In a multiprocessor computer system, individual vector processors are provided with priority switching signal control circuits, respectively, and a storage control unit incorporating a priority control circuit. Priority bit information is provided for priority circuits incorporated in the storage control unit. Paths for priority switching signal issued in accordance with a number of requests as generated and types of instruction generating the requests are provided between the priority switching signal control circuits and the priority control circuit of the storage control unit, while paths for the priority switching signal as generated are provided between the priority control circuit and all the priority circuits.

The present invention generally relates to a computer system in which a single memory system or a single storage is shared by a plurality of processing elements such as vector processors. More particularly, the invention is concerned with a computer system in which an access conflict arbitration scheme is adopted for preventing access performance of a main storage from being degraded when an access instruction issued to the main storage includes a plurality of access requests.
There are known several arbitration schemes for priority circuits adapted for selecting one or some from a plurality of access requests. For example, there are known an arbitration schemes in which access requests are selected in accordance with priorities allocated fixedly to the requests, in which requests are selected orderly, starting from the oldest one, in which a request is selected at random from plural ones, and in which a request not selected is newly allocated with a higher priority (disclosed in JP-A-63-66662) and so forth.
A system in which access conflict taking place when a plurality of requesters issue access requests to a plurality of storages is solved by resorting to an arbitration scheme such as mentioned above is disclosed in JP-A-63-66662. This system will first be described by reference to FIG. 17.
In the figure, reference numerals 151, 152, 153 and 154 denote requesters (REQ) which issue access requests to a main storage 168, a numeral 159 denotes a storage control unit (SCU) for sending the requests to the main storage 168 by arbitrating conflict or competition among the requests sent from the requesters (REQ), and a numeral 173 denotes a fetched data buffer for rearraying data read or fetched from the main storage 168 in the order in which the requests were issued by the requesters 151 (REQ0), 152 (REQ1), 153 (REQ2) and 154 (REQ3).
The requesters 151, 152, 153 and 154 are incorporated in associated vector processors (not shown), respectively, and include request senders 155, 156, 157 and 158, respectively, for sending out the requests.
The storage control unit 159 is comprised of request queues 160 (labeled QUE0), 161 (QUE1), 162 (QUE2) and 163 (QUE3) and priority circuits 164 (PR0), 165 (PR1), 166 (PR2) and 167 (PR3) for determining the priority to thereby select the request which is to be first processed upon occurrence of conflict between or among the requests.
The main storage 168 is comprised of four bank groups (memory modules) 169 (labeled BG0), 170 (BG1), 171 (BG2) and 172 (BG3), wherein the bank group or memory module BG0 includes a plurality of memory banks BK0 TO BK3, while the bank group BG1 includes memory banks BK4 to BK7 with the bank group BG2 including memory banks BK8 to BK11 and the bank group BK3 including memory banks BK12 to BK15. The time taken for one requester to make access to the memory bank amounts to several clocks. This time will be referred to as the memory access time. In case any one of the memory banks is being accessed by one of the requests, the other requests are inhibited from accessing that one memory bank.
Concerning the structure of the fetched data buffer 173 in detail, reference may have to be made to JP-A-60-136849, the disclosure of which is herein incorporated by reference.
Next, referring to FIG. 21, a configuration of the priority circuit will be described in detail by taking as example the priority circuit 164.
In FIG. 21, reference numerals 208, 209, 210 and 211 denote registers for holding priority bits of the associated requesters, respectively, numerals 200, 201, 202 and 203 denote set/reset logic, respectively, 213 denotes a priority logic, 212 denotes an OR circuit, 214 denotes a decoder, and a numeral 215 denotes a request register. In the priority circuit 164, the requests issued by the requesters 151 to 154 (FIG. 17) are once latched by request buffer registers 204, 205, 206 and 207, respectively, and selected by the priority logic 213 in accordance with the priority information bits held by the priority bit registers 208, 209, 210 and 211, respectively, wherein the access request as selected is held by the request register 215. At the same time, the request buffer registers 204, 205, 206 and 207 inform the set/reset circuits 200, 201, 202 and 203 of the requests being issued, respectively. The priority logic 213 issues an identification (ID) number of the vector processor to which the requester issued the selected request belongs. This ID information of the vector processor is decoded by the decoder 214 and be sent to one of the set/reset circuits 200, 201, 202 and 203 which corresponds to the vector processor indicated by the decoded ID. On the other hand, the values placed in the priority bit registers 208, 209, 210 and 211 are sent to the set/reset circuits 200, 201, 202 and 203, respectively, after having been logically ORed by the OR circuit 212.
Next, description will turn to a method of setting/resetting the priority bit register 208, 209, 210 or 211 by the corresponding set/reset circuit 200, 201, 202 or 203.
The priority bit register 208, 29, 210 or 211 is set, provided that the request is present in the associated request register 204, 205, 206 or 207, the signal delivered from the decoder 214 is "0" indicating that the above-mentioned request is not selected by the priority logic 213, and that the output value of the OR circuit 212 is "0" indicating that none of the priority bit registers is set.
The priority bit register is reset when the signal outputted from the decoder 214 is "1", i.e., when the request held by the associated requester is selected by the priority logic 213.
Next, description will be directed to the request processing flow.
Referring to FIG. 17, the requesters 151 (REQ0), 152 (REQ1), 153 (REQ2) and 154 (REQ3)are designated to issue the respective requests each having a bank group ID number, a bank ID number and an intrabank address for the destination. The requests as issued are temporarily held by the request queues QUE0, QUE1, QUE2 and QUE3 which correspond to the above-mentioned requesters, respectively, and which are incorporated in the storage control unit 159.
In the state in which the requests are held by the request queues QUE0, QUE1, QUE2 and QUE3, the bank group ID numbers of the requests held in these queues are discriminatively identified to thereby allow the requests to partake in the conflict arbitrations effected by the priority circuits 164 (PR0), 165 (PR1), 166 (PR2) and 167 (PR3) which are provided in correspondence to the bank groups 169, 170, 171 and 172, respectively.
Each of the priority circuits PR0, PR1, PR2 or PR3 selects the request which partakes in the conflict arbitration and which has the priority bit of "1", whereby one of the selected requests is outputted. In case none of the requests having the respective priority bits of "1" exists, one request is selected from all the requests partaking in the conflict arbitration, and subsequently the priority bits of the requests not selected are all set to "1", respectively. Since the priority bits are managed by the respective priority circuits independent of one another, the priority may differ from one to another priority circuit.
By way of example, let's consider the request selected by the priority circuit PR0. This request is sent to one of the memory banks BK0, BK1, BK2 and BK3 belonging to the bank group BG0 in accordance with the destination memory bank ID number added to the selected request. Same holds true for the priority circuits PR1, PR2 and PR3.
In case the instructions being executed by the vector processors are load instructions, data read out from the respective memory banks after lapse of the memory access time (which is assumed to correspond to four clocks in this case) are rearrayed in the fetched data buffer 173 in the order in which the corresponding requests were issued, whereon the data are sent to the respective requesters. On the other hand, when the instructions as executed are store instructions, data (as resulted from the execution are written in the corresponding memory banks, whereupon the access processing comes to an end.
As will be understood from the above, according to the conflict arbitration technique known heretofore, the priority circuits determine the priorities of the requests independent of one another so as to prevent any given one of the requests from being forced to wait for processing for a long time.
The inventors have however found that the system shown in FIG. 17 and described above suffers problems mentioned below when the requesters issue the requests for the instructions which differ from one another.
More specifically, let's assume that instructions A and B are issued simultaneously by the requesters REQ0 and REQ1, respectively, wherein the instructions A and B include request sets {a.sub.0, a.sub.1, a.sub.2, a.sub.3 } and {b.sub.0, b.sub.1, b.sub.2, b.sub.3 }, respectively, and that the memory banks BK0, BK4, BK8 and BK12 are to be accessed sequentially in this order for executing the instructions A and B.
FIG. 18 illustrates in a time chart the processing of requests mentioned above.
Referring to FIG. 18 along with FIG. 17, the requesters 151 (REQ0) and 152 (REQ1) issue sequentially access requests for the instructions A and B, respectively. The access requests are held by the request queues at a succeeding clock generated by the requesters REQ0 and REQ1 and at the same time undergo the conflict arbitration effected by the priority circuits PR0, PR1, PR2 and PR3.
In this case, the requests a.sub.0 and b.sub.0 conflict with each other in the priority circuit PR0, the requests a.sub.1 and b.sub.1 conflict each other in the priority circuit PR1, the requests a.sub.2 and b.sub.2 conflict in the priority circuit PR2, and the requests a.sub.3 and b.sub.3 conflict each other in the priority circuit PR3. It is now assumed that in the priority circuits PR0, PR2 and PR3, the priority bit of the requester REQ0 is "1" with the priority bits of the requesters REQ1, REQ2 and REQ3 being "0", respectively, while in the priority circuit PR1, the priority bit of the requester REQ1 is "1" with those of the requesters REQ0, REQ2 and REQ3 being "0". There, the requests a.sub.0, b.sub.1, a.sub.2 and a.sub.3 are selected in the priority circuits PR0, PR1, PR2 and PR3, respectively.
The requests a.sub.0, b.sub.1, a.sub.2 and a.sub.3 as selected are sent to the memory banks BK0, BK4, BK8 and BK12 of the bank groups BG0, BG1, BG2 and BG3, respectively, at a succeeding clock. From these memory banks accessed by the above-mentioned requests, data are read out after time lapse corresponding to four clocks to be thereby transferred to the fetched data buffer 173.
The memory banks accessed by the requests are inhibited from being accessed for the memory access time corresponding to the four clocks. Consequently, the requests b.sub.0, a.sub.1 , b.sub.2 and b.sub.3 remaining unselected can partake in the conflict arbitration only after completion of the access request processing for the selected requests a.sub.0, b.sub.1, a.sub.2 and a.sub.3.
In the fetched data buffer 173, a set of data as read out from the memory banks are rearrayed in the order in which the corresponding requests were issued and then sent to the requesters issued these requests. Consequently, even a delay in reading the data constituting a member of the data set mentioned above will prohibit the sending of the other data to the concerned requesters. In the case of the example now under consideration, the access request a.sub.1 of the instruction A is processed with a delay of four clocks while the requests b.sub.0, b.sub.2 and b.sub.3 of the instruction B are processed with a delay of four clocks, respectively, involving a delay of four clocks in sending the data to the requester REQ0 and REQ1. Thus, executions of the instructions A and B are both delayed by four clocks, respectively.
In this conjunction, it will be noted that when the request a.sub.1 of the instruction A is allocated with higher priority than the request b.sub.1 for the instruction B, no delay takes place in the processing of the instruction A. In other words, execution of the instruction A can be completed without any delay.
As is apparent from the above discussion, in the circuit configuration in which one set of requests is outputted from each of the requesters to a plurality of priority circuits and in which the priority circuits manage the priorities of the requests independent of one another and change the priorities upon every selection of the requests, occurrence of conflict between or among the requests belonging to the different sets may provide a cause for delay in the processing of the requests of both sets.
In a multiprocessor system operating in a computer center or the like, there may arise a situation in which a particular one of the processors is imparted with a high priority for execution of the processing allocated thereto. In that case, in order to prevent the system performance from degradation due to the conflict with the main storage access instruction(s) for the other processor(s), it becomes necessary to allocate a higher priority to the main storage access request of the particular processor.

Priority control with concurrent switching of priorities of vector processors, for plural priority circuits for memory modules shared by the vector processors


A method for processing water-bound wastes and for adjusting quantities and for combining ingredients to achieve a desired mechanical property of the mixture. The process includes the establishment of at least one input parameter for the ingredients. The ingredients include heated granular solids and contaminated water-bound wastes. The mixing process causes the water-bound waste to be heated to a temperature which assures neutralization or purification of any waste borne contamination and which simultaneously cools the granular solid. The method includes testing the mixture for satisfaction of at least one of the established mixture physical property limits and, if necessary, adjusting at least one input parameter to achieve the desired physical property value.

Among the greatest benefits which accrue to a civilized society are those which cause garbage and sewage wastes to "disappear". Although a city resident might generate only 3.5 lb of garbage waste and 1.5 lb. of sewage waste per day, even a small city of 250,000 population will have to dispose of 875,000 pounds of garbage and 375,000 pounds of sewage waste each day. Our political system has provided huge infrastructures to collect and dispose of this waste. Most garbage waste is deposited in landfills. Typically a landfill owner charges from fifty to one hundred dollars per ton for accepting garbage. At the $50.00 rate the above municipality has to budget $8,000,000.00 annually just to pay these "tipping" fees. The costs of collection and transport are extra.
To make matters worse, local landfills are filling up, mandating that garbage be transported further from its source. Our highways become clogged with huge trucks performing this odorous task.
In an effective attempt to address and minimize this problem, municipalities have established trash to energy plants which burn the garbage producing heat, use the heat to generate steam and the steam to generate electricity. The electricity is in turn sold to the local utility or sold to a local bulk electricity consumer.
The burning process reduces the mass of material to be disposed of by 85 to 90 percent, thereby reducing tipping costs and also extending the life of local landfills. However, the trash burning plant must first cool the fiery ash by soaking it with water which it must buy from the local water company and then pay a hauler to cart away the, now much heavier, wet ash. Water has become a scarce resource. Persistent droughts and high rates of usage have lowered water levels in lakes and rivers. Threats of water shortage abound.
Haulers in the past have always transported the cooled wet ash to the landfill and paid to tip it.
In other places, huge quantities of earth which have been contaminated by oil or in other ways are being incinerated to vaporize the contaminant oils. The hot earth must then be cooled and disposed of, just like the hot ash from the trash to steam plant or from coal burning power plants.
To address the sewage problem municipalities have invested in sewage disposal plants. Here settling tanks, water treatment and disinfectant facilities have been provided to separate the water from the solids and treat, purify and dispose of the water in rivers or streams. Even though the solids are squeezed to press out much of the water, the average water content of the pressed solids is 75 to 85 percent. In some locations the wet solids are heated by fuel burning furnaces to dry and disinfect them, and again disposed of in landfills. Fuel costs to achieve this drying and sterilization function by evaporating the residual water are high. This is because while it take considerable amounts of heat to heat water to the boiling point, it takes 7.5 times as much heat to evaporate the hot water as to heat it to the boiling point. Even without evaporating much of the water the fuel costs for heating the wet solids is very high because it takes roughly five times as much heat to raise the water component of the wet solids to a temperature of 190.degree. F., the temperature required for effective sterilization, as it would have taken to heat the solids to that temperature if they had been dry.


Solid, shaped and fired fibers of Ti4O7 and Ti5O9 are made by firing TiO2 fibers in a reducing atmosphere. In a first aspect, the TiO2 fibers are made by extruding into air a viscous TiO2 gel and heat treating the resulting green fibers to remove solvent, decompose and to volatilize undesired constituents to form electrically conductive, refractory fibers of Ti4O7 and Ti5O9. In a second aspect, solid, shaped and fired fibers of Ti4O7 and Ti5O9 are made by firing extruded fibers from mixtures of TiO2.

Conductive titanium suboxide(s) such as Ti4O7 and Ti5O9 are known. The manufacture of fibers which have consistent properties from these suboxides, however, is difficult. This is due, in part, to lack of reproducible oxygen stoichiometry in the suboxides.
There is great potential for improvements in battery performance through incorporation of conductive titanium suboxide fibers into the anodes and cathodes of a wide range of batteries, as well as into the grids of these batteries. The lack of reproducible stoichiometry in electrically conductive titanium suboxides, however, is a problem that has hindered realization of this potential.
A need therefore exists for conductive ceramic fibers and their manufacture, such as conductive titanium suboxide fibers, which have reproducible stoichiometry.

Electrically conductive fibers of Ti4O7 and Ti5O9


Composite foams are provided including a metal template and a conformal atomic-scale film disposed over such metal template to form a 3-dimensional interconnected structure. The metal template includes a plurality of sintered interconnects, having a plurality of first non-spherical pores, a first non-spherical porosity, and a first surface-area-to-volume ratio. The conformal atomic-scale film has a plurality of second non-spherical pores, a second non-spherical porosity, and a second surface-area-to-volume ratio approximately equal to the first surface-area-to-volume ratio. The plurality of sintered interconnects has a plurality of dendritic particles and the conformal atomic-scale film includes at least one of a layer of graphene and a layer of hexagonal boron nitride.

The present technology relates to a composite foam, and more particularly to the composite foam including a conformal atomic-scale film having a high surface-area-to-volume ratio.
In an electronics packaging industry, composite foams are typically used for providing at least one of a thermal, an electrical, and a mechanical property to an underlying electronic product and/or to one or more components used to build the electronics product.
Such composite foams used for a thermal management application may include a matrix and a nano-scale fillers deposited within the matrix. Generally, the fillers deposited within the matrix form multiple islands with no direct interconnection between the fillers. The composite foam may be made of a single layer or multiple layers of the matrix material to provide a macro-scopic structure to the composite foam.
Typically, individual fillers provide thermal and electrical property enhancements, and the matrix provides mechanical (i.e. strength) and thermal property to the composite foam. However, overall properties of such filler-matrix composite foam are typically limited by the performance of interface regions of the filler-matrix. The interface regions between the filler and the matrix typically present a very high thermal and electrical resistance respectively thereby affecting the overall properties of the conventional filler-matrix composites.
Further, the overall properties of the filler-matrix composite foam are sensitive to a volume fraction of the filler within the matrix. As a means to increase the overall properties of the filler-matrix an increase in volume fraction of the filler within the matrix is desired. However, with conventional nano-scale fillers, there exist several practical limits to deposit filler within the matrix due to the tendency for nano-scale fillers to agglomerate, thereby losing their nano-scale properties in the agglomerated form. Thus, the volume fraction of the nano-scale filler within the matrix is limited by processing-related limitations.
Thus, there is a need for improved composites for efficient thermal management in an electronic product, and an associated method of manufacturing such composite foam.

High specific area composite foam and an associated method of fabrication


The invention is drawn to anti-thrombin proteins from the salivary glands of the species, Simulium. Methods for recombinant production of the protein as well as biomedical uses are provided.

Thromboembolic diseases are among the most important circulatory diseases. A thrombin is a blood clot that partially or completely blocks blood flow through a blood vessel. An embolus is a thrombus that has formed elsewhere in the body, broken free, and traveled to the site where blockage occurs. Blockage in the brain results in a stroke, i.e., a cerebral infarction, a localized area of dead cells. An embolus in a lung can produce pulmonary embolism, one of the principal lung diseases in bed-ridden patients. Bed ridden and elderly persons are also particularly prone to thrombophlebitis, which is a blockage of circulation in a leg caused by an embolus. An embolus or thrombus lodging in one of the blood vessels serving the heart causes necrosis of part of the heart tissue, a myocardial infarction, commonly called a heart attack.
The initiating event of many myocardial infarctions is the hemorrhage into atherosclerotic plaques. Such hemorrhage often results in the formation of a thrombus (or blood clot) in the coronary artery which supplies the infarct zone. This thrombus is composed of a combination of fibrin and blood platelets. The formation of a fibrin-platelet clot has serious clinical ramifications. The degree and duration of the occlusion caused by the fibrin-platelet clot determines the mass of the infarct zone and the extent of damage.
The formation of fibrin-platelet clots in other parts of the circulatory system may be partially prevented through the use of anticoagulants, such as heparin. Unfortunately, heparin has not been found to be universally effective in preventing re-occlusion in myocardial infarction victims in which the degree of blood vessel occlusion is greater than or equal to 70%, particularly in those patients with severe residual coronary stenosis. Among the more promising of the agents are hirudin and its analogs, which bind to and inactivate thrombin. Hirudin has a theoretical advantage over heparin as an anti-thrombotic agent. Thrombin bound to thrombi or platelets is relatively protected from inhibition by heparin while hirudin, at least in vitro, is still effective. Other promising investigational agents include fibrinogen receptor antagonists, which block platelet aggregation and dense granule release by a mechanism distinct from that of aspirin, and inhibitors of thromboxane production.
There is therefore a need for additional antithrombin agents which exhibit low toxicity, little or no antigenicity, and a very short clearance time from circulation.

This patent is subject to a terminal disclaimer.

Antithrombin protein and DNA sequences from black fly


An image displayer having a function of automatically eliminating an afterimage, comprises a signal processing unit for processing signals inputted from an external device and outputting video signals and audio signals to a display and a speaker, respectively, a detecting sensor for detecting whether there exists a user within a predetermined range from the display when a still picture corresponding to video signals of an identical pattern outputted from the signal processing unit is displayed on the display beyond a pre-set time, and a control unit for controlling the signal processing unit to display an afterimage-eliminating picture on the display when a signal corresponding to the non-presence of the user within the predetermined range is outputted from the detecting sensor, thereby eliminating the afterimage caused due to the still picture. Accordingly, the afterimage eliminating function is automatically performed without manipulation input of the user.

1. Field of the Invention
The present invention relates to an image displayer, and more particularly, to an image displayer having an afterimage-elimination function.
2. Description of the Related Art
Generally, displayers such as a Cathode Ray Tube (CRT), a Liquid Crystal Display (LCD), a Plasma Display Panel (PDP), and the like for displaying an image have a drawback that their fluorescent substance or light emitting device is deteriorated or deformed when a display of a still picture continues for a long time. For example, when an image displayer displays stock quotations, since a still picture having characters and graphs concentrated on specific pixels of the image displayer is displayed for a long time, it is often the case that the lifespan of the specific pixels become shorter than those of their neighboring pixels. In the case of a PDP, which uses ultraviolet rays generated during a gas discharging to display an image, the problem of deterioration of pixels becomes more serious. The PDP applies an electric field to a tube having helium and a xenon gas injected therein in order to generate light. Even though the supply of the electric field is stopped, the electric field still remains for a predetermined time, causing an electric discharge to occur. That is, the PDP displays the still picture including the characters and the graphs for the stock quotations program, with a result that the specific pixels corresponding to the still picture continues emitting the light and the specific pixels become brighter than required. Due to such remaining electric field, the pixels have an afterimage of the still picture which remains when the still picture is changed into another picture.
In order to minimize the afterimage, a variety of methods have been conventionally suggested. For example, one of them, as shown in FIG. 1, is to reduce the afterimage by moving a picture position up and down and right and left at regular time intervals when a still picture is displayed on a screen and/or a display beyond a predetermined time. According to this method, the time interval and the length of the movement of the picture position can be adjusted for the user's convenience. Accordingly, the picture as displayed returns to the original position after a predetermined time and the pixels of the still picture can be protected to some degree. However, the user feels inconvenience because the picture has to be moved when he/she is viewing the picture. Also, since the moving path is determined at each time interval, the pixel having the moving path as determined cannot be completely prevented from deteriorating and thus the afterimage cannot be prevented.
Another method has the aim of reducing a luminosity of each of the pixels consisting a still picture to 50%. However, this method cannot prevent the deterioration of the pixels and the afterimage occurring when the still picture is displayed for a long time.
Still another method is to convert a picture itself to a reverse picture in accordance with a user's selection of a menu as shown in FIG. 1B, and then return it to the original picture. In this case, if a user is not aware of the features of a product, it is difficult for the user to execute this method. Especially, in the case of an expensive PDP, the problem of the afterimage becomes more serious.

Image displayer having function of automatically eliminating afterimage and a method thereof


A high voltage electrical insulator formed from a curable liquid silicone rubber composition, and subsequently cured, a composition consisting essentially of. (A) 100 weight parts of a fluid mixture of polyorganosiloxane comprising PA0 (B) 1 to 100 weight parts microparticulate silica, PA0 (C) polyorganohydrogensiloxane that contains at least 2 silicon-bonded hydrogen atoms in each molecule, in a quantity that provides a value from 0.5:1 to 20:1 for the ratio of the number of moles of silicon-bonded hydrogen in the instant composition to the number of moles of silicon-bonded alkenyl in component (A), and PA0 (D) a catalytic quantity of a platinum catalyst.. (a) at least 5 weight percent of a polyorganosiloxane resin comprising repeating units selected from the group consisting of SiO.sub.4/2 and RSiO.sub.3/2, where R is a monovalent hydrocarbon group, and PA1 (b) polydiorganosiloxane having a viscosity in the range from about 100 mPa.multidot.s to 100,000 mPa.multidot.s, that contains at least 2 silicon-bonded alkenyl groups in each molecule,. The liquid silicone rubber composition, prior to its cure, evidences a desirable fluidity and excellent moldability. Upon its cure the composition produces very mechanically strong silicone rubber moldings that have excellent high-voltage insulating properties tracking resistance, erosion resistance, arcing resistance without the use of fillers such as aluminum oxide, aluminum hydroxide or quartz.

Silicone rubbers have excellent electrical characteristics and as a result are frequently used for high-voltage insulators and articles such as anode caps, plug boots, insulators, flame-retardant wire and cable, and the like. The silicone rubber compositions used for these applications have typically contained large amounts of inorganic filler, e.g., aluminum hydroxide powder, aluminum oxide powder, or quartz powder. See, for example, Japanese Patent Publication 53-35982, Japanese Patent Publication 62-26124, and Japanese Patent Application Laid Open Number 4-209655.
However, liquid silicone rubber compositions that are highly loaded with these inorganic fillers have very high viscosities. This gives these compositions poor moldability, and makes them difficult to use in applications that require the fluidities appropriate for injection molding or casting materials. In addition, the silicone rubber moldings afforded by the cure of highly filled silicone rubber compositions have low mechanical strengths. Under conditions of exposure to severe soiling or the weather, these compositions will also suffer from such deterioration phenomena as tracking and erosion due to the high electrical stresses, which results in a drastic decline in their high-voltage insulating properties and has prevented these compositions from being completely acceptable.
Therefore, there is a need for a liquid silicone rubber composition that prior to its cure has a desirable fluidity and excellent moldability, and that can be cured to give very mechanically strong silicone rubber moldings that have excellent high-voltage insulating properties.

Liquid silicone rubber composition for application to high-voltage electrical insulators and articles


The present invention relates to a novel process for the preparation of a diastereomeric mixture of piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib:

The present invention relates to a novel process for the preparation of a diastereomeric mixture of piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib:
and pharmaceutically acceptable salts thereof, wherein
R1 is C1-C6 alkyl;
R2 is C1-C6 alkyl, halo C1-C6 alkyl or phenyl or substituted phenyl;
R3 is hydrogen or halo;
m is zero, one or two.
Further, the present invention also relates to a process for the preparation of a diastereomeric mixture of compounds of formulae Ia and Ib, and pharmaceutically acceptable salts thereof, highly enriched in the compound of formula Ia. The process of the present invention permits via selective crystallization the isolation of diastereomeric mixtures of compounds of formula Ia and Ib wherein the ratio of compounds of formula Ia to Ib are in excess of 90:10.
In addition, the present invention relates to novel processes for the preparation of a compound of formula II:
an intermediate compound useful in the preparation of compounds of formulae Ia and Ib. In addition, the present invention is also directed to other novel intermediates useful in the process for preparing the mixture of compounds of formulae Ia and Ib. The present invention is also directed to a novel process for the purification of certain intermediates for use in the methods of the invention.
The compounds of formula Ia and Ib, particularly compounds of formula Ia, and pharmaceutically acceptable salts thereof, are useful as antagonists of substance P, a naturally-occurring undecapeptide belonging to the tachykinin family of peptides that is widely involved in the pathophysiology of numerous diseases, including central nervous system disorders such as depression, anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn""s disease, and in the transmission of pain, including migraine.
The diastereomeric mixture of compounds of formulae Ia and Ib and a process of making that diastereomeric mixture are described in International Patent Publication No. WO 99/25714, published May 27, 1999. That reference refers to methods of preparing the diastereomeric mixture using methods other than those of the present invention, and is hereby incorporated by reference in its entirety. The present invention provides a more practical, more direct and higher yielding process for preparing a mixture of diastereomers of compounds of formulae Ia and Ib, highly enriched in the compound of formula Ia, via novel synthetic pathways.
The present invention relates to a process for the preparation of a mixture of compounds of formulae Ia and Ib:
highly enriched in the presence of the compound of formula Ia, and pharmaceutically acceptable salts thereof, wherein
R1 is C1-C6 alkyl;
R2 is C1-C6 alkyl, halo C1-C6 alkyl or phenyl or substituted phenyl;
R3 is hydrogen or halo;
m is zero, one or two;
comprising the steps of (a1) reacting a mixture of compounds of formulae Ia and Ib:
with an acid of formula HX, wherein HX is selected from the group consisting of (S)-(+)-mandelic acid, D-(xe2x88x92)-tartaric acid, di-p-toluoyl-D-tartaric acid, ((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, acetic acid and hydrobromic acid, to form a mixture of diastereomeric compounds of formulae Va and Vb, respectively, enriched in the presence of a compound of formula Va:
(b1) permitting the HX salt of the diastereomeric product mixture of step (a1) to crystallize out of a solution thereof in an appropriate solvent; and
(c1) treating the resulting mixture of compounds obtained from step (c1) with a base.
A most preferred embodiment of the invention is where the acid HX of step (a1) is (S)-(+)-mandelic acid. A more preferred embodiment of the invention is where the appropriate solvent of step (a1) is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, diisopropyl ether, toluene, acetonitrile, acetone, water and a mixture of any of the foregoing solvents. A most preferred embodiment is where the appropriate solvent of step (a1) is ethanol. A more preferred embodiment of the invention is where the base of step (c1) is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
The present invention also relates to the preparation of the pharmaceutically acceptable salts of the mixture of compounds of formula Ia and Ib, highly enriched in the compound of formula Ia, which comprises treating the mixture of compounds Ia and Ib that is enriched in one of the diastereomeric compounds of formula Ia with a proton acid, H+Yxe2x88x92, wherein the anion, Yxe2x88x92, is selected from the group consisting of hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)), to form a mixture of compounds VIa and VIb, highly enriched in the diastereomeric compound acid addition salt of formula VIa:
wherein n is determined by the intrinsic characteristics of the form of the compounds Ia and Ib when complexed with the particular acid HY, and n is an integer from one to two. The process of the invention also relates to the preparation of the hydrates of the compounds of formula VIa and VIb, in which between zero and three molecules of water may be associated with each molecule of the compounds of formula VIa and VIb, said hydrates being formed in the step in which compounds of formula Ia and Ib are treated with a proton acid.
A more preferred embodiment of the invention is where the proton acid used is hydrochloric acid, and n is 2. A preferred embodiment of the invention is where the ratio of compound VIa and VIb obtained is 90:10 or greater. A more preferred embodiment of the invention is where the ratio of compound VIa and VIb obtained is 98:2 or greater.
The present invention also relates to a process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, further comprising the step of reacting a compound of formula III:
with a compound of formula IV:
in the presence of a reducing agent to obtain a mixture of compounds of formula Ia and Ib.
A preferred embodiment of the invention is where the reducing agent is selected from the group consisting of sodium triacetoxyborohydride, sodium cyanoborohydride and sodium borohydride. A more preferred embodiment of the invention is where the reducing agent is sodium triacetoxyborohydride.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, further comprising the step of formylating a compound of formula II:
wherein R1, R2 and R3 are as defined above; m is 0, 1 or 2 with hexamethylenetetramine, in the presence of an acid to form a compound of formula III. A preferred embodiment of the invention is where the acid in the formylation reaction is trifluoroacetic acid, glyceroboric acid, acetic acid or hydrochloric acid. The most preferred acid is trifluoroacetic acid.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, wherein the compound of formula II:
wherein R1, R2 and R3 are as defined above; m is 0, 1 or 2; is prepared by a process comprising the steps of
(a2) reacting a compound of formula VII:
xe2x80x83with a compound of formula CF3SiR43, wherein R4 is (C1-C6)alkyl or phenyl, in the presence of a fluoride source to form a compound of formula VIII:
(b2) removing the silyl protecting group from the product of step (a2) via treatment with a base or a fluoride source to form a compound of formula IX:
(c2) hydrolyzing the ester group of the product of step (b2) in the presence of a base to form a compound of formula X:
and (d2) performing a ring cyclization reaction on the product of step (c2) in the presence of a base and an activating agent selected from the group consisting of methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride and triflic anhydride.
A more preferred embodiment of the present invention is where the fluoride source in step (a2) is selected from the group consisting of cesium fluoride, potassium fluoride and an alkylammonium fluoride. The most preferred alkylammonium fluoride is tetrabutylammonium fluoride. A most preferred embodiment of the invention is where the fluoride source in step (a2) is cesium fluoride. Preferred solvents for step (a2) are dimethylformamide, dimethylacetamide, toluene, dichloromethane, dichloroethane and tetrahydrofuran. The most preferred solvent for step (a2) is dimethylformamide.
In step (b2), the preferred bases are sodium hydroxide or potassium hydroxide, and the preferred fluoride sources are tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid-pyridine complex and hydrofluoric acid. The most preferred fluoride source is tetrabutylammonium fluoride. Preferred solvents for step (b2) are tetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butyl ether, dichloromethane and toluene. The most preferred solvent for step (b2) is tetrahydrofuran.
The preferred bases in step (c2) are sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate. The preferred base in step (c2) is sodium hydroxide. Preferred solvents for step (c2) are water, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane and a combination of any of these solvents. The most preferred solvent for step (c2) is a mixture of water and tetrahydrofuran.
In step (d2), the most preferred activating agent is methanesulfonyl chloride. Preferred bases for step (d2) are triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate. The most preferred base for step (d2) is triethylamine. Preferred solvents for step (d2) are dichloromethane, tetrahydrofuran, toluene, diisopropyl ether and methyl-tert-butyl ether. The most preferred solvent for step (d2) is dichloromethane.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, wherein the compound of formula II:
wherein R1, R2 and R3 are as defined above; m is 0, 1 or 2; comprising the steps of
(a3) reacting a compound of formula XI:
xe2x80x83with an alcohol of formula R1OH in the presence of an acid, wherein R1 is as defined above, to form a compound of formula XII:
(b3) reacting the product of step (a3) with compound of formula CF3SiR43, wherein R4 is (C1-C6)alkyl or phenyl, to form a compound of formula XIII:
(c3) reacting the product of step (b3) with a fluoride source to obtain a lactone compound of formula XIV:
(d3) reacting the lactone product of step (c3) with a reducing agent optionally in the presence of a Lewis acid to obtain a compound of formula XV:
and (e3) reacting the product of step (d3) with a reducing agent optionally in the presence of a Lewis acid to obtain a compound of formula II.
Another preferred embodiment of the invention is where the acid of step (a3) is chosen from the group consisting of sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid and methanesulfonic acid. The most preferred acid for step (a3) is sulfuric acid.
In step (b3), preferred fluoride sources are cesium fluoride, potassium fluoride and an alkylammonium fluoride, such as tetrabutylammonium fluoride. The most preferred fluoride source is cesium fluoride. Preferred solvents for step (b3) are dimethylformamide, dimethylacetamide, dichloromethane and tetrahydrofuran. The most preferred solvent for step (b3) is dimethylformamide.
Preferred fluoride sources for step (c3) are tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid-pyridine complex and hydrofluoric acid. The most preferred fluoride source for step (c3) is tetrabutylammonium fluoride. Preferred solvents for step (c3) are tetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butyl ether, dichloromethane and toluene. The most preferred solvent for step (c3) is tetrahydrofuran.
Preferred reducing agents for step (d3) are sodium borohydride, borane tetrahydrofuran complex, borane dimethylsulfide complex, diborane, lithium borohydride, calcium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, L-selectride and K-selectride. The most preferred reducing agent is sodium borohydride. The preferred Lewis acid for step (d3) is boron trifluoride diethyl ether complex. Preferred solvents for step (d3) are tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether and dimethoxyethane. The most preferred solvent for step (d3) is tetrahydrofuran.
The preferred reducing agents for step (e3) are triethylsilane or triphenylsilane, in the presence of a Lewis acid such as boron trifluoride etherate or trifluoroacetic acid, preferably trifluoroacetic acid. Preferred solvents for step (e3) are dichloromethane, dichloroethane and chloroform. The most preferred solvent for step (e3) is dichloromethane.
Another preferred embodiment is where in step (e3) a compound of formula XIV is treated with a catalyst such as platinum, platinum oxide, or palladium hydroxide, preferably platinum, in a solvent such as methanol, ethanol, or isopropanol, preferably ethanol, under an atmosphere of hydrogen, optionally under pressure greater than atmospheric pressure.
The present invention also relates to the process for the preparation of compounds of formulae Ia and Ib, highly enriched in the presence of a compound of formula Ia, wherein the compound of formula III:
is purified by a method comprising the steps of (a4) forming a hydrazone via the reaction of a compound of formula III with a hydrazone of formula XVI:
in the presence of an acid to afford a compound of formula XVII:
and (b4) hydrolyzing the product of step (a4) via treatment with a reagent selected from the group consisting of copper(II) chloride, copper(II) iodide, copper(II) acetate, copper sulfate, sulfuric acid, acetic acid and hydrochloric acid.
Preferred acids for step (a4) include acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid and p-toluenesulfonic acid. The most preferred acid for step (a4) is acetic acid. Preferred solvents for step (a4) are methanol, ethanol, isopropanol, tetrahydrofuran, water and a mixture of any of the foregoing solvents. The most preferred solvent for step (a4) is a mixture of methanol and water.
The more preferred reagent for step (b4) is copper(II) chloride. Preferred solvents for step (b4) are tert-butyl alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water and a mixture of any of the forgoing solvents. The most preferred solvent for step (b4) is a mixture of tert-butyl alcohol and water.
In addition, methods for the preparation of pharmaceutical compositions of mixtures of the compounds of formula Ia or Ib or pharmaceutically acceptable salts thereof are encompassed by the present invention. A method for the preparation of such a pharmaceutical composition comprises the addition of a mixture of compounds of formula Ia and Ib or pharmaceutically acceptable salts thereof to a pharmaceutically acceptable carrier or diluent.
The present invention is also directed to the novel intermediates used in the methods of the invention, including but not limited to those compounds of formula VII, IX, XIII, XIV, XV and XVII and salts thereof.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
The term xe2x80x9csubstituted phenylxe2x80x9d, as used herein, unless otherwise indicated, means phenyl substituted by one or more, preferably one or two substituent(s) such as halogen, hydroxy, (C1-C6)alkyl or (C1-C6)alkoxy.
The term xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d, as used herein, unless otherwise indicated, means fluorine, chlorine, bromine or iodine.
The term xe2x80x9csuitable solventxe2x80x9d or xe2x80x9cappropriate solventxe2x80x9d, as used herein, unless otherwise indicated, means a medium which serves to dissolve particular indicated substance(s), compound(s) or reagent(s) to form a uniformly dispersed mixture of that substance or compound at the molecular or ionic level.
The term xe2x80x9cproton acidxe2x80x9d used to prepare acid addition salts of the compounds of the process of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
The term xe2x80x9cenrichedxe2x80x9d, as used herein, unless otherwise indicated, means to predominate in a ratio of greater than 1:1 of one particular compound or isomer over another or other components in a mixture. The term xe2x80x9chighly enrichedxe2x80x9d, as used herein, unless otherwise indicated, means to predominate in a ratio of at least 90:10 of one particular compound or isomer over another or other component in a mixture. Unless otherwise indicated, this invention relates to all optical isomers, tautomers and stereoisomers of the any of compounds described herein.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d, as used herein, unless otherwise indicated, refers to an acid addition salt of a proton acid, as defined herein, or a hydrate of an acid addition salt.
A diastereomeric mixture of piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib, highly enriched in a compound of formula Ia, may be prepared in accordance with the novel method shown in reaction scheme 1 below. Novel methods for the preparation of a critical intermediate in the preparation of piperidinylaminomethyl trifluoromethyl cyclic ether compounds, a compound of formula II, may be carried out in accordance with schemes 2 and 3, below. A novel means for purifying a key intermediate in the process of scheme 1 is shown in scheme 4. Unless otherwise indicated, the variables R1, R2, R3, R4, m and n are as described above.
Step 1 of scheme 1 is a formylation. A compound of formula II is treated with hexamethylenetetramine, in the presence of an acid such as trifluoroacetic acid, glyceroboric acid, acetic acid or hydrochloric acid, preferably trifluoroacetic acid, optionally in a solvent such as dichloromethane, dichloroethane, heptane, or nitromethane, preferably without a solvent at a temperature between 0 and 100xc2x0 C., preferably at 70xc2x0 C., for a period of time between 10 minutes and 24 hours, preferably 3 hours, followed by addition of water, to afford a compound of formula III. At this point, the compound of formula III may be purified according to the method of the invention as set forth below at scheme 4 prior to proceeding with step 2.
Step 2 of scheme 1 is a reductive coupling. An aldehyde of formula III is treated with an amine of formula IV, or a salt thereof, in the presence of a reducing agent, such as sodium triacetoxyborohydride, sodium cyanoborohydride, or sodium borohydride, preferably sodium triacetoxyborohydride, in a solvent, such as dichloromethane, dichloroethane, tetrahydrofuran, toluene, acetic acid, diisopropyl ether, or methyl-tert-butyl ether, preferably dichloromethane, at a temperature between xe2x88x9220 and 60xc2x0 C., preferably 0xc2x0 C., for a period of time between 30 minutes and 24 hours, preferably 3 hours, to afford a mixture of compounds of formulae Ia and Ib.
Step 3 of scheme 1 is a salt formation. The mixture of compounds Ia and Ib is treated with an acid of formula HX, such as (S)-(+)-mandelic acid, D-(xe2x88x92)-tartaric acid, Di-p-toluoyl-D-tartaric acid, ((1R)-endo,anti)-(+)-3-bromocamphor-8-sulfonic acid, quinic acid, acetic acid, hydrobromic acid, preferably (S)-(+)-mandelic acid, in a solvent, such as methanol, ethanol, isopropanol, tetrahydrofuran, ethyl acetate, isopropyl acetate, methyl-tert-butyl ether, diisopropyl ether, toluene, acetonitrile, acetone, water, or a mixture of the foregoing solvents, preferably ethanol, at a temperature between xe2x88x9220 and 70xc2x0 C., preferably room temperature, for a period of time between 30 minutes and 48 hours, preferably 18 hours, to afford a mixture of compounds of formula Va and Vb which is enriched in compound of formula Vb. Step 3 permits the isolation of mixtures of compounds of formula Va and Vb wherein the ratio of compounds of formula Va to Vb is greater than 70:30, and generally 80:20 or greater.
Step 4 of scheme 1 is the formation of an acid addition salt. The mixture of compounds of formula Va and Vb highly enriched in compound Va is treated with a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate, in water in the presence of a cosolvent such as toluene, diisopropyl ether, methyl-tert-butyl ether, ethyl acetate, or dichloromethane, preferably diisopropyl ether, at a temperature between 0 and 40xc2x0 C., preferably room temperature, for a period of time between 10 minutes and 48 hours, preferably 18 hours, to afford a mixture of compounds of formula Ia and Ib which is enriched in compound of formula Ia. The ratio of compound Ia to Ib, obtained from this part of step 4 is 70:30 or greater, but in general 80:20 or greater. This mixture is treated with a proton acid, HY, as defined above, preferably hydrochloric acid, in a solvent, such as methanol, ethanol, isopropanol, tetrahydrofuran, diisopropyl ether, water or a mixture of the foregoing solvents, preferably a mixture of methanol and water, at a temperature between 0 and 60xc2x0 C., preferably room temperature, for a period of time between 1 hour and 48 hours, preferably 18 hours, to afford a mixture of compounds of formula VIa and VIb which is highly enriched in compound of formula VIa, and wherein n is as defined above. Step 4 permits the isolation of mixtures of compounds of formula VIa and VIb wherein the ratio of compounds of formula VIa to VIb are greater than 90:10, and may approach 98:2 or better. Step 4 may be repeated to obtain higher ratios if needed.
Step 1 of scheme 2 is an acylation of an arene which proceeds with protection of an alcohol in a way similar to a known procedure (Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49, 1574-1583). An arene of formula XVIII is treated with an acylating agent of formula R2(Cxe2x95x90O)xe2x80x94Xxe2x80x2, wherein R2 is as defined above and Xxe2x80x2 is halo, R2(Cxe2x95x90O)xe2x80x94Oxe2x80x94, or other suitable group in an acylating agent recognized by those of skill in the art, in the presence of an acid such as aluminum tribromide, aluminum trichloride, tin tetrachloride, titanium tetrachloride, or polyphosphoric acid, preferably aluminum tribromide, in a solvent such as dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide, or chlorobenzene, preferably dichloromethane, at a temperature between xe2x88x9220xc2x0 C. and 125xc2x0 C., preferably between 0 and 20xc2x0 C., for a period between 10 minutes to 10 hours, preferably about 1 hour, to afford a compound of formula VII.
Step 2 of scheme 2 is the addition of a trifluoromethyl group to a ketone using a modification of a known method (Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395). Ketone of formula VII is treated with a compound of formula CF3SiR43, wherein R4 is defined above, in the presence of a fluoride source such as cesium fluoride, potassium fluoride, or an alkylammonium fluoride such as tetrabutylammonium fluoride, preferably cesium fluoride, in the presence of a solvent such as dimethylformamide, dimethylacetamide, toluene, dichloromethane, dichloroethane, or tetrahydrofuran, preferably dimethylformamide, at a temperature between xe2x88x9278xc2x0 C. and 50xc2x0 C. preferably at room temperature, for a period of time between 10 minutes and 18 hours, preferably 45 minutes, to afford a compound of formula VIII.
Step 3 of scheme 2 is the deprotection of an alcohol. A compound of formula VIII is treated with a reagent such as sodium hydroxide, potassium hydroxide, or a fluoride source such at tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid-pyridine complex, or hydrofluoric acid, preferably tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butyl ether, dichloromethane, or toluene, preferably tetrahydrofuran, at a temperature between xe2x88x9240 and 60xc2x0 C., preferably room temperature, for a period of time between 5 minutes and 5 hours, preferably one hour, to afford a compound of formula IX.
Step 4 of scheme 2 is the hydrolysis of an ester. A compound of formula IX is treated with a reagent such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, preferably sodium hydroxide, in a solvent such as water, tetrahydrofuran, methanol, ethanol, isopropanol, 1,4-dioxane, or a combination of the above solvents, preferably a mixture of water and tetrahydrofuran, at a temperature between 0 and 75xc2x0 C., preferably room temperature, for a period of time between 1 and 48 hours, preferably 12 hours, to afford a compound a formula X.
Step 5 of scheme 2 is a cyclization. A compound of formula X is treated with an activating agent such as methanesulfonyl chloride, methanesulfonic anhydride, p-toluenesulfonyl chloride, p-toluenesulfonic anhydride, or triflic anhydride, preferably methanesulfonyl chloride, and a base such as triethylamine, diisopropylethylamine, 2,6-lutidine, pyridine, sodium hydroxide, potassium hydroxide, cesium carbonate, or potassium carbonate, preferably triethylamine, in a solvent such as dichloromethane, tetrahydrofuran, toluene, diisopropyl ether, or methyl-tert-butyl ether, preferably dichloromethane, at a temperature between xe2x88x9240 and 75xc2x0 C., preferably between 0xc2x0 C. and room temperature, for a period of time between one and 48 hours, preferably 12 hours, to afford a compound of formula II.
Step 1 of scheme 3 an acylation of an arene. An arene of formula XIX is treated with an acylating agent of formula R2(Cxe2x95x90O)xe2x80x94Xxe2x80x2, wherein R2 is as defined above and Xxe2x80x2 is halo, R2(Cxe2x95x90O)xe2x80x94Oxe2x80x94 or other suitable group in an acylating agent recognized by those of skill in the art, in the presence of an acid, such as aluminum tribromide, aluminum trichloride, tin tetrachloride, titanium tetrachloride, or polyphosphoric acid, preferably aluminum tribromide, in a solvent such as dichloromethane, dichloroethane, nitromethane, nitrobenzene, carbon disulfide or chlorobenzene, preferably dichloromethane, at a temperature between xe2x88x9220xc2x0 C. and 125xc2x0 C., preferably between 0 and 20xc2x0 C., for a period between 10 minutes to 10 hours, preferably about 1 hour, to afford a compound of formula XI.
Step 2 of scheme 3 is an esterification. A carboxylic acid of formula XI is treated with an alcohol of formula R1OH, wherein R1 is defined above, in the presence of an acid such as sulfuric acid, hydrochloric acid, hydrobromic acid, trifluoroacetic acid or methanesulfonic acid, preferably sulfuric acid, at a temperature between 0 and 100xc2x0 C., preferably at room temperature, for a period between 10 minutes to 48 hours, preferably 16 hours, to afford a compound of formula XII.
Step 3 of scheme 3 is the addition of a trifluoromethyl group to a ketone using a modification of a known method (Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am. Chem. Soc. 1989, 111, 393-395). Ketone of formula XII is treated with a compound of formula CF3SiR43, wherein R4 is defined above, in the presence of a fluoride source such as cesium fluoride, potassium fluoride or an alkylammonium fluoride, such as tetrabutylammonium fluoride; preferably cesium fluoride, in the presence of a solvent such as dimethylformamide, dimethylacetamide, dichloromethane or tetrahydrofuran, preferably dimethylformamide, at a temperature between xe2x88x9278xc2x0 C. and 50xc2x0 C. preferably at 0xc2x0 C., for a period of time between 10 minutes and 18 hours, preferably 7 hours, to afford a compound of formula XIII.
Step 4 of scheme 3 is a lactonization. A compound of formula XIII is treated with a fluoride source such at tetrabutylammonium fluoride, cesium fluoride, hydrofluoric acid-pyridine complex or hydrofluoric acid, preferably tetrabutylammonium fluoride, in a solvent such as tetrahydrofuran, diisopropyl ether, acetonitrile, methyl-tert-butyl ether, dichloromethane or toluene, preferably tetrahydrofuran, at a temperature between xe2x88x9240 and 60xc2x0 C., preferably room temperature, for a period of time between 5 minutes and 5 hours, preferably one hour, to afford a compound of formula XIV.
Step 5 of scheme 3 is the reduction of a lactone. A compound of formula XIV is treated with a reducing agent such as sodium borohydride, borane tetrahydrofuran complex, borane dimethylsulfide complex, diborane, lithium borohydride, calcium borohydride, lithium aluminum hydride, diisobutylaluminum hydride, L-selectride or K-selectride, optionally in the presence of a Lewis acid, such as boron trifluoride diethyl ether complex; preferably sodium borohydride in the presence of boron trifluoride diethyl ether complex, in a solvent, such as tetrahydrofuran, diisopropyl ether, methyl-tert-butyl ether or dimethoxyethane, preferably tetrahydrofuran, at a temperature between xe2x88x9278 and 60xc2x0 C., preferably between 0xc2x0 C. and room temperature, for a period of time between 30 minutes and 48 hours, preferably 16 hours, to afford a compound of formula XV.
Step 6 of scheme 3 is a reduction. A compound of formula XV is treated with a reducing agent such as triethylsilane or triphenylsilane, in the presence of a Lewis acid such as boron trifluoride etherate or trifluoroacetic acid preferably trifluoroacetic acid, in a solvent such as dichloromethane, dichloroethane, or chloroform, preferably dichloromethane at a temperature between xe2x88x9278 and 60xc2x0 C., preferably room temperature, for a period of time between 5 minutes and 5 hours, preferably 2 hours, to afford a compound of formula II. Alternatively, a compound of formula XV is treated with a reducing agent that is a catalyst, such as platinum, platinum oxide, or palladium hydroxide, preferably platinum, in a solvent such as methanol, ethanol, or isopropanol, preferably ethanol, under an atmosphere of hydrogen, optionally under pressure, at a temperature between room temperature and 100xc2x0 C., preferably room temperature, for a period of time between 1 and 48 hours, preferably 5 hours, to afford a compound of formula II.
Alternatively, compound III can be purified by derivatization. Step 1 of scheme 4 is the formation of a hydrazone. A compound of formula III is treated with a hydrazone of formula XVI with an acid such as acetic acid, sulfuric acid, hydrochloric acid, methanesulfonic acid or p-toluenesulfonic acid, preferably acetic acid, in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, water or a mixture of any of the foregoing solvents, preferably a mixture of methanol and water, at a temperature between 0 and 110xc2x0 C., preferably at reflux, for a period of time between 30 minutes and 10 hours, preferably 90 minutes, to afford a compound of formula XVII.
Step 2 of scheme 4 is the hydrolysis of a hydrazone. A compound of formula XVII is treated a reagent such as copper(II) chloride, copper(II) iodide, copper(II) acetate, copper sulfate, sulfuric acid, acetic acid or hydrochloric acid, preferably copper(II) chloride, in a solvent such as tert-butyl alcohol, methanol, ethanol, isopropanol, tetrahydrofuran, water or a mixture of any of the foregoing solvents, preferably a mixture of tert-butyl alcohol and water, at a temperature between 0 and 110xc2x0 C., preferably at 70xc2x0 C., for a period of time between 30 minutes and 10 hours, preferably 2.5 hours, to afford a compound of formula III.
The preparation of other compounds of the present invention not specifically described in the foregoing experimental section can be accomplished using combinations of the reactions described above that will be apparent to those skilled in the art.
In each of the reactions discussed or illustrated in Schemes 1-4 above, pressure is not critical, unless otherwise indicated. Pressures from about 0.9 atmospheres to about 2 atmospheres are generally acceptable and ambient pressure, i.e., about 1 atmosphere, is preferred as a matter of convenience.
Intermediate compounds of invention referred to above may contain chiral centers, and therefore may exist in different enantiomeric and diastereomeric forms; this invention is directed to all such optical and stereoisomers of said intermediate compounds, as well as mixtures thereof.
This invention is also directed to isotopically-labeled compounds identical to those recited in formulae Ia or Ib, or pharmaceutically acceptable salts thereof, but for the fact that one or more atoms are replaced therein by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively.
Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds, or of said prodrugs, which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful, for example, in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Furthermore, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances.
Isotopically labeled compounds of formulae Ia and Ib of this invention and prodrugs thereof can generally be prepared by carrying out the procedures set forth herein, by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.
The activity, methods for testing activities, dosages, dosage forms, methods of administration and background information concerning the compounds of formula Ia and Ib are set forth in International Patent Publication No. WO 99/25714, published May 27, 1999. The piperidinylaminomethyl trifluoromethyl cyclic ether compounds prepared by the methods of the present invention exhibit significant substance P receptor-binding activity and are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of said substance P activity. Such conditions include cardiovascular diseases, allergic disorders, angiogenesis, gastrointestinal disorders, central nervous system disorders, inflammatory diseases, emesis, urinary incontinence, pain, migraine, sunburn, and diseases, disorders and conditions caused by Helicobacter pylori, in a mammal, especially humans. For treatment of emesis, these compounds may preferably be used in combination with a 5-HT3 antagonist.
The active piperidinylaminomethyl trifluoromethyl cyclic ether compounds of formulae Ia and Ib may be administered via either oral, parenteral (e.g., intravenously, intramuscularly or subcutaneously) or topical routes to mammals. These compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the routes indicated above, and may be carried out in single or multiple doses. The compounds prepared by the methods of the invention may be administered in a wide variety of different dosage forms, e.g., combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, trochees, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups and the like.

Process for the preparation of piperidinylaminomethyl trifluoromethyl cyclic ether compounds

Abstract: and pharmaceutically acceptable salts thereof, wherein R1 is C1-C6 alkyl; R2 is C1-C6 alkyl, halo C1-C6 alkyl or phenyl or substituted phenyl; R3 is hydrogen or halo; m is zero, one or two, and wherein said mixture is highly enriched in the compound of formula Ia, and to novel processes for the preparation and purification of intermediate compounds useful in the preparation of compounds of formulae Ia and Ib.


A byte boundary information recovery mechanism locates the first bits of respective bytes of an asynchronous transfer mode (ATM)-based serial data stream, used by a frame synchronization mechanism to delineate respective cells of the ATM stream, and thereby enables transceiver equipment to successfully receive and parse ATM traffic. The invention employs a counter offset-based scheme that generates an output signal in potential alignment with the (first bit) boundary of a byte of the data stream, in response to the contents of a counter reaching a prescribed count value. It then iteratively shifts, as necessary, the bit time at which the output signal is produced relative to the counting operation of the counter, until the output signal is aligned with the boundary of a byte of the data stream.

The ability to conduct high-speed data communications between remotely separated data processing systems and associated subsystems has become a requirement of a variety of industries and applications, such as business, educational, medical, financial and personal computer uses. Moreover, it can be expected that current and future applications of such communications will continue to engender more such systems and services. One technology that has attracted particular interest in the telecommunication community is digital subscriber line (DSL) service. DSL technology enables a public service telephone network (PSTN) to use existing telephone copper wiring infrastructure to deliver a relatively high data bandwidth digital communication service, that is selected in accordance with expected data transmission rate, the type and length of data transport medium, and schemes for encoding and decoding data.
FIG. 1 is a reduced complexity diagram of the general architecture of a DSL system, having a pair of mutually compatible digital communication transceivers 1 and 3 installed at remotely separated 'west' and 'east' sites 2 and 4, respectively, and coupled to a communication link 10, such as a twisted pair of an existing copper plant. One of these transceivers, for example, the west site transceiver 1, may be installed in a digital subscriber line access multiplexer (DSLAM) 6 of a network controller site (such as a telephone company central office (CO)). The DSLAM is coupled with an associated network backbone 5 that provides access to information sources 7 and Internet-sourced data 8. As such, the west site transceiver 1 is used for the transport of digital communication signals, such as asynchronous transfer mode (ATM)-based serialized data, from the west central office site 2 over the communication link 10 to the DSL transceiver 3 at the east end of the link. The DSL transceiver 3 may be coupled with a computer 9 at a customer premises, such as a home or office.
In order to delineate respective cells of a received asynchronous transfer mode (ATM)-based serial data stream, transceivers of digital communication networks, such as the transceivers 1 and 2 in the system of FIG. 1, are often equipped with a mechanism that relies upon a priori knowledge of the boundaries (e.g., beginning) of respective bytes of an incoming serial (ATM) data stream. Unfortunately, some wide area network interface devices provide no information concerning the start of payload or start of respective octets, making it impossible for the transceiver equipment to successfully receive and parse ATM traffic.

Mechanism for providing octet alignment in serial ATM data stream


A problem associated with field emission displays is that of `smearing` where an otherwise sharp image appears to be surrounded by a diffuse halo of light. Our investigations have suggested that this is due to spurious reflections from the surface of the gate electrode layer. To eliminate these we have deposited an anti-reflection coating on the top surface of the gate electrode layer. This prevents the reflection of light rays travelling away from the phosphor layer towards the cathode. Such rays, if their reflection were allowed, would emerge at a different spot in the display from what was intended, resulting in a false image. A method for manufacturing a field emission display based on this approach is also described.

(1). Field of the Invention
The invention relates to the general field of field emission displays with particular reference to problems of image smearing.
(2). Description of the Prior Art
Cold cathode electron emission devices are based on the phenomenon of high field emission wherein electrons can be emitted into a vacuum from a room temperature source if the local electric field at the surface in question is high enough. The creation of such high local electric fields does not necessarily require the application of very high voltage, provided the emitting surface has a sufficiently small radius of curvature.
The advent of semiconductor integrated circuit technology made possible the development and mass production of arrays of cold cathode emitters of this type. In most cases, cold cathode field emission displays comprise an array of very small conical emitters, each of which is connected to a source of negative voltage via a cathode conductor line or column. Another set of conductive lines (called gate lines) is located a short distance above the cathode lines at an angle (usually 90.degree.) to them, intersecting with them at the locations of the conical emitters or microtips, and connected to a source of relatively positive voltage.
The electrons that are emitted by the cold cathodes accelerate past openings in the gate lines and strike a layer of phosphor that is located some distance above the gate lines. Thus, one or more microtips serves as a sub-pixel for the total display. The number of sub-pixels that will be combined to constitute a single pixel depends on the resolution of the display and on the operating current that is to be used. In general, even though the local electric field in the immediate vicinity of a microtip is in excess of 1 million volts/cm., the externally applied voltage is under a 100 volts.
A number of factors affect the sharpness of the images that are formed in displays of this type, for example the degree to which the electron beam diverges after it has passed through the gate electrode. A problem, known to be associated with this type of display, is that of `smearing` where an otherwise sharp image appears to be surrounded by a diffuse halo of light. The origins of this defect are not entirely clear but our own investigations suggest that it is due to spurious reflections from the surface of the gate electrode layer.
We will amplify this by reference to FIG. 1. Seen there is a schematic cross-section of a cold cathode display of the type that we have been discussing above. Cathode electrode 11 (normally in the form of extended columns) lies on lower dielectric substrate 10. Immediately above cathode 11 is dielectric layer 12 which serves to support gate electrode 13 (normally in the form of rows running at right angles to the cathode columns) as well as to electrically insulate it relative to 11. Holes, such as 18, have been formed in the gate electrode and these holes extend down to the surface of cathode layer 11. In each such hole a conical microtip, made of material such as molybdenum or silicon, is seated. Positioned some distance above the microtips by means of insulating spacers (not shown) is upper dielectric substrate 16 on whose downward facing surface layer 15 of transparent conducting material, indium tin oxide (ITO), has been deposited. The ITO in turn is covered with layer 14 of a suitable phosphor which will emit light in some desired wavelength range when it is struck by electrons coming from the microtips.
Continuing our reference to FIG. 1, we show there a phosphor particle 21 that, having been subjected to bombardment by electrons coming from microtip 19, emits phosphorescent light rays 22 in all directions, both outwardly (and hence seen as part of the display) and inwardly where the majority of them are lost and not seen by an external viewer. However, a small fraction of rays 22, represented in the figure as ray 23, arrive at the surface of gate electrode layer 13. The latter is typically made of niobium or molybdenum and provides a good reflecting surface. The resulting reflected ray (shown as 24 in the figure) is then returned to the upper substrate, passing through phosphor layer 14 on its way. As it passes through the phosphor layer, ray 24 may get diverted by refraction. The net result is the emergence of rays 25 which give an outside viewer the impression that they originated from microtip 20 instead of from microtip 19. This we believe to be the origin of the smearing phenomenon discussed above.
In the prior art, as far as we are aware, the only way in which the smearing problem has been dealt with has been to increase the thickness of the phosphor layer. This is illustrated in FIG. 2 which can be seen to be the same as FIG. 1 except that phosphor layer 114 is substantially thicker than corresponding phosphor layer 14 in FIG. 1. The result of this change is that reflected ray 24 is now subject to significant attenuation on its way to the surface so that the cone of emitted light 125 which is visible to an external viewer is significantly fainter than corresponding cone 25 in FIG. 1. While this approach does reduce the amount of smearing, it does so at the cost of a fainter image since the light associated with a given electron has more material to penetrate on its way to the surface.
Wei et al. (U.S. Pat. No. 5,517,031 May 1996) shows a photosensor array where the photosensors are backed up by an opaque layer to eliminate false imaging effects. Hashimoto (U.S. Pat. No. 5,478,611 December 1995) describes a type of black matrix for an LCD display while Kim (U.S. Pat. No. 5,338,240 August 1994) also describes a black matrix for an LCD display based on using two substrates.

Reduction of smearing in cold cathode displays

Industrial Technology Research Institute


The invention relates to a method for operating a magnetohydrodynamic pump 5 for a liquid-metal anode 1 of an X-ray source.

The invention relates to a method for operating a magnetohydrodynamic pump for a liquid-metal anode of an X-ray source, with an X-ray arrangement and with a liquid-metal anode for an X-ray source with a liquid metal which is located in a line, wherein one part of the line is formed as a region of focus, and with a pump for circulating the liquid metal in the line and with a cooling system for the liquid metal.
It has been known since recently to produce X-ray beams, not via a solid-metal anode which is bombarded by electrons, but with a liquid-metal anode. This technique is called LIMAX (Liquid Metal Anode X-ray). Such a liquid-metal anode requires the following components for its operation. There is located in a line a liquid metal which must have a high average atomic number in order to achieve a good X-ray yield when bombarded with electrons. An anode module in which the electron beam strikes the liquid metal and the X-ray beam is produced is inserted into the line around the region of focus. At this point, the anode module must be formed such that it displays only a weaker interaction with the electrons passing through it. As a rule, this is achieved with a so-called electron window in which the electrons passing through are only slightly slowed down. To remove the heat produced in the region of focus, a pump is used which circulates the liquid metal through the line and thus also the region of focus. If a closed circuit of the liquid metal is used, a cooling of the heated liquid metal is achieved via a heat exchanger. Due to the predetermined framework conditions, it is necessary—as already stated above—for the liquid metal to have a high average atomic number and also an average melting point. Furthermore, the liquid-metal anode must be designed extremely compact. Thus there are marked restrictions for all of the above-named individual parts of the liquid-metal anode in respect of their interactions, because the individual parts must fit together well. This also applies in particular to the pump for circulating the liquid metal.

X-ray emitter, liquid-metal anode for an x-ray source and method for operating a magnetohydrodynamic pump for the same

Abstract: It is provided according to the invention that it can be operated in at least two modes, wherein the first mode is a thawing mode in which the liquid metal 2 is melted in a line 3 of the liquid-metal anode 1, the second mode is an operating mode in which the liquid metal 2 is pumped through the line 3 and X-ray beams are produced. In addition, the invention relates to a liquid-metal anode 1 for an X-ray source with a liquid metal 2 which is located in a line 3, wherein an anode module 15 is inserted into the line 3 in the region of focus 4, with a pump 5 for circulating the liquid metal 2 in the line 3 and with a cooling system 6 for the liquid metal 2. According to the invention, such a liquid-metal anode 1 has a magnetohydrodynamic pump 5 as described above.


This invention provides a liquid container apparatus and method to prevent spilling of a liquid, such as oil, while adding liquid to an engine or other component, without the use of a funnel and without inverting the container, and to make the liquid-adding operation easier and safer for a user, providing a smart cap with a smart-cap opening turnably mounted upon an opening protrusion on a container body such that the smart cap can be closed and opened without detaching the smart cap from the container body, the liquid can be dispensed without inverting the container, and the rate of liquid flow can be controlled by a user, providing a container able to be placed upon or near an engine for the required time, providing a container that dispenses liquid without being inverted, and providing a container that visually indicates the amount of liquid within, consequently simplifying the use of the container.

This invention provides a smart liquid container apparatus and method providing for opening and closing a smart cap without detaching the smart cap from the container body.
The prior art does not provide for an oil container, or a related liquid container, apparatus and method providing a smart cap with a smart-cap opening turnably mounted upon an opening protrusion on a container body such that the smart cap can be closed and opened without detaching the smart cap from the container body, consequently preventing misplacement or loss of the smart cap and simplifying the use of the container. With the currently available fluid (e.g., motor oil, anti-freeze, transmission oil, etc.) containers on the market today, when the user needs to add fluid to the engine, for example, he or she must either use a funnel to avoid spilling of the liquid or make their best effort to prevent the liquid from spilling during the pouring process; but unfortunately, more often than not, the liquid will spill and contaminate other components of the engine. While this is seemingly a benign issue, it may certainly result in a disastrous outcome for the user or even others. For instance, if oil spill contaminates the alternator, then the spilled oil might ruin the alternator. Aside from the cost and inconvenience of replacing a ruined part, the malfunction of the alternator will cause the vehicle to stall, and perhaps without warning. Moreover, if such an incident occurs in a high traffic and/or high-speed area, it could result in serious or fatal injuries to the operator of the vehicle and others as well.
For example, U.S. Pat. No. 9,714,123 for a "Dispensing Closure," issued on Jul. 25, 2017 to assignee Again Innovations Ltd., provides for a dispensing closure for covering an opening of a container including a liquid. The dispensing closure includes an engagement element that fits over the opening of the container and defines a pouring orifice for allowing pouring of the liquid. The pouring orifice having a side defining an air channel for allowing air to flow into the container when liquid during the pouring. The engagement element also includes outer walls and a cap having a hollow including inner walls tightly conforming to the outer walls, a first orifice generally conforming in shape to the pouring orifice, and a second orifice generally conforming in shape to the air channel.
U.S. Pat. No. 6,494,344 for a "Liquid Dispensing Container," issued on Dec. 17, 2002 to inventor Joseph A. Kressel, Sr., provides for a liquid dispensing container for conveniently storing and dispensing various types of fluids. The liquid dispensing container includes a container capable of storing a volume of fluid, a strap attached to an upper surface of the container, a fill cap removably attached to a threaded nipple, a transparent or semi-transparent viewing portion within at least one side of the container, a dispensing hose fluidly connected to a lower portion of the container, a dispensing nozzle attached to the end of the dispensing hose, and a clasp attached to the container for catchably receiving the dispensing hose. A plurality of marker lines and relevant indicia are preferably positioned adjacent the viewing portion which has an elongate vertical structure thereto for allowing an individual to determine the amount of fluid within or dispensed from the container. The dispensing hose and the nozzle are preferably comprised of a relatively smaller structure for allowing the individual to fit the nozzle into compact areas.
U.S. Pat. No. 6,082,591 for a "Graduated Sight Glass Container," issued on Jul. 4, 2000 to inventor Thomas J. Healey, provides for a graduated sight glass container for retaining a substance therein and minimizing the possibility of spillage during dispensing of the substance therefrom. The graduated sight glass container includes a housing having a shape of a quadrilateral and including an indented section on a first side thereof. A spout is connected to extend from the indented section of the housing and at most up to the first side. A pool is formed within the indented section and surrounding the spout, wherein, when the container is tilted from a vertical at-rest position causing the spout to be positioned adjacent an opening through which the substance contained within the container is to flow, the pool is caused to at least partially receive an edge of the opening. Extending along a second side of the housing is a first graduated scale and a second graduated scale extends along a base of the housing for measuring an amount of the substance within said container and an amount of the substance dispensed from the container during dispensing. The first and second graduated scales are both made of a clear material allowing a user to view the substance within the container therethrough and include indicia printed therealong indicative of a volume of said container at predetermined positions.
U.S. Pat. No. 3,198,406 for a "Dispenser Cap with Deformable Cone Assembly," issued on Aug. 3, 1965 to inventor Ahron W. Kopelman, provides for a dispenser cap having controllable valve means for dispensing liquids or pastes from a container, and more particularly, a dispenser cap comprising an outer cap rotatably retained on an inner cap, the outer cap having a resiliently expandable conical sleeve to permit assembly to be achieved by elastic deformation.
U.S. Patent Application Publication No. 2017/0283135 for a "Container for Viscous Liquid Comprising a Cap Provided with a Tap," published on Oct. 4, 2017 by applicant Total Marketing Services, discloses a container including an upper wall, a lower wall, and a side wall defining an inner space, a single opening extending along a main axis, a cap including a flow duct provided with an outlet extending along an axis substantially perpendicular to the main axis, and a pipe including a first end in fluid communication with the outlet and a second end intended for extending above the level of the liquid in the container, the pipe being rotatably secured with the cap and extending essentially along a tilted axis forming an angle of 25° to 75° with the main axis and having a length no less than half the length of the container.
U.S. Patent Application Publication No. 2016/0137361 for a "No Spill Cap Assembly," published on May 19, 2016 by inventors Gary Lee Snow et al., discloses a cap assembly connected to a container for dispensing the contents of the container that includes an inner cap and an outer cap. The inner cap includes a cylindrical inner cap surface between a proximal end and a distal end that includes an inner cap opening. The outer cap is positioned over and secured to the inner cap. The outer cap includes a cylindrical outer cap surface between the proximal end and distal end, and the cylindrical outer cap surface includes an outer cap opening. The cap assembly includes an open configuration and a closed configuration. The outer cap can be rotated about the inner cap between the open configuration and the closed configuration.
U.S. Pat. No. 1,555,383 for a "Spout Can," issued on Sep. 29, 1925 to inventor Harold Ramslie, provides for a spout can, specifically claiming a venting means for a can comprising a flat strip secured at one end only to the outside of the can, a pointer pivotally secured to the free end of the flat strip adapted to lie flat against the outside of the can or turn in its pivotal connection to a position at right angles to the can.
Lastly, U.S. Pat. No. 2,022,343 for a "Pouring Means for Canisters," issued on Nov. 26, 1935 to inventor Harry Drood, provides a filling opening closure for a liquid container can, the closure being of a formation and adapted for assembly with a rotatable pouring spout, the device being adapted for either the top or the bottom wall of the can.
What is needed is a liquid container that can be opened and closed without detaching a cap from a container body, preventing misplacement or loss of the cap, and simplifying the use of the container.


Kits provide management of implantable lead extensions being implanted by providing a kit body with features that retain the extension in a configuration, with amounts being removed as needed during the implantation procedure. The kit can be present within a sterile field, and the kit body features may be arranged so that a length of a path that the extension forms is approximately equal to a length of the extension needed for the tunnel. The kit body may include features that allow the connectors of the extension as well as implantation tools to be retained within the kit body while being easily accessed when needed during the procedure. The kit may be coupled to the patient during the trial period, as the extension may have an implanted distal connector while having a proximal connector coupled to an external stimulator and while being retained on the kit body.

When a patient is a candidate for stimulation therapy such as sacral nerve stimulation or spinal cord stimulation therapy to treat incontinence, chronic pain, or related conditions, it is often desirable to conduct a trial period of stimulation. This trial period allows an external stimulator to be used so that the patient is not required to undergo a full stimulation device implantation procedure. If the trial is successful, then an implantable stimulator is fully implanted into the patient.
When implanting the trial system, an implantable medical lead is implanted with a distal end being routed to the stimulation site. An implantable lead extension is typically then routed subcutaneously from the location of the proximal end of the implanted medical lead to an exit site nearby the location where the external device will be mounted to the patient. An external lead is then used to interconnect the exposed proximal end of the implantable lead extension to the external device.
One issue with the external lead is that it requires a step of connecting the external device and to the lead extension. While this allows the lead extension to be shorter, and thus less burdensome during implantation and during the trial period, the external lead itself introduces the burden of having to install it and then have it be present during trialing. Thus, the external lead has two external connections, and both must be maintained during the trial period.
In addition to the burdens of the external lead, the implantation procedure has additional burdens related to accessing the tools needed to complete the implantation procedure. A nurse within a non-sterile field provides the packaging of the tools. A sterile nurse must then access the tools from the packaging and place the tools on a surgical tray within the sterile field. Meanwhile, the packaging is discarded. These steps add to the time and inefficiencies of the implantation procedure.

Kits and methods for implanting an implantable lead extension


The invention provides a fluorine-containing acetophenone derivative which is useful as an additive that can impart excellent antifouling properties and scratch resistance to the surface of a cured coating and that also offers high transparency of the coating; a fluoroadditive and an active energy ray curable composition which each include the above derivative; a cured product of the composition; and an article having a cured coating of the composition. Specifically, this object is achieved by using a fluorine-containing acetophenone derivative, typically represented by the structural formula below, that is obtained by introducing an acryloyl group into a poly(perfluoroalkylene ether) chain and thereafter introducing, using Michael addition reaction, an α-aminoacetophenone-based structural unit capable of generating radical species by photocleavage

Plastic films produced using polyethylene terephthalate resins (PET), acrylic resins, polycarbonate resins, acetyl cellulose resins and the like have found wide applications in industry such as polarizer protective films included in flat panel displays, and surface protective films for touch panels. These plastic films themselves are prone to scratches on the surface, are low in workability, and are easily broken or cracked. To make up for such poor performance, the surface is usually provided with a coating layer which is formed from, for example, an active energy ray curable resin. A coating obtained by the application of such a material serves as a skin layer, and thus needs scratch resistance. A known approach to enhancing scratch resistance is to coat the surface of a substrate with a crosslinked coating obtained using a hard coating agent including a polyfunctional monomer such as a polyfunctional (meth)acrylate. Methods have been also proposed which further add, to the hard coating agent, a silicone or fluorine leveling agent, inorganic compound particles such as silicon dioxide or aluminum oxide, carbon, or synthetic resin particles such as polyurethane resin, polystyrene resin or acrylic resin.
A specific example of the hard coating agents that is known is an active energy ray curable composition which includes a silicone compound having a radically polymerizable unsaturated group in the molecule (see, for example, Patent Literature 1).
As known in the art, fluorine-containing curable resins which are polymers having a poly(perfluoroalkylene ether) chain, a photopolymerization initiating functional group and a polymerizable unsaturated group are added as surface modifiers to photopolymerizable compositions to impart long-lasting antifouling properties to the surface of coatings that are obtained (see, for example, Patent Literature 2). It is also known that fluorine-containing polymerizable resins which are polymers having a poly(perfluoroalkylene ether) chain and containing an adamantyl group and a polymerizable unsaturated group as structural constituents are added as surface modifiers to active energy ray curable compositions to impart excellent antifouling properties, liquid repellency and scratch resistance to the surface of coatings that are obtained (see, for example, Patent Literature 3).

Fluorine-containing acetophenone derivative, fluroine based additive, curable composition including same, and cured product thereof