The method of driving a display apparatus, in which the gradation scale is represented, by the subfield method, with less flicker even when driven at a frequency of 50 Hz has been disclosed. In this method, the two most weighted subfields (subfields of Bn brightness and Bn−1 brightness when it is assumed that the frame is composed of n subfields and the brightness of n subfields is Bi (i=1−n; B1≦B2 . . . Bn−1≦Bn)) are arranged at the interval of about half the length of the frame. Because of this, there exist two peaks of the light emission intensity in a frame, the interval being about half the length of the frame, and if the display apparatus is driven at a frequency of 50 Hz and the length of the frame is 20 ms, the variation period of the light emission intensity is 10 ms and the light emission intensity varies at 100 Hz, therefore, flicker is not detected.

The present invention relates to a method of driving a display apparatus in which the gradation scale is represented by a subfield structure. More particularly, the present invention relates to a method of driving a display apparatus such as a plasma display in which each subfield has at least an address period and a light period.
Description is made below with an example of a plasma display (simply referred to as a PDP hereinafter). The present invention, however, is not limited to a PDP but applicable to any type of display apparatus as long as the gradation scale is represented by a subfield structure and each subfield has at least an address period and a light period.
Since information about a PDP has been disclosed in, for example, Japanese Unexamined Patent Publication (Kokai) No. 7-271325, a detailed description is omitted here and only an outline of the structure and the driving method is given.
FIG. 1 is a block diagram that shows a structure of a display apparatus that uses a three-electrode type PDP 101. Address electrodes A1, . . . , Am of the PDP 101 are connected to an address driver 105, respectively, and address pulses are applied in the address period by the address driver 105. Y electrodes Y1, Y2, . . . , Yn are connected to a Y scan driver 102, respectively. A Y common driver 103 is connected to the Y scan driver 102. The Y scan driver 102 applies generated address pulses to the Y electrodes sequentially in the address period, and in the sustain discharge period, applies the sustain pulses generated in the Y common driver 103 to the Y electrodes in common. X electrodes are connected in common to all the display lines of the panel and sustain pulses are applied in common in the sustain period by an X common driver 104. These driver circuits are controlled by a control circuit 106. The control circuit 106 comprises a display data control portion 107 and a panel drive control portion 109. The display data control portion 107 expands the display data supplied from the outside on a frame memory 108, converts it into the data for the subfield structure to represent the gradation scale of PDP, and outputs it to the address driver 105. The panel drive control portion 109 generates control signals using the vertical sync. signals (VSYNC) and the horizontal synch. signals (HSYNC) and applies them to each portion.
FIG. 2 is a diagram that shows an example of drive waveforms of a PDP. These waveforms represent a subfield in the so-called "address/sustain period separated type-write address method." In this example, a subfield comprises a reset period, an address period, and a sustain discharge period.
In the reset period, first, all the Y electrodes are set to 0 V level, and at the same time entire surface write pulses of Vs+Vw voltage are applied to the X electrodes, pulses of Vaw voltage are applied to the address electrodes and, thus, the reset discharge is caused to occur in all the cells regardless of the previous display conditions. Subsequently, the potential of the X electrodes and the address electrodes becomes 0 V, and discharge is caused to occur in all the cells because the voltage of the wall charges themselves exceeds the discharge start voltage. Because there is no difference in potential between electrodes, no wall charges are generated by these discharges, and the discharges end with the self-neutralization of space charges. This discharge is the so-called self-neutralization discharge. By this self-neutralization discharge, all the cells reach a uniform state without wall charges. This reset period acts so that all the cells reach an identical state regardless of the lighting conditions in the previous subfield, and contributes to the stable address discharge that follows.
In the next address period, address discharges are caused to occur line-sequentially in order to set each cell to a state in correspondence with the display data. First, scan pulses of −VY are applied to the Y electrodes and, in synchronization with this, address pulses of Va voltage are applied selectively to the address electrodes that correspond to the cells that will carry out sustain discharges, that is, those to be lit, in the address electrodes, then discharges are caused to occur between the address electrode and the Y electrode of the cell to be lit, and this serves as the priming (pilot) to cause discharge to occur immediately between the X electrode and the Y electrode. The former discharge is called "priming address discharge" and the latter, "main address discharge." This causes the wall charges sufficient for the sustain discharge to accumulate on the X electrode and the Y electrode of the selected cell on the selected line.
Similar operations are carried out sequentially on the other display lines and the display data is written to the entire display lines.
In the next sustain discharge period, the sustain discharge pulses of Vs voltage (about 180 V) are applied to the X electrodes and the Y electrodes in turn to cause the sustain discharge to occur and the image display of a subfield is attained. In this "address/sustain period separated type-write address method," the brightness of each subfield is determined by the number of sustain pulses to be applied in the sustain period, that is, the length of the sustain period.
The drive waveforms in FIG. 2 are only examples, and there are various other methods. For example, there is a method in which a pulse that changes gradually is applied to decrease the light emission due to the reset discharge so that the display contrast is improved, or another method in which wall charges are left uniformly in the reset period and address discharge is caused to occur in the cell that is not lit in the address period, and so on.
In the display apparatus that uses a PDP, a frame is composed of plural subfields and the subfields to be lit are combined for each cell to represent the gradation scale. FIG. 3 shows an example in which a frame is composed of the eight subfields SF1 through SF8. Each subfield comprises the reset period, the address period, and the sustain discharge period, respectively. There can be a case in which a difference appears in the total between the period of the display data supplied from the outside and that of all the subfields, and in such a case, a rest period is provided in the frame. For example, there are two methods for TV display, that is, the Vsync frequency can be 60 Hz or 50 Hz. If the plasma display apparatus is manufactured for 60 Hz and when the apparatus is used at 50 Hz, a rest period is provided to adjust the period of a frame. In this rest period, no display operation is performed and the length of the rest period is determined in accordance with the display data supplied from the outside. It may be a case where the length remains constant after being determined once, but there can be another case where the total number of pulses, that is, the sum of sustain pulses in all the cells in a frame, is controlled for power control, or another case where the number of the sustain pulses is adjusted in order to keep the brightness ratio among subfields constant regardless of the display load of each subfield, and so on, in other words, when the sustain period (light period) is varied, the length of the rest period is varied according to the display data. As described later, there may be a case where a reset period is not provided to some subfields to improve the display contrast or to abbreviate the reset period.
The brightness ratio among subfields is typically set to, for example, 1: 2: 4: 8: . . . , where each term is a power of 2, and this brightness ratio has advantages in that the largest number of levels of the gradation scale can be attained with a small number of subfields. For example, if there are four subfields, 16 levels of the gradation scale from 0 through 15 are available, if there are six subfields, 64 levels of the gradation scale from 0 through 63, and if there are eight subfields, 256 levels, from 0 through 255, are available.
When the gradation scale is attained by the subfield method in a display apparatus of "address/sustain period separated type-write address method", the sustain periods where light emission takes place are separate from each other because an address period exists in each subfield, and a problem of the degradation of display quality such as flicker and color false contour is caused depending on the displayed image, because the lengths of the sustain periods are not equal. In Japanese Unexamined Patent Publication (Kokai) No. 3-145691, an art to suppress flicker has been disclosed, in which the most brightness-weighted subfield is arranged in the center and other subfields are arranged on both sides in order of brightness weight in the subfield structure of a frame, with the above-mentioned brightness ratio, each term of which is set to a power of 2. This art, however, cannot provide a sufficient quality of display.
Therefore, the present applicants have disclosed a driving method in which the disturbance of halftones is suppressed by providing plural subfields having a similar brightness and by combining the subfields to be lit adequately according to the level of the gradation scale.
Generally, it is known that it is a characteristic of human eyes to detect flicker with a frequency lower than 60 Hz. In the NTSC method, the Vsync frequency is 60 Hz, but it is 50 Hz in the PAL/SECAM methods employed in Europe, and so on. In a plasma display, images with a high quality are required even in operations with a frequency of 50 Hz. It was found that flicker is not a problem when the arts disclosed in the above-mentioned Japanese Unexamined Patent Publication (Kokai) No. 3-145691 and Japanese Unexamined Patent Publication (Kokai) No. 7-271325 are applied to the plasma display apparatus using the NTSC method to improve the quality of image, but in the case of the plasma display apparatus using the PAL method, flicker remains a problem even when the above-mentioned arts are applied. These phenomena are described with reference to FIG. 4. In FIG. 4A, the reset period and the address period are shown as a RESET & ADDRESS PERIOD of a single diagonal line cross-hatch although the portion of a single diagonal line cross-hatch designates the address period in FIG. 3A. This representation of FIG. 4A is used in later figures.
FIG. 4A shows an example of a frame structure in which the plural subfields having similar brightness disclosed in Japanese Unexamined Patent Publication No. 7-271325 are provided, and FIG. 4B shows the variation of the light emission intensity in the case of the frame structure in FIG. 4A, when driven at a frequency of 50 Hz. As shown in FIG. 4A, a total of 10 subfields, that is, subfields of 24, 16, 8, and 4 brightness weight in pairs, respectively, and subfields of 2 and 1 brightness weight each, respectively, are provided in the frame structure and they are arranged from both ends to the center in order of brightness weight by turns. As described above, light emission periods are separate from each other, because light is emitted in the sustain period in each subfield. If higher-harmonic waves are removed from the variation of the light emission intensity, the light emission intensity is high at both ends of the frame and low in the vicinity of the center, as shown in FIG. 4B. In the actual operation, these states are repeated, therefore, it is necessary to take the neighboring frames into account. In the neighboring frames also, the intensity is high at both ends, resulting in the light emission intensity being repeated with a frequency of 50 Hz.
FIG. 5 shows the resulting graph of the frequency analysis of the variation of the light emission intensity in the frame structure in FIG. 4. As shown in FIG. 5, the difference between the components of 0 Hz and 50 Hz visible to human eyes is small and the absolute value of the 50 Hz component is large. This means that the human eyes see the flicker of 50 Hz considerably when operating at a frequency of 50 Hz in a frame structure in which subfields are arranged as shown in FIG. 4.
FIG. 6A is a diagram that shows the frame structure disclosed in Japanese Unexamined Patent Publication (Kokai) No. 3-145691, and FIG. 6B is a diagram that shows the variation of the light emission intensity. In this case, the light emission brightness is high in the center and low on both sides of the frame. Therefore, the difference between the components of 0 Hz and 50 Hz is small and the absolute value of the 50 Hz component is large, similarly, resulting in a strong flicker at a frequency of 50 Hz.
As described above, the plasma display apparatus that operates at a frequency of 50 Hz generates a strong flicker and thus a problem in the image quality occurs.
Moreover, as shown in FIG. 3, when the plasma display apparatus is driven by the subfield method, a rest period is provided and the length of the rest period varies when the power is controlled or when the brightness ratio among subfields is maintained constant. As shown in FIG. 3, a rest period is provided at the end of the frame and when the rest period is lengthened, the position of the sustain period, that is the light emission period, of each subfield varies. The frame structure is determined in accordance with the display method, and it may be a case where the image quality is degraded if the position of the sustain period of each subfield varies. For example, when driven at a frequency of 50 Hz, a problem in that the intervals between the sustain periods of each subfield are narrowed, the frequency component of 50 Hz is increased and the image quality is degraded, is caused.
Among various items that relate to the image quality, the above-mentioned flicker and the degradation of the contour in animation are problems relating to the subfield method. The problem of the degradation of the contour in animation, for example, results in the color false contour, in which the contour of a moving part is colored, when animation is shown on the color display apparatus. The art disclosed in Japanese Unexamined Patent Publication No. 7-271325 suppresses the occurrence of color false contour, but if a plasma display apparatus to which this art is applied is driven at a frequency of 50 Hz, the problem of flicker occurs. It is thus found impossible to improve every item relating to the image quality with a limited number of subfields.

Method of driving display apparatus and plasma display apparatus


The invention includes a method and system for distributing and executing executable code. Before sending executable code to a client, a distributing authority associates a privilege request code with the executable code. The privilege request code indicates a requested set of privileges that the executable code will potentially exercise during execution. The distributing authority digitally signs the executable code and associated privilege request code and then distributes it for eventual execution by clients. Before executing the executable code, a client verifies the digital signature to confirm the authenticity and integrity of the executable code and associated privilege request code. This verification utilizes a hierarchy of certifying authorities. While the code executes, the client monitors it and prevents it from exercising privileges that are not in the requested set of privileges.

There has been a dramatic increase in reliance upon service providers accessible via electronic data communications networks such as the Internet. Such service providers are generally interested in providing access to the widest possible client audience at the lowest cost. Very recently, a number of solutions have emerged that allow service providers to achieve these goals. In particular, there has been very rapid growth in the use of the standardized hypertext capabilities of the World Wide Web (WWW) on the Internet. The standardized nature of the WWW, as well as the very low costs involved in accessing the Internet, have eliminated many of the previous hurdles to service development and distribution.
While the Internet's World Wide Web and other similar environments allow service providers to build systems that can efficiently deliver information to potentially large numbers of clients, they also impose limitations. These limitations are a direct consequence of the desire to provide a simple, generic processing model for multiple purposes.
It has been recognized that these limitations can be addressed to some degree by allowing servers to send executable code to clients, for execution by the clients themselves. This allows a server to build client software for a specific purpose, thereby allowing the service provider to add functionality to existing client software. An advantage of this approach is that it can in many cases reduce both the processing burdens on the server and the communications requirements between the server and the client.
While it might be very desirable for a client to execute server-provided software, the potential threat to security is a serious drawback. For a client to be willing to execute server-defined functionality, the client must be assured that no adverse effects will occur. Specifically, there must be a guarantee that existing client data will not be read or modified and that hostile code (viruses, Trojan horses, etc.) will not be generated and installed on the client system.
This is particularly problematic in the public network environment since mechanisms for establishing trust between a client and server are not widely deployed, and data communications channels are open to eavesdropping and tampering. Because of this, general purpose compiled programming languages are not a solution. It is inherently unsafe in a public network environment for a client to accept binary executable images from a server and execute them. Since the server-provided programs would have access to the full resources of the client computer environment, they could potentially perform any of various different types of dangerous or hostile operations.
Binary executable code also has the disadvantage of being architecture-specific. It is a significant complication for the server to determine the computer hardware in use by the client and the operating system, and to provide different executable modules for use with different systems.
These issues lead naturally to consideration of an interpreted language. This approach allows a server to create program scripts that can be executed on the client to extend its functionality, while providing a more controlled execution environment and architecture neutrality. Interpreters can be implemented on a variety of computer platforms and operating systems to provide an isolation layer between the language specification and the underlying architecture. Hence, a server can provide scripts for extensions that are executable on a variety of client machines. Interpreters can also perform runtime checking of various sorts to enforce access of specific resources and to detect when scripts have been tampered with. Sun Microsystem's recently announced Java language is an example of this approach.
From a client's perspective, the optimal situation is one in which it needs only trust the interpreter. Once a client has an interpreter from a trusted source, the client should be able to execute any script with complete safety. This is where existing approaches fail. Java, for example, is a general purpose programming environment which allows the generation of complex applications including I/O operations. Java is specifically designed to allow easy access to network facilities, hence it has the potential to surreptitiously transmit client confidential information; destroy client data, and perform other hostile actions. The protection against such behavior relies on the ability to validate Java scripts and determine their authenticity. Importantly, however, Java and many other systems rely on a trust relationship between the server and the client as the basis for their safety. We believe that this is a significant limitation which our invention addresses.
In addition to eliminating the requirement of a trust relationship between the client and server, our invention provides for situations in which a client may wish to execute server-provided code that performs I/O and other potentially dangerous operations. Our invention provides a secure extension mechanism that enables servers to download general purpose executables with full client validation of their origin and authenticity.

System and method for safety distributing executable objects


Methods of forming a multi-segment chip or integrated circuit device are provided. The multi-segment chip may comprise at least two blocks, such as an analog integrated circuit block and a digital integrated circuit block, with substrates that are isolated from each other. Thus, each block may have independent operation voltage or other characteristics.

Many state-of-the-art chips are expected to perform complicated tasks, which may require portions of an integrated circuit device to have different electrical characteristics. These different portions of the integrated circuit device may be referred to as "sub-circuits," which may require contradictory electrical characteristics, such as high voltage versus low voltage, analog (high precision) versus digital logic and/or mixed signal, low frequency versus high frequency, high immunity to noise versus relative insensitivity to noise, parasitic crosstalk and so on. A major challenge in forming integrated circuit devices is trying to combine various sub-circuits within one integrated circuit device without compromising quality of signal, functionality, size and cost.
At present, there are several methods that attempt to solve this major challenge. None of these methods are fully successful or cost effective. These methods can be generally categorized into two groups: "multi-die" solutions and "on-chip" solutions.
For "multi-die" solutions, there are presently two methods called "multi-chip-module" and "multi-package." "Multi-chip-module" employs packaging several separate but functionally related dies, i.e., chips, into a single electrical package. The separate dies within the single electrical package are electrically connected in order to perform the combined task. This method may suffer from several serious drawbacks and may not completely answer cost, size and other challenges. This method may have a high fabrication cost due to the multiplicity of dies and a larger package, and it may increase package complexity (e.g., complicate design of each die). It may compromise performance quality since signals need to be driven across wire bonds pads versus submicron on-chip interconnects, and thus increase power dissipation, noise and reduce speed.
"Multi-package" employs packaging several separate but functionally related dies i.e.,—chips, each into separate electronic packages. All packages then must be mounted and connected on a printed circuit board (PCB) in order to perform the combined task. This method may also suffer from several serious drawbacks. First, like the "multi-die" method, the multi-package method may increase total cost of the solution and complexity. The method may degrade quality of performance even more since driving PCB wires in addition to the wire bonds pads impedes speed further and increases power dissipation and noise.
For "on-chip" solutions, there are presently two methods called "on-chip-compensation" and "grounding-and-isolation-network." Compensation circuitry employs various specially designed electronic circuits that do not perform part of the intended task but rather attempt to compensate for the problems that occur as a result of the existence of mixed electrical characteristics on a single die. This method may suffer from serious drawbacks. The method may significantly increase design complexity and hence design cost. The method may also increase development risk due to additional new sub-circuits, and to present additional sub-circuits is only a partial solution at best.
Extensive "grounding-and-isolation-network" employs additional ground planes and power buses beyond those required for performing the task itself. This method may also suffer from serious drawbacks. It may increase die area and number of pads, and may increase package size, all of which increases total cost. The method may add additional design complexity to the chip and may increase the complexity of the external circuitry that is required to rout and supply the extra ground and power lines. This method may be only a partial solution that suffers from parasitic substrate coupling and compromises quality of performance.

Forming a multi segment integrated circuit with isolated substrates


A driving apparatus for at least one recording head comprises a first waveform signal receiver, a first drive signal provider, a first delay circuit, and a second drive signal provider. The first waveform signal receiver receives, through signal lines, a plurality of waveform signals representing various recording modes. The first drive signal provider generates drive signals on the basis of the plurality of waveform signals received by the first waveform signal receiver, and supplies the drive signals to one of recording element groups included in the at least one recording head. The first delay circuit delays the waveform signals received by the first waveform signal receiver. The second drive signal provider generates drive signals on the basis of the waveform signals delayed by the first delay circuit, and supplies the drive signals to another recording element group.

1. Field of the Invention
The present invention relates to a driving apparatus for a recording head or beads capable of ejecting inks of different colors, applicable to a color inkjet printer or the like, and also relates to an image recording apparatus including the driving apparatus.
2. Description of Related Art
Color inkjet printers are generally classified into two types. The first type has a single recording head including nozzle rows corresponding to the respective colors, for example, four colors of yellow (Y), magenta (M), cyan (C), and black (B). The second type has recording heads corresponding to the respective colors. Actuators are provided so as to correspond to the respective nozzles. Inks are ejected through nozzles by driving the corresponding actuators.
In printers of the above constructions, if a large number of actuators corresponding to the respective nozzles are driven at the same time, there may arise a problem of overcurrent or crosstalk. To relieve the problem, JP-A-5-138900 discloses a technique in which timings for supplying drive signals to actuators are staggered little by little. More specifically, a timing generator block generates waveform signals in which timings of rising edges of pulses are staggered from one another. Each recording head selects one of the waveform signals to be used as a drive signal for the actuators of the recording head. In this manner, the actuators of each recording head can be driven at timings different from the actuators of the other recording heads. The above problem can be relieved thus.
On the other hand, in recent years, for tone control and hysteresis control, a technique is adopted in which waveform signals different from one another in shape for one dot are selectively used as actuator driving signals, as disclosed in JP-A-2000-158643. The hysteresis control is for relieving a problem in which vibration upon driving an actuator remains to affect the later driving operation. More specifically, a waveform signal to be used to form a present dot is selected depending on the absence or presence of a dot immediately before and/or after the present dot. In this technique, the waveform signals for forming one dot differ from each another in the number of pulses, pulse width, pulse height, and the like. For example, the various numbers of pulses for one dot can vary the number of ink ejections for one dot and therefore the total quantity of dropped ink for one dot. This can realize tone control. On the other hand, the various widths of pulse to form one dot, for example, can realize hysteresis control.
In the former of the above-described two techniques, waveform signals generated in the timing generator block are identical in the number of pulses for one dot, and pulse width, and pulse height. The waveform signals differ from one another only in timing of rising edge of pulse. In the former technique, therefore, tone control and hysteresis control are impossible.
In the latter of the above-described two techniques, waveform signals are repeatedly output at constant intervals and the waveform signals themselves are used as timing signals for driving actuators. Therefore, if this technique is applied to a color printer and each color recording head is intended to be time-divisionally driven like the former technique, the waveform signals must be supplied to each recording head. As a result, a great number of signal lines are required between the recording heads and the printed circuit board in the printer body. This brings about a problem of difficulty of routing of the signal lines. In addition, there may arise problems of increasing the manufacturing cost of the printer and complicating the construction.

Driving apparatus for recording head and image recording apparatus including the driving apparatus


Novel chimeric fusion proteins comprising immunodominant epitopes of GAD and insulin are provided. Also provided are immunomodulatory methods for the use of such proteins for both the prevention and treatment of Type 1 diabetes mellitus. The chimeric fusion proteins of the invention are useful in predicting risk of onset of Type I diabetes, determining prognosis of Type 1 diabetes patients early in disease progression, and in evaluating patients for suitability as recipients of transplants of pancreatic cells or tissues. The administration of the proteins of the invention in accordance with the immunomodulatory methods of the invention results in beneficial effects on disease development and severity in patients suffering from or predicted to be at risk of developing Type 1 diabetes, as well as on the outcome of transplants of pancreatic cells or tissues in Type I diabetes patients.

The discussion in this section is not limited to subject matter that qualifies as "prior art" against the present invention. Therefore, no admission of such prior art status shall be implied or inferred by reason of inclusion of particular subject matter in this discussion, and no declaration against the present inventors' interests shall be implied by reason of such inclusion.
Diabetes Mellitus
Diabetes mellitus is the most common endocrine disease, and is characterized by abnormalities of glucose metabolism. The abnormal glucose metabolism associated with this disease results in hyperglycemia (high blood glucose levels) and eventually causes complications of multiple organ systems, including eyes, kidneys, nerves, and blood vessels. Patients with persistent hyperglycemia or abnormal glucose tolerance are generally diagnosed with the disease, although most commonly patients initially present with excessive urination (polyuria) and frequent drinking due to extreme thirst (polydipsia). These typical initial symptoms result from the osmotic effects of hyperglycemia.
The pathogenesis of diabetes mellitus is typically associated with pancreatic dysfunction, particularly of the beta cells of the pancreatic islets of Langerhans. This dysfunction may lead to destruction of the islet beta cells, which produce insulin, a glucose regulatory peptide hormone. Diabetes mellitus has been generally categorized as insulin dependent or type 1, versus non-insulin dependent, or type 2. However, this terminology has evolved as the disease has become better understood. For example, it has been found that in some patients suffering from non-insulin dependent diabetes, the disease progresses into an insulin dependent form, while in other patients insulin dependence does not develop.
Patients are thus often categorized in terms of the mechanisms of pathogenesis of islet destruction, and the designation type 1 is now used to refer to autoimmune islet pathogenesis, i.e., to diabetes caused by islet-specific autoimmune attack, and is so used herein. The term insulin dependent diabetes mellitus (IDDM) refers to Type 1 diabetes that has progressed to a stage where enough autoimmune destruction of the pancreatic beta cells has occurred to produce overt symptoms. The term pre-IDDM refers to an autoimmune condition that can be detected by biopsy or by analysis of autoimmune responses, in which pancreatic islet beta cells are being subject to a specific autoimmune attack to an extent where some cells may be subject to destruction. In pre-IDDM, however, the destruction (if any) has not progressed to an extent sufficient to require the administration of insulin. Since there can be a point in the early stages of Type 1 diabetes in which overt symptoms are observed but some islet function remains (known as the "honeymoon period", not all Type 1 diabetes is classified as IDDM, and not all pre-IDDM presents without overt symptoms.
Complications of Type 1 Diabetes The metabolic complications associated with the abnormal metabolism caused by insulin insufficiency can affect numerous organ systems. The most common acute metabolic complication is that of diabetic ketoacidosis, characterized by severe hyperglycemia (and resulting hypovolemia caused by osmotic diuresis) as well as metabolic acidosis induced by excess free fatty acid release and the production of ketone bodies.
In addition to the acute metabolic complication of ketoacidosis, the diabetic patient is susceptible to a series of late complications that cause considerable morbidity and premature mortality. Atherosclerosis occurs more extensively and earlier in diabetics than in the general population as a result of abnormalities in both glucose and lipid metabolism. This vascular pathology can lead to, inter alia, coronary artery disease, stroke, and peripheral vascular disease with gangrene. Retinopathy is another vascular complication of diabetes. Diabetic retinopathy is a leading cause of blindness, and is initiated by increased permeability of retinal capillaries which can progress to occlusion, hemorrhage, aneurysm formation, and neovascularization known as proliferative retinopathy.
In addition to vascular complications, kidney and neurological diseases (nephropathies and neuropathies) are common complications of diabetes. Diabetic nephropathy causes about half of end-stage renal disease in the United States. Histologically, the nephropathy is characterized by glomerular basement membrane widening and mesangial thickening. Initial signs include increasing proteinuria, with azotemia ultimately leading to renal failure. Diabetic neuropathy can affect any part of the nervous system, with the possible exception of the brain. The neuropathy is most commonly seen as peripheral polyneuropathy, with symptoms including numbness, paresthesias, severe hyperesthesias, and pain. Autonomic neuropathy can cause gastrointestinal dysfunction, orthostatic hypotension, bladder dysfunction or paralysis, and impotence. Diabetic foot ulcers represent a special problem of diabetics, and appear to be due primarily to abnormal pressure distribution secondary to diabetic neuropathy. The ulcerous lesions are often worsened by concomitant peripheral vascular disease and infection.
As mentioned above, meticulous control of blood glucose has been associated with amelioration of the late complications of Type 1 diabetes, suggesting that that preservation or restoration of beta cell function could reduce or eliminate the majority of the pathologic complications of the disease.
Pathogenesis of Type 1 Diabetes Type 1 diabetes only develops in genetically susceptible individuals, and symptoms generally appear before age 40, with the peak incidence of onset of overt symptomology occurring in the second decade of life. The pathogenesis of Type 1 diabetes is characterized by an initial phase of leukocyte infiltration into the islets, referred to as insulitis, followed over a period of time by the actual destruction of the islet beta cells by autoimmune attack. The insulitis phase is characterized by infiltration of pancreatic islets by both lymphocytes and cells of the monocyte/macrophage lineage, and entails both cell-mediated inflammation as well as attack by islet-specific cytotoxic antibodies. Overt clinical symptoms of diabetes mellitus are generally manifested when over 90% of the islet beta cells are destroyed; however, as discussed more fully below, it is now possible to accurately detect individuals undergoing earlier stages of type 1 pathogenesis, i.e., before enough islet beta cells have been lost to produce overt clinical symptoms.
The autoimmune process is generally thought to be induced by an environmental stimulus. One reason for this belief is that an identical twin has only a fifty/fifty chance of developing IDDM if his identical sibling has the disease.
T Cells The autoimmune destruction of the beta cells of the pancreatic islets in Type 1 diabetes is believed to be initiated by white blood cells (leukocytes), most importantly T cells. T cells, or T-lymphocytes, are mononuclear white blood cells that provide many essential immune functions. The importance of T cells in human autoimmune diseases has been increasingly appreciated in the past two decades. Studies using treatments that result in generalized immunosuppression have defined a critical role for a subset of T cells, known as CD4+ or helper T cells, as primary regulators of all immune responses (both cellular and humoral) to protein or peptide antigens.
T cells mediate tissue injury by indirect and direct means. T cells of both CD8+ (cytotoxic) and CD4+ (helper) subsets secrete a variety of inflammatory cytokines that can damage tissues indirectly by activating various other types of white blood cells. Examples of such T cell effects include activation of antibody secreting B cells (stimulating humoral immune activity) and activation of macrophages, which can cause acute tissue damage and inflammation by releasing hydrolytic enzymes, reactive oxygen species, and additional pro-inflammatory cytokines. In addition to these indirect effects of T cell activity, direct tissue damage can be mediated by CD8+ cytotoxic T cells attacking cells displaying target antigens.
One unique aspect of the physiology of T cells is the presence of membrane bound antibody-like binding structures called T cell receptors (TCRs) on their cell surfaces. Like antibodies, TCRs bind with high specificity to particular antigens. Like antibody-producing cells, which develop as multitudinous clones of cells, each clone producing antibodies with unique specificities, T cells develop as a vast number of distinct clones, and any particular T cell clone expresses a single type of TCR with a defined binding specificity. T cell clones with TCRs that bind specifically to self antigens are responsible for the development of autoimmune diseases.
Studies of the interactions of antibodies and TCRs with their specific antigens have shown that a particular polypeptide antigen typically comprises numerous submolecular features, known as epitopes, that each can serve as a distinct binding site for a particular antibody or TCR.
T Cells and Autoimmune Diseases In autoimmune diseases, only a 25 limited number of T cell clones, reactive with various epitopes of a small number of autoantigens, become activated and are involved in pathogenesis. Even in individuals suffering from autoimmune diseases, only a small percentage of T cell clones (0.1-1%) are known to recognize autoantigens.
Various mechanisms have been postulated to play a role in the pathogenic activation of disease-causing autoreactive T cells. Primary activation of antigen presenting cells (APCs) by infection or local inflammation is implicated in one such mechanism. APCs activated in this way can then provide powerful co-stimulation for hitherto unreactive T cells.
Other proposed mechanisms involve the polyclonal activation of previously quiescent autoreactive T cells by superantigens, such as bacterial toxins; or a coincidental molecular mimicry between foreign and self antigens (Abbas et. al. 1994). In this last case, the host immune system mounts a response to an epitope on a protein expressed by a pathogen, such as a virus, that resembles a homologous epitope on a host protein. Autoimmune attack then results from the cross-reactive immune response that ensues.
In addition to external factors, underlying the emergence of all T cell-mediated autoimmune disease is a complex pattern of inherited susceptibility determined by multigenic factors. For further discussions of these various factors, Steinman, 1995, reviews current theories of autoimmunity.
Alterations in the T cell repertoire occur naturally during T cell development. Only a small fraction of thymocytes (immature T cells) survive the intrathymic development and selection events that result in emigration of developing T cells to the peripheral circulation and the completion of their maturation (von Boehmer, 1988; Marrack and Kappler, 1987). Experimental evidence strongly suggests that a large number of thymocytes that bear receptors for autoantigens are initially present in the thymus. Recent studies have yielded evidence suggesting that a process referred to as programmed cell death, or apoptosis, destroys these autoreactive thymocytes in the thymus while sparing thymocytes that are not autoreactive. Apoptosis thus plays a large role in shaping and maintaining the T cell repertoire and contributes to the establishment of self-tolerance by actively eliminating cells expressing autoreactive TCRs.
It has recently been discovered that T cells are sensitive to apoptotic cell death induced by a variety of stimuli at multiple points in their lifespan (see, for example, Lenardo 1991; Boehme and Lenardo 1993; Critchfield et al. 1994). Positive selection factors are also believed to play a role in regulating the survival of specific T cell clones. The reduction or expansion of the number of individual T cells of a particular clone in an organism by these and other mechanisms serve to modulate the responsiveness of the organism's immune system to a particular antigen. It is now firmly established in several autoimmune disease models, as well as in certain viral infections, that apoptosis can be induced (upon exposure to antigen under certain defined conditions) in mature peripheral antigen-specific T lymphocytes as well as in immature thymocytes.
Apoptosis occurs in many biological systems (see, for example, Kerr et al. 1991; Lockshin and Zakeri, 1991; Cohen et al. 1992; Duvall and Wyllie, 1986; Cotter et al. 1990). A cell undergoing apoptosis undergoes a specific program of events—cellular and biochemical processes that depend upon active metabolism and contribute to the cell's self-destruction. In apoptotic T cells, the nucleus shrinks, the chromatin condenses, the genetic material (DNA) progressively degrades into small (nucleosomal repeat sized) fragments, there is cytoplasmic compaction, the cell membrane forms blebs, and the cell eventually collapses (Kawabe and Ochi, 1991; Smith et al. 1989). Cells cannot recover from apoptosis, it results in irreversible cell death (Kawabe and Ochi, 1991; Smith et al. 1989).
Recent reports have suggested a role for the TNF-related cytokine known as the FAS ligand and its receptor, CD95 (the FAS receptor), in the induction of apoptosis in T cells (Crispe et al. 1994; Nagata and Suda, 1995; Strasser, 1995; Dhein et al., 1995; Brunner et al., 1995; and Ju et al., 1995).
Islet Beta Cell Autoantigens As discussed above, the onset of Type 1 diabetes is considered to be mediated by T cells. The disease is believed to be a consequence of inappropriate T cell responses specific to certain islet beta cell proteins that act as autoantigens. In addition to autoreactive T cells, autoantibodies against various self antigens have also been reported in IDDM patients. The antigens reported to be bound by these autoantibodies include many of those that have been reported to be recognized by autoreactive T cells.
Autoantigens that are subject to autoimmune responses in Type 1 patients include the 64-65 kDa GAD (glutamate decarboxylase) and the 67 kDa GAD autoantigens; insulin; sialyglycolipid; a 38 kD antigen from the secretory granules of beta cells; an antigen cross reactive with antibodies to bovine albumin known as the beta cell p69 protein, PM-1, or disease-modifying antigen, a beta cell cytoskeletal protein known as peripherin, glucose transporter proteins, including GLUT-2; heat shock protein 65 (HSP 65), including the p277 peptide; carboxypeptidase H; a 52 Kd molecular mimic of Rubella virus antigen; a beta cell membrane associated protein of 150 kDa; a protein antigen located at the secretory pole of the rat insulinoma cell line RINm38, referred to as the RIN polar antigen; and (at first) poorly characterized antigens isolated by immunoscreening of an islet cDNA expression library, referred to as ICAl2 and ICA512. ICA512, now also known as IA-2, is immunologically related to phogrin, which is also subject to autoimmune responses in Type 1 patients (Hatfield et al., 1997).
The relative importance of these various autoantigens to autoimmune pathogenesis, and the timing with which each plays a role during the course of disease onset and development, are the subject of considerable uncertainty and consequent controversy in the art. Further uncertainty stems from the fact that each supposed autoantigen comprises numerous epitopes, some of which may be have disease promoting effects while others may have disease suppressive effects.
While not wishing to be bound by any particular theory of operation, in accordance with certain aspects of the invention insulin and GAD are believed to provide the most effective therapeutic effects on the development of Type 1 diabetes of any of the autoantigens implicated as playing a role in the pathogenesis of the disease. In accordance with certain other aspects of the invention, IA-2 is also believed to provide effective therapeutic effects.
Autoantibodies to 64-65 kD GAD (hereinafter GAD 65) normally are detected before the onset of clinical insulin dependent Type 1 diabetes mellitus, and among nondiabetic relatives of patients with IDDM as well as others at risk. These autoantibodies have been suggested to be the best predictive autoantibody marker for impending Type 1 diabetes.
GAD 65 and GAD 67 are encoded by different genes on different chromosomes, the genes being about 70% homologous. Human islets only express GAD 65, although both protein forms are found in the brain. Evidence of lymphocyte specific immunity to GAD 65 has been demonstrated and found to be closely associated with IDDM. Recent studies in the NOD mouse model of diabetes have indicated that T cell responses to GAD 65 precede those to other putative autoantigens and that early induction of T cell tolerance to GAD 65 can prevent onset of disease.
Kaufman et al (1993) and Tisch et al (1993) have presented data that suggest that GAD responses are the most important in disease development, as they were reported to arise first during the development of Type 1 diabetes, with responses to other beta cell autoantigens only appearing much later in the course of the disease, with insulin reactivity being amongst the last to appear. These findings were interpreted as indicating that GAD 65 is the key autoantigen in Type 1 diabetes, and that modulation of autoimmune reactivity with GAD would be the most appropriate target for reducing disease pathology. In accordance with this theoretical understanding of disease progression, modulation of insulin reactive T cells would be closing the barn door after the horses had gone, the anti-insulin reactions being observed so late in disease progression that their modulation would not be expected to affect the onset or severity of disease.
Insulin autoantibodies (IAA) can be detected in around 50% of new onset patients, and are highly associated with islet cell autoantibodies (ICA) and the HLA-DR4 phenotype. Other studies suggest that individuals with both ICA and IAA have a much higher risk for developing overt Type 1 diabetes than those with either marker alone. T cell responses to insulin as an autoantigen have also been described. In one study cellular responses to human insulin were present in almost 90% of ICA-positive first degree relatives of IDDM patients. Also, as discussed below in the examples, insulin reactive T cells from diabetic NOD mice can transfer diabetes to non-diabetic NOD mice.
Responses of T cells from Type 1 diabetes patients or from at-risk individuals to undefined islet cell preparations have suggested that T cells also respond to other islet cell antigens. These include a 38 kD antigen from the secretory granules of beta cells, and serum albumin. In addition, heat shock protein (HSP) 65 has been implicated as a T cell autoantigen based upon the finding that HSP-specific T cells transfer disease in NOD mice.
Carboxypeptidase H is a molecule found in islet secretory granules and is associated with the production of peptide hormones and neurotransmitters. It was identified as a potential islet autoantigen by the screening of cDNA expression libraries with sera from IDDM or pre-IDDM patients.
Several other putative islet cell antigens, such as ICAl2 and ICA512, have also been identified by screening of cDNA expression libraries.
Intra-antigenic and inter-antigenic spread of autoreactivity ("epitope spreading") are related phenomena associated with autoimmune diseases in which additional epitopes within an antigen, or additional antigens within a target tissue, become targeted by autoreactive T cells during disease progression. Such antigen spreading has been observed during the course of the inflammatory autoimmune process in the murine models of experimental allergic encephalomyelitis (EAE) and insulin-dependent diabetes (Lehmann et al. 1992; McCarron et al. 1990; Kaufman et al. 1993; Tisch et al. 1993).
These findings of antigen/epitope spreading suggest that for a therapeutic treatment to provide effective immune tolerance to islet beta cell autoantigens, the treatment will need to target a heterogeneous population of specific autoreactive T cells. Therefore, in order for antigen administration to be maximally effective in the prevention and treatment of Type 1 diabetes, it is desirable that a plurality of the immunodominant epitopes of both insulin and GAD 65 be presented to the disease producing autoreactive T lymphocytes.
Prediction and Diagnosis of Type 1 Disease As discussed above, there is a genetic aspect to the incidence of Type 1 diabetes. Accordingly, genetic tests can identify certain individuals at increased risk of developing the disease (see, for example, Walston et al. 1995). Furthermore, individuals with a known family history of the disease can be monitored for early, preclinical signs of disease development, e.g., by monitoring levels of the autoantibodies and autoreactive T cells discussed herein.
Autoantibodies Among the autoantibodies known to be associated with Type 1 diabetes, those directed against GAD 65 are the ones that appear earliest and are present in the largest number of patients. Overall, recent studies have shown that over 80% of individuals with preclinical diabetes have GAD-specific autoantibodies. In this case an individual with preclinical disease is defined as a first degree relative of a Type 1 diabetes patient with ICA. The antigens identified by ICA are ill-defined, but together with IAA and GAD-specific autoantibodies, they yield a high predictive value for onset of diabetes in preclinical individuals. Interestingly, in actual early onset disease, the frequency of GAD-specific antibodies declines. This could be due to the fact that GAD 65 reactivity declines with beta cell destruction.
Prediction of Type 1 diabetes may also be facilitated by monitoring of the subject's blood sugar levels, preferably, in conjunction with the administration of a glucose tolerance test to the subject. Such procedures are preferably carried out in combination with the monitoring of titers of the subject's circulating IAA, ICA, and GAD autoantibodies.
In accordance with the present invention, the chimeric proteins of the invention are fusion proteins that may be used as antigenic substrates for the detection of circulating autoantibodies, particularly IAA and/or GAD 65 autoantibodies, in diagnostic assays such as Western blot, ELISA, RIA, ELISPOT, and the like.
T cells Assays for the detection of T cells with specific reactivities are well known in the art, and include the mixed lymphocyte reaction (MLR) and the ELISPOT assay. ELISPOT assays are described, for example in Taguchi et al., J Immunol Meth 1990, 128:65 and Sun et al., J Immunol 1991 146:1490. In accordance with the invention, the chimeric fusion proteins of the invention may be used as substrates in such assays for the detection and quantification of insulin reactive T cells and/or GAD 65 reactive T cells and/or IA-2 reactive T cells.
Current Methods for Prevention and Treatment of Type 1 Diabetes. While diabetes has been studied for centuries, only a few effective treatments are available for type 1 disease. The first line of treatment is diet, with appropriate caloric intake based on ideal body weight and a defined distribution among protein, glucose, and fat. However, in IDDM patients, the most important component of therapy is the administration of insulin, the goal of which is to maintain glucose levels as close to the normal range as possible throughout the day. Insulin is available in rapid, intermediate, and long-acting formulations which vary in onset, peak, and duration of action, and can be used in varying schedules of administration to attempt to optimally regulate plasma glucose levels.
Intensive insulin therapy refers to a rigorous regimen of administration of hormonally effective insulin and monitoring of blood sugar levels. This regimen is designed to control blood glucose as precisely as possible. The results of the multicenter Diabetes Control and Complication Trial established that complications of diabetes are significantly diminished by better control of blood glucose levels, and thus demonstrated the desirability of intensive insulin therapy. One problem with this approach is that intensive insulin therapy requires a high level of patient awareness and compliance, as well as a highly skilled care team of physicians, nurses, and dietitians. The goals of intensive insulin therapy are thus extremely difficult to achieve, even with motivated and educated patients. Another problem is that a higher rate of hypoglycemia is seen in such rigorously treated patients than in patients receiving standard, less rigorous, insulin regimens.
The Diabetes Control and Complication Trial highlighted not only the benefit to overall metabolic health of maintaining normal blood glucose levels, but also a fundamental problem associated with the treatment of Type 1 diabetes, namely that the overt symptoms of the disease are manifested only when essentially all of the patients' islets are destroyed. Oral agents for diabetes, such as the sulfonylureas, act primarily by stimulating the release of insulin from dysfunctional beta cells, and thus are not useful for most patients with type 1 disease, i.e. for those patients with IDDM.
A major goal in the treatment of diabetes has been to develop therapies capable of aborting the autoimmune attack on the islet beta cells prior to their complete destruction, thereby preserving enough endogenous function to maintain normal metabolic control.
Induction of tolerance In the NOD (non-obese diabetic) mouse model of diabetes, it has been shown that oral feeding of insulin delayed the onset and reduced the severity of the disease. The mechanism proposed to explain oral tolerance is that oral antigen administration induces populations of antigen-specific Th2 T cells that secrete antiinflammatory cytokines such as IL-4, IL-10, and TGF-beta. These T cells circulate and are activated to secrete cytokines only in the presence of their specific antigen. Thus, insulin-specific Th2 T cells would be activated only in the pancreas where they would produce suppressive cytokines to modulate the autoimmune process. This mechanism does not require, therefore, that the oral antigen actually represent a disease-specific autoantigen, but rather only that it is expressed in a tissue specific fashion.
In contrast, methods designed to produce T cell tolerance (e.g., by anergy or apoptosis) require the identification of the actual disease-specific autoantigens that are targeted by autoimmune attack. Such antigens are then administered to patients in an appropriate tolerizing fashion (which may also induce non-antigen-specific tolerizing effects). Given that Type 1 diabetes is in significant measure a disease mediated by islet-specific autoreactive T cells, therapy of this type should be feasible in principle. Thus, induction of neonatal tolerance to GAD 65, as referred to above, prevented onset of disease in NOD mice. In addition, injection of crude islet extracts intrathymically, where tolerization of developing T cells takes place, has also protected both NOD mice as well as pre-diabetic BB rats from developing clinical disease.
One approach taken to induce insulin tolerance involves the parenteral administration of insulin, in combination with a conventional adjuvant (e.g., Freund's adjuvant). Typically this approach involves the administration of doses of insulin that would not be large enough to be expected to cause insulin shock in the patient. Notably, the insulin moieties of the chimeric fusion proteins of the present invention are hormonally ineffective, and are thus suitable for use in accordance with the methods of U.S. application Ser. No. 08/565,769, filed in the name of Yi Wang, which is incorporated herein by reference.
Apoptosis Apoptosis is a form of programmed cell death that occurs in many biological systems (Kerr et al., 1991; Lockshin and Zakeri, 1991; Cohen et al., 1992; Duvall and Wyllie, 1986; Cotter et al., 1990). As discussed above, an apoptotic cell undergoes a specific program of events that depend upon active metabolism and contribute to its own self-destruction. T cells that do not undergo apoptosis, but which have become activated, will carry out their "effector" functions by causing cytolysis, or by secreting lymphokines that cause B cell responses or other immune effects (Paul, 1989, pp. 3-38). These "effector" functions are the cause of tissue damage in autoimmune and other diseases. A powerful approach to avoiding disease is thus to permanently eliminate by apoptosis only those T cells reactive with autoimmune disease-inciting antigens, while leaving the majority of the T cell repertoire intact. The use of auto-antigens to carry out this approach is described in PCT patent publication No. 94/28926, filed in the name of Michael J. Lenardo, and entitled Interleukin-2 Stimulated T Lymphocyte Cell Death for the Treatment of Autoimmune Diseases, Allergic Disorders, and Graft Rejection, and PCT patent publication No. 94/03202, filed in the name of Michael J. Lenardo, Stefen A. Boehme, and Jeffrey Critchfield and entitled Interleukin-4 Stimulated T Lymphocyte Cell Death, both of which patent publications are incorporated herein by reference.
Transplantation Transplantation of healthy pancreata, pancreatic tissue, or isolated pancreatic islets into patients suffering from Type 1 diabetes provides an effective treatment modality. Unfortunately, the duration of the therapeutic benefit of such transplants is currently limited by the same autoimmune phenomena that cause type 1 disease in the first place. Accordingly, treatment of a diabetic patient using the chimeric fusion proteins of the invention in accordance with the methods of the present invention, when carried out prior to, concomitantly with, and/or shortly after such a transplant, will increase the longevity of such transplants and thereby enhance the therapeutic benefit of such transplantation procedures.
The accompanying figures, which are incorporated in and constitute part of the specification, illustrate certain aspects of the invention, and together with the description, serve to explain the principles of the invention. It is to be understood, of course, that both the figures and the description are explanatory only and are not restrictive of the invention.

Chimeric insulin-gad proteins for treating patients with type 1 diabetes or at risk of developing type 1 diabetes


Techniques for placing a first fiber channel (FC) switch into maintenance mode in a virtualized computing environment in which each data store is connected to at least one host computing system via at least two FC switches are described. In one embodiment, a first active input/output (I/O) path from a data store to a host computing system via the first FC switch is identified. Further, a path change is initiated from the data store to the host computing system via any other FC switch coupled to the data store and the host computing system.

Computer virtualization is a technique that involves encapsulating a representation of a physical computing machine platform into a virtual machine (VM) that is executed under the control of virtualization software running on hardware computing platforms (also referred to herein as "hosts" or "host computing systems"). A group of hardware computing platforms may be organized as a cluster to provide hardware resources for VMs. VMs may use virtual machine disks (VMDKs) to store its operating system, program files, and other data associated with its activities. The VMDKs that the VMs can access may reside on a data store connected to host computing systems via fibre channel (FC) switches. In a data center, it is common to see multiple FC switches and multiple VMs running on multiple clusters of hosts with each host connected to at least one data store via the multiple FC Switches.

Placing a fibre channel switch into a maintenance mode in a virtualized computing environment via path change


A clearing apparatus which includes a clearing device for use in clearing operations, and a carriage for supporting a clearing device during use. The clearing device is a clearing device of any conventional type and includes an elongated support member, a power unit at one end of the support member and a clearing head at the other end of the support member. The carriage comprises a frame structure having a lower end portion and having an upper end portion to extend upwardly from the lower end portion during use of the apparatus, a single support wheel having a wheel axis about which the support wheel is rotatably mounted to the lower end portion of the frame strut to support the frame strut on a support surface during use, a pivot mount intermediate the lower and upper end portions of the frame strut mounting the support member of the clearing device to the frame strut to allow the clearing head to be displaced laterally relative to the wheel plane, and a guide handle extending from the upper end portion of the frame strut for use in guiding the support wheel during use.

This invention relates to a clearing apparatus for use in clearing operations. The invention further relates to a carriage for use in supporting a clearing device.
The clearing apparatus of this invention is, in one aspect, in the form of a trimmer apparatus. The clearing apparatus is, in another aspect, in the form of a blower apparatus. The clearing apparatus is, in other aspects of the invention, in the form of a vacuum apparatus, in the form of a cultivator apparatus, in the form of a power broom, in the form of a snow blower, or snow thrower, or the like. The clearing apparatus may also, in another aspect, be convertible between the various aspects of the invention.
Where the clearing apparatus of this invention is in the form of a trimmer apparatus, it has particular application in the cutting of vegetation in the form of grass, weeds, shrubs, brush and the like. The trimmer apparatus has particular application in regard to a trimmer or cutter of the type which uses a cutting line for cutting or trimming vegetation. The trimmer apparatus can, however, also have application in regard to a trimmer which uses a cutter blade or various types of cutter blades for cutting or trimming vegetation, wood or other objects. The cutter blade may conveniently be in the form of a circular or annular blade or blade system. It may also, for example, be in the form of a reciprocating blade or blade system.
Where the clearing apparatus of this invention is in the form of a blower apparatus or a vacuum apparatus, it may have application in clearing indoors or outdoors areas of dust, debris, leaves, etc.
Where the clearing apparatus of this invention is in the form of a cultivator apparatus, it may have rotatably driven cultivator blades of any conventional type for use in cultivating soil. Where the clearing apparatus of this invention is in the form of a power broom, it may have a rotatably driven broom of any of suitable or conventional type for use in clearing areas. Where the clearing apparatus of this invention is in the form of a snow blower or snow thrower, it may have a snow handling system of any suitable or conventional type for use in clearing or blowing snow.
Applicant is aware of a number of prior patents which disclose various forms of wheeled carriages for supporting trimmers. These patents include U.S. Pat. No. 3,221,481--Mattson et al.; U.S. Pat. No. 4,845,929--Saki et al.; U.S. Pat. No. 3,977,078--Pittenjar; U.S. Pat. No. 4,936,886--Quillen; U.S. Pat. No. 4,182,100--Litter; U.S. Pat. No. 4,891,931--Holland; U.S. Pat. No. 4,442,659--Enbusk; U.S. Pat. No. 4,981,012--Claiborne; U.S. Pat. No. 4,829,755--Nance; and U.S. Pat. No. 5,408,816--Cartier. These patents do, for the most part, present a number of disadvantages.
Some of these disadvantages are that the operator has to support a major portion of the weight of the apparatus; that the apparatus is not supported near its center of gravity; that the apparatus is designed to be operated lawn-mower fashion so that lateral maneuverability of the apparatus is limited; that the operator can not position himself near the center of gravity of the apparatus during use; that the apparatus can not readily traverse obstacles during use; that the apparatus is bulky and difficult to handle, and that the apparatus restricts the reach of the clearing head of the apparatus during use.
Applicant is also the patentee of U.S. Pat. No. 5,279,102 which issued Jan. 18, 1994.
Applicant's prior patent relates to a clearing apparatus and to a carriage for a clearing apparatus which can reduce or overcome one or more of the disadvantages presented by the prior patents discussed above, and by the prior patents and the publication made of record during prosecution of Applicant's U.S. Pat. No. 5,279,102.
Applicant is also the patentee of U.S. Pat. No. 5,613,354 which issued Mar. 25, 1997, and of U.S. Pat. No. 5,603,205 which issued Feb. 19, 1997.
These two prior patents relate to a clearing apparatus and a carriage for clearing apparatus, and to a trimmer and edger apparatus respectively. These two prior patents relate to certain additions, modifications, changes, developments and/or improvements in or relating to aspects of a clearing apparatus and a carriage for a clearing apparatus of the general type described in Applicant's prior U.S. Pat. No. 5,279,102.
Applicant's present invention relates to certain changes, modifications, additions, developments and/or improvements relating to the general types of apparatus forming the subject matter of applicant's prior patents.
Applicant hereby refers to and makes of record all art of record in applicant's prior U.S. Pat. Nos. 5,279,102, 5,613,354 and 5,603,205.
It is one of the objects of this invention to provide a clearing apparatus, and to provide a carriage for a clearing device, which can reduce or overcome one or more of the disadvantages of the prior art.
It is a further object of this invention to provide a clearing apparatus and a carriage for a clearing device which are easy to use and are easy and convenient to handle.

Clearing apparatus and carriage for a clearing device


Cathode-anode voltage across free-wheeling diodes in an active rectifier is used in the determination of switching points when the free-wheeling diode is forward biased. Hysteretic switching is accomplished through the selection of conductive and non-conductive switching threshold. The switching thresholds are further selected to prevent voltage oscillations at zero current crossings and reduce delays during deactivation to prevent cross-conduction.

The statements in this section merely provide background information related to the present disclosure and may not constitute prior art.
Electric power generators, e.g., for automotive applications, include multiphase alternator devices that generate alternating current (AC) electric power when mechanically rotated, such as by coupling to an internal combustion engine. Known rectifier bridge circuits can convert the AC electric power to direct current (DC) electric power to meet electric load requirements. Known rectifier bridge circuits include diode bridges and MOSFET bridges.
Known electric machines and rectifier bridge circuits have power losses associated with resistance of copper wire of the electric machine, rectifier diode losses, hysteresis and eddy current, and machine friction. Known electric machines and rectifier bridge circuits have design considerations that increase mass and/or manufacturing costs including shaped conductor stator windings to reduce copper losses, thin stator laminations to reduce iron losses, low friction bearings, laminated rotor construction, and permanent magnet excitation.

Rectifying circuit for a multiphase electric machine


A chip scale package structure formed by adhering a glass sheet having a pattern of holes matching a pattern of bond pads on a semiconductor wafer so that the pattern of holes on the glass sheet are over the pattern of bond pads on the semiconductor wafer. Metallized pads are formed on the glass sheet adjacent to each hole and in one embodiment a conductive trace is formed from each metallized pad on the glass sheet to the bond pad on the semiconductor wafer under the adjacent hole. In a second embodiment, a pad is formed on the glass sheet adjacent to each hole and the pad extends down the sides of the adjacent hole. The hole is filled with a metal plug that electrically connects the pad on the glass sheet to the bond pad on the semiconductor wafer. In each embodiment a solder ball is formed on each pad on the glass sheet.

1. Field of the Invention
This invention relates generally to flip chip packaging technology and even more specifically, this invention relates to chip scale flip chip packaging technology for semiconductor die.
2. Discussion of the Related Art
Chip Scale Packages (CSP) for semiconductor die currently embody some form of solder ball or bump to attach the die to the next higher assembly in the total package. In the simplest form of a CSP, the CSP is a flip chip semiconductor die that has additional solder bumps to be connected to normal bond pads on a substrate which are used to wire bond interconnects to a package or substrate. The semiconductor die is inverted and the solder is reflow melted which structurally attaches the die to the metallized pads or to traces on the substrate.
The solder-bump flip-chip interconnection technology was initiated in the early 1960s to eliminate the expense, unreliability, and low productivity of manual wirebonding. The so-called controlled-collapse-chip connection C4 or C4 utilizes solder bumps deposited on wettable metal terminals on the chip which are joined to a matching footprint of solder wettable terminals on the substrate. The upside-down chip (flip chip) is aligned to the substrate and all joints are made simultaneously by reflowing the solder.
The most recent innovations to the flip chip technology involve the relocation of the solder ball/bump sites from the close pitch pads which are normally placed around the perimeter of the semiconductor die to an array located across the surface of the die. This is accomplished by creating new traces from the perimeter locations to the new array locations on top of a passivation layer. The passivation layer is typically a glass protective layer deposited on the surface of the die with openings to expose the bond pads or by adding an interposer connector, which is bonded to the existing pads and reroutes traces to the array. An interposer connector is a connector structure that is routed between two parts to be connected.
A current interposer connector process reroutes connectors to the pads by extending them into the space between adjacent die as created on the semiconductor wafer, laminating a piece of glass to either side of the wafer and then through a complex series of mechanical cutting, metal deposition and etching operations, the connectors to the pads are extended to the surface of the glass. This produces an array on the top of the glass sheet covering the die, which is in turn adhesively bonded to the passivation surface of the die. The advantage of this process and structure is that the glass sheet provides a protective surface for the delicate surface of the passivated die and allows some degree of differential expansion between the die surface and the array of solder balls due to the non rigid nature of the adhesive layer. The disadvantages are that the extension of the connectors to the pads on the wafer are difficult to implement and often prevent the process from being possible, the glass cutting operation is costly and requires special equipment, the process is implemented on a completed semiconductor wafer which is very sensitive and costly and any error causes the entire wafer to be scrapped, and two sheets of glass are always required.
Therefore, what is needed is a chip scale flip chip process that is easy to implement, uses one glass sheet and is inexpensive.


Embodiments of the present invention relate to water leakage detection. Data obtained by a smart electricity meter during a predefined time period is collected, where the smart electricity meter is associated with a water-consuming unit. Usages of certain electric appliances in the water-consuming unit during the predefined time period are determined based on the collected data. The electricity consumption of those appliances is correlated to water consumption. The legitimate water consumption of the water-consuming unit during the predefined time period is then determined based on the usages of the electric appliances.

The present invention relates generally to public water system leak detection and more specifically, to detecting water system leaks based on smart electricity meter monitoring.
Every year leakage from water transmission and distribution networks wastes a considerable amount of water. Further, the transmission and distribution networks deliver additional water resources to consumers but the consumers are not billed because of leakage, theft, poor metering or corruption. The waste of water resources leads to significant economic loss. More importantly, statistics show that half of the wasted water would supply an additional 100 million people each year worldwide.
Night flow analysis is an important technology for identifying water leakages. In general, the analysis is performed on the basis of the minimum night flow (MNF) which refers to the water flow that occurs during a given time period in the night (for example, from 12:00 am to 4:00 am) when the consumption in a water system is assumed to be lowest. Net night flow (NNF) of the water system, which discovers the water leakages, can be determined by subtracting legitimate night flow (LNF) from MNF. LNF refers to the water flow consumed by the consumers. For a target area such as a community, MNF can be directly read, e.g., from a main water meter of the target area. Therefore, the critical point in the night flow analysis is to determine LNF in an accurate and cost-effective way.

Water leakage detection based on smart electricity meter

International Business Machines Corporation


Phenylamino benzoic acid, benzamides, and benzyl alcohol derivatives of the formula

This invention provides benzoic acid and amide derivatives of anthranilic acids which inhibit certain dual specificity kinase enzymes involved in proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Cancer, for example, is commonly caused by a series of defects in these signaling proteins, resulting from a change either in their intrinsic activity or in their cellular concentrations. The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, which is a G-protein that is activated when bound to GTP, and inactivated when bound to GDP.
The above mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras.GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras.GTP for its own activation is the Raf family. These in turn activate MEK, (eg, MEK1 and MEK2) which then activates MAP kinase. Activation of MAP kinase by mitogens appears to be essential for proliferation, and constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyro sine, Y185, and a threonine residue, T183, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold, and it can now catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, whether it be another kinase, a transcription factor, or other cellular protein. MEK is also activated by several kinases other than Raf-1, including MEKK, and itself appears to be a signal integrating kinase. As far as is currently known, MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than MAP kinase has been demonstrated to date, and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.
This invention provides compounds which are highly specific inhibitors of the kinase activity of MEK. Both in enzyme assays and whole cells, the compounds inhibit the phosphorylation of MAP kinase by MEK, thus preventing the activation of MAP kinase in cells in which the Ras cascade has been activated. The results of this enzyme inhibition include a reversal of transformed phenotype of some cell types, as measured both by the ability of the transformed cells to grow in an anchorage-independent manner and by the ability of some transformed cell lines to proliferate independently of external mitogens.
The compounds provided by this invention are 2-(phenylamino)benzoic acid, tetrazole, ester, amide, and benzyl alcohol derivatives, in which the phenyl ring is substituted at the 4-position with bromo or iodo. U.S. Pat. No. 5,155,110 discloses a wide variety of fenamic acid derivatives, including certain 2-(phenylamino)benzoic acid derivatives, as anti-inflammatory agents. The reference fails to describe the compounds of this invention or their kinase inhibitory activity.
This invention provides 4-bromo and 4-iodo phenylamino benzoic acid derivatives which are selective MEK kinase inhibitors and as such are useful for treating proliferative diseases such as cancer, psoriasis, and restenosis. The compounds are defined by Formula I
wherein
R1 is hydrogen, hydroxy, C1-C8 alkyl, C1-C8 alkoxy, halo, trifluoromethyl, or CN;
R2 is hydrogen;
R3, R4, and R5 independently are hydrogen, hydroxy, halo, trifluoromethyl, C1-C8 alkyl C1-C8 alkoxy, nitro, CN, or xe2x80x94(O or NH)mxe2x80x94(CH2)nxe2x80x94R9, where R9 is hydrogen, hydroxy, CO2H, or NR10R11;
n is 0-4;
m is 0 or 1;
R10 and R11 independently are hydrogen or C1-C8 alkyl, or taken together with the nitrogen to which they are attached, can complete a 3-10 member cyclic ring optionally containing one, two, or three additional heteroatoms selected from O, S, NH, or Nxe2x80x94C1-C8 alkyl;
Z is COOR7, tetrazolyl, CONR6R7, CONHNR10R11, or CH2OR7;
R6 and R7 independently are hydrogen, C1-C8 alkyl, C2-C8 alkenyl,
xe2x80x83aryl, heteroaryl, C3-C10 cycloalkyl, or C3-C10 (cycloalkyl optionally containing one, two, or three heteroatoms selected from O, S, NH, or N alkyl); or R6 and R7 together with the nitrogen to which they are attached complete a 3-10 member cyclic ring optionally containing 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl;
and wherein any of the foregoing alkyl, alkenyl, and alkynyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, and the pharmaceutically acceptable salts thereof.
Preferred compounds have Formula II
where R1, R3, R4, R5, R6, and R7 are as defined above. Especially preferred are compounds wherein R1 is methyl or halo, and R3, R4, and R5 are halo such as fluoro or bromo.
The compounds of Formula II are carboxylic acids when R7 is hydrogen, and are esters when R7 is other than hydrogen. Compounds which are analogous to the acids in physical and biological properties are tetrazolyl derivatives of Formula IIa
Another preferred group of compounds are amides Formula III
and hydrazides of Formula IIIa
The benzyl alcohols of the invention have Formula IV
The most preferred compounds are those wherein R1 is methyl, R3 is hydrogen or halo such as fluoro, R4 is halo such as fluoro, and R5 is hydrogen or halo such as fluoro, bromo, or chloro. Representative compounds have the formulas
This invention also provides pharmaceutical formulations comprising a compound of Formula I together with a pharmaceutically acceptable excipient, diluent, or carrier. Preferred formulations include any of the foregoing preferred compounds together with an excipient, diluent, or carrier.
The compounds of Formula I are potent and selective inhibitors of MEK1 and MEK2 kinase enzymes. They are, therefore, useful to treat subjects suffering from cancer, stroke, diabetes, Alzheimer""s disease, cystic fibrosis, viral disease, heart failure, and proliferative diseases such as psoriasis, restenosis, autoimmune disease, and atherosclerosis. The compounds are especially well suited to treat cancers such as breast cancer, colon cancer, prostate cancer, skin cancer, and pancreatic cancer. They are particularly well-suited for use in conjunction with conventional radiation therapy. The compounds are also immunomodulatory agents and can be used to treat degenerative diseases where change in MEK activation leads to pathologies such as hepatomegaly and cardiomegaly. The invention provides a method of inhibiting MEK enzymes and the foregoing diseases by administering to a subject an effective amount of a compound of Formula I.
As used herein, the term xe2x80x9carylxe2x80x9d means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from five to twelve carbon atoms. Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl. The aryl may be substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Typical substituted aryl groups include 3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl, 2-methyl-4-chloro-7-aminofluorenyl, and the like.
The term xe2x80x9caryloxyxe2x80x9d means an aryl group bonded through an oxygen atom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and 4-methyl-1-fluorenyloxy.
xe2x80x9cHeteroarylxe2x80x9d means a cyclic, bicyclic, or tricyclic aromatic ring moiety having from four to eleven carbon atoms and one, two, or three heteroatoms selected from O, S, or N. Examples include furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl, benzinnidazolyl, and triazinyl. The heteroaryl groups can be unsubstituted or substituted by one, two, or three groups selected from fluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino, alkylamino, or dialkylamino. Examples of substituted heteroaryl groups include chloropyranyl, methylthienyl, fluoropyridyl, amino-1,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.
The heteroaryl groups can be bonded through oxygen to make heteroaryloxy groups, for example thienyloxy, isothiazolyloxy, benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.
The term xe2x80x9cC1-C8 alkylxe2x80x9d means straight and branched chain aliphatic groups having from one to eight carbon atoms, preferably one to four. Typical C1-C8 alkyl groups include methyl, ethyl, isopropyl, tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groups can be unsubstituted or substituted by halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, or heteroaryloxy, as those terms are defined herein. Typical substituted alkyl groups include chloromethyl, 3-hydroxypropyl, 2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryl and aryloxy substituted alkyl groups include phenylmethyl, 2-phenylethyl, 3-chlorophenylmethyl, 1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl. Examples of alkyl groups substituted by a heteroaryl or heteroaryloxy group include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl, 4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkyl substituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl, piperidyl-2-methyl, 2-(piperidin-1-yl)-ethyl, 3-(morpholin-4-yl)propyl.
xe2x80x9cC2-C8 Alkenylxe2x80x9d means a straight or branched carbon chain having one or more double bonds. Examples include but-2-enyl, 2-methyl-prop-2-enyl, 1,1-dimethyl-hex-4-enyl, 3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenyl groups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino, dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example 2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl, 3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and 4-naphthyloxy-hex-2-enyl.
xe2x80x9cC2-C8 Alkynylxe2x80x9d means a straight or branched carbon chain having from two to eight carbon atoms and at least one triple bond. Typical alkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl, 3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups can be substituted as the alkyl and alkenyl groups, for example, by aryl, aryloxy, heteroaryl, or heteroaryloxy, for example 4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent4-ynyl, 3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.
The alkenyl and alkynyl groups can have one or more double bonds or triple bonds, respectively, or a combination of double and triple bonds. For example, typical groups having both double and triple bonds include hex-2-en-4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and 3-thienyloxy-hex-3-en-5-ynyl.
The term xe2x80x9cC3-C10 cycloalkylxe2x80x9d means a nonaromatic ring or fused rings containing from three to ten carbon atoms. Examples include cyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl, adamantly, and cyclohexyl. The ring can optionally contain one, two, or three heteroatoms selected from O, S, or NR9. Such groups include tetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl, piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, and octahydrobenzothiofuranyl. The cycloalkyl groups can be substituted with the same substituents as an alkyl and alkenyl groups, for example, halo, hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl, 2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.
R6 and R7 can be taken together with the nitrogen to which they are attached to complete a cyclic ring having from 3 to 10 members, which may contain 1, 2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl. Examples of such cyclic rings include piperazinyl, piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl, and the like. Such rings can be substituted with halo, hydroxy, alkyl, alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, and heteroaryloxy. Typical examples include 3-hydroxy-pyrrolidinyl, 2-fluoro-piperindyl, 4-(2-hydroxyethyl)-piperidinyl, and 3-thienylmorpholino.
The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivatives of Formula I can be prepared from commercially available starting materials utilizing synthetic methodologies well-known to those skilled in organic chemistry. A typical synthesis is carried out by reacting a 4-bromo or 4-iodo aniline with a benzoic acid having a leaving group at the 2-position to give a 2-(phenylamino)-benzoic acid. This process is depicted in Scheme 1.
where L is a leaving group, for example halo such as fluoro.
The reaction of aniline and the benzoic acid derivative generally is accomplished by mixing the benzoic acid with an equimolar quantity or excess of the aniline in an unreactive organic solvent such as tetrahydrofuran or toluene, in the presence of a base such as lithium diisopropylamide, n-butyl lithium, sodium hydride, triethylamine, and Hunig""s base. The reaction generally is carried out at a temperature of about xe2x88x9278xc2x0 C. to about 100xc2x0 C., and normally is complete within about 2 hours to about 4 days. The product can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The 2-(phenylamino)-benzoic acid (eg, Formula I, where R7 is hydrogen) can be reacted with an organic or inorganic base such as pyridine, triethylamine, calcium carbonate, or sodium hydroxide to produce a pharmaceutically acceptable salt. The free acids can also be reacted with an alcohol of the formula HOR7 (where R7 is other than hydrogen, for example methyl) to produce the corresponding ester. Reaction of the benzoic acid with an alcohol can be carried out in the presence of a coupling agent. Typical coupling reagents include 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), 1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphonium hexafluorophosphate (PyBrOP), and (benzotriazolyloxy)tripyrrolidino phosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acid and alcohol derivative normally are mixed in approximately equimolar quantities in an unreactive organic solvent such as dichloromethane, tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of the coupling reagent is added. A base such as triethylamine or diisopropylethylamine can be added to act as an acid scavenger if desired. The coupling reaction generally is complete after about 10 minutes to 2 hours, and the product is readily isolated by removing the reaction solvent, for instance by evaporation under reduced pressure, and purifying the product by standard methods such as chromatography or crystallizations from solvents such as acetone, diethyl ether, or ethanol.
The benzamides of the invention, Formula I where Z is CONR6R7, are readily prepared by reacting the foregoing benzoic acids with an amine of the formula HNR6R7. The reaction is carried out by reacting approximately equimolar quantities of the benzoic acid and amine in an unreactive organic solvent in the presence of a coupling reagent. Typical solvents are chloroform, dichloromethane, tetrahydrofuran, benzene, toluene, and xylene. Typical coupling reagents include DCC, EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about 10 minutes to about 2 hours when carried out at a temperature of about 0xc2x0 C. to about 60xc2x0 C. The product amide is readily isolated by removing the reaction solvent, for instance by evaporation, and further purification can be accomplished by normal methods such as chromatography, crystallization, or distillation. The hydrazides (z=CONHNR10R11) are similarly prepared by coupling a benzoic acid with a hydrazine of the formula H2HNR10R11.
The benzyl alcohols of the invention, compounds of Formula I where Z is CH2OR6 and R6 is hydrogen, are readily prepared by reduction of the corresponding benzoic acid according to the following scheme
Typical reducing agents commonly employed include borane in tetrahydrofuran. The reduction normally is carried out in an unreactive organic solvent such as tetrahydrofuran, and generally is complete within about 2 hours to about 24 hours when conducted at a temperature of about 0xc2x0 C. to about 40xc2x0 C.
The following detailed examples illustrate specific compounds provided by this invention.

2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives

Abstract: where R1, R2, R3, R4, R5, and R6 are hydrogen or substituent groups such as alkyl, and where R7 is hydrogen or an organic radical, and Z is COOR7, tetrazolyl, CONR6R7, or CH2OR7, are potent inhibitors of MEK and, as such, are effective in treating cancer and other proliferative diseases such as inflammation, psoriasis and restenosis, as well as stroke, heart failure, and immunodeficiency disorders.