be read out simultaneously by having the bit lines 136-1 to 136-C brought to minus one point five (−1.5) volts. Each bit line 136-i is connected to a sense amp 130-i in sense amp block 130 thus allowing the states of the memory cells 11 to 1C to be read out simultaneously.
The alternative prior art structure shown in FIG. 1d allows programming of each floating gate transistor in the memory array with a lower voltage but results in an unpredictable increase in the capacitance sensed on the column line (i.e. the bit line) when reading out a floating gate transistor. This slows down the read out of data from each memory cell. As shown in FIG. 1d, this particular structure has floating gate transistor F11 with a P-type region "b" connected to column line 146-1 and P-type region "a" connected in series with P-type region "b" of control transistor Q11. P-type region "a" of control transistor Q11 is connected to grounded interconnect 148-1.
To program the floating gate transistor F11 in memory cell 11 of the memory cell array in FIG. 1d, the floating gate transistor F11 has its drain "b" held to about minus five (−5) volts by the voltage on column 146-1 being brought to minus five (−5) volts through Y-line decoder 141. Source "a" of floating gate transistor F11 is connected to drain "b" of control transistor Q11 and source "a" of control transistor Q11 is connected to grounded (i.e. at zero volts) interconnect 148-1 . A minus two (−2) volt potential is then applied to the gate 143-11 of select transistor Q11 from X-decoder 142 by means of row line 147-1. This same minus two (−2) volts is also applied to the gates 143 of all other control transistors Q1c connected to row line 147-1. Consequently, current flows from the source "a" of Q11 through Q11 to source "a" of floating gate transistor F11. This current passes through turned-on floating gate transistor F11 and some of the electrons from this current then charge the floating gate 149-11 of floating gate transistor F11 thereby resulting in a negative charge being stored on floating gate 149-11. Consequently, the channel region 103 underlying floating gate 149-11 is inverted resulting in current being capable of passing through floating gate transistor F11 whenever control transistor Q11 is turned on and a voltage is applied across the memory cell.
The prior art structure shown in FIG. 1d requires less of a voltage range to turn on and charge the floating gate of transistor F11 than the structure shown in FIG. 1c. However, in the embodiment of FIG. 1d, each floating gate transistor Frc which is turned on and attached to column 146-c (only columns 146-1 and 146-C are shown in FIG. 1d), allows the capacitance of that floating gate transistor to affect the turn-on speed of the sense amp 140-c in sense amp block 140 attached to that column. The sense amp 140-c attached to column 146-c senses the current through the floating gate transistor in the memory cell attached to that column being read. However, the speed of this sense amp 140-c is affected by the capacitances of all other floating gate transistors Frc with an inverted channel attached to that column.
For example, to read the state of a given memory cell in the memory array of FIG. 1d such as memory cell 11 made up of floating gate transistor F11 and select transistor Q11, minus three (−3.0) volts is applied from row line 147-1 to the gate 143-11 of transistor Q11 to turn on Q11. Minus one point five (−1.5) volts is applied from Y line decoder 141 to column line 146-1. Since lead 148-1 is grounded, a current will flow through transistor Q11 and floating gate transistor F11 (which has been turned on by the charge stored on floating gate 149-11). The sense amp 140-1 in sense amp structure 140 connected to column lead 146-1 will detect this current. If floating gate 143-11 contains no charge, then no current will flow through floating gate transistor F11 and no current will flow out to bit line 146-1 and no current will be detected by sense amp 140-1. The other cells attached to row line 147-1 with minus three (−3) volts applied thereto will remain off because their column lines 146-2 through 146-C will, in one embodiment, be maintained at zero volts during the reading of memory cell 11 attached to column line 146-1. However, if desired, all memory cells connected to row line 147-1 can be read out simultaneously.
In the memory array of FIG. 1c, the sense amp reading out the signal is impacted by only one channel capacitance, namely the channel capacitance associated with the control transistor of the floating gate transistor being read. For example, if there are 1,000 rows in the memory array, the sense amp senses only the channel capacitance associated with the control transistor connected to the bit line and turned on by the negative voltage on its row line and not the other 999 capacitances associated with the other 999 control transistors.
In the second prior art embodiment described above in FIG. 1d, the bit line capacitance is not fixed. The capacitance of a bit line can vary depending upon how many floating gate transistors Frc which are attached to the bit line have been programmed to be on because each turned-on floating gate transistor introduces additional capacitance to the bit line. The embodiment described in FIG. 1c above is more stable but the embodiment of FIG. 1d uses lower programming voltages so there is a trade-off between which embodiment to use.
Accordingly, it would be desirable to have the advantages of both of the prior art embodiments in one given structure. In particular, it would be desirable to have a structure which would provide both the low voltage capability of the prior art embodiment described in FIG. 1d together with the low capacitance of the embodiment described in FIG. 1c when a memory cell is being read.

Low voltage low capacitance flash memory array


An extrusion-type liquid application device having a simple construction but in which the width of the coating slit can easily be adjusted, even during a coating operation. Thick members are mounted on the doctor portion of a coating head extending perpendicular to the liquid discharge portion of the coating head. The thick members have acting portions at their upper ends abutting the surface of the doctor portions, central fulcrum portions, and opposite end portions provided with adjusting members. By adjusting the adjusting members, the slit width can be adjusted.

The present invention relates to an application device for applying a coating liquid such as a photographic photosensitive liquid, a magnetic liquid or a surface-protective liquid to a moving flexible carrier made of a plastic film, paper, a metal sheet or the like and hereinafter referred to as a web.
Conventional application devices for applying a liquid to a web include those of the roll type, the bead type, the slide coating type, and the extrusion type. In the application device to which the present invention relates, the liquid is discharged under appropriate pressure from the slit of an application head of the device, as in the conventional application device of the extrusion type. Since the width of the conventional application device of the extrusion type corresponds to that of the web, which is about 0.5 m to 3.0 m, the device has the problem that it is difficult to make the thickness of the applied liquid on the web uniform along the width thereof In particular, when a magnetic liquid of high viscosity is applied to a web with the conventional application device of the extrusion type, the liquid is discharged under prescribed pressure from the slit of the application head of the device while the head is urged against the moving web to apply the liquid thereto In this device, it is very difficult to make the distribution of the pressure of the magnetic liquid uniform along the length of the slit. Therefore, the thickness of the liquid applied to the web is not uniform along the width of the web.
In order to solve this problem, various application devices in which the width of the slit of an application head for applying a liquid to a web can be adjusted to enhance the uniformity of the thickness of the applied liquid on the web have been proposed, as disclosed, for instance, in Japanese Unexamined Published Patent Applications Nos. 291117/86 and 2610225/86.
In the application device disclosed in application No. 291117/86, the liquid discharge portion of the application head 20 is provided with a lip 21, a recess 22, and a plurality of screws 24, as shown in FIG. 8. The lip can be moved forward & and aft by manipulating the screws. However, it is very difficult and hardly possible to manipulate the screws 24 during the application of the liquid to the web. Since the liquid discharge portion of the application head 20 is provided with the lip 21, the recess 22, and the screws 24, the head is difficult to manufacture and the maintenance thereof is cumbersome. The freedom of design of the head is also quite limited.
In the application device disclosed in Application No. 261022/86, a force is applied to the lip 22 of the liquid discharge portion of the application head 20 by screws 24, as shown in FIG. 9. Also, the head 20 is provided with heaters 25 capable of heating the shanks of the screws 24 to expand them. Thus, the screws 24 do not need to be manually manipulated. However, the construction of the application head 20 is again complex, its maintenance difficult, and the freedom of design limited. Moreover, the cost of this application head is high.


A compression molding apparatus and method for the manufacture of abrasive layers for abrasive tooling which provides a compression mold space defined between an inflexible wall surface and a flexible wall surface. The apparatus and method of the present invention is particularly well suited to making annular or hollow cylindrical shaped abrasive layers of novel configurations during a single mold cycle useful for grinding wheel and the like, as well as other shapes such as laps, wherein the flexible wall expanded with fluid pressure provides a highly uniform distribution of pressure against the surface of the mold composition being formed. In an annular configuration, the flexible wall is used to radially direct pressure against a molding composition disposed in an annular configuration wherein the axial length of the annular mold shape formed may be many times greater than priorly obtained by the prior art means.

1. Field of the Invention
This invention relates generally to an apparatus and method of making improved superabrasive tools, such as a centerless grinding wheel, for example.
2. Description of the Related Art
Many types of abrasive tools, such as centerless grinding wheels for example, have been manufactured using a compression molding process to form the outer abrasive surface of the wheel. Large presses involving heat and high pressures, such as 1,000 to 10,000 psi, are employed to compact a powdered composition comprising a resin, metal or ceramic binder, filler materials and superabrasive particles, such as diamonds, for one example, in a mold.
The largest number of such abrasive grinding wheels comprise a resin bonding composition with a variety of such compositions well-known to those skilled in the art and designed for particular applications or as a matter of designer's choice.
One of the problems of the prior conventional molding apparatus and process of this type is the limitation of the axial length dimension which may be acceptably made. This limits the effective width of the annular configuration formed. Typically, only a relatively narrow wheel configuration having an axial length dimension of no more than about 1 to 2 inches may be formed depending upon the particular components of the abrasive composition used and the thickness of the layer of abrasive molding composition formed. Many industrial applications require a grinding surface having up to about 24 inches of width or axial length. Using conventional methods, this requires the separate molding of a plurality of 1 to 2 inch long annular or tubular forms and then adhesively stacking one upon the other to obtain the required axial length. Clearly, this is a costly, labor intensive effort which results in a grinding wheel with seams formed between each of the stacked narrow annular components. Further, since each annular component is made during a separate molding process, uniformity of the properties of each component may vary more than desired.
Since the conventional compression molding apparatus uses annular mold spaces and axially moveable plungers having inflexible surfaces to compact the abrasive composition, the ability to compress the abrasive filled molding composition in an acceptable uniform manner is limited to these narrow axial dimensions. Prior attempts to compress greater depths were unsuccessful as the range of pressure applied throughout the molding composition varied too much to achieve a sufficient uniformity of density and surface hardness for practical industrially acceptable products. Further, axial depths greater than about 2 or 3 inches would require compression molding machines which apply excessively greater pressure and at some point are impractical for this use.
It should be noted that the abrasive molding compositions used typically are a mixture of relatively fine powder size components. The object of the process is to reduce the porosity of the final compacted and molded product to as close to zero as feasible. However, the fine powder component mixture represents solids during the initial compaction. The binder component eventually becomes somewhat viscous or semi-solid during the heating and pressing cycle in order to wet and bond the remaining solid particles in a strong, dense final product.
The filler and abrasive particles have limited flow properties within the mold cavity even under high pressure. Therefore, in the conventional axially directed pressing method, the axial length of the composition in the mold tends to be limited to between the 1 to 2 inches noted to obtain a practical industrially accepted final product. The use of press platens having inflexible surfaces tends to limit the uniformity of density and surface hardness achieved even in non-annular shapes such as in laps and similar abrasive tools.
It should be noted that once the annular abrasive molding composition is processed, the interior volume is filled with a suitable core material. Often the core is a plastic material which is bonded to the inner surface of the abrasive layer ring-shaped configuration and completes the grinding wheel tool.
Prior to the present invention, significant improvement of compression molding of annular shapes of abrasive products, such as described, has eluded those skilled in the art.

Apparatus and method for manufacturing abrasive tools


An automatically resettable smoking paraphernalia includes the following components: an outer upper shell, a smoking cup provided inside the outer upper shell, a pushing key, and a spring, etc., wherein the smoking cup, the spring, the outer upper shell can be detached and replaced as a whole, the smoking cup can stick out of the outer upper shell by a distance to extract and unload the cigarette, and then automatically reset. Besides, the smoking cup is hidden inside the upper outer shell, so as to prevent the exposed smoking cup with an excessively high temperature from burning users, meanwhile avoiding a risk of losing the smoking cup.

With smoking paraphernalia products for novel cigarettes stepping into the market, feedback from consumers is increasingly detail-oriented, and higher requirements for the humanized designs targeting at various components of the smoking paraphernalia are raised. Thereinto, inserting and extracting cigarettes is a focus of research for the researchers. For the existing smoking paraphernalia products for novel cigarettes, a cigarette generally needs to be manually inserted, and the cigarette sticking out of the heating cavity is manually disassembled after smoking. The operation mode readily breaks the cigarette or makes fragments of the cigarette remain in the heating cavity, greatly increasing difficulties in the subsequent cleaning.
A Chinese patent of Philip Morris International having an application number of 201280063987.0 discloses an extractor for a smoke product, wherein the extractor is formed by riveting two components, the outer shell is provided with a protrusion to handily fix to a main body, and an inner sleeve is provided with a step to handily engage with an upper end portion of the heating cavity. The extractor needs a relatively large thrust applied upward along the outer shell to realize an unloading process of the cigarette, and after completing the unloading process of the cigarette, the outer shell should be applied with a downward external force to reset, failing to automatically reset. The operating process is excessively complicated, meanwhile increases a risk that the outer shell may get misplaced after unloading the cigarette. Moreover, the temperature of the smoking cup after heating is excessively high and may readily burn the user, greatly lowering the user's smoking experience.

Automatically resettable smoking paraphernalia

CHINA TOBACCO YUNNAN INDUSTRIAL CO., LTD


An ultrasonic diagnostic apparatus according to one embodiment includes correlation matrix calculating circuitry, calculating circuitry, image generating circuitry, and controlling circuitry. The correlation matrix calculating circuitry calculates a correlation matrix of a scanned region consisting of a plurality of scan lines, from a data array of pieces of reflection wave data collected from the same position by transmitting and receiving ultrasonic waves in the scanned region across a plurality of frames. The calculating circuitry calculates a filter coefficient for suppressing a clutter generated by a tissue, by performing principal component analysis using the correlation matrix, and by performing a matrix operation of approximating a clutter component as a principal component and of suppressing the clutter component. The image generating circuitry generates ultrasound image data from blood flow information estimated using the filter coefficient. The controlling circuitry causes a display to display the ultrasound image data.

Ultrasonic diagnostic apparatuses have conventionally been widely used for diagnosing or observing blood flows in living organisms. An ultrasonic diagnostic apparatus generates and displays blood flow information using Doppler imaging, which visualizing ultrasonic reflection waves based on the Doppler shift. Examples of blood flow information generated and displayed by an ultrasonic diagnostic apparatus include color Doppler images and Doppler waveforms (Doppler spectrums).
A color Doppler image is an ultrasonic image achieved by color flow mapping (CFM). In CFM, an ultrasonic wave is transmitted and received a plurality of number of times along each of a plurality of scan lines. In CFM, an array of data acquired from the same position is then applied with moving target indicator (MTI) filtering so as to suppress the signals resulting from stationary or slow moving tissue structures (clutter signals) and to extract signals representing blood flows. In CFM, blood flow information such as velocity, variance, and power of blood flows are estimated based on the blood flow signals, and the resultant distribution of the estimation results is displayed as, for example, a two-dimensional color ultrasonic image (color Doppler image).
While a filter with a fixed coefficient, such as Butterworth infinite impulse response (IIR) filter or a polynomial regression filter, is usually used as an MTI filter, an adaptive MTI filter in which the coefficient is changed based on the input signal is also known.
An exemplary adaptive MTI filter calculates a tissue velocity from the signals before input to the MTI filter, and acquires signals having their phase difference cancelled out. The filter then selects one of MTI filter coefficients prepared in advance, based on the resultant signals. Another type of adaptive MTI filter generally referred to as an "eigenvector regression filter" is also known. To acquire a signal with its clutter component suppressed, this type of adaptive MTI filter calculates eigenvectors from a correlation matrix, and calculates the coefficient to be used in the MTI filter directly from the calculated eigenvectors. The approach is an application of the technique used in the principal component analysis, Karhunen-Loeve transform, or the eigenspace method. Also known as real-time implementation of the method that uses the "eigenvector regression filter" is a method using the "iterative power method" in calculating the eigenvectors.
The adaptive MTI filter described above calculates eigenvectors from a correlation matrix. The image quality of a video visualized with the adaptive MTI filter using eigenvectors, however, changes depending on what conditions the correlation matrix is calculated with. Therefore, the adaptive MTI filter using eigenvectors has not always resulted in a video with better image quality.

Ultrasonic diagnostic apparatus, image processing apparatus, and image processing method


A battery module includes a battery array including a plurality of battery cells arranged in a first direction and a plurality of separation barriers respectively interposed among the battery cells, side frames at two opposite sides of the battery array along the first direction, and at least one reinforcing barrier between two adjacent battery cells in the battery array, the reinforcing barrier having a metal member in a surface facing a corresponding side frame, and the metal member being fixed to the corresponding side frame.

1. Field
Embodiments relate to a battery module, and more particularly, to a battery module available for an electric vehicle or hybrid electric vehicle.
2. Description of the Related Art
In general, unlike primary batteries which are not rechargeable, secondary batteries are rechargeable and dischargeable. The secondary batteries are used as energy sources of, e.g., mobile devices, electric vehicles, hybrid electric vehicles, electric bicycles, uninterruptible power supplies, etc. The secondary batteries may be used in the form of a single battery or in the form of a battery module in which a plurality of batteries are electrically connected and packed as a single unit, according to the type of an external device to which the secondary batteries are applied.
Small-sized mobile devices, e.g., cellular phones, can be operated for a predetermined amount of time by using the power and capacity of a single battery. On the other hand, since the power and capacity of a single battery may be insufficient, battery modules are frequently used in devices, e.g., electric vehicles and hybrid electric vehicles, consuming large amounts of power for a long time. The battery modules are used by connecting a required number of batteries in parallel or series according to output and capacity.

Battery module having reinforcing barrier with metal member


A base station of the present invention includes a transmitting section that transmits a plurality of pieces of downlink control information each including a first field value to be used for control of a transmission power of an uplink control channel and a second field value to be used to determine a resource for the uplink control channel; and a control section that controls, in a case that second field values each corresponding to the second field value are configured to be a same value, configuration of first field values each corresponding to the first field value. With this, it is possible to appropriately control a transmission power of an uplink control channel.

In the UMTS (Universal Mobile Telecommunications System) network, the specifications of Long Term Evolution (LTE) have been drafted for the purpose of further increasing high speed data rates, providing lower latency, and so on (see Non-Patent Literature 1). For the purpose of further high capacity, advancement of LTE (LTE Rel. 8, Rel. 9), and so on, the specifications of LTE-A (LTE-Advanced, LTE Rel. 10, Rel. 11, Rel. 12, Rel. 13) have been drafted.
Successor systems of LTE (referred to as, for example, "FRA (Future Radio Access)," "5G (5th generation mobile communication System)," "5G+ (plus)," "NR (New Radio)," "NX (New radio access)," "FX (Future generation radio access)," "LTE Rel. 14," "LTE Rel. 15" (or later versions), and so on) are also under study.
In existing LTE systems (for example, LTE Rel. 8 to Rel. 13, also simply referred to as "LTE" below), a user terminal controls a transmission power of an uplink control channel (for example, a PUCCH (Physical Uplink Control Channel)), based on a TPC command indicated by a certain field (transmission power control (TPC) field) value in downlink control information (DCI).


The present invention relates compounds of the formula (I):

This invention relates to a class of azabicyclic compounds which are useful as tachykinin antagonists. More particularly, the compounds of the invention are substituted benzylether derivatives of 1-phenyl-8-azabicyclo[3.2.1]octane, which are useful as neurokinin 1 (NK-1) receptor antagonists.
The present invention provides compounds of the formula (I):
wherein
X represents hydrogen, C1-4alkyl optionally substituted by a hydroxy, methoxy or benzyloxy group, or CO2(C1-2alkyl);
Z is xe2x80x94CR9R10CH2xe2x80x94 or xe2x80x94CH2CR9R10xe2x80x94;
R1 is hydrogen, halogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl, fluoroC1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, wherein Ra and Rb each independently represent hydrogen or C1-4alkyl;
R2 is hydrogen, halogen, C1-6alkyl, fluoroC1-6alkyl or C1-6alkoxy substituted by C1-4alkoxy;
R3 is hydrogen, halogen or fluoroC1-6alkyl;
R4 represents hydrogen, halogen, C1-6alkyl, C1-6alkoxy, CF3, OCF3, NO2, CN, SRa, SORa, SO2Ra, CO2Ra, CONRaRb, C2-6alkenyl, C2-6alkynyl or C1-4alkyl substituted by C1-4alkoxy, where Ra and Rb are as previously defined;
R5 represents hydrogen, halogen, C1-6alkyl, CF3 or C1-6alkoxy substituted by C1-4alkoxy;
R6 represents hydrogen, hydroxy, CORa, CO2Ra, COCONRaRb, COCO2Ra, C1-6alkyl, C2-6alkenyl, or C1-6alkyl substituted by a group selected from CO2Ra, CONRaRb, hydroxy, CN, CORa, NRaRb, C(NOH)NRaRb, CONHphenyl(C1-4alkyl), COCO2Ra, CONHNRaRb, C(S)NRaRb, CONRaC1-6alkylR14, CONR11C2-6alkenyl, CONR11C2-6alkynyl, COCONRaRb, CONRaC(NRb)NRaRb, CONRaheteroaryl, and phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen and trifluoromethyl;
or R6 represents a group of the formula xe2x80x94CH2Cxe2x89xa1CCH2NR7R8 where R7 and R8 are as defined below;
or R6 represents C1-6alkyl, optionally substituted by oxo, substituted by a 5-membered or 6-membered heterocyclic ring containing 1, 2 or 3 nitrogen atoms optionally substituted by xe2x95x90O or xe2x95x90S and optionally substituted by a group of the formula xe2x80x94Yxe2x80x94NR7R8 where
Y is C1-6alkylene or C3-6cycloalkyl;
R7 represents hydrogen or C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or C2-4alkyl substituted by C1-4alkoxy or hydroxyl;
R8 represents hydrogen or C1-6alkyl, C1-6alkoxy, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, phenyl or C1-4alkyl substituted by a group selected from C1-4alkoxy, hydroxyl, CO2Ra, NRaRb, aryl, aryloxy, heteroaryl or a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S;
or R7, R8 and the nitrogen atom to which they are attached form a heteroaliphatic ring of 4 to 7 ring atoms, optionally substituted by one or two groups selected from methyl, hydroxy, CO2(C1-2alkyl), phenyl, benzyl or C1-4alkoxy optionally substituted by a C1-4alkoxy or hydroxyl group, and optionally containing a double bond, which ring may optionally contain an oxygen or sulphur ring atom, a group S(O) or S(O)2 or a second nitrogen atom which will be part of a NH or NRc moiety where Rc is C1-4alkyl, hydroxyC1-4alkyl, C1-4alkoxyC1-4alkyl, phenyl or benzyl;
or R7, R8 and the nitrogen atom to which they are attached form a non-aromatic azabicyclic ring system of 6 to 12 ring atoms;
or Y, R7 and the nitrogen atom to which they are attached form a heteroaliphatic ring to 4 to 7 ring atoms which may optionally contain an oxygen ring atom;
R9 represents hydrogen, hydroxy, oxo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, fluoroC1-6alkyl, C1-6alkoxy, fluoroC1-6alkoxy, hydroxyC1-6alkyl, C1-6alkoxyC1-4alkyl, C1-6alkoxyC1-4alkoxy, fluoroC1-6alkoxyC1-4alkyl, C2-6alkenyloxy, C2-6alkynyloxy, C3-7cycloalkoxy, C3-7cycloalkylC1-4alkoxy, aryl, aryl(CH2), aryloxy, aryl(CH2)oxy, cyano, halogen, NR7R8, CH2NR7R8, SR12, SOR12, SO2R12, OSO2R12, NRaCOR12, CH(OH)R12, COR12, CO2R12, CONR7R8, CONHNH2, CH2OR13, heteroaryl or heteroarylC1-4alkyl, wherein Ra is as previously defined;
R10 represents hydrogen, halogen or hydroxy;
R11 represents hydrogen or C1-6alkyl;
R12 represents hydrogen, C1-6alkyl, C1-6alkoxy, fluoroC1-6alkyl or phenyl optionally substituted by one, two or three substituents selected from C1-6alkyl, C1-6alkoxy, halogen or trifluoromethyl;
R13 represents C1-4alkyl substituted by a group selected from hydroxy, CORa, CO2Ra, CONRaRb and heteroaryl, where Ra is as previously defined;
R14 represents ORa, CONRaRb or heteroaryl;
and pharmaceutically acceptable salts or N-oxides thereof.
A preferred class of compound of formula (I) is that wherein X is hydrogen, methyl or hydroxymethyl.
Another preferred class of compound of formula (I) is that wherein R1 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
Another preferred class of compounds of formula (I) is that wherein R2 is hydrogen, C1-4alkyl, C1-4alkoxy, halogen or CF3.
Also preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
A particularly preferred class of compounds of formula (I) is that wherein R1 is fluorine, chlorine or CF3.
Another particularly preferred class of compounds of formula (I) is that wherein R2 is hydrogen, fluorine, chlorine or CF3.
Also particularly preferred is the class of compounds of formula (I) wherein R3 is hydrogen, fluorine, chlorine or CF3.
Preferably R1 and R2 are in the 3 and 5 positions of the phenyl ring.
More preferably R1 is 3-fluoro or 3-CF3.
More preferably R2 is 5-fluoro or 5-CF3.
More preferably R3 is hydrogen.
Most preferably R1 is 3-F or 3-CF3, R2 is 5-CF3 and R3 is hydrogen.
A further preferred class of compound of formula (I) is that wherein R4 is a hydrogen atom or a fluorine atom.
Another preferred class of compound of formula (I) is that in which R5 is a hydrogen atom.
A further preferred class of compound of formula (I) is that wherein R6 is a hydrogen atom or a C1-6alkyl group (especially methyl) or a C1-3alkyl group, in particular CH2, CH(CH3) and CH2CH2 and especially CH2, substituted by a 5-membered heterocyclic ring containing 2 or 3 nitrogen atoms as previously defined.
In particular, the 5-membered ring is a heterocyclic ring selected from 1,3-imidazol-4-yl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, 2-oxo-1,3-imidazol-4-yl and 3-oxo-1,2,4-triazol-5-yl, any of which rings being optionally substituted by the group xe2x80x94Yxe2x80x94NR7R8.
Particularly preferred heterocyclic rings are selected from:
Most especially, the 5-membered heterocyclic ring is a 1,2,4-triazol-3-yl or 3-oxo-1,2,4-triazol-5-yl group.
Another preferred class of compound of formula (I) is that wherein R9 represents hydrogen, hydroxy, oxo, C1-6alkoxy, C1-6alkoxyC1-4alkyl, hydroxyC1-4alkyl, cyano, NR7R8, CH2NR7R8, SO2Rd, CH(OH)R12, COR12, CO2R12, CONR7R8, phenyl, heteroaryl, heteroarylC1-4alkyl or CH2OR13, where said phenyl is optionally substituted by one or two substituents selected from C1-4alkyl, C1-4alkoxy, halogen or trifluoromethyl.
A further preferred class of compound of formula (I) is that wherein R9 represents hydrogen, hydroxy, C1-4alkoxyC1-2alkyl (especially methoxymethyl), hydroxyC1-2alkyl (especially hydroxymethyl), cyano, CH2NR7R8, SO2R12 (especially where R12 is phenyl), CH(OH)R12 (especially where R12 is phenyl), COR12 (especially where R12 is phenyl), CO2R12 (especially where R12 is C1-2alkyl, e.g. methyl), CONR7R8, heteroaryl, or CH2OR13.
When the group R9 represents NR7R8, CH2NR7R8 or CONR7R8, R7 is preferably hydrogen, or C1-4alkyl (especially methyl); and R8 is preferably hydrogen, C1-6alkyl, C1-4alkoxy or C1-3alkyl substituted by a group selected from methoxy, hydroxy, amino, methylamino, dimethylamino, phenyl, phenyloxy, or heteroaryl, wherein said phenyl or phenyloxy groups may be optionally substituted by one, two or three halogen atoms or methoxy groups, and wherein said heteroaryl group is preferably furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, pyridyl or quinolinyl, each of which heteroaryl groups may be optionally substituted by a methyl or phenyl group; or R7 and R8, together with the nitrogen atom to which they are attached, represent a heteroaliphatic ring selected from azetidinyl, pyrolidinyl, piperidinyl, morpholinyl, or piperazinyl, wherein said piperidinyl group may be optionally substituted by a methyl, CO2(C1-2alkyl), phenyl or benzyl group and, optionally, a hydroxy group, and wherein said piperazinyl group may be optionally substituted on the free nitrogen atom by a phenyl or benzyl group.
When the group R9 represents a heteroaryl group, said group is preferably oxazolyl, thiazolyl, triazolyl or tetrazolyl, each of which groups may be optionally substituted by C1-4alkyl, C1-2alkoxyC1-2alkyl, hydroxyC1-4alkyl, fluoroC1-4alkyl, CH2CONRaRb, CH2CORa, CH2CO2Ra, CH2SR12, CH2SOR12 or CH2SO2R12.
Another preferred class of compounds of formula (I) is that wherein R10 represents hydrogen, fluorine or hydroxy, and in particular that wherein R10 is hydrogen.
One favoured group of compounds of the present invention are of the formula (Ia) and pharmaceutically acceptable salts thereof:
wherein R1, R3, R4 and X are as defined in relation to formula (I) and Z is preferably xe2x80x94CR9R10OCH2xe2x80x94.
With respect to compounds of the formula (I), Y (where present), may be a linear, branched or cyclic group. Favourably Y contains 1 to 4 carbon atoms and most favourably 1 or 2 carbon atoms. A particularly favourable group Y is CH2.
Where the group NR7R8 represents a heteroaliphatic ring of 4 to 7 ring atoms and said ring contains a double bond, a particularly preferred group is 3-pyrroline.
Where the group NR7R8 represents a non-aromatic azabicyclic ring system, such a system may contain between 6 and 12, and preferably between 7 and 10, ring atoms. Suitable rings include
5-azabicyclo[2.1.1]hexyl, 5-azabicyclo[2.2.1]heptyl, 6-azabicyclo[3.2.1]octyl,
2-azabicyclo[2.2.2]octyl, 6-azabicyclo[3.2.2]nonyl, 6-azabicyclo[3.3.1]nonyl,
6-azabicyclo[3.2.2]decyl, 7-azabicyclo[4.3.1]decyl,
7-azabicyclo[4.4.1]undecyl and 8-azabicyclo[5.4.1]dodecyl, especially
5-azabicyclo[2.2.1]heptyl and 6-azabicyclo[3.2.1]octyl.
Where R8 represents a C1-4alkyl group substituted by a 4, 5 or 6 membered heteroaliphatic ring containing one or two heteroatoms selected from N, O and S, suitable rings include azetidinyl, pyrrolidino, piperidino, piperazino, morpholino, or thiomorpholino. Particularly preferred are nitrogen containing heteroaliphatic rings, especially pyrrolidino and morpholino rings.
Particularly suitable moieties xe2x80x94Yxe2x80x94NR7R8 include those wherein Y is CH2 or CH2CH2 and xe2x80x94NR7R8 is amino, methylamino, dimethylamino, diethylamino, azetidinyl, pyrrolidino and morpholino.
In particular, Y is preferably CH2 and NR7R8 is preferably dimethylamino, azetidinyl or pyrrolidino, especially dimethylamino.
When any variable occurs more than one time in formula (I) or in any substituent, its definition on each occurrence is independent of its definition at every other occurrence.
It will be appreciated that, where R9 represents an oxo (xe2x95x90O) group, then R10 will be absent and the group Z will in fact represent xe2x80x94C(O)CH2xe2x80x94 or xe2x80x94CH2C(O)xe2x80x94.
As used herein, the term xe2x80x9calkylxe2x80x9d or xe2x80x9calkoxyxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl and t-butyl. Examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy and t-butoxy.
As used herein, the terms xe2x80x9cfluoroC1-6alkylxe2x80x9d and fluoroC1-6alkoxyxe2x80x9d mean a C1-6alkyl or C1-6alkoxy group in which one or more (in particular, 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Similarly, the term xe2x80x9cfluoroC1-4alkylxe2x80x9d means a C1-4alkyl group in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by fluorine atoms. Particularly preferred are fluoroC13alkyl and fluoroC13alkoxy groups, for example, CF3, CH2CH2F, CH2CHF2, CH2CF3, OCF3, OCH2CH2F, OCH2CHF2 or OCH2CF3, and most especially CF3, OCF3 and OCH2CF3.
As used herein, the term xe2x80x9chydroxyC1-6alkylxe2x80x9d means a C1-6alkyl group, in which one or more (in particular 1 to 3) hydrogen atoms have been replaced by a hydroxy group. Preferred are hydroxyC1-3alkyl groups, especially where one hydrogen atom has been replaced by a hydroxy group, for example, CH2OH, CH2CH2OH and C(CH3)2OH.
The cycloalkyl groups referred to herein may represent, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. A suitable cycloalkylalkyl group may be, for example, cyclopropylmethyl.
Similarly cycloalkoxy groups referred to herein may represent, for example, cyclopropoxy or cyclobutoxy.
As used herein, the terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d as a group or part of a group means that the group is straight or branched. Examples of suitable alkenyl groups include vinyl and allyl. A suitable alkynyl group is propargyl.
As used herein, the term xe2x80x9carylxe2x80x9d as a group or part of a group means a monocyclic, fused-bicyclic or linear bicyclic aromatic ring containing 6, 10 or 12 carbon atoms, any of which rings is optionally substituted by one, two or three substituents selected from halogen, C1-6alkyl, C1-6alkoxy, or trifluoromethyl. Particular examples of such groups include phenyl, naphthyl and biphenyl. Phenyl is especially preferred.
As used herein, the term xe2x80x9cheteroarylxe2x80x9d as a group or part of a group means a monocyclic or fused-bicylic heteroaromatic ring containing between 5 and 10 ring members, of which 1 to 4 may be heteroatoms selected from N, O and S, and wherein any of which rings is optionally substituted by one or two substituents selected from halogen, C1-6alkyl, C1-6alkoxy, CO2Ra, trifluoromethyl or phenyl. Particular examples of such groups include pyrrolyl, furanyl, thienyl, pyridyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazolyl, oxadiazolyl, thiadiazolyl, triazinyl, tetrazolyl, indole, benzofuran, benzthiophene, benzimidazole, benzoxazole, benzthiazole and quinolinyl. Furanyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl and pyridyl are particularly preferred. Where said rings are substituted, preferred substituents include methyl and phenyl groups.
When used herein the term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine and iodine. The most apt halogens are fluorine and chlorine of which fluorine is preferred, unless otherwise stated.
In a further aspect of the present invention, the compounds of formula (I) may be prepared in the form of a pharmaceutically acceptable salt, especially an acid addition salt.
For use in medicine, the salts of the compounds of formula (I) will be non-toxic pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds according to the invention or of their non-toxic pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound according to the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid or sulphuric acid. Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen atom carries a suitable organic group such as an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where the compounds of the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include metal salts such as alkali metal salts, e.g. sodium or potassium salts; and alkaline earth metal salts, e.g. calcium or magnesium salts.
The salts may be formed by conventional means, such as by reacting the free base form of the product with one or more equivalents of the appropriate acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is removed in vacuo or by freeze drying or by exchanging the anions of an existing salt for another anion on a suitable ion exchange resin.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in xe2x80x9cDesign of Prodrugsxe2x80x9d, ed. H. Bundgaard, Elsevier, 1985.
A prodrug may be a pharmacologically inactive derivative of a biologically active substance (the xe2x80x9cparent drugxe2x80x9d or xe2x80x9cparent moleculexe2x80x9d) that requires transformation within the body in order to release the active drug, and that has improved delivery properties over the parent drug molecule. The transformation in vivo may be, for example, as the result of some metabolic process, such as chemical or enzymatic hydrolysis of a carboxylic, phosphoric or sulphate ester, or reduction or oxidation of a susceptible functionality.
The present invention includes within its scope solvates of the compounds of formula (I) and salts thereof, for example, hydrates.
The compounds according to the invention have at least three asymmetric centres, and may accordingly exist both as enantiomers and as diastereoisomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention.
The preferred compounds of formula (I) and (Ia) will have the stereochemistry of the 1, 2 and 5 positions as possessed by, for instance, the compound of Example 1, i.e. as shown in formula (Ib)
It will be appreciated that the preferred definitions of the various substituents recited herein may be taken alone or in combination and, unless otherwise stated, apply to the generic formula for compounds of the present invention as well as to the preferred class of compound represented by formula (Ia) and formula (Ib).
The present invention further provides pharmaceutical compositions comprising one or more compounds of formula (I) in association with a pharmaceutically acceptable carrier or excipient.
Preferably the compositions according to the invention are in unit dosage forms such as tablets, pills, capsules, powders, granules, solutions or suspensions, or suppositories, for oral, parenteral or rectal administration, or administration by inhalation or insufflation. Oral compositions such as tablets, pills, capsules or wafers are particularly preferred.
A more detailed description of pharmaceutical compositions that are suitable for the formulation of compounds of the present invention is disclosed in U.S. Pat. No. 6,071,927, the content of which is incorporated herein by reference (see in particular, column 8, line 50 to column 10, line 4).
The present invention further provides a process for the preparation of a pharmaceutical composition comprising a compound of formula (I), which process comprises bringing a compound of formula (I) into association with a pharmaceutically acceptable carrier or excipient.
The compounds of formula (I) are of value in the treatment of a wide variety of clinical conditions which are characterised by the presence of an excess of tachykinin, in particular substance P, activity. A comprehensive listing of clinical conditions, uses and methods of treatment for which the compounds of the present invention will be useful is disclosed in U.S. Pat. No. 6,071,927, the content of which is incorporated herein by reference (see, in particular, column 10, line 14 to column 22, line 18).
In particular, the compounds of the present invention are useful in the treatment of a variety of disorders of the central nervous system. Such disorders include mood disorders, such as depression or more particularly depressive disorders, for example, single episodic or recurrent major depressive disorders and dysthymic disorders, or bipolar disorders, for example, bipolar I disorder, bipolar II disorder and cyclothymic disorder; and anxiety disorders, such as panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobias, for example, specific animal phobias, social phobias, obsessive-compulsive disorder, stress disorders including post-traumatic stress disorder and acute stress disorder, and generalised anxiety disorders.
The compounds of the present invention are also particularly useful in the treatment of nociception and pain. Diseases and conditions in which pain predominates, include soft tissue and peripheral damage, such as acute trauma, osteoarthritis, rheumatoid arthritis, musculo-skeletal pain, particularly after trauma, spinal pain, myofascial pain syndromes, headache, migraine, episiotomy pain, and burns.
The compounds of the present invention are also particularly useful in the treatment of respiratory diseases, particularly those associated with excess mucus secretion, such as chronic obstructive airways disease, bronchopneumonia, chronic bronchitis, cystic fibrosis and asthma, adult respiratory distress syndrome, and bronchospasm; in the treatment of inflammatory diseases such as inflammatory bowel disease, psoriasis, fibrositis, osteoarthritis, rheumatoid arthritis, pruritis and sunburn; and in the treatment of allergic disorders such as eczema and rhinitis.
The compounds of the present invention are also particularly useful in the treatment of gastrointestinal (GI) disorders, including inflammatory disorders and diseases of the GI tract such as ulcerative colitis, Crohn""s disease and irritable bowel syndrome.
The compounds of the present invention are also particularly useful in the treatment of emesis, including acute, delayed or anticipatory emesis, such as emesis induced by chemotherapy, radiation, toxins, pregnancy, vestibular disorders, motion, surgery, migraine, and variations in intercranial pressure. Most especially, the compounds of formula (I) are of use in the treatment of emesis induced by antineoplastic (cytotoxic) agents, including those routinely used in cancer chemotherapy; by radiation including radiation therapy such as in the treatment of cancer; and in the treatment of post-operative nausea and vomiting.
The excellent pharmacological profile of the compounds of the present invention offers the opportunity for their use in therapy at low doses thereby minimising the risk of unwanted side effects.
In the treatment of the conditions associated with an excess of tachykinins, a suitable dosage level is about 0.001 to 50 mg/kg per day, in particular about 0.01 to about 25 mg/kg, such as from about 0.05 to about 10 mg/kg per day.
For example, in the treatment of conditions involving the neurotransmission of pain sensations, a suitable dosage level is about 0.001 to 25 mg/kg per day, preferably about 0.005 to 10 mg/kg per day, and especially about 0.005 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of emesis, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
In the treatment of psychiatric disorders, a suitable dosage level is about 0.001 to 10 mg/kg per day, preferably about 0.005 to 5 mg/kg per day, and especially 0.01 to 3 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day, preferably once or twice per day.
It will be appreciated that the amount of a compound of formula (I) required for use in any treatment will vary not only with the particular compounds or composition selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will ultimately be at the discretion of the attendant physician.
As used herein, the term xe2x80x9ctreatmentxe2x80x9d includes prophylactic use to prevent the occurrence or recurrence of any of the aforementioned conditions.
According to a general process (A), compounds of formula (I) may be prepared by the reaction of a compound of formula (II) with a compound of formula (III)
wherein LG represents a leaving group; in the presence of a base, followed by deprotection, if required.
Suitable leaving groups include halo, for example, chloro, bromo or iodo, or sulphonate derivatives such as tosylate, mesylate or triflate.
Favoured bases of use in the reaction include alkali metal amides and hydrides, such as potassium bis(trimethylsilyl)amide, sodium hydride or potassium hydride.
The reaction is conveniently carried out in a suitable organic solvent, such as dimethylformamide or an ether, for example, 1,2-dimethoxyethane, at a temperature in the region of 0xc2x0 C.
According to another general process (B), compounds of formula (I), in which X is methyl or hydroxymethyl, may be prepared by the reaction of a compound of formula (IV)
under either:
(a) (where R6 is methyl) catalytic hydrogenation conditions (e.g. H2, Pd(OH)2 on carbon) in a suitable solvent such as an ester, for example, ethyl acetate or an alcohol, for example, ethanol, or a mixture thereof; or (b) (where R6 is hydroxymethyl) reducing conditions (e.g. borane or BH3.THF) followed by treatment with hydrogen peroxide and a base such as sodium hydroxide, conveniently in a solvent such as an ether, for example, tetrahydrofuran, or water, or a mixture thereof.
According to another general process (C), compounds of formula (I) may be prepared by the interconversion of a corresponding compound of formula (I) in which R6 is H, hereinafter referred to as formula (V)
by reaction with a compound of formula (VI):
LG-R6axe2x80x83xe2x80x83(VI)
where R6a is a group of the formula R6 as defined in relation to formula (I) (other than H) or a precursor therefor and LG is a leaving group such as an alkyl- or arylsulphonyloxy group (e.g. mesylate or tosylate) or a halogen atom (e.g. bromine, chlorine or iodine); and, if R6a is a precursor group, converting it to a group R6 (in which process any reactive group may be protected and thereafter deprotected if desired).
This reaction may be performed in conventional manner, for example in an organic solvent such as dimethylformamide in the presence of an acid acceptor such as potassium carbonate.
Suitable alternative methods for introducing the group R6 are described, for instance, in International Patent Specification No. WO 95/18124.
According to another general process (D), compounds of formula (I), wherein X is hydrogen, may be prepared by the reduction of a compound of formula (VII)
Suitable reducing conditions include: catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, or an organic acid e.g. acetic acid, or a mixture thereof; or reduction using trifluoroacetic acid and triethylsilane.
According to another general process (E), compounds of formula (I), wherein X is CO2CH3 may be prepared by the reaction of a compound of formula (II) with a diazo compound of formula (VIII)
The reaction is conveniently effected in the presence of a rhodium catalyst such as rhodium (II) acetate dimer, in a suitable solvent such as a halogenated hydrocarbon, for example, 1,2-dichloroethane, or an aromatic hydrocarbon, for example, benzene. The reaction is preferably effected at an elevated temperature, for example at the reflux temperature of the solvent.
Compounds of formula (I) wherein X is CH2OH or CH3 may be prepared from a corresponding compound of formula (I) wherein X is CO2CH3 by convention methodology. For instance, by reduction to the primary alcohol using a borohydride such as sodium borohydride in a suitable solvent such as an alcohol, for example, methanol, at a reduced temperature, for example, at between 0xc2x0 C. and 15xc2x0 C., preferably at between 5xc2x0 C. and 10xc2x0 C. The corresponding compound of formula (I) wherein X is CH3 may be prepared from the primary alcohol by a two-step reaction. Firstly, reaction with iodine in the presence of imidazole and triphenylphosphine converts the CH2OH group to a CH2I group. The desired compound is then obtained by treatment of the iodide under conditions of catalytic hydrogenation, for instance, hydrogen in the presence of palladium on charcoal catalyst and triethylamine, in a suitable solvent such as methanol.
Further details of suitable procedures will be found in the accompanying Examples.
Intermediates of formula (II) may be prepared by reduction of a corresponding compound of formula (IX):
Suitable reducing agents will be readily apparent to one skilled in the art and include, for example, metallic hydrides, such as lithium aluminium hydride or, preferably, sodium borohydride. The reduction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, methanol, or a mixture thereof.
Where they are not commercially available, the intermediates of formula (III) above may be prepared by the procedures described in the accompanying Examples or by alternative procedures which will be readily apparent to one skilled in the art.
Compounds of formula (IX) may be prepared from a compound of formula (X)
by catalytic hydrogenation using a metal catalyst such as palladium or platinum or hydroxides or oxides thereof, preferably in a suitable solvent such as alcohol, for example, methanol or ethanol, or an ester, for example, ethyl acetate, or an organic acid, for example, acetic acid, or a mixture thereof.
Intermediates of formula (II) may also be prepared from a compound of formula (X) by treatment with K-Selectride(trademark) (potassium tri-sec-butylborohydride) in tetrahydrofuran.
Compounds of formula (X), wherein R6 is xcex1-methylbenzyl, benzyl or allyl, may be prepared from a compound of formula (XI)
(or a corresponding compound wherein the Oxe2x88x92 is OH, and the compound is associated with a counterion, such as a bromide or chloride ion) by reaction with a vinyl compound of the formula R9CHxe2x95x90CH2, in particular where R9 is cyano, SO2R13 (especially where R13 is phenyl) or CO2R13 (especially where R13 is tert-butyl), in the presence of an organic base such as a trialkylamine, for example, triethylamine. The reaction is conveniently effected in an aprotic solvent such as an aromatic hydrocarbon, for example, toluene.
The reaction of a compound of formula (XI) with acrylonitrile is particularly suitable for preparing compounds where the R9 substituent is situated on either of the carbon atoms of the two-carbon bridge.
Compounds of formula (IV) may be prepared from a compound of formula (XII)
by reaction with dimethyltitanocene in a solvent such as toluene, pyridine or tetrahydrofuran, or a mixture thereof.
Compounds of formula (XII) may be prepared by the reaction of a compound of formula (II) with L-Selectride(trademark) (lithium tri-sec-butylborohydride) followed by treatment with a compound of formula (XIII)
wherein Hal is a halogen atom, preferably chlorine.
Compounds of formula (VII) may be prepared by reaction of a compound of formula (XIV)
with a compound of formula (III) according to the method of general process (A), above.
Compounds of formula (XIII) may be prepared from the corresponding compound of formula (X) by reduction using, for example, metallic hydrides, such as lithium aluminium hydride or, preferably, sodium borohydride. The reduction is conveniently effected in a suitable solvent such as an ether, for example, tetrahydrofuran, or an alcohol, for example, methanol, or a mixture thereof.
In a preferred embodiment of the aforementioned processes, R6 is a benzyl group. The various reduction reactions described above may conveniently replace the benzyl group with a hydrogen atom. It will be appreciated from the discussion above that compounds of formula (I) wherein R6 is a hydrogen atom are particularly preferred precursors to other compounds of formula (I).
Compounds of formula (VIII) are either known compounds or may be prepared by methods analogous to those known in the literature (see, for instance, R. T. Lewis et al., J. Org. Chem. (2000) 65:2615).
Compounds of formula (XI) and (XIII) are either known compounds or may be prepared by methods analogous to those described herein.
It will be appreciated that the general methodology described above may be adapted, using methods that are readily apparent to one of ordinary skill in the art, in order to prepare further compounds of the present invention.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The exemplified compounds of this invention were tested by the methods set out at pages 36 to 39 of International Patent Specification No. WO 93/01165. The compounds were found to be active with IC50 at the human NK1 receptor of less than 100 nM on said test method.

Azabicyclic ether derivatives and their use as therapeutic agents

Abstract: wherein

Abstract: and R1, R2, R3, R4, R5 and R6 are as defined herein.

Abstract: The compounds are of particular use in the treatment or prevention of depression, anxiety, pain, inflammation, migaine, emesis or postherpetic neuralgia.


A power generation system for feeding electrical power from a generation unit into a three-phase grid via three AC terminals is disclosed. The system includes a relay arrangement for disconnecting the system from the grid having at least three relays. Each of the three relays includes a control coil and two switching contacts operated by the corresponding control coil. Each of the AC terminals is connectable to the grid via a first and a second switching contact, each of which is assigned to a different one of the relays. Further disclosed are a relay arrangement and an inverter with a relay arrangement.

The invention relates to a power generation system with a relay arrangement for disconnecting the system from a three-phase grid. The invention also relates to an inverter for providing power to a three-phase grid, and a corresponding relay arrangement.
Power generation systems are used to provide electrical power to a grid. Their importance is increasing as natural resources to run large power plants are limited and becoming more expensive. One example of such a system is an inverter, which may be used to convert a direct current (DC) into an alternating current (AC), and typically includes a semiconductor bridge circuit that functions as a DC-AC converter.
The direct current may come from any DC source such as a battery, for example. The DC source may be a photovoltaic generator that is used to feed energy into a grid.
Photovoltaic inverters intended for installation on relatively small surfaces should be as compact, easy to handle, and as lightweight as possible to minimize the need for tools during installation. Such inverters should have weight and dimensions that allow one to two people to transport and install them largely unaided.
The necessary electronic components, semiconductors, filter chokes, capacitors, and similar elements are contained within the housing. An increase in the permissible output power of the device may result in an increase in the dimensions of the individual components. Therefore, a device or its housing must be as tightly equipped as possible if it is to be compact.
To receive approval for grid parallel feeding, the applicable standards and regulations (e.g. DIN V VDE V 0126-1-1) require that power generation systems are to be connected to the grid via an automatic switching circuit. The main purpose of this device is to prevent unintentional feeding into a sub-grid or stand-alone grid, often referred to as anti-islanding, and hence serves a protective function.
To eliminate the need for an additional housing or additional installation aids, the switching circuit may be integrated into the existing inverter housing. However, this increases the size of the housing.
The aforementioned standard also requires that this switching circuit is able to interrupt the feed in process for each active conductor via two serially connected and independently activated switches. The disconnection is to be established in such a way as to ensure the safety function, even in the event of a single error.
A common practice for meeting this requirement is to use a single-pole relay with sufficient switching capacity for medium power ranges up to 10 kW or higher. This relay usually includes an independent controller and corresponding monitoring device.
Three-pole relays or contactors are only available for higher power ranges and require significantly more installation space than printed circuit board (PCB) relays. Furthermore, their assembly is labor-intensive, error-prone, and unsuitable for large-batch production. A standards-compliant solution would therefore require the use of six single-pole relays, which is not only costly but also takes up installation space.
According to an aspect of the invention, a power generation system for feeding electrical power from a generation unit into a three-phase grid via three AC terminals is provided. The system includes a relay arrangement for disconnecting the inverter from the grid. The relay arrangement includes at least three relays, each of which is equipped with a control coil and two switching contacts operated by the control coil. Each AC terminal of the system is connectable to the grid via a first and a second switching contact, each of which is assigned to a different one of the relays.
The system may include an inverter, such as a photovoltaic inverter, in particular a transformerless photovoltaic inverter. The relay arrangement may be integrated into the system's housing, and may be arranged on a circuit board of the system, thus leading to a compact system design.
In a further aspect of the invention, an inverter for converting a DC power into an AC power provided to a three-phase grid via three AC terminals is provided. The inverter includes a relay arrangement for disconnecting the inverter from the grid. The relay arrangement includes at least three relays, each of which includes a control coil and two switching contacts operated by the corresponding control coil. Each AC terminal is connectable to the grid via a first and a second switching contact, each of which is assigned to a different one of the relays.
In yet a further aspect, a relay arrangement for disconnecting an inverter from a three-phase grid with three active conductors is provided. The relay arrangement includes at least three relays, each of which includes a control coil and two switching contacts operated by the corresponding control coil. Each switching contact is connected to another switching contact that is assigned to a different one of the relays.
Other objects, advantages, and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.
The drawings below provide a more detailed description of the invention, and are intended to illustrate specific embodiments. They are not intended to limit the scope of the invention.

Power generation system and inverter for feeding power into a three-phase grid