A tire initiated vehicle control system 110 for vehicles 100 is described. The vehicles 100 have vehicle components including a power train 140, a suspension system 180, a steering mechanism 160, a plurality of wheel brake mechanisms 130, one wheel brake mechanism 130 being at each wheel position 104a, 104b, 104c, and 104d location, a fuel or vehicle speed throttle 144 with or without a cruise control system, the vehicle control system 110 has a tire pressure detection device 120 and a control means 200, which preferably has a computer 208 for receiving data from the tire pressure detection device 120. The control means 200 processes the received tire pressure data and upon a preset pressure or rate of change value in tire pressure the control means 208 directs a change in response rates of one or more of the above listed vehicle components.

This invention relates to vehicle control systems, more specifically to control systems for automobiles or other vehicles employing pneumatic tires.
Advances in technology have enabled vehicles to incorporate computer-controlled features into the operation of the vehicle. Most notably, these features were implemented early on in aircraft and in that technical field the use of xe2x80x9cfly by wire systemsxe2x80x9d or computer-augmented manual control systems has advanced to a fully integrated vertical flight path and speed control system as described in U.S. Pat. No. 4,536,843. The Total Energy Control System (hereinafter referred to as TECS or TEC system) develops fundamental solutions to the problem of coordinated elevator and throttle control to produce performance levels exceeding those generally known in the flight control systems art and is described in U.S. Pat. No. 6,062,513.
Embedded within the TECS are sub systems controlled by TECS including a variety of computer controlled flight systems. Many of these systems automatically react to flight parameters and in various situations these systems sense equipment breakdowns and prevent the pilot from directing the controls in a way that could inadvertently cause a loss of control of the aircraft.
In several aircraft, the reaction of a pilot to equipment failure may overcorrect causing the situation to worsen. The use of computers that have pre-programmed responses to equipment failures insures that the response to a situation is quick and accurate and has been carefully analyzed in test lab conditions to insure a reliable and quick response. The best-experienced pilot may take precious seconds to isolate a problem manually and then he must select from a variety of options and choose the best course of action under a stressful situation.
Historically, airplanes had large amounts of time and usually sufficient airspace and altitude to allow pilots to make optimal choices. Nevertheless, in today""s crowded airspace the use of computers to assist the pilots has been widely adapted.
In automobiles, we are just beginning to see applications of computer-controlled systems and equipment-controlled components. Anti-lock brakes, load-leveling suspensions, cruise control and traction control devices are commonly available.
Some car manufacturers are evaluating and testing computer controlled driverless systems. Advertisements show a string of driverless vehicles traveling at highway speeds on a California expressway. While this advanced technology is currently being tested, it is going to be years before fully automatic driverless vehicles are commercially or socially accepted.
Most importantly, the driver in the near term must be able to act and make good choices. Unlike pilots, driver training in simulated adverse conditions is almost non-existent. Driver error due to fatigue, inexperience or bad judgment is the leading cause of accidents.
In U.S. Pat. No. 6,263,282, issued July 2001, a System and Method for Warning of Dangerous Driving Conditions is disclosed. That patent warns a driver when he is closing too fast on a vehicle such that a reduction in speed or a veering or turn is required. This patent basically gives the driver a xe2x80x9cheads upxe2x80x9d or signal that he should be careful. The driver initiates all action.
In U.S. Pat. No. 6,282,498, a Traveling Direction Correction Apparatus is disclosed. This patent is particularly useful if the driver dozes into a sleep mode and starts to drift out of it""s driving lane. This device enable or activates a brake steering sequence to try to keep the car on the pavement while also sounding an alarm to regain the drivers attention. Falling asleep or driver fatigue behind the wheel of an automobile is one of the leading causes of accidents.
In each of the above referenced patents the attempt is to avoid a driver error before the onset of an accident.
Another opportunity for driver error occurs at the initiation of a flat tire. At one time or another most drivers will experience a flat tire while driving. This problem is basically an inconvenience for most drivers in most situations. Other times, particularly at high speed, a sudden loss of pressure in a tire can be very problematic. If the driver reacts quickly by slamming on the brakes, he can lose control or be run into by following or trailing vehicles. If the driver quickly swerves or turns the steering wheel to maneuver to the side of the road he can easily oversteer the vehicle causing a loss of control. Generally the best advice is to hold steady and allow the vehicle to slow by simply removing the foot from the accelerator or by disengaging the cruise control.
After the vehicle has slowed the application of brakes or steering has a less dramatic affect.
While this seems obvious that every driver should understand this simple concept, it is more apparent that the driver often times reacts quicker than he thinks and therefore simply makes a bad situation worse.
Drivers from areas having icy or snowy conditions learn that loss of traction is not corrected by slamming on brakes. Vehicle control is your first objective in such conditions and slowing down is achieved by a deceleration based on removing the foot from the gas pedal. These common sense rules are easy for those who have practiced driving in these conditions. Drivers in warm climates simply do not have as much opportunity to learn these aspects of driving and therefore snowy or slick driving conditions, usually results in higher accident rates when they occur in the warmer climates.
When a tire experiences a flat or a more rapid rate of pressure loss due to a gash, the vehicle suddenly changes in several ways. The load balance on the vehicle shifts as the flattened tire deflates causing the center of mass to actually shift toward the flattened tire. If the brakes are applied the three inflated tires provide the contact patches that try to stop the vehicle. The deflated tire simply cannot apply an equal braking force to the ground compared to the remaining inflated tire. If the rear tire is flat, braking causes the front of the vehicle to nose down as the rear part of the vehicle starts to lift this causes the center of mass to move dynamically forward and off-center. It is as though the four-wheeled vehicle has become a three-wheeled vehicle with a center of mass outside the triangular footprint of the three remaining tires. Needless to say the vehicle suspension is operating in a far from optimal condition. Steering inputs become exaggerated causing an oversteer condition to exist. Braking in combination with steering can exacerbate the problem.
The driver in his best attempts to react may simply make matters worse. In the aircraft industry, trained pilots were found to, in attempts to correct for equipment malfunctions, simply make the wrong choices, this is called xe2x80x9cpilot errorxe2x80x9d. Often times what appears to be an appropriate corrective response simply is not in today""s sophisticated aircraft. Similarly xe2x80x9cdriver errorsxe2x80x9d in flat tire situations occur not so much because the driver failed to do something but precisely because he did react and the actions taken made the situation worse. These problems all seem to be greatly exaggerated at higher speeds.
At very high speeds such as NASCAR racing vehicles where speeds reach 200 mph. Each wheel position has an inner tire called a safety shield. A cut outer tire can occur while the driver decelerates to control the vehicle. These trained drivers have vehicles that created downward forces on the tires and racing suspensions designed very stiff and low to better handle these occurrences.
Advances in run flat tires for passenger tires have minimized the occurrence of rapid loss of tire inflation. Nevertheless the wrong reactions of the driver to low pressure in any pneumatic tire or a sudden loss of air pressure is still an issue. Therefore, recent legislation has mandated tire inflation warning systems been installed in vehicles in some countries, the United States being most notable.
The present invention advances that state of the art form a warning to a more integrated vehicle controlled system that compensate for erroneous driver reactions by either overriding the drivers braking input or steering input or by correcting the input to match the vehicles change in responsiveness due to the loss of pressure in the tire. What makes this invention described hereinafter, truly valuable is the initiation on all vehicle response changes are initiated by a change in the tire condition. When one contemplates the fact that the four tire contact patches formed by the tread touching the roadway initiate all vehicle movements, forward, turning, stopping and ride dampening it is absolutely true that transportation is really enabled and controlled by the tires. It is therefore most logical that the fastest most reliable system or components to feedback information to the vehicle should dictated by the tires. The following description shows very useful application of tire initiated vehicle control.
A tire initiated vehicle control system for automobile type vehicles having vehicle components including a power train, a steering mechanisms, a plurality of wheel brake mechanisms, one wheel brake mechanism being at each wheel position, four or more pneumatic tires, a fuel or vehicle throttle with or without a cruise control system and a vehicle suspension system is disclosed.
The vehicle control system has a tire pressure detection device for sensing tire pressure of each pneumatic tire and a control means for receiving data from the pressure detection device. The control means processes the received data and upon a preset pressure or rate of change value in tire pressure the control means directs a change in the response rate of one or more of the following vehicle components; the power train, the steering mechanism, the fuel or vehicle speed throttle, or the vehicle suspension system.
At the onset of a loss of air pressure in any of the pneumatic tires as evidenced by the tire pressure detecting device indicating a preset pressure or rate of change in tire pressure has occurred the control means receives a signal, processes the data and directs a change in response rate of one or more of the vehicle components. The changes can include lowering the vehicle suspension at one or more wheel position, shifting the center of mass of the vehicle directly away from the deflated tire, changing the steering response rate thereby lowering the wheel movement relative to steering input to minimize oversteering, disengaging the cruise control mechanism, having the control means take over the fuel or vehicle speed throttle to regulate vehicle speed, initiating xe2x80x9cbrake steeringxe2x80x9d programs to the brake mechanisms to maintain a controlled vehicle deceleration.
At the time of the flat tire occurrence, the vehicle control system will have initiated changes in one or more of the response rates and thereby will be bringing the vehicle to a controlled speed or to enable the driver to more safely pull the vehicle over for a tire changeover.
In this fashion driver error input can be minimized preventing over braking input or oversteering input. The fact that the pressure detection device can respond in close to real time means the response rate of the control means directing this changes can occur almost, instantaneously. This feature insure that the driver cannot intervene faster that the control means can initiate overriding controls at least in terms of steering and braking inputs. Some systems such as activating a lowering of the suspension or shifting the weight of the suspension or shifting the weight balance of the vehicle may in fact take additional time due to the pneumatic or hydraulic systems used. However it can be appreciated that such actions are when used in combination with the brake, steering and throttle control with or without a cruise control system and a vehicle suspension system as described is capable of achieving vehicle controls far faster than the typical driver will be able to perceive a low pressure or flat tire condition.
It is believed preferable that the control means include a computer or microprocessor having sufficient memory capable of storing preset algorithms that upon known variable such as vehicle speed and vehicle yaw or lateral cornering forces may dictate certain alternative response rate changes of the various vehicle components that are subjected to control input changes.
Ideally the driver should only be aware that the vehicle has initiated a flat tire mode by an audible or visual signal. Preferably all vehicle system such as steering and braking will be controlled such that over braking and oversteering is not an issue regardless of the drivers input. In this fashion, driver error can be compensated for in a more reliable manner.
The added benefit of this vehicle control system is runflat type tires can be employed more easily due in part to weight shifts and suspension adjustments being made at the time of the flat tire occurrence. Maximum vehicle speeds under such conditions can be controlled by the control means. This insures the tires when operated uninflated will not be overheated. Furthermore the control means can advise how many miles the tire was operated in the uninflated condition. This more reliably would enable the tire to be inspected for structural damage upon repair.
The tire pressure detection device may be internal of the tire using a microprocessor chip for sending a signal to the controller as is taught in Patent Publication WO01/19626. Alternatively the tire pressure detection device may be incorporated into the ABS brake mechanisms as is taught in the DWS systems. In such a case the variation in tire response to the brake system can predictably identify a tire operating at a low pressure and can, based on known parameters, predict when a preset pressure condition has occurred.
Definitions
xe2x80x9cAntilock Brakes (ABS)xe2x80x9d means any means for preventing the application of a braking input from the driver causing the tires to stop rotating as the vehicle comes to a rapid stop.
xe2x80x9cBraking Mechanismxe2x80x9d means any mechanical or electrical means for retarding the wheel rotation including but not limited to drum brakes, disk brakes, with or without ABS systems.
xe2x80x9cCruise Controlxe2x80x9d means any system or device that controls throttle input to the power train to maintain the vehicle at a constant rate of velocity.
xe2x80x9cElectronic Suspension Programxe2x80x9d means any computer software program used in conjunction with a vehicle""s suspension or antilock brakes to adjust vehicle ride performance on demand.
xe2x80x9cFuel or Vehicle Speed Throttlexe2x80x9d means the entire system that controls the rate of fuel or power inputted to the power train to increase or decrease vehicle speed including the foot or accelerator pedal associated linkages and supply times for feeding gasoline to the engine""s fuel injection or carburetion devices for gasoline burning engines or the similar counterparts for hybrid engines employing fuel cells, or electric motors.
xe2x80x9cPneumatic tirexe2x80x9d means a laminated mechanical device of generally toroidal shape (usually an open torus) having beads and a tread and made of rubber, chemicals, fabric and steel or other materials. When mounted on the wheel of a motor vehicle, the tire through its tread provides traction and contains the fluid or gaseous matter, usually air that sustains the vehicle load.
xe2x80x9cTire pressure sensor or detection devicexe2x80x9d means any system or device capable of measuring the inflation condition of the tires. The measurement can be done directly by monitoring the tires internal pressure condition as occurring or alternatively it can signal when a rate of change in pressure is observed. The measurement can be indirectly achieved wherein changes in torque at the wheel location is measured or changes in radial tire deflection is measured at known speeds and is sensed by any system such as the Antilock brake System. Whether the measurement is direct or indirect the sensing or detection device simply must send a signal to a control means to advise when a measured or predicted tire pressure condition exist evidencing a flat or low pressure in one or more tires.
xe2x80x9cTraction Controlxe2x80x9d means any system designed to adjust for wheel slippage by controlling the drive axle or braking system to achieve a more controllable tire response to the road surface conditions.


A pole for supporting a tool includes an elongate body extending along an axis. The elongate body defines a plurality of outwardly facing facets about the axis. The elongate body preferably includes a first tube and a second tube telescopically received within the first tube for adjusting a length of the pole. The two tubes are locked relative to one another by a locking mechanism that is fixedly coupled to the first tube with a detent engaging member that extends from the locking mechanism into engagement with a detent defined by the first tube. The locking mechanism preferably comprises a collet which is threadably coupled to a chuck that defines a plurality of outwardly facing facets. Rotation of the chuck causes the chuck to overlap the detent engaging member and to frictionally clamp the collet against the second tube.

Poles are commonly used for supporting a variety of tools to access otherwise unaccessible or unreachable areas. For example, poles are frequently used to support rollers in the application of paint, stains, varnishes or other coatings to ceilings and unreachable surfaces. Poles are also used to support a variety of other tools in the performance of other tasks such as dusting, tree pruning and the like.
Conventional tool supporting poles have a generally round cross-section. Alternatively, where additional strength is required of the pole, the round poles are frequently fluted along their length. Because conventional poles are round or fluted, users frequently have a difficult time gripping the poles and maneuvering the tools located at the end of the poles. This difficulty is intensified when the pole has a large length which increases the moment arm that must be supported and maneuvered by the user.
Many poles today are adjustable in length to provide increased flexibility and maneuverability when work needs to be done on surfaces having various heights and distances. To achieve adjustability, the poles generally include a first tube and a second tube telescopically received within the first tube. Once the tubes are telescopically extended or retracted so as to provide the pole with the desired length, the tubes are locked to one another by various means, including twist locks and tab locks.
Twist locks generally consist of a collet having a housing adhesively mounted to the first tube and a round sleeve or chuck which threadably engages the housing to comprise or clamp the collet against the second tube. Pole length adjustment is achieved by twisting or turning the chuck in a first direction to unclamp the collet so as to permit the tubes to be telescopically adjusted relative to one another. Once the pole is at the desired length, the chuck is twisted in a second opposite direction to once again clamp the collet against the second tube. One of the main advantages associated with the conventional twist lock is its ability to lock the first tube relative to the second tube anywhere along the length of the second tube. At the same time, however, threading the chuck onto the collet often requires multiple turns and large torques. Consequently, adjusting the length of the pole is frequently tedious, time consuming and fatiguing.
Tab locks generally consist of a housing adhesively mounted to the first tube and a pin that is pivotally biased towards the second tube. The second tube includes a plurality of spaced holes along its axis for receiving the pin to lock the first tube relative to the second tube. Pole length adjustment is achieved by activating a button, lever or the pin directly to withdraw the pin from one of the holes to enable the tubes to be telescopically adjusted relative to one another. At the desired length, the pin is inserted into a second one of the holes to secure the tubes relative to one another. Although easier to adjust than poles having a twist lock, poles having a tab lock have limited adjustability because the various lengths of the pole are strictly limited to the locations of the holes along the axis of the second tube. In addition, unintended rotation of the second tube relative to the first tube will misalign the pin and the holes to make length adjustment more difficult.
Although both the conventional twist lock and the conventional tab lock effectively lock the tubes relative to one another at a desired length, both the twist lock and the tab lock lack the durability required for many applications. Because the housing of both the twist lock and the tab lock is typically adhesively bonded to the first pole, the housing frequently becomes detached from the first tube upon impact or upon the pole undergoing severe expansion and contraction in response to temperature changes. Detachment of the twist lock or tab lock housing from the first tube renders the locking mechanism, and many times the pole itself useless.
As a result, there is a continuing need for a durable, light weight, tool supporting pole that is easy to grip and maneuver. There is a also a continuing need for an extendable pole that is durable and easy to adjust.


Apparatus and a method for rapidly replacing a tool set included in a bodymaker are disclosed. A bodymaker is used in connection with tin box manufacture and typically includes a mandrel and a set of forming wings disposed above the mandrel and specifically designed for a particular shape of mandrel so that a planar bland disposed above the mandrel can be formed therearound by the forming wings. A support plate mounted on a totally and translatable axially of the mandrel on guide means is rolled into place adjacent the tool set, and the support plate is moved towards the free ends of the tools within the set and connected within the bodymaker. As the support plate approaches the free ends of the tools, latch means provided on the support plate in front of a suitably shaped recess are deflected laterally by a plug formation provided at least on the mandrel.

This invention relates to a method for replacing for a mandrel and associated tooling, and suitably designed apparatus for performing this operation specifically for use in machinery adapted for the automated manufacture of tin boxes. A description of such machinery is provided immediately below to enhance the understanding of the reader.
Automated tin box manufacture is accomplished by juxtaposing several different pieces of machinery and providing transfer means therebetween. Tin boxes can be manufactured in a vast number of different shapes and sizes and accordingly a single piece of machinery is required to be sufficiently versatile to enable manufacture of tin boxes in a large number of said shapes and sizes. It will be understood by those skilled in the art that the machinery used has a number of different components which can be exchanged to facilitate the manufacture of different boxes and currently the length of time taken to exchange all these various components to enable a particular set of machines to manufacture a different box shape can be up to an entire day. The invention hereinafter set forth, and also set forth in out co-pending applications have as their object the reduction of this time period. Any reduction achievable in the xe2x80x9cchangeoverxe2x80x9d time is especially desirable when it is considered that tin box production rates using the machinery described hereinafter may reach 40 per minute.
Tin boxes can contain a wide variety of different goods, such as bottle, chocolates, biscuits, tea, coffee and the like. Manufacturers of such products commonly consider the containment of their product in tins because of the rigidity and durability which the sheet steel, from which such tins are commonly made, provides. Additionally, the containment of a product in a tin box may also suggest that the product therein is of a certain quality, especially as ornate and detailed print effects can be obtained on the surface of the metal plates from which the tin boxes are manufactured. Such effects cannot be achieved, or are achieved only to a much lesser degree by the containment of products in cardboard cartons or receptacles of plastics materials. A tin box in which such a product is contained has the further advantage of being reusable to contain other household items such as screws, nuts bolts, pencils and pens, etc. after the product originally contained therein has been consumed or otherwise utilised.
The various separate machines required in the manufacture of tin boxes are an xe2x80x9cAutomatic Curling Notching and Beadingxe2x80x9d machine, a xe2x80x9cbodymakerxe2x80x9d, a xe2x80x9cround and irregular seamerxe2x80x9d, and an xe2x80x9cend feederxe2x80x9d, each of which has a specific task to perform during the process of tin box manufacture. Each of these is now described.
The first stage in the process of automated tin box manufacture is the profiling of a simple sheet steel, and generally rectangular, blank from which the walls of the tin box are ultimately constituted. The blank is fed through an xe2x80x9cAutomatic Notching, Curling and Beadingxe2x80x9d machine, referred to hereinafter as an ANCB machine. This machine consists of a plurality of consecutively driven rollers disposed both above and below the blank as its passes therebetween, each of said rollers performing a forming step on the blank. The particular profile of each blank as it exits the ANCB machine depends on the ultimate shape of the tin, but in general the blank is substantially flat with the exception of a hem provided parallel with one of the longer edges of the blank and proximate thereto, a bead is provided on one of said longer edges, a partial curl is provided around the alternate longer edge, and a pair of hooks oppositely disposed with respect to one another on the shorter edges. Additionally, the ANCB machine has cutting means which notch the corners of the blank to preclude any interference effects which may be caused by said corners either when the blank is profiled and provided with the hooks along its shorter edges, when it is formed into the cross-sectional shape of the tin box, or when wrapped around and attached to the base of said tin box.
The hem provides a surface behind which the beaded lip of a tin lid can engage to inhibit the removal of a lid separately formed and applied around the uppermost edge of the tin box, the bead is provided to hide the sharp longer edge of the blank which ultimately forms said uppermost edge of the tin box, the partial curl on the alternate longer edge of the blank is provided to facilitate the attachment of the blank, after same has been formed into the desired cross-sectional shape, to the base of the tin box, and the hooks provided along the shorter edges of the blank facilitate the connection of said edges to one another after a subsequent forming operation.
The profiled blank is then fed from the ANCB machine into a xe2x80x9cbodymakerxe2x80x9d by suitable transport means which generally comprises a pair of reciprocating feed bars in conjunction with xe2x80x9cdisappearing guidesxe2x80x9d which simultaneously urge the profiled blank towards and over a forming mandrel and precisely align said blank thereon. The disappearing guides are rotated away from the blank when it is held in contact with the uppermost portion of the mandrel, which is generally of similar shape to the desired cross-sectional shape of the tin box to be manufactured, by a mandrel clamping arrangement. The removal of the disappearing guides (so-called because they xe2x80x9cdisappearxe2x80x9d within the machine during the forming of the blank around the mandrel) allows a pair of forming wings pivotally connected together or to a jig or frame rigidly secured within the bodymaker and disposed above the mandrel rotate about their pivot and form said blank, which is at this stage still substantially planar, around the said mandrel. The forming operation performed by the wings also constrains the oppositely disposed hooks on the shorter edges of the blank to interlock on the underside of the mandrel whereupon a second forming tool compresses the meta of the blank in the interlocked region to form the vertical seam within the wall of the tin box. During all forming operations the blank is clamped against the upper surface of said mandrel by said mandrel clamping arrangement.
The connection of the mandrel and the frame or jig to which the mandrel forming wings are pivotally connected has heretofore been achieved by bolting the various components to the surrounding structure of the bodymaker. It will be appreciated this means of connection of these components is difficult and time-consuming to disengage when the components are to be replaced with other like components when adapting the bodymaker to accommodate different sizes of blanks and when such blanks are to be formed around mandrels of different shapes.
This invention is specifically concerned with the provision of a novel method and apparatus for replacing the mandrel and mandrel forming wings, which are generally provided together as a tooling set.
Currently, as mentioned above, the mandrel and the mandrel forming wings associated therewith are rigidly secured between two walls which form the structure of the bodymaker. Also connected between these walls are the disappearing guides referred to above and mechanical levers which are in turn connected to the mandrel wings above and on either side of the mandrel and cause the mandrel wings to move back and forth away from and around the mandrel. Although all the various components can be disconnected and/or rotated away from mandrel wings and mandrel to permit access thereto and to facilitate the exchange of these particular components, there is no provision for supporting the components as they are removed. The common practice is to place packing blocks on the hammer disposed underneath the mandrel and which impacts same during the formation of the scan on the tin box to support the mandrel during its disconnection and removal from the bodymaker structure. The mandrel wings are first disconnected from their associated mechanical levers are subsequently un-bolted from their pivots to be removed individually.
It is important to mention that these components are weighty and accordingly unwidely and may require the support of many humans during their removal.
It is an object of this invention to provide a method and apparatus which drastically simplifies the changeover process and reduces the labour intensive nature of the operation.
According to the invention there is provided a method of exchanging working components releasably mounted within a bodymaker comprising the steps of disconnecting said components from actuating means within the bodymaker which effect working motion of said components, bringing support means translatable axially of said components adjacent said components at one end thereof and into locking engagement therewith to provide support for said components, releasing said components from their mounting with the bodymaker, and translating said support means with components engaged thereto away from said bodymaker until the components are without the structure of said bodymaker.
Preferably the direction of translation away from the bodymaker is parallel with the longitudinal axes of the components when mounted within said bodymaker. In usual circumstances, the longitudinal axes of said components will be exactly horizontal.
Preferably, the components are a mandrel and associated mandrel forming wings, which will be hereinafter referred to as a mandrel tool set.
Preferably the support means is provided with releasable connection means which receive or compliment corresponding connection means provided at the said one end of the components which can thus be connected thereto.
Preferably the engagement of the respective connection means provided on the components and on the support means ensures that the said component can move only axially, as opposed to angularly, as the connection is made.
Preferably the support means comprises a vertical plate mounted on horizontal guide means and provided with translating actuation means which allow a user to control the horizontal translation of the support means along said guide trails. The extent of travel of the support means must be sufficient to ensure that the components are withdrawn completely from the bodymaker to allow the support means to be moved safely away and without interference from the structure of the bodymaker.
Preferably the support means can rotate with respect to the guide means to allow the components connected thereto to be rotated away from the bodymaker.
Preferably, the connection of the at least one of the components to the support means is effected simultaneously as the said support means is translated towards the said one end of said component.
Most preferably the connection between said support means and said one end is completed exactly at the end of the extend of travel of said support means.
Preferably the support means is disposed on a table which is rotatably indexable with respect to the guide means, said table being latched in at least two positions.
According to a second aspect of the invention there is provided a set of components for use in a bodymaker, said components being provided at one end with connection means which facilitate their connection to a translatable support means and at their other end with connection means which allow for their connection to and release from said bodymaker.
Most preferably the connection of the components within the bodymaker is effected by hydraulically actuated clamp means.
Preferably, the bodymaker is provided with secondary support means which receive at least one of the components connected to the primary support means as it is translated towards and into the bodymaker.
According to a third aspect of the invention there is provided a bodymaker adapted to receive components mounted on translatable support means disposed externally of said bodymaker and which translate towards and into said bodymaker, said bodymaker being provided with secondary support means which receive at least one of said components and support same during its travel into the machine, and further provided with clamp means to rigidly clamp at least one of said components internally of the bodymaker.
Preferably the support means is mounted on trolley means which can be rolled into position laterally of the bodymaker, preferably on rails, and which can be locked in said position immediately prior to translation of the support means and associated components connected thereto in a direction along the axes of said components which thus enter the bodymaker.
The invention will be better understood with reference to the accompanying specific embodiment, but it will be immediately appreciated by those skilled in the art the time taken to change relevant components in a bodymaker can be drastically reduced by the invention. In particular, the facility of the invention for removing both the mandrel forming wings and the pivotal mounting member, together with the mandrel associated therewith is unprecedented. The invention stems from the realisation of the inventor that the mandrel forming wings and the associated mandrel are design as a tool set and one cannot generally be used independently of the other in the bodymaker.
A specific embodiment of the invention is now described by way of example only and with reference to the accompanying diagrams wherein:
FIG. 1 shows a sectional view of a component support means according to the invention;
FIG. 2 shows a front elevation on IIxe2x80x94II as shown in FIG. 1,
FIG. 2B shows a sectional view of one embodiment of the mandrel wing support member,
FIG. 3 shows a sectional view of the device of FIG. 1 with the component support means in a retracted position,
FIG. 4 shows a side elevation of the support plate assembly which comprises the majority of the component support means of FIG. 1,
FIGS. 5A and 5B show an enlarged front elevation of the support means according to a first embodiment of the invention and a sectional view on line VB,
FIGS. 6A and 6B show an enlarged end elevation and corresponding sectional view of a further modified embodiment of the invention, and paragraph FIG. 6C provides a schematic illustration of the manner in which components engage with and are received by the Support means in accordance with the invention.

Mandrel and tooling replacement and apparatus therefor


Disclosed herein are probiotic compositions comprising a mixture of at least two probiotic bacteria, including Streptococcus salivarius K12® (BLIS K12®) and at least a Lactobacillus bacteria. The Streptococcus salivarius K12® (BLIS K12®) may comprise Streptococcus salivarius K12® (BLIS K12®) BAA1024. The Lactobacillus bacteria may be selected from those known to be suitable for oral administration, for example from those known to improve recipient health, particularly recipient oral health.

The oral cavity shelters numerous and varied microbial flora. When the equilibrium is compromised and when an imbalance appears amongst the indigenous bacteria, pathologies such as dental caries or periodontitis can occur. The beneficial effects of probiotic therapy are achieved in part through the modulation of existing microbial flora associated with the host, thus attaining a balanced and healthy microbes-host relationship.
S. salivarius BLIS K12 is a natural human commensal that was isolated from the oral cavity of a healthy New Zealand child. S. salivarius is a naturally occurring bacterium, a predominant inhabitant of the back of the tongue and the throat area of humans. S. salivarius becomes established in the human oral cavity within two days after birth. The levels of S. salivarius in swab samples taken from newborn infants represent 10% of the total streptococci isolated, increasing to 25-30% by one month of age. S. salivarius produces two antimicrobial bacteriocins that have been shown to inhibit the growth of oral pathogens.
Probiotic compositions can be enhanced in certain circumstances through the addition of prebiotics to the composition. A prebiotic "feeds" microbial flora; a probiotic adds beneficial cultures to populations of microbial flora. The term "synbiotic" describes a composition that contains both prebiotics and probiotics, for example, one that contains both fructooligosaccharides (FOS) (a prebiotic) and bifidobacteria (a probiotic). Research in the area is devoted to the synergy between the types of ingredients to obtain a better understanding of how growth and survival of probiotics may be enhanced by the presence of complementary prebiotic ingredients. There is no guarantee that a prebiotic will enhance the efficacy of a probiotic composition in all cases, nor of the relative amounts of prebiotics required relative to probiotics to achieve a beneficial effect in a particular composition.
Although a large number of probiotic compositions are known, each composition has unique characteristics and particular health benefits. However, there is always a need for improved formulations of probiotic compositions, particularly formulations that result in one or more of improved oral health, improved oral bioavailability, improved shelf-life, decreased incidence of side effects, and additional improvements, as well as methods of administration or uses thereof.


A method for processing seismic data. The method includes predicting seismic data according to an earth model representing seismic properties of subterranean formations in the earth, determining a difference between seismic data acquired from one or more seismic receivers and the predicted seismic data, projecting the difference into a model space in traveltime, and updating the earth model according to the projected difference. As a result, the updated earth model more accurately represents the seismic properties of subterranean formations in the earth.

1. Field of the Invention
Implementations of various technologies described herein generally relate to seismic data processing.
2. Description of the Related Art
The following descriptions and examples are not admitted to be prior art by virtue of their inclusion within this section.
Seismic exploration is widely used to locate and/or survey subterranean geological formations for hydrocarbon deposits. Since many commercially valuable hydrocarbon deposits are located beneath areas of land and bodies of water, various types of land and marine seismic surveys have been developed.
In a typical land or marine seismic survey, seismic sensors are installed in specific locations around an area of the earth in which hydrocarbon deposits may exist. Seismic sources, such as vibrators or air guns, may move across the area and produce acoustic signals, commonly referred to as "shots," directed down to the earth, where they are reflected from the various subterranean geological formations. Reflected signals are received by the sensors, digitized, and then transmitted to a survey database. The digitized signals are referred to as seismic data. The ultimate aim of this process is to build a representation of the subterranean geological formations beneath the surface of the earth. Analysis of the representation may indicate probable locations of hydrocarbon deposits in the subterranean geological formations.
Full-waveform inversion (FWI) is one approach in analyzing the seismic data. Specifically, FWI is an approach to build a seismic velocity earth model that minimizes a misfit between seismic data received by sensors and predicted seismic data obtained from an earth model. Since the misfit is sensitive to both the amplitude and phase of the seismic data, FWI has the potential to deliver velocity earth models with higher resolution than conventional earth modeling techniques. Furthermore, given modern optimization techniques, FWI now has the potential to work with minimal user input. This has significant advantages over conventional velocity earth model building practices in complex areas such as salt provinces, which involve manually intensive workflows.

Full-waveform inversion in the traveltime domain


Tightening device adjustable on the adjustable parts of a boot in a direction transverse to that of the tightening force that it is capable of exerting by means of a tension lever. It has, on an adjustable part, a tension lever whose baseplate is adjustable in position in a transverse direction by a fastening means and a cutout, which cooperate, respectively, with a succession of fastening points and a boss. On the other adjustable part, a retaining element is guided in translation in a slot which extends parallel to the transverse direction of adjustment of the baseplate, located on the other adjustable part of the boot. The direction of the tightening force is allowed to be modified the direction of the tightening force to be applied on the adjustable parts of the boot.

1. Field of the Invention
The present invention relates to a tightening device for a boot adapted to bring two adjustable parts thereof closer together and relates more specifically to a tightening device that can be adjusted in position on these parts in a direction transverse to that of the tightening force that it is capable of exerting by means of a tension lever with which it is provided.
2. Description of Background and Relevant Information
Tightening devices of the aforementioned type are described in German Publication Nos. 19 41 025 and 24 14 439, as well as in Swiss Patent No. 668 682. In these tightening devices, the relative position of the elements constituting them and connecting the adjustable parts of the boot can be adjusted in view of modifying the direction of the tightening force to be applied on these adjustable parts, and in view of respecting the morphology of the user's foot.
More specifically, in the example of DE 24 14 439, a tightening device has a tension lever with a baseplate that is adjustable in an angular position on a rigid notched plate fixed by rivets on one of the adjustable parts of the boot in the area of the instep girth. This lever is adapted to pull on a tie whose ends are connected to the same adjustable part of the boot as that which has the lever. Between these two ends, the tie takes support on two fixed returns located on the other adjustable part of the boot, another lever ensuring the adjustment of the active length of the tie and the opening-closing of the upper of the boot. According to a construction feature, the returns of the tie are fixed in position, one in the area of the upper and the other in the area of the toe-end of the foot, and it is the adjusting of the tension lever position on the rigid plate which modifies the direction of the tightening force. This tightening device is consequently adjustable in position with respect to the adjustable parts of the boot due to the notched plate, in the direction transverse to that of the tightening force that it exerts by means of the tension lever, the resulting force being directed to the area of the instep girth.
As this appears from this construction, there is no effective pulling on the adjustable part of the boot extending opposite of the tension lever in the area of the instep girth. Furthermore, given that the tie is retained at its two ends on one of the adjustable parts of the boot, and that it takes support on the other adjustable part by means of two returns between which the tension lever operates, the tightening force that the latter can produce is reduced by about twice as much in the area of the upper and of the toe-end of the foot. Consequently, to obtain the right tightening force in these areas, it is necessary to apply a very substantial force on the tension lever in the area of the instep girth. Moreover, it is not possible to adjust the tightening force at a preferred area of the boot. Finally, such a tightening device is complicated given the high number of parts that it has for retaining the baseplate of the tension lever on the plate and of the parts that it must use to obtain the actual tightening.
In the example of DE 19 41 025, the tightening device has two rigid slides which extend substantially parallel to one another and which are each fixed by rivets on one of the adjustable parts of the boot. An articulated assembly having a tension lever, to which is tied an adjustable tie rod, is slidably mounted by sectional end pieces on the two slides thus connected to one another. The tightening device is therefore adjustable in position on the adjustable parts of the boot by means of slides in a direction transverse, even perpendicular, to that of the tightening force that it exerts by means of the tension lever. This type of tightening device allows for an effective pulling on the adjustable part of the boot which extends opposite of the tension lever, and allows adjusting the tightening force with respect to the morphology of the user's foot. However, given that the articulated assembly does not have any positive stopping means with respect to the slides, it is susceptible of sliding thereon as soon as it is opened. In reality, to avoid any loss of adjustment, it is necessary to reposition it on the slides after each opening operation. In addition, when the tightening force is relatively weak, the articulated assembly with its lever can have an ill-timed sliding along the slides, even when it is closed. This tightening device proves to be relatively complex given the numerous pieces to be implemented at the level of the articulated lever assembly to allow adjusting the tension, and difficult to obtain as it involves making very specific sectional slides.
One solution to the above-mentioned type of problem is described in Swiss Patent No. 668 682. Indeed, the tightening device described is adjustable in position on one of the adjustable parts of the upper of the boot, in a direction transverse to that of the tightening force that it exerts by a tension lever, by means of a rigid insert provided with several fastening points on which the baseplate of a locking tie rod secured to the lever is positively fixed. In this type of tightening device construction, it is possible to adjust the tightening force with respect to the morphology of the user's foot, without having to reposition it after each opening operation. However, since it is adjustable in position only on one of the adjustable parts of the upper, therefore asymmetrically adjustable, the tightening device imposes, on all of the adjustable part of the boot without the insert, a relatively substantial general elastic deforming especially when the end fastening points are used. In addition, the direction of the tightening force also varies, but in a direction opposite of that of the adjusting done on the insert, unlike the devices previously disclosed. Indeed, in this type of tightening device, when the highest fastening point is used on the upper of the boot, it is on the lower edge of the upper that the tightening force is mainly exerted. Inversely, in a position of use of the lowest fastening point, it is on the upper edge of the upper that the tightening force is the highest. In fact, this device allows above all adapting the adjustable parts of the upper of the boot to the morphology of the lower part of the user's leg between two end positions where the upper takes on a conical shape, whether widened towards the top or widened towards the bottom.


A supply of gas such as oxygen is provided to a person in need of such gas supply. The delivery system includes an alarm to alert the recipient of the gas or another when and if the gas supply is disrupted. The alarm system preferably includes a reset and on-off switch that is recessed sufficiently to prevent accidental disabling of the alarm system.

1. Field of the Invention
The purpose of this invention is to employ a gas flow alarm in a personal gas supply delivery system
2. Description of the Art Practices
Hospitals, nursing homes, dental offices, clinics and a number of other health care institutions utilize medical gasses in rendering care to patients. It is well known to administer oxygen, air, and nitrous oxide to patients for treatment of a variety of different conditions or during surgical operations.
A number of medical institutions now employ medical gas systems which use a central gas supply source for providing a positive flow of medical gasses. These systems often utilize a network of conduits or supply lines to deliver the medical gas remote from the central source of the medical gas. The networks often include main and branch shut-off valves to enable isolation of a portion of the network in the event of damage or fire, or to effect needed repairs.
The lives of patients may depend on receiving a reliable source of the medical gas, a real need has developed to ensure that the medical gas system is functioning properly, and to annunciate an alarm in the event a malfunction or alarm condition is detected. Such conditions may occur, for example, when the shut-off valve is either partially or fully closed. In such circumstances, the necessary supply of gas may be insufficient or non-existent.
A further inadvertent interruption of the medical gas supply may occur when the medical gas is humidified. Commonly employed humidifying systems utilize a threaded plastic vessel that is screwed into a threaded plastic cap. If the threads of the threaded plastic vessel or threaded plastic cap are damaged or misaligned the medical gas may be lost to the surrounding environment with the consequent non-delivery of the medical gas to the patient.
There is a further need to detect other defects in the system that may impair the medical gas system effectiveness. For example, usage of the system may eventually result in low pressure conditions in the supply tank when the supply of gas is nearly exhausted. There is a further need for early detection of these problems so that replacement sources of medical gas may be provided to the patient before the medical gas delivery system becomes completely inoperative.
Finally, due to the escalating costs associated with medical care and the shortage of trained nurses and technicians, monitoring of the medical gas delivery systems should be easy and capable of instant recognition of system faults. In particular, the recipient of the medical gas or a visitor of the patient should be able to recognize system faults.
Several methods using various apparatus have been employed to determine if a supply of a gas is within operating parameters. Such methods and aparrati are disclosed below.
U.S. Pat. No. 6,067,022 granted to Laswick, et al., on May 23, 2000 describes an in-line low supply pressure alarm device powered solely by supply flow of pressurized gas from a gas supply for providing an alarm signal when supply gas pressure is below a selected minimum pressure. The alarm device includes a manifold having an input port for communicating with the supply gas supply, an output port for conducting the gas downstream and a manifold chamber disposed therebetween.
The Laswick, et al., patent utilizes gas powered alarms such as an audible reed alarm or a visual pneumatic alarm are connected to the manifold chamber via an alarm supply conduit, and produce an alarm signal when pressurized gas passes to the alarms. According to the Laswick, et al., patent a supply gas pressure sensor, in communication with the manifold chamber, produces an actuating flow of pressurized gas by activating a pressure switch, in response to sensing of an supply gas pressure below the selected minimum pressure.
U.S. Pat. No. 6,067,022 to Laswick, et al., further provides a pneumatic alarm output switch, in the alarm supply conduit and in communication with the pressure sensor and pressure switch via an actuation conduit, controls gas flow to the alarms in response to the actuating flow. The Laswick, et al., patent preferably includes an alarm oscillation system is included for alternating the direction of the actuating flow to and from the alarm output switch, to open and close the alarm output switch thereby turning the alarm on and off in a cyclical fashion.
U.S. Pat. No. 4,674,321 issued to Joshi on Jun. 23, 1987 describes a leak detector employing an ion-conducting membrane is disclosed. The Joshi patent describes an oxygen-ion conducting membrane which employs a high vacuum on one side is used to detect very small quantities of oxygen flowing through a minute fissure in a part to be tested for leaks. The Joshi patent further describes an oxygen-ion conducting membrane which is biased with direct current voltage to drive oxygen-ions through the membrane away from the high vacuum side.
U.S. Pat. No. 3,133,997 to Greene issued May 19, 1964 describes a fluid-pressure activated switch. Pressure activated switches are described in the MPL publication available at firstname.lastname@example.com 555 SW 12 th Avenue Pompano Beach, Fla. 33069. Further disclosures of pressure activated switches are found at World Magnetics 810 Hastings Street Traverse City, Mich. 49686, telephone: 231-946-3800 and fax: 231-946-0274 and located on the web at http://www.worldmagnetics.com.
U.S. Pat. No. 5,057,822 to Hoffman issued Oct. 15, 1991 describes a medical gas alarm system is provided which includes a sensor unit pneumatically connected to a medical gas supply line and a switch connected to a valve in the supply line for detecting the open condition of the valve.
In the Hoffman patent, in the event either the sensor detects a high pressure or low pressure condition in the supply line or closing of the valve activates the switch, an alarm signal is received by an alarm module and an alarm is activated. The alarm of the Hoffman patent may be visual, audible or both. During normal operations, the alarm module of the Hoffman patent displays both a system on condition and a digital display indicating the pressure in the supply line.
The Hoffman patent also includes a method of monitoring the condition of a medical gas delivery system which includes sensing the pressure in the gas supply line, detecting the open condition of the valve, transmitting an alarm signal to an alarm module in response to alarm conditions detected either as a result of improper pressure or valve closure, and generating a humanly perceptible alarm warning in response to receipt of an alarm signal.
Fukui in U.S. Pat. No. 5,457,333 issued Oct. 10, 1995 describes a gas sensor comprises a precious metal electrode, a semiconductor layer entirely or partly covering the precious metal electrode, a barrier layer having a high potential formed at an interface between the precious metal electrode and the semiconductor layer. The Fukui patent recites a gas sensor for use in a leak detector for detecting a fuel gas such as town gas, the sensor comprising a precious metal electrode; and a semiconductor layer at least partly covering said precious metal electrode, wherein the semiconductor layer includes, as a main component, at least one substance selected from the group consisting of tin oxide, zinc oxide and indium oxide. The Fukui patent precious metal electrode is formed of a substance selected from the group consisting of platinum, gold, ruthenium, lead, silver, iridium, and alloys thereof and has a barrier layer having a high potential formed between said precious metal electrode and said semiconductor layer and on a surface of said precious metal electrode. The barrier layer described in the Fukui patent comprises either a substance formed by electrodeposition and selected from the group consisting of platinum, palladium, gold and rhodium, or a substance formed by thermal decomposition and selected from the group consisting of platinum, palladium and gold, said barrier layer being capable of enhancing sensitivity to isobutane gas relative to other gases.
U.S. Pat. No. 5,293,866 issued to Padula Mar. 15, 1994 provides a description of an indicator device which can be attached to a standard oxygen flow meter is disclosed. The indicator device described in the Padula patent has a rod along which a pointer can be moved and locked into position. The pointer in the Padula patent can be set at the oxygen flow level prescribed by the physician as indicated by the scale on the oxygen flow meter. If the oxygen flow level, as described in the Padula patent, is changed or if oxygen is discontinued for any period of time, the attendant can then set the oxygen flow to the prescribed level by controlling the valve on the oxygen flow meter so that the float, which indicates oxygen flowing liters per minute is positioned opposite the position of the pointer. The foregoing mechanism recited in the Padula patent prevents erroneous or improper setting of oxygen flow levels to patients after interruption or change of oxygen flow level, which can be dangerous, and life threatening.
To the extent that the foregoing references are relevant to the present invention, they are herein specifically incorporated by reference. Where temperatures are given, they are in degrees C. unless otherwise indicated. Pressure measurements are reported in KPa. Percentages and ratios given herein are by weight unless otherwise indicated. Measurements herein are stated in degrees of approximation and where appropriate the word "about" may be inserted before any measurement.


The present disclosure relates to a strain relief. In various embodiments, the strain relief includes a strain relief body and at least one alignment feature. The strain relief body is configured to provide support for connection of a cable and/or a wire lead of the cable to a frame. The alignment feature is configured to facilitate alignment of the strain relief relative to the frame. In various embodiments, provided are methods of manufacturing a sensor with a strain relief. The methods may include forming the strain relief about a cable and/or wire leads, wherein the strain relief comprises at least one alignment feature, aligning the alignment feature of the strain relief to a complementary alignment feature of a frame, engaging the complementary alignment feature of the frame with the alignment feature of the strain relief, and electrically coupling the cable and/or wire leads to a circuit.

The present disclosure relates generally to medical devices and, more particularly, to sensors used for sensing physiological parameters of a patient.
This section is intended to introduce the reader to various aspects of art that may be related to various aspects of the present disclosure, which are described and/or claimed below. This discussion is believed to be helpful in providing the reader with background information to facilitate a better understanding of the various aspects of the present disclosure. Accordingly, it should be understood that these statements are to be read in this light, and not as admissions of prior art.
In the field of medicine, doctors often desire to monitor certain physiological characteristics of their patients. Accordingly, a wide variety of devices have been developed for monitoring physiological characteristics. Such devices provide doctors and other healthcare personnel with the information they need to provide the best possible healthcare for their patients. As a result, such monitoring devices have become an indispensable part of modern medicine.
One such monitoring technique is commonly referred to as pulse oximetry. Pulse oximetry may be used to measure various blood flow characteristics, such as the blood-oxygen saturation of hemoglobin in arterial blood and/or the rate of blood pulsations corresponding to each heartbeat of a patient.
The devices based upon pulse oximetry techniques are commonly referred to as pulse oximeters. Pulse oximeters typically utilize a non-invasive sensor that is placed on or against a patient's tissue that is well perfused with blood, such as a patient's finger, toe, forehead or earlobe. The pulse oximeter sensor emits light and photoelectrically senses the absorption and/or scattering of the light after passage through the perfused tissue. The data collected by the sensor may then be used to calculate one or more of the above physiological characteristics based upon the absorption or scattering of the light. More specifically, the emitted light is typically selected to be of one or more wavelengths that are absorbed or scattered in an amount related to the presence of oxygenated versus de-oxygenated hemoglobin in the blood. The amount of light absorbed and/or scattered may then be used to estimate the amount of the oxygen in the tissue using various algorithms.
Pulse oximetry sensors may include a flex circuit that electrically connects various electrical components of the sensor. For example, components of the flex circuit may include an optical emitter, such as an LED, a photodetector and wires forming conductors which electrically connect the sensor components and/or allow connection of the sensor components to a pulse oximeter monitor via wire leads contained in a cable. During use of such a sensor, mechanical stresses may be placed on the location where an external cable and its wire leads are attached to the sensor frame and associated flex circuit. Generally, a strain relief may be provided to reduce the effect of the mechanical stresses at the point where the cable attaches to the sensor frame.
During the manufacturing process it may be labor intensive to secure a strain relief to the sensor frame and cable prior to and during the process of connecting the wire leads of the cable to the flex circuit. Further, aligning the wire leads for proper connection may be a labor intensive task, the difficulty of which may result in wires being improperly seated, resulting in the production of poorly functioning or non-functioning sensors.

Method and apparatus for aligning and securing a cable strain relief


Disclosed herein are materials and compositions comprising: an oxidized carbon black having a BET surface area ranging from 50 to 700 m2/g, a DBP oil adsorption number ranging from 50 to 200 mL/100 g, and a primary particle size ranging from 7 to 30 nm; and a polyetheramine comprising ethylene oxide and propylene oxide monomers, wherein the polyetheramine coats the oxidized carbon black. Also disclosed are coatings and coating compositions comprising these materials and methods of making the same.

Carbon black is the most widely used black pigment in both water- and solvent-based formulations for surface coatings, which typically include resins. The color of the coating depends on several factors including carbon black loading, the quality of a carbon black dispersion in the resin matrix, the specific carbon black grade, and primary particle size and aggregate size. Accordingly, there remains a need to improve coating formulations.

Oxidized carbon blacks treated with polyetheramines and coating compositions comprising same


The invention provides compounds for use in a method of treating and/or preventing a bacterial infection in a human or non-human mammal, said method comprising administration of said compound in combination with (either simultaneously, separately, or sequentially) a β-lactam antibiotic, wherein said compound has the general formula I: (I) (wherein: Q is a lipophilic, zinc chelating moiety which is selective for Zn2+ ions and which comprises at least one, preferably two or more (e.g 2, 3 or 4), optionally substituted, unsaturated heterocyclic rings, e.g. 5 or 6-membered heterocyclic rings (such rings preferably include at least one heteroatom selected from N, S and O, preferably N); wherein any optional substituents may be selected from C1-6 alkyl, C1-6 alkoxy, halogen, nitro, cyano, amine, and substituted amine; each L, which may be the same or different, is a covalent bond or a linker; each W, which may be the same or different, is a non-peptidic hydrophilic group which comprises one or more hydroxy groups; and x is an integer from 1 to 3) or a stereoisomer, pharmaceutically acceptable salt or prodrug thereof.

In a number of disease states, biological zinc is present in concentrations outside the normal range for cells to have a healthy function. The disease state may be affected by biological factors such as enzymes dependent on zinc, e.g. as described in Prasad et al, Journal of Trace Elements in Medicine and Biology (2014), 28(4), 357-363 or in Shai et al, ChemMedChem (2015), 10 (3), 441-450. Herein, the group of diseases that may be affected or regulated by selectively and safely altering the zinc homeostasis is denoted the "disease".
A key element necessary for normal life of a cell is the homeostasis of zinc. Zinc is the second most abundant transition metal in the human body and is responsible for the catalytic function and structural stability of over 6000 enzymes and proteins (Bertini et al, Journal of Inorganic Biochemistry (2012), 111, 150-156). The biological concentration range of zinc maintaining healthy cells is narrow and is well described, e.g. by Maret in Biometals (2011) 24:411-418. Manipulation of the freely available zinc inside a cell has been shown to affect a great range of diseases and conditions (Que et al, Chem. Rev. (2008), 108, 1517-1549; Peterson, et al Mol. Biol. (2009), 388, 144-158; BarKalifa et al, Eur. J. Pharmacol. (2009), 618, 15-2; Maret et al, Mol. Med. (2007), 13, 371-375).
The concentration of free zinc varies in biological tissues depending on zinc buffering capacity. In PC12, HeLa, and HT-29 cell lines, as well as in primary cultures of cardiac myocytes and neurons in vitro, the concentration of free zinc has been determined to be approximately 5 nM (Bozym et al, Exp. Biol. Med. (2010), 235, 741-750). Zinc is a soft metal, mainly found in nature as salpherite or zinc sulfite, with an oxidation state +2 (Emsley, J. "Zinc". Nature's Building Blocks: An A-Z Guide to the Elements; Oxford University Press: New York, 2001). In order to chelate zinc selectively and safely and with high efficacy, the use of soft basic ligands is needed.
Non-limiting examples of disease states related to an imbalance in zinc homeostasis are cancer, Alzheimer's disease, stroke, edema, diabetes and intoxications by heavy metals like cadmium.
In Khan et al, Journal of Diabetes and Metabolic Disorders (2014), 13, 16/1-16/6, 6 pp., imbalance in zinc homeostasis is discussed as a factor in the development of diabetes.
In neurological disorders, it is well documented that in states of edema and stroke, there is an extraceullular zinc overload in CNS affecting the severity of the disease, e.g. as discussed by Liao et al in Toxicology Letters (2011), 204, 108-117. At the same time, zinc chelators may have a neuroprotective role, e.g. as discussed by Cho et al. in Neurotox. Res. (2010) 17:156-166. Recently, it was shown that zinc chelators may have a neuroprotective effect if they do not penetrate cell membranes in zebra fish, as described by Yu et al. in Zebrafish (2013), 10(1), 30-35. This is possible because both too high and too low concentrations of zinc, outside the normal concentration range, may be toxic for cells.
Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of b-amyloid (Ab) fibrils accompanied with progressive neurite loss. In these diseases, often a higher concentration of zinc is described, e.g. in Huang, RSC Advances (2014), 4(94), 52088-52099. In Neuropharmacology (2015), 92, 146-157, Chang et al. show how a metal chelator can reverse the development of the disease. However, the chelators used in the prior art are not zinc selective and log P (which is a measure of hydrophilicity) is high enough to provide cell penetration of the chelators in all cells. An example of a zinc chelator that has been used clinically to regulate extracellular zinc is the chelating agent DP-b99. A phase II study reported by Diener et al in Stroke (2008), 39(6), 1774-1778 reported positive results with DP-b99 on ischemic stroke. However, DP-b99 is a chelating agent with log P>5 and significant membrane penetration which would be expected to result in toxicity. Thus there is a medical need for a selective zinc chelator with negligible issues related to toxicity.
Also in a variety of cancer forms, zinc concentrations outside the normal range play a vital role. For example, in prostate cancer, zinc acetate has been used therapeutically, as described by Shah et al. in Journal of Experimental & Clinical Cancer Research (2009), 28:84, pp. 1-10. However, zinc acetate provides a very water-soluble formulation with low ability to transport zinc over biological membranes.
Matrix Metalloproteinases (MMPs) are a group of extracellular zinc-dependent enzymes vital to the growth of cancer cells and cancer tissue in general. General metal chelators have been shown to affect MMPs in the extracellular space, and thereby development of cancer, e.g. as discussed by Rouffet et al. in JACS (2010), 132, 8232-8233.
Also in hypoxic states related to cancer, zinc balance plays a role, e.g. zinc induces the accumulation of hypoxia-inducible factor (HIF)-1a, as discussed by Chun et al. in Biochemical and Biophysical Research Communications (2000), 268, 652-656. Zinc chelators may have a documented and significant effect on death of cancer cells as discussed by Ding et al., Cancer Letters (2008), 271, 251-259, by Lee et al. in Biochemical and Biophysical Research Communications (2007), 362, 766-772 and by Zuo in Journal of Cellular Biochemistry (2012), 113, 2567-2575. In the latter reference, derivatives of N,N-bis(2-pyridyl-methyl)-amine, including the well described zinc chelators TPEN (N,N,N″,N″-tetra(2-pyridyl-methyl)-ethylene diamine) strongly induce cancer cell death related to cellular zinc depletion and destabilization of the X-linked inhibitor of apoptosis protein (XIAP).
However, these chelating agents may not be used as therapeutic agents clinically because of high lipophilicity (log P) and high ability to penetrate also normal cells, inducing an unacceptable general toxicity. These agents have no structural or molecular features providing biological selectivity for the target organ or disease area.
One especially important disease area is resistant microbes. Infectious diseases are a leading cause of death worldwide and account for more than 13 million deaths annually including nearly two-thirds of all childhood mortality at less than 5 years of age. There is serious concern regarding new and re-emerging infectious diseases, in which effective therapies are lacking (World Health Organization reports 1999, 2012 and 2014).
Antimicrobial resistance is escalating and affects a very broad range of human diseases including tuberculosis, cholera, malaria, and AIDS. Of particular concern is the number of human pathogens developing multidrug resistance to conventional antibiotics and it is estimated that the burden of resistance will surpass that of e.g. cervical cancer (de Kraker M E A. et al, PLoS Med. (2011), e1001104, and cancer as a whole by 2050 (O'Neill J. Tackling drug-resistant infections. Final report and recommendations).
The introduction of new, more potent derivatives of existing antibiotics provides only temporary solutions, since existing resistance mechanisms rapidly adapt to accommodate the new derivatives (Theuretzbacher U. Curr. Opin. Pharmacol. (2011), 11, 433-438). Although resistant Gram-positive bacteria pose a significant threat, the emergence of multidrug resistant (MDR) strains of common Gram-negative pathogens such as Escherichia coli are of special concern. Pan-resistance or extreme drug resistance are now commonly used terms to describe clinically important isolates of Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacteriaceae that are resistant to virtually all antibiotics (Patel et al., Front. Microbiol. (2013), 4, 48). Unfortunately, there are few, if any, antimicrobial agents effective against Gram-negative bacteria either in or entering phase 1 clinical trials that will address this critical need (Butler M S. et al., J. Antibiotics (2013), 66, 571-591).
One important feature of bacteria, especially gram negative bacteria is that they have two cell membranes, one outer more permeable membrane and one inner cell membrane. One important group of enzymes involved in antimicrobial resistance is the β-lactamases (Bush K. et al., Annu. Rev. Microbiol. (2011), 65, 455-478). They are excreted into the volume between these membranes, the periplasmic space, thus this space is more accessible, for example for drugs.
The β-lactamases are enzymes that hydrolyse β-lactam antibiotics compromising the efficacies of β-lactams, our largest group and mainstay of antimicrobial chemotherapy for >70 years. Clearly, there is a need for inhibitors directed against these classes of enzymes that will restore the activity of their substrates—antibiotics that are cheap, non-toxic and normally effective. Serine β-lactamase inhibitors (clavulanic acid, sulbactam and tazobactam) have been a phenomenal success in extending the therapeutic life of β-lactam antibiotics and are also employed as diagnostic tools in clinical microbiological laboratories worldwide. In contrast, there is no clinical inhibitor available for metallo-β-lactamases (MBLs; Drawz et al., Antimicrob. Agents Chemother. (2014), 58, 1835-1846). The latter has now become one of the most clinically important families of β-lactamases showing global dissemination.
The β-lactamases are the most prevalent and clinically important resistance mechanism inactivating β-lactams by hydrolysis. They are classified according to sequence criteria (Ambler class A, B, C and D) and can be structurally grouped into two super families; the serine β-lactamases (class A, C, and D) and MBLs (class B). In contrast to the serine β-lactamases, which are characterized by a serine moiety in the active site, MBLs require divalent cations, usually zinc, as a metal co-factor of enzyme activity (Palzkill T. Ann. N. Y. Acad. Sci. (2013), 91-404).
MBLs belong to a large group of proteins only found in bacteria, and like penicillin-binding proteins (PBPs) have the ability to interact with β-lactams. Examples of PBPs and enzymes that bind β-lactams are MBLs, serine β-lactamase-like protein (LACTB), D,D-transferase, D-Ala(D,D)-carboxypeptidase, the D-Alanyl-D-alanine Dipeptidases VanA, VanX, VanY and others, as reviewed by Sauvage E. et al. in FEMS Microbiol. Rev. (2008), 32, 234-258. This class of proteins is only found in bacterial biology. Examples of compounds having affinity for PBPs are β-lactam antibiotics. β-Lactams have been the historical anchor of antibacterial chemotherapy and include penicillins, cephalosporins, monobactams and carbapenems (Bush K. et al, Annu. Rev. Microbiol. (2011), 65, 455-478).
MBLs are emerging as one of the most clinically important family of β-lactamases (Patel et al., Front. Microbiol. (2013), 4, 48, Walsh et al, Int. J. Antimicrob. Agents (2010), S8-S14) for the following reasons: The clinically most important MBLs, the IMP-, VIM-, GIM- and NDM-groups, are now widespread in a variety of Gram-negative species. In particular, VIM- and NDM-enzymes have emerged as the dominant MBLs. The unprecedented global dissemination of NDM highlights the enormity of the problem. Since the first report in 2008, NDM has been identified in Australia, Africa, North-America, Asia and many European countries (Johnson A P. et al, J. Med. Microbiol. (2013), 62, 499-513). Worryingly, NDM is found in numerous Gram-negative species and in the environment (Walsh T R. et al, Lancet Infect. Dis. (2011), 11, 355-362).
Successful inhibitors of class A serine β-lactamases are clinically available, but lack inhibitory activity against MBLs (Drawz S M. et al, Clin. Microbiol. Rev. (2010), 23, 160-201). Inspired by the commercial success of the paradigm Augmentin (clavulanic acid—a suicide substrate for serine β-lactamases—and amoxicillin) several research groups have focused on similar approaches to develop inhibitors, but as yet no molecules that combine potency with activity against multiple MBL targets have reached clinical trials (Drawz S M. et al. Antimicrob. Agents Chemother. 2014).
For the three clinically most threatening MBLs—the IMP, NDM and VIM groups—most inhibitors are reported for IMP-1, while few inhibitors are found for VIM-2 and NDM. For NDM, a fungal natural product, aspergillomarasmine A has been identified as an MBL inhibitor and shown in vivo activity in mouse models (King A M. et al. Nature (2014), 510, 503-506). However, relatively high doses of aspergillomarasmine A are required to reverse carbapenem resistance. Other therapeutic options (Martinez, Future Med. Chem. (2012), 4(3), 347-59) include the use of tri-β-lactam therapy incorporating a monobactam; however, the MICs are not impressive and their in vivo activity is severely compromised by the bacterial inoculum (Page et al., Antimicrob. Agents Chemother. (2011), 66, 867-73). Thus, there is a strong clinical need for an MBL inhibitor.
Important β-lactam antibiotics are the penicillins, cephalosporin and carbapenem classes. Many compounds have been reported as having MBL inhibiting activities. In WO 98/117639, WO 97/30027, WO 98/40056, WO 98/39311, and WO 97/110225, a class of β-thiopropionyl-amino acid derivatives has been described as the inhibitors against the MBLs.
Other compound classes that may act as MBL inhibitors are thioesters (Biol. Pharm. Bull. (1997), 20, 1136; FEMS Microbiology Letters (1997), 157, 171; Antimicrob. Agents Chemother. (1997), 41, 135; Chem. Commun. (1998), 1609; Biochem. (1998), 1, 331, 703; WO 00/076962) and succinic acid derivatives (WO 01/030148 and WO 01/030149).
In bacteria, zinc sensing is carried out by regulators of different families, including SmtB/ArsR, MerR, TetR, MarR, and the Fur family (Napolitano et al., Journal of Bacteriology (2012), 2426-2436). In some cases the MBL inhibitors contain a Zn2+-binding group that can interact strongly with the central metal ion(s). Thus, in the prior art, compounds binding metal ions, so called metal "chelators", have been shown to affect bacterial biological mechanisms. The term "chelating" relates to the greek term "chelos" denoting a crab claw binding an object via at least two contact points. The person skilled in the art will appreciate the variety of substances described in the prior art capable of chelating metal ions, and will select an appropriate chelator for different purposes. Examples are chelators comprising variations of amino groups and hydroxyl groups, e.g. 1,10-phenanthroline, clioquinol, 1,2-dimethyl-3-hydroxy-4-pyridinone (DMHP), 1,2-diethyl-3-hydroxy-4-pyridinone (DEHP), deferasirox. In the prior art, zinc chelators have been described as inhibitors of multiple diseases simultaneously, e.g. in WO 2006/117660, WO 2001/60349, U.S. Pat. No. 6,410,570, and in WO 2009/140215.
Zinc chelators have also been suggested as inhibitors of biofilm formation, e.g. in WO 2011/63394 and WO 2009/155088, or as antiviral agents, e.g. in WO 2004/71425 and WO 2006/43153. Attractive bacterial zinc-dependent targets involved in resistance mechanisms are known in the prior art to be inhibited by zinc chelating agents. Three examples are the tightly regulated bacterial zinc uptake system Zur (Ellison et al. in PLOS ONE (2013), 8, e75389), biofilms (Conrady et al., PNAS (2008), 105 (49), 19456-19461) and the peptidase HmrA in MRSA. All these targets are inhibited by state of the art non-selective, toxic zinc chelators like TPEN, EDTA or the phenanthrolines.
Biofilm formation is an important bacterial resistance mechanism that contributes to the growing therapeutic concern globally. Biofilms consist of extracellular polymeric substances (EPS). They are natural hydrophilic carbohydrate polymers of high molecular weight secreted by microorganisms into their environment, and determine the physiochemical properties of a biofilm. Biofilm formation with the nocosomial infections produced by multidrug-resistant gram-negative species producing metallo-β-lactamases, e.g. Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiella pnemoniae and E. coli is problematic since they affect all traditional activity at hospitals, like surgery and wound healing. Of particular concern is MBL-producing Acinetobacter baumannii, as described by Peymani et al., Jpn. J. Infect. Dis. (2011), 64, 69-71. MBL-production was also found to be significantly higher in biofilm-positive isolates of Pseudomonas aeruginosa, as described by Heydari et al., Jundishapur J Microbiol. (2015), 8(3), e15514. Thus, there is a medical need for new drugs with acceptable toxicity and selectivity that are active against gram-negative bacteria harboring MBL.
Another example of vital zinc-dependent machineries is bacterial use of the efflux pumps (Nikaido, et al., FEMS Microbiology Reviews (2012), 36, 340-363), adapting almost all modern antibiotics as substrates, excreting them from the bacterial cell.
Yet another example is the zinc-dependent deacetylase LpxC (Liang et al., J. Med. Chem. (2013), 56, 6954-6966). Another example is the highly zinc-dependent bacterial ribosomal function (Graham et al., J. Biol. Chem. (2009), 284, 18377-18389). The latter uses 8 zinc atoms on the 70S ribosomal unit. Administration of zinc has also been used as a therapy against bacterial infections, e.g. as different formulations of zinc oxide ZnO, often as particulate matter, e.g. as described in Shi et al., Food Additives & Contaminants, Part A: Chemistry, Analysis, Control, Exposure & Risk Assessment (2014), 31(2), 173-186. However, where there is a need to provide zinc to compartments protected by biological membranes, particulate ZnO has a low penetration over such membranes.
The most widely used groups of metal chelators are the so called amino-polycarboxylates, denoted hereinafter as APC chelators, comprising variations of aliphatic amino groups, hydroxyalkyl groups and carboxyalkyl groups. Common examples are ethylenediaminetetra-acetic acid (EDTA), ethylenediamine-N,N′-diacetic-N,N′-di-β-propionic acid (EDPA), diethylenetriamine pentaacetic acid (DTPA), trans-1,2-cyclohexane-diamine-N,N,N′,N′-tetraacetic acid (CyDTA), carnosine, dihydroxyethylglycine (DHEG), 1,3-diamino-2-hydroxypropane-N,N,N′,N′-tetraacetic (DTPA-OH), ethylenediamine-N,N′-diacetic acid (EDDA), ethylenediamine-N,N′-dipropionic acid (EDDP), N-hydroxy-ethylenediamine-N,N′,N′-triacetic acid (EDTA-OH), N,N′-bis(2-hydroxybenzyl)ethylenediamine-N,N′-diacetic acid (HBED), hexamethylene-1,6-diaminetetraacetic acid (HDTA), hydroxyethyliminodiacetic acid (HIDA), iminodiacetic acid (IDA), methyl-EDTA, nitrilotriacetic acid (NTA), nitrilotripropionic acid (NTP), triethylenetetraaminehexaacetic acid (TTHA), ethylenediamine-di(O-hydroxyphenylacetic acid) (EDDHA), ethyleneglycol bis(2-aminoethyl ether)-N,N,N′,N′-tetraacetic acid (EGTA), trans-1,2-cyclohexanediaminetetraacetic acid (CDTA), N-(2-hydroxyethyl) ethylenedinitrilotriacetic acid (HEDTA), N-(2-hydroxyethyl) iminodiacetic acid (HEIDA), citric acid, 7,19,30-trioxa-1,4,10,13,16,22,27,33-octaazabicyclo[11,11,11] pentatriacontane (O-Bistren), penicillamine, chelators also comprising sulfur or phosphorus, e.g. diethyldithiocarbamate(DEDTC), 2,3-dimercapto-1-propanesulfonic acid (DMPS), ethylmaltol (EM), 4-(6-methoxy-8-quinaldinyl-aminosulfonyl)benzoic acid potassium salt (TFLZn), dithiozone, N-(6-methoxy-8-quinolyl)-para-toluenesulfonamide (TSQ), ethylenediamine-N,N′-bis(methylphosphonic) acid (EDDPO), ethylenediaminetetra(methylenephosphonic) acid (EDTPO), nitrilotrimethylenphosphonic acid (NTPO), dimercaptosuccinic acid (DMSA), carboxymethyl-derivatives of 1,4,7-triaza-cyclononane or 1,4,7,10-tetra-aza-cyclododecane like DOTA, DO3A or NOTA, deferoxamine, dimercaprol, dimercaptosuccinic acid, and etidronic acid.
The APC chelators are well known in the prior art, e.g. in Smith, R. M.; Martell, A. E. NIST Critically Selected Stability Constants of Metal Complexes, Version 2.0; U.S. Department of Commerce: Gaithersburg, Md., 1995. They are non-selective and often strong chelating agents with no molecular targeting moieties affecting their affinity for desired biological targets relevant for the disease. Thus they usually also have antibacterial effect which is well described in the prior art, e.g. use of metal chelators against virus or bacteria in WO 2011/63394, WO 2004/71425, WO 2006/109069, WO 2001/60349, U.S. Pat. No. 6,410,570, US 2003/0225155, WO 2006/43153 and WO 2006/43153. Zinc chelators have also been suggested as antibacterial agents, e.g. in WO 2009/140215, as inhibitors of biofilm formation, e.g. in WO 2011/63394 and WO 2009/155088, or as antiviral agents, e.g. in WO 2004/71425 and WO 2006/43153, but in these cases, the claimed compounds lack biological or metal-chelating selectivity or have high solubility in fat, high log P, and are therefore often toxic to eukaryotic cells.
This lack of selectivity may lead to undesired toxicity and other biological effects when treating specific infections by a target organism in a host organism, e.g. when it is desirable to affect only specific microorganisms whilst a low toxicological effect on the host organism or other species (which are not a target for the treatment in question) is desired. One particularly serious adverse event exerted by non-selective chelating agents like the APC chelating agents is hemolytic effects even at low concentrations. A final report on the safety assessment of EDTA, calcium disodium EDTA, diammonium EDTA, dipotassium EDTA, disodium EDTA, TEA-EDTA, tetrasodium EDTA, tripotassium EDTA, trisodium EDTA, HEDTA, and trisodium HEDTA, ethylene diamine tetra acetic acid, EDTA, confirms that these have a swelling effect on erythrocytes after intravenous injections concentrations below 4 μM, eventually leading to hemolysis. This is well described in the prior art, e.g. by Witeska et al., in Turk. J. Vet. Anim. Sci. (2011), 35(2), 99-104, or by Igbokwe et al., Journal of basic and clinical physiology and pharmacology (2015), 26(2), 171-9.
EDTA is also a potent anticoagulant because of its unselective metal chelation, resulting in chelation of e.g. Ca2+. However, this ability to bind calcium may lead to hypocalcemia, a deadly condition causing the US Food and Drug Administration (FDA) to withdraw the market approval of disodium EDTA because of the death of three patients related to hypocalcemia, as reported by P. M. Wax, J. Med. Toxicol. (2013) 9:303-307. A report by R. S. Lanigan and T. Yamarik in International Journal of Toxicology, (2002), 21(Suppl. 2), 95-142 concluded that EDTA, being a weaker chelating agent than other PACs, e.g. DTPA or DOTA, is a compound with biological effects incompatible with the demands for safe agents used clinically, especially for intravenous injection.
EDTA has recently been used as an adjuvant in a formulation denoted Elores or Sulbactomax comprising the β-lactam antibiotic ceftriaxone. Sulbactam and EDTA administered intravenously have a good antibacterial effect, e.g. as described by Attili et al. in International Journal of Pharmaceutical Sciences and Research (2015), 6(6), 2569-2578. However, no description of studies of the hemolytic or anti-coagulant effects of the formulation are mentioned.
Attractive bacterial zinc-dependent targets involved in resistance mechanisms are known in the prior art to be inhibited by zinc chelating agents. An example of vital zinc-dependent machineries is bacterial use of the efflux pumps (see Nikaido et al., FEMS Microbiology Reviews (2012), 36, 340-363), adapting almost all modern antibiotics as substrates, excreting them from the bacterial cell.
Ligands based on the 2-pyridyl-methyl units (see Scheme 1) demonstrate remarkably high selectivity for the group IIB elements zinc and cadmium (Xu et al., JACS, (2010), 132, 601), although the latter is not a natural metal ion in biological systems. Zinc chelating agents are also suggested in the prior art to act as MBL inhibitors. In WO 2012/088283 thiazolidines and analogous compounds are suggested as MBL inhibitors together with β-lactams. The use of the di-picoylamine group in zinc chelators is not mentioned herein. Also, the IC50 values are above the micro molar range in MBL assays in WO 2012/088383.
In Ganta et al., Bioorganic & Medicinal Chemistry Letters (2009), 19, 1618-1622, a group of compounds have been reported having a hydroxamate group as a zinc-chelating moiety with affinity for MBLs. However, the hydroxamate group is a non-selective chelating group. In particular, its binding of Fe2+/Fe3+ and also its binding of many other metal ions makes hydroxamate ligands less specific, and more prone to interaction with human biology leading to higher human toxicity.
In the above descriptions of the prior art, there is no guidance on how to obtain selective effects of the zinc chelation therapy in the target tissue whilst the healthy part of the organism is not affected with serious adverse advents. Likewise, there is no guidance on how to avoid toxic effects like hemolysis by metal chelators whilst maintaining their desired biological effect.
Not only may a deficiency of zinc provoke the abnormal function of a cell, but also an excess of zinc may lead to abnormal cell functionality and unacceptable toxicity. Thus there is a medical and technological need within this field for new therapeutic and diagnostic agents harnessing toxicity related to uncontrolled zinc depletion in healthy tissue and cells, whilst exerting the desired therapeutic effect. Many of the disease states in mammals related to zinc imbalance are caused by enhanced zinc concentration outside the eukaryotic cells in the extracellular space. Often the disease is related to excess zinc outside the cells. Thus, there is a medical need for new zinc chelating agents that have a low ability to pass eukaryotic cell membranes, and which at the same time have a high and selective affinity for divalent zinc.
The lipophilic zinc chelators N,N,N-tris(2-pyridylmethyl) amine (TPA, structure III, Scheme 1) and N,N,N′,N′-tetrakis(2-pyridylmethyl) ethylenediamine (TPEN, structure IV, Scheme 1), have been reported to display many interesting biological activities due to their zinc chelating properties as well as their lipophilic character, allowing cell-membrane penetrating abilities, e.g. as described by Huang et al., Metalomics (2013), 5, 648-655 and Donadelli et al. in J. Cell. Biochem (2008) 104, 202-212).

In TPA and TPEN, the zinc-binding ability is based on the binding of all nitrogen atoms to the metal atoms. Both TPA and TPEN have been widely reported to exert cytotoxic effects on a number of cell types because of their high lipophilicity. The main property affecting the toxicity of zinc chelating agents having a relatively high log P is the zinc-binding ability, expressed as the dissociation constant, Kd, or expressed as the log Kd or pKd. TPEN is known to have a pKd of about 16, while the pKd of TPA is about 12.
Thus, TPA and TPEN are not suitable in themselves as potential drugs since they are too toxic to normal cells, as described by Sheridan et al. in In Vitro & Molecular Toxicology (1998), 11 (2), 161-169 or by Huang et al., Metalomics (2013), 5, 648-655. The EC50 values were reported by Huang et al. to be 38±1 μM for TPA and 25±1 μM mM for TPEN in an MTT assay in HeLa cells. In neurons, TPEN is known to be even more toxic, and the EC50 for TPEN in neurons was reported by Canzoniero et al., Neuropharmacology (2003), 45, 420-428, to be about 5 μM.
Thus, the toxicity of zinc-selective chelating agents is a combination of their high log P value and their zinc-binding ability, pKd. A high value for both evidently results in lower toxicity EC50 values.
Toxicity issues are further demonstrated for example in Zuo in Journal of Cellular Biochemistry, (2012), 113, 2567-2575. The prior art is not teaching how to synthesize analogues or derivatives of, for example, TPEN with lower toxicity than TPEN itself, according to Scheme 1.
It has now surprisingly been found that in the above defined diseases, the biological zinc concentration can generally be affected safely using a novel zinc complexing moiety bound to a molecular moiety W which is a non-peptidic, hydrophilic group as defined herein.


A resonator assembly comprising a semiconductor substrate, a resonator gyroscope, the resonator gyroscope including a first resonator formed in a layer of a first material, and an oscillator on the semiconductor substrate, the oscillator including a second resonator formed of a second material, wherein the second resonator is attached in a cavity; the cavity comprising a first recess in said layer of a first material and the edges of the first recess being attached to the substrate, or the cavity comprising a second recess in said substrate and the edges of the second recess being attached to said layer of a first material.

1. Field
This disclosure is generally related to MEMS (Micro Electro Mechanical Systems) technology assemblies, in particular a resonator assembly comprising two resonators, for example made of different materials such as a silicon resonator and a quartz resonator, for example suitable for use in an Inertial Navigation System.
2. Description of Related Art
Typically, an INS (Inertial Navigation System) in an aircraft consists of three angular rate sensors, three accelerometers, and GPS (Global Positioning System) made up electronic boards with custom ASICs (Application Specific Integrated Circuits), RF (Radio Frequency) hybrids, and commercial off-chip oscillators and filters. These components are packaged in multiple boxes which can be decoupled mechanically and thermally. An INS can in particular comprise a gyroscope and a clock.
It is known to make a gyroscope having a MEMS resonator, for example a High-Aspect-Ratio Si Resonator. A High Aspect Ratio structure as recited in the present application is a structure in which the height or thickness of the structure is much greater than lateral dimensions defined within, the structure. For example, a ring structure having a ratio height/gap spacing >2 for the rings is a High Aspect Ratio structure. An example of a High-Aspect-Ratio Si Resonator is a Si Disc Resonator Gyroscope (DRG) as described in U.S. Pat. No. 7,581,443, where the resonator layer is bonded to a Si substrate and then etched with deep reactive ion etching.
It is also known to make a MEMS quartz resonator for a quartz clock that can be bonded and integrated to a Si substrate, as described in U.S. Pat. No. 7,459,099.
U.S. Pat. No. 8,151,640 teaches using planar bonding techniques to first integrate a quartz clock resonator on a semiconductor substrate, followed by the integration of a High-Aspect-Ratio Si DRG Resonator on the substrate.
However, depending on the material used in the fabrication of the quartz resonator, the quartz resonator can be damaged or its frequency modified by the etching of the Si when forming the Si resonator. This is particularly important if the quartz resonator has Au electrodes as used commonly for HF and VHF shear-mode resonators.
There exists a need for an integrated structure comprising two resonators such that the fabrication of the later fabricated resonator does not detrimentally affects the properties of the earlier fabricated resonator.

Resonator assembly comprising a silicon resonator and a quartz resonator