A database system is able to receive a query that specifies an inequality join involving at least a first relation and a second relation. A plurality of segments of the first relation are sorted in the cache. Each sorted segment of the first relation in the cache is compared with the second relation.

A database is a collection of logically related data that is accessible by one or more users. A popular type of database system is the relational database management system, which includes relational tables made up of rows and columns. Each row represents an occurrence of an entity defined by the table, with an entity being a person, place, or thing about which the table contains information.
To extract data from a relational table, queries according to a standard database query language (e.g. Structured Query Language or SQL) can be used. Examples of SQL statements include INSERT, SELECT, UPDATE, and DELETE. The SELECT statement is used to retrieve information from the database and to organize information for presentation to the user or to an application program. The SELECT statement can also specify a join operation to join rows of multiple tables. A common type of join operation is a simple join (or equijoin), which uses an equal (=) comparison operator to join rows from multiple tables. Another type of join is a non-equijoin, or inequality join, which is based on operators other than the equal comparison (e.g., >, <, ≧, ≦, etc.).
Conventionally, join algorithms have been implemented to enable efficient performance of equijoins. However, if no equality terms are present in a join predicate of a query, an inequality join is specified and then a product join is typically performed. In a product join, every left relation row is compared with every right relation row. The terms "left relation" and "right relation" refer to the relations on the left and right sides, respectively, of an inequality operator (e.g., <, >, ≦, ≧). Efficient algorithms have typically not been provided for inequality joins.


A communication system comprising an access system configured to provide a plurality of end devices with access to a packet communication network, a first end device of the plurality of end devices configured to transmit a first query to the access system, receive a first response indicating a first identifier for the access system, transmit a registration message indicating the first identifier and a second identifier for the first end device, and transmit a first call request for a call wherein the first call request indicates the second identifier, and a call processing system in communication with the first end device and configured to receive the registration message, store the first identifier in association with the second identifier, receive the first call request, process the second identifier to determine the first identifier stored in association with the second identifier, and transmit a second call request indicating the first identifier.

1. Field of the Invention
The invention relates to emergency call service capabilities, and in particular, to determining the location of callers obtaining emergency call services.
2. Description of the Prior Art
Emergency service call handling capabilities are offered by most telecommunication service providers. For example, users of plain old telephone service (POTS) are typically accustomed to dialing 911 for emergency service. In addition to connecting the user to a public service answering point (PSAP), emergency service call handling capabilities include additional capabilities, such as determining the location of a caller.
Recent advances in telecommunication technologies have made the task of determining the location of a caller more difficult than in the past. In past circuit switched networks, the location of a caller could be easily determined by performing a database look-up to a table holding the calling number stored in association with a physical address. In contrast, new types of voice service technologies do not always associate calling numbers with physical addresses. For example, voice over Internet protocol (VoIP) service users are able to roam wherever there is adequate Internet access. As a result, the location of VoIP callers cannot be reliably determined.
In one prior art solution to the problem of determining the location of VoIP callers, a static relationship is assumed between the calling number and the physical location of the caller. However, this solution only suffices in cases where users are not able to port their phones to new locations.
In another prior art solution, a central server system in a local area network (LAN) actively searches for new VoIP phones. Upon determining a new phone, the central server system queries the switch element closest to the phone for the identity of the switch element. The central server system then determines the approximate location of the phone based on the location of the switch element. Unfortunately, such a solution requires the central server system to have visibility into the network and the ability to query switch elements. In addition, such a solution places an added processing burden on the central server system beyond its regular call processing responsibilities.

Location determination capabilities for emergency call services


A packaging machine having multiple modules each performing a separate function in a packaging sequence. The modules are building blocks that are assembled to define a packaging machine. An infeed conveyor/lane divider module, a blank magazine and infeed tray module, a collation and synchronization module, a gluing and closing module, a turning module, a stacking module, a film cutting module, a film wrapping module and a heat shrink module are selectively assembled in various combinations to define machines that pack articles into trays, wrap the articles with heat shrink film, turn the packages, stack the packages for multi-tier packages, or any combination of these functions. The modules each have an independent conveyor driven by an onboard servo drive. The servo drives are coordinated to provide controlled flow of articles from module to module. The servo drives are all connected to and controlled by a supervisory computer such that no mechanical connection between modules is required.

The present invention relates to packaging machines, particularly a wraparound packer, tray shrink packer, pad shrink packer and shrink packer machines, having modular components.
The explosion of consumer items that are mass manufactured and sold to the public has resulted in the packaging of such items becoming an important and significant step in production. As a result, specialized packaging machines have been developed which are generally dedicated to a specific item, and which provide identical packaging with little flexibility to change the size, type or arrangement of the package or to adapt the machine to the item being packaged.
A number of packaging machines are well known in the art, including wraparound packers, tray shrink packers, pad shrink packers and shrink packer machines. Wraparound packers (WP), for instance, package consumer items in cardboard or paperboard cartons by folding and sealing a blank to form a box around the articles. Tray shrink packers (TSP), on the other hand, package articles by forming a cardboard tray around a group of articles, including folding and gluing upright panels of the tray, then wrapping heat shrinkable film around the tray and articles. Heat is applied and the film shrinks to define the TSP package. Pad shrink packers (PSP) position a pad beneath a group of articles, without forming a tray, and wrap the pad and articles in heat shrinkable film, after which heat is applied to shrink the film. A shrink packer (SP) wraps a sheet of heat shrinkable film around a group of articles without any support from a tray or pad, and applies heat to shrink the film and make the package rigid.
The various packaging machines (WP, TSP, PSP, SP) discussed above are used as efficiency dictates based upon the weight, rigidity and size of the articles and packages produced. If a small package is desired, for instance, which does not require a pad or tray for structural support, a shrink packer (SP) would be used because the expense and step of inserting a pad or tray is not necessary. For heavier or larger articles, however, a tray or pad may be necessary to give a package adequate rigidity and integrity.
In a number of specific examples, packaging machines have been designed to act as more than one type of the above described packaging machines (WP, TSP, PSP, SP). One specific application has been the use of a machine used as a tray shrink packer, pad shrink packer or shrink packer in the packaging of upright cylindrical articles, such as beverage bottles or cans. It is well known in the art that such articles can be conveniently and efficiently packaged in six pack, twelve pack, twenty-four pack, or forty-eight pack packages utilizing a tray shrink packer (TSP) machine. In prior art devices of this type, the articles are organized into a set to be packaged and a tray blank is positioned on a conveyor. The articles are then placed upon the tray blank and the tray blank is folded and glued to form a tray around the articles. Then, a film of heat shrinkable material is wrapped around the articles and tray, secured and heat shrunk to provide a package suitable for shipment to retailers or consumers. Bottles or cans may also be packaged in smaller packages utilizing a pad shrink packer (PSP) or shrink packer (SP) machines. In a pad shrink packer (PSP) machine, a simple pad, rather than a tray blank, is placed under the articles and the step of forming the tray, the step just prior to the wrapping with and heating of film, is eliminated. In a shrink packer machine, no tray blank or pad is placed beneath the articles. The film is wrapped and heat shrunk, without a need for additional support from a pad or tray, to complete the package.
A number of prior art packaging machines have provisions for performing additional operations during the packaging sequence. Specifically, some prior art packaging machines include provisions for turning the packages prior to exiting the machine to aid in further handling and shipment. Also, it is known in the art that successive groups of articles can be stacked by a properly equipped packaging machine to provide a two-tiered package. In tray shrink packer (TSP) machines, for instance, prior art devices have included stacking between the folding and gluing tray forming step and the application of the heat shrinkable film, so that twenty-four packs of cans in trays can be placed in a two-tier stack to provide a forty-eight article package. Heat shrinkable film is then wrapped, secured and heated to shrink it to provide a secure rigid two-tier package.
In the prior art packaging machines described above, packaging of articles is generally performed in a multiple step sequence. Initially the articles, such as beverage cans or bottles, are received in random, unordered arrangement. An infeed conveyor arranges the articles into lanes for further processing. A group of the laned articles is then separated out by a collator which separates the laned articles into package groups by using separator bars mounted on the conveyor which receive the laned articles from the infeed conveyor/lane divider.
In a wraparound packer (WP), a cardboard blank is then provided from a tray magazine and positioned beneath the group of articles being packaged. The blank is then folded and glued to form a box around the packaged articles.
In a tray shrink packer (TSP) machine, the next step in the sequence after the formation of package groups is to register the articles onto a cardboard blank. A blank is supplied from a magazine and is positioned beneath the group of articles being packaged. Outer extending flanges of the tray are then folded upright and glued together around the group of articles to form a packed tray. In a pad shrink packer (PSP), a pad, rather than a tray blank, is positioned beneath the articles being packaged and there is no step of folding and gluing the flanges.
In tray shrink packer (TSP), pad shrink packer (PSP) and shrink packer (SP) machines, a sheet of heat shrinkable film is wrapped around the articles and the pad (PSP machine), and the tray (TSP machine). The film is secured and the package wrapped in film, is conveyed into an oven wherein heat is applied to shrink the film into tight engagement. In prior art packaging machines equipped for such, the steps of turning or stacking packages are performed prior to the application of heat shrinkable film.
In prior art packaging machines utilizing the multiple step packaging sequence described above, it is desirable to keep the machine operating continuously, without interruption, for maximum efficiency. While the articles are moved from section to section in sequence in a packaging machine, it is necessary to control the movement so that the number of articles being processed in every section is the same or appropriately cycled to allow continuous operation. To effect continuous processing in every section of the machine, prior art packaging machines have utilized, either a single conveyor which moves the articles through the packaging sequence, or a number of individual conveyors which are mechanically linked to ensure same speed processing in all sections of the packaging machine. A single mechanical drive providing the motive force for all of the conveyors in a packaging machine solves the continuity problem by having all the sections operating at the same speed, but it has the significant disadvantage of having complicated mechanical interconnections that make it difficult to isolate sections of the machine for maintenance.
The prior art packaging machines described above have equipment to perform all of the desired functions mechanically interconnected and mounted on a large frame. Even when multiple conveyors are used to move the articles through the various steps in the packaging sequence, the conveyors are mechanically interconnected and a large frame is provided on which the conveyors and other packaging equipment are mounted and affixed.
A significant disadvantage of the prior art packaging machine wherein multiple sequential steps are performed is that a breakdown or malfunction of any step in the sequence incapacitates the entire machine. To remove a portion of a prior art packaging machine it is necessary to mechanically disconnect and remove the problem equipment from the large frame. When a single drive motor with multiple belts or couplings is utilized, the isolation of a single section is difficult and time consuming. Particularly in the case of a major breakdown requiring the manufacturer of the machine to repair or adjust it, it is a significant expense and effort for the user to either ship the entire frame mounted packaging machine in for repair or to have a specialist come on site to effect the repair. The size of a packaging machine performing multiple sequential steps, particularly the large frame on which equipment is mounted, along with the complicated mechanical interconnections therein, make the prior art packaging machines undesirable because a catastrophic equipment failure of any single step in the sequence abruptly halts packaging and manufacturing. Performing repairs on these prior art packaging machines is difficult because the complicated mechanical interconnections make accessibility difficult.
In addition to the foregoing shortcomings, the prior art packaging machines are also disadvantageous in that they are not flexible or easily altered to package different articles or provide different kinds of packages. Until now, when a desired packaging scheme was identified, a machine was designed to perform the various steps of lane dividing, collation, tray or pad positioning, tray forming, shrinkwrapping, stacking, etc. to repetitively provide the desired package. To eliminate a step from the sequence, such as removing the step of stacking, tray forming, etc. mechanically disengagement of equipment, including coordinated conveyors, and provision for the package group to pass through the disengaged section were necessary. It is a complicated endeavor to remove mechanically linked equipment in the machine.
In addition to the above-described disadvantages, maintenance of prior art packaging machine is problematic. Mechanical linkages between steps and equipment in the sequence must continually be fine tuned to ensure systematic processing and to ensure that all sections operate at the same speed or under controlled cycling.
It is desirable to provide a packaging machine which is not mounted on a large frame wherein steps in the packaging sequence comprise individual steps performed by separate, compartmentalized modules. Such a packaging machine can be easily modified to alter the packaging sequence by inserting or deleting a module. One embodiment of the present invention provides for each module to be driven independently without mechanical linkages to the preceding and proceeding modules in the sequence, and thus requires precise control of the speed with which each module is operating. To ensure continuous operation, the speed at which the modules operate must be coordinated, so a supervisory control over all of the modules is required. Another embodiment discloses the use of quick connect mechanically couplings between consecutive modules to take advantage of their modular nature while allowing multiple modules to be driven by a single drive.
Accordingly, it is an object of the present invention to provide a packaging machine comprising multiple modules that may be inserted or removed to alter the packaging machine and sequence to define the package produced thereby.
It is also an object of the present invention to provide a packaging machine wherein the means for moving articles and a package group therethrough are linked between modules by simple disengageable mechanical couplings.
It is also an object of the present invention to provide a packaging machine comprising interconnected modules that do not require a frame for structure or support.
It is a further object of the present invention to provide a packaging machine wherein multiple independent modules have independent conveyors driven by mechanically independent servo drives.
It is another object of the present invention to provide a modular packaging machine wherein a supervisory computer coordinates and controls independent servo drives on each of various modules in such a manner that continuous packaging is accomplished.
It is yet another object of the present invention to provide a modular packaging machine wherein multiple modules share a drive means through the use of quick connect means.
It is a further object of the invention to provide a modular packaging machine wherein separate modules may be easily inserted or removed from the stream of packaging without complex mechanical attachment or detachment.
It is a further object of the present invention to provide a modular packaging machine wherein it is not necessary to mount equipment performing discrete functions in the packaging process on a continuous frame.
It is another object of the present invention to provide a modular packaging machine wherein the speed with which each module operates is computer controlled to allow flexibility to speed up or slow down the module by simply reprogramming the computer without the need for mechanical adjustment or modification.
These and other objects of the present invention are satisfied by the embodiments of the invention described in more detail herein. These objects are meant to be illustrative and not limiting. The manner of operation, novel features and further objects and advantages of this invention may be better understood by reference to the description and drawings set forth herein.
According to the foregoing objectives, this invention is a packaging machine comprising multiple modules, each of the modules performing a separate function in the packaging sequence. Articles being packaged are conveyed through the machine by individual conveyors provided on each of the modules. The flow of articles through the packaging machine is controlled to allow continuous packaging by providing a controller which coordinates the speeds at which each of the modules and individual conveyors operate.
A significant advantage of the present invention is that, as a result of the modular nature of the components which do not require or depend on a frame for mounting, individual modules performing discrete packaging functions may be selectively added or removed to define or redefine the packaging machine. The full impact of this advantage is that a variety of different size, shape and format packages may be produced by simply inserting or removing modules into the stream of packaging. Functionalities can be provided to make the packaging machine a tray shrink packer, pad shrink packer, shrink packer, stacker, turner, or various combinations thereof, by inserting and removing modules to perform the specific and discrete packaging functions desired. The modules performing each of those functions are driven by independent and easily severed drive means, allowing each to function as if they are individual machines.
A preferred embodiment of the present invention is advantageously modular compared to prior art packaging machines because the compartmentalization of the steps in the packaging sequence into modules allows addition or removal of functionality without requiring mechanical redesign or complex retrofitting. A module can be physically positioned in the packaging machine between other modules and plugged into a supervisory computer or quickly connected to another computer controlled drive, the computer defining the speed with which the module operates and the packaging function is performed. The speed is controlled such that articles are processed through each module at a speed consistent with the rest of the machine, comprising other modules, to allow continuous packaging.
In a preferred embodiment of the present invention each module of the present invention has an onboard servo drive which provides the motive force and drives the conveyor responsible for moving the package group through the module. In addition, some modules are equipped with a second servo drive to provide the motive force for another element in the module, such as a film wrapper arm in a film wrapper module. These additional servo drives are also controlled by the supervisory computer and may be driven at nonuniform speeds as necessary for the rest of the packaging operation to continuously package articles.
In another preferred embodiment of the present invention two or modules share a drive means that are quickly and easily connected and disconnected. Specifically, a drive means comprising a drive shaft is positioned below the module""s conveyor means. The drive shafts on successive modules are positioned and designed such that, when the modules are positioned next to one another, the drive shafts line up so that a quick connect coupling allows the modules to be quickly and easily linked together.
The present invention contemplates the use of nine (9) modules which may be combined to provide a wide variety of package formats. More modules may be added to provide additional discrete packaging functions without departing from the principles of the present invention. Each module performs a specific discrete function in the packaging sequence and, in the preferred embodiment wherein each module has an independent servo drive, each is plugged into the supervisory computer to become part of the packaging machine. An infeed conveyor/lane divider module receives articles and separates them into lanes. An onboard servo drive controlled by the supervisory computer determines the speed of the conveyor and the speed with which the articles are laned.
A collation and synchronization module is provided which separates the laned articles into package groups for further processing and, when it is desired to provide a pad shrink packer or tray shrink packer, a pad or blank is received from the blank magazine and registered under the package group. The computer controls the speed of the conveyor and, thus the speed with which package groups are processed, as well as the speed with which the pad or blank is received and registered under the package group.
When the machine is to function as a tray shrink packer, the next step in the packaging sequence is performed by a gluing and closing module, inserted to perform a function in the packaging sequence wherein the blank is folded and glued to form a tray around the package group. An onboard servo drive which drives the conveyor and thereby defines the speed of processing through the gluing and closing module is controlled by the supervisory computer to be consistent with other modules.
When it is desired to either turn the package for reorientation or to stack two (2) packages to create a two-tier package, separate modules are available to do both under the principles of the present invention. A turning module includes an onboard servo drive which defines the speed with which packages are processed through the turning module and which is controlled by the supervisory computer. The stacker module, on the other hand, includes an onboard servo drive on the conveyor which defines the speed with which packages are processed through the stacker, but it also includes a second servo drive which drives the lift arms at an accelerated pace. The supervisory computer provides for the acceleration and deceleration of the lift arm drive to effect the stacking. The supervisory computer controls the two (2) drives independently and at a speed consistent with the rest of the machine.
Whenever it is desired to provide heat shrink wrapping functionality, as with a shrink packer, pad shrink packer or tray shrink packer, three (3) additional modules are added. A film cutting module is provided which provides appropriately sized sheets of heat shrinkable film for the package group. An onboard servo drive on the film cutting module is controlled by the supervisory computer to generate the proper length of film and to deliver it when necessary. A film wrapping module receives the sheet of film and wraps it around the package group through the use of a wrapping arm. An onboard servo drive on the film wrapping conveyor defines the speed with which packages are processed through the module, while a second servo drive on the film wrapping arm drives the arm at an accelerated speed that allows the film to be completely wrapped around the package group including the pad or tray. Finally, a heat shrink tunnel module is provided wherein heat is applied to shrink the film into tight engagement with the package group. A variable speed drive on the heat shrink conveyor defines the speed with which the package groups are processed through the heat shrink tunnel.
In another embodiment of the present invention, a modular packaging machine of the type described above is provided wherein successive modules share drive means that are quickly and easily coupled and uncoupled. Specifically, individual compartmentalized modules, such as the nine described above, are provided. The conveyor in a specific module is mechanically linked to and driven by, in this embodiment, a drive shaft mounted below the conveyor. The modules are designed such that the center line of the drive shaft is identical in all modules so that, when two modules are positioned in succession in the packaging sequence, the drive shafts may be quickly and easily mechanically coupled together. Multiple modules are driven by a single motor in this way while the modularity of the packaging machine is retained. The function of the packaging machine thus remains flexible through the insertion or removal of modules as desired.
Although the present invention discloses the use of nine (9) modules, additional modules providing other packaging functionalities are contemplated. Specifically, modules providing functions which include onboard servo drives or which provide means for quick insertion or removal into the stream of packaging to change the functionality of the packaging machine do not depart from the principles of the present invention.


Processes for producing an activated chromium catalyst are disclosed, and these processes comprise contacting a supported chromium catalyst with a gas stream containing from 25-60 vol % oxygen at a peak activation temperature of 550-900° C. to produce the activated chromium catalyst. The linear velocity of the gas stream is 0.18-0.4 ft/sec, and the oxygen linear velocity of the gas stream is 0.05-0.15 ft/sec. The resultant activated chromium catalyst and an optional co-catalyst can be contacted with an olefin monomer and an optional olefin comonomer in a polymerization reactor system under polymerization conditions to produce an olefin polymer.

Supported chromium catalysts are activated by exposure to an oxygen-containing atmosphere (e.g., air) at elevated temperatures to convert at least a portion of lower valence chromium to an oxidation state of +6 (hexavalent chromium). However, in commercial practice, activation of large quantities of supported chromium catalysts often results in relatively low conversion to Cr(VI), which is undesirable. Accordingly, it is to these ends that the present invention is generally directed.

Methods for chromium catalyst activation using oxygen-enriched fluidization gas


A colorless malt beverage product. To produce the product, malt and water are combined in a mash. An enzyme is preferably added to convert non-fermentable sugars to fermentable sugars. The mash is heated, and liquid extracted therefrom. The liquid is combined with a fermentable carbohydrate to yield a mixture which is boiled and combined with yeast. The resulting yeast-fermented product is decolorized to produce a clear/colorless base which is combined with a sweetener, tartaric acid, a buffer, and a flavoring agent, followed by carbonation until the product is about 0.48-0.57% by weight CO.sub.2. The completed product is clear/colorless, has an alcohol : real extract weight % ratio of 1 : 0.4 to 1 : 1.5, and has 8-15 calories/ounce. These parameters minimize consumer sensations of fullness and excess tartness/sweetness/astringency, while producing desirable taste characteristics and an attractive appearance.

The present invention generally relates to the production of alcohol-containing malt beverages, and more particularly to the production of a clear, colorless, and flavored alcohol-containing malt beverage which minimizes sensations of fullness, excess tartness, excess sweetness, and astringency typically experienced by consumers of traditional flavored malt beverages.
In order to satisfy consumer demand for new and different alcohol based beverages, substantial research has been conducted regarding the development of flavored malt beverage products. For example, the production of flavored malt beverages and other malt beverage products is disclosed in the following U.S. Pat. Nos.: 1,455,397; 2,803,546; 3,332,779; 3,798,331; 3,908,021; 4,021,580; 4,495,204; and 4,816,280. Notwithstanding the foregoing patents and products/processes disclosed therein, a need remains for a flavored alcohol-containing malt beverage which minimizes and/or substantially avoids sensations of fullness experienced by individuals upon consuming moderate quantities of the beverage. Typical sensations of fullness experienced by consumers of conventional malt beverages involve feelings of over-consumption and satiation after consuming only moderate amounts of product. Sensations of fullness experienced by malt beverage consumers are normally caused by substantial quantities of non-fermentable sugars in the beverages being consumed. Exemplary non-fermentable sugars include but are not limited to malt-based oligosaccharides such as maltotetraose, maltopentaose, and various branched beta-limit dextrins.
In addition, a need/demand exists for a flavored alcohol-containing malt beverage which minimizes and/or substantially avoids sensations of excess tartness, excess sweetness, and astringency typically experienced by consumers of traditional flavored malt beverages. In general, the palatability of malt beverage products is not only influenced by the specific ingredients being used, but also how such ingredients interact with each other. For example, the use of different acid materials in malt beverage products ultimately results in distinctive flavors which interact in an unpredictable manner with dissolved CO.sub.2 (e.g. carbonation) to produce varying levels of tartness, sweetness, and/or astringency. Excess levels of tartness, sweetness, and/or astringency can produce a final product which is unacceptable to the consuming public. Thus, with respect to malt beverage products, the development of specific beverages with desired/acceptable levels of tartness, sweetness, and astringency does not merely involve the addition of an acid, a flavoring agent, or the like when a specific taste characteristic is desired. Instead, the creation of a malt beverage product with desired taste characteristics not only requires the addition of specific acids, flavoring agents, and the like, but also requires the consideration of a wide variety of other factors. These other factors again include but are not limited to carbonation level, as well as the alcohol level, sugar levels, the relative proportions of alcohol and sugar levels, and the raw materials (e.g. malt and/or fermentable carbohydrates) which are used. Accordingly, the development of flavored malt beverages and other brewed products with desired taste characteristics is an unpredictable process which requires substantial amounts of research and development activity.
In addition to avoiding the above-described sensations of fullness, excess sweetness, excess tartness, and astringency, a need exists for a malt beverage product which is not visually perceived by consumers as being filling or satiating. For example, consumers typically associate darkly-colored malt beverage products with heaviness and a high alcohol content. Thus, a need exists for a malt beverage product having a pleasant, non-heavy appearance which is attractive to consumers.
The present invention effectively satisfies all of the foregoing needs and demands, and results in a product with highly desirable and unique taste characteristics. Accordingly, the product and process described herein represent an advance in the art of malt beverage production, as described in greater detail below.

Colorless flavored malt beverage and method for making the same


A differential amplifier circuit comprises a first differential transistor circuit, a grounded base transistor circuit and a second differential transistor circuit. A pair of transistors of the second differential transistor each produces a current based on an emitter voltage of each of a pair of transistors of the grounded base transistor circuit for cancelling non-linear components of transistors of the first differential transistor circuit. The currents produced by the second differential transistor circuit are each cross-added to an alternating current component of each of the first differential transistor circuit at a collector of each of the pair of transistors of the grounded base transistor circuit. Non-linear components of the first differential transistor circuit are thus cancelled out.

1. Field of the Invention
The present invention relates to a differential amplifier circuit having first and second transistors wherein an input voltage is applied between base electrodes thereof and an emitter feedback resistor is inserted between emitter electrodes thereof.
2. Description of the Related Art
FIG. 1 is schematic circuit diagram showing a differential amplifier circuit as a most basic elementary circuit of a bipolar transistor circuit. In the figure, Q1 and Q2 each indicate a transistor. I represents a current source of a current of 2Io. E is an input voltage source of a voltage `v`.
Equation (1) below gives a relation between an input voltage v and an amount of change (an alternating current component) `i` in a collector current Io of the transistors Q1 and Q2 in the circuit, that is, a transfer characteristic thereof. EQU i=Io*exp(v/Vt)/{1+exp(v/VT)} (1)
VT represents a thermal voltage (=kT/q; where k is Boltzmann's constant, T is the absolute temperature, and q is a charge of an electron). The thermal voltage is approximately 26 mV at room temperature.
The circuit has a very narrow range of linearity. In order to improve the linearity, a feedback resistor R is inserted between emitter electrodes and the current source I is divided into current sources I1 and I2 as shown in FIG. 2. A transfer characteristic of the circuit is analytically insoluble. Input voltage v expressed by output current I is given by equation (2) below. EQU v=VT*1n{(Io+i)/(Io-i)}+2*i*RE (2)
where RE is a resistance of feedback resistor R.
Equation (3) below is given by calculating a higher order derivative of v from equation (2) and converting the derivative into a derivative of i, utilizing a differential characteristic of an inverse function thereof. EQU i=Io[(1/2)(v/VE) EQU -(1/24)(VT/VE)(v/VE).sup.3 EQU -(1/480){3-(5*VT/VE)} EQU (VT/VE)(V/VE).sup.5 ] (3)
VE is expressed by equation (4) below. EQU VE=Io*RE+VT (4)
(VE/VT) represents a reduction rate of a gain of feedback resistor R. Equation (4) indicates that a dynamic range widens roughly in proportion to an increase in (VE/VT).
FIG. 3 shows differential gains of input voltage v normalized by 2*VE when (VE/VT)=3, 5 and 10. A degree of linearity required greatly depends on application areas. When (VE/VT)=10, a differential gain changes by as much as 1 percent with a signal amplitude of half of 2*VE.
When a very high degree of linearity is required, however, too much increase in (VE/VT) causes problems. The problems are mainly: a reduction in gain; an increase in signal-to-noise ratio; and an increase in direct current offset voltage.
A typical application where a high degree of linearity and a low noise are required is, for example, a first amplification stage of a radio communication circuit. In such an application a trade-off between a noise characteristic and linearity has been sought or a large current has been required for improving a noise characteristic.

Differential amplifier circuit having non-linerity cancellation feature


An optical beam scanning device and an image forming apparatus are capable of suppressing adverse effect due to ambient temperature change on plural optical elements. The optical beam scanning device includes a single light deflector, a pre-deflection optical system which is entered a beam from a light source into the light deflector, and a post-deflection optical system which images a reflection beam from the light deflector on a scanned surface, and integrates at least one optical element of the pre-deflection optical system and at least one optical element of the post-deflection optical system. For example, the integrated optical element of the post-deflection optical system is an fθ lens, and the optical element of the pre-deflection optical system is a correction lens which alleviates an influence by temperature change of the post-deflection optical system.

The present invention relates to an image forming apparatus such as a laser printer or digital copier, and an optical beam scanning device available in such an image forming apparatus. Further, the invention relates to an optical component applied to an optical beam scanning device.
Conventionally, in order to suppress the variations in beam positions and defocus generation caused by the influence of temperature and humidity change or the like, there has been an optical beam scanning device with a correction optical element for producing opposite beam position change to the beam position change produced in a post-deflection optical system due to temperature and humidity change and generating opposite defocus to the amount of defocus generation provided in a pre-deflection optical system. For example, U.S. Pat. No. 6,337,757 discloses an optical beam scanning device having such a correction optical element.
In the case of such an optical beam scanning device, the device has been designed on the assumption that the temperature and humidity relationship between an optical element in a post-deflection optical system and the above described correction optical element in the pre-deflection optical system is a predetermined relationship. When the actual use conditions are different form the design conditions, sometimes the correction does not work properly, or contrary deteriorate the characteristics thereof.
For example, assuming that the correction optical element is designed under condition that the temperature and humidity are the same with the optical element in the post-deflection optical system and the correction optical element in the pre-deflection optical system and, when the temperature changes by ΔT, the amount of defocus generation in a sub-scanning direction in the post-deflection optical system is ΔDFCS (sub) and the amount of defocus generation in a main scanning direction is ΔDFCS (main), for canceling the amounts, the pre-deflection optical system is designed so that the amount of defocus generation in the sub-scanning direction is generated by—ΔDFCS (sub) and the amount of defocus generation in the main scanning direction is generated by —ΔDFCS (main) when the temperature change of the correction optical element in the pre-deflection optical system is ΔT (given that there is no temperature change in the post-deflection optical system). By the combination of them, when the temperature of the optical element of the post-deflection optical system and the correction optical element in the pre-deflection optical system changes by the same ΔT, the total defocus in the main scanning direction and the sub-scanning direction can be made zero. However, when there is no temperature change in the post-deflection optical system and only the temperature of the correction optical element in the pre-deflection optical system changes by ΔT, overall, the amount of defocus generation in the sub-scanning direction is generated by—ΔDFCS (sub) and the amount of defocus generation in the main scanning direction is generated by—ΔDFCS (main).
In practice, the post-deflection optical system and the correction optical element in the pre-deflection optical system are provided within an image forming apparatus as equal elements in the optical beam scanning device; however, in the image forming apparatus, heat sources such as a fixing unit for fixing toner on paper and cooling units such as a radiation fan are variously provided, and the conduction direction and convection of the heat from the heat sources and cooling units are not simple, and thereby, there is a possibility that the temperature changes are different between the post-deflection optical system and the correction optical element in the pre-deflection optical system.
Further, generally, the optical element of the post-deflection optical system is large under the necessity of passing a deflected beam, and the optical element of the pre-deflection optical system is located prior to scanning and small. Accordingly, the responsiveness to ambient temperature change is different, and there is a possibility that temperature changes are different between the post-deflection optical system and the optical element of the pre-deflection optical system.
When the size as a component is different, the complication of work for mounting with precision is also different. The mounting work takes a longer time for a smaller optical element, and even if it takes a long time to mount the element, the above described defocus problem occurs. In the case where mounting precision is not adjusted, when the distance between mounting reference planes is short, the influence by an error of the mounting planes or the mounting parts of the optical elements on the mounting angle becomes greater. The size is desirably larger for suppressing the inclination at the time of mounting of optical elements.

Optical beam scanning device and image forming apparatus


A combustion device for treating wastes is suitable for family use and includes a barrel disposed in a body for accommodating the wastes, an inner wall fixed in the barrel, a heating coil disposed between the inner wall and the body for heating and combusting the wastes, a motor disposed in the body, and a rotatable blade fixed on the spindle of the motor for comminuting the wastes when the motor is energized.

1. Field of the Invention
The present invention relates to a combustion apparatus, and more particularly to a combustion apparatus for treating wastes, particularly the combustible wastes.
2. Description of the Prior Art
Typical incinerators which are provided for treating wastes are generally the incinerators of great bulk. As far as applicant is aware, no combustion apparatus of small sizes are provided for family use and for treating family wastes.
The present invention has arisen to provide a novel combustion apparatus for treating wastes.

Combustion apparatus for treating wastes


In an elevator control apparatus, a control apparatus main body includes a program storage portion for storing a program concerning operational control of an elevator and a processing portion for performing a plurality of calculation processings based on the program. Further, the control apparatus main body writes pieces of processed information corresponding to the calculation processings, respectively, into the RAM when the calculation processings are performed, and monitors whether or not a sequence of performance of the calculation processings is normal by reference to a pattern of the pieces of the processed information written into the RAM.

In a conventional terminal slowdown apparatus for an elevator as disclosed in, for example, JP 58-6885 A, when a terminal detector operates, a terminal slowdown command signal is generated in accordance with a distance from a position of the elevator corresponding to the operation of the terminal detector to the terminal floor. Such the terminal slowdown command signal is generated through a calculation carried out by a digital computer.
However, in an attempt to perform various calculation processings for controlling the operation of the elevator by using the computer, the calculation processings may be performed out of sequence for reasons of a program abnormality, a problem concerning hardware capacity, and the like. In this case, the elevator continues to be operated as it is until a secondary abnormality is detected. In particular, a self-looping abnormality ascribable to the program abnormality cannot be detected with ease.


A series of 2-(Purin-9-yl)-tetrahydrofuran-3,4-diol derivatives with broad anti-inflammatory properties which inhibit leukocyte recruitment and activation and which are agonists of the adenosine 2a receptor are described.

This invention relates to new chemical compounds, processes for their preparation, pharmaceutical formulations containing them and their use in therapy.
Inflammation is a primary response to tissue injury or microbial invasion and is characterised by leukocyte adhesion to the endothelium, diapedesis and activation within the tissue. Leukocyte activation can result in the generation of toxic oxygen species (such as superoxide anion), and the release of granule products (such as peroxidases and proteases). Circulating leukocytes include neutrophils, eosinophils, basophils, monocytes and lymphocytes. Different forms of inflammation involve different types of infiltrating leukocytes, the particular profile being regulated by the profile of adhesion molecule, cytokine and chemotactic factor expression within the tissue.
The primary function of leukocytes is to defend the host from invading organisms such as bacteria and parasites. Once a tissue is injured or infected a series of events occurs which causes the local recruitment of leukocytes from the circulation into the affected tissue. Leukocyte recruitment is controlled to allow for the orderly destruction and phagocytosis of foreign or dead cells, followed by tissue repair and resolution of the inflammatory infiltrate. However in chronic inflammatory states, recruitment is often inappropriate, resolution is not adequately controlled and the inflammatory reaction causes tissue destruction.
There is evidence from both in vitro and in vivo studies to suggest that compounds active at the adenosine A2a receptor will have anti-inflammatory actions. The area has been reviewed by Cronstein (1994). Studies on isolated neutrophils show an A2 receptor-mediated inhibition of superoxide generation, degranulation, aggregation and adherence (Cronstein et al, 1983 and 1985; Burkey and Webster, 1993; Richter, 1992; Skubitz et al, 1988. When agents selective for the A2a receptor over the A2b receptor (eg CGS21680) have been used, the profile of inhibition appears consistent with an action on the A2a receptor subtype (Dianzani et al, 1994). Adenosine agonists may also downregulate other classes of leucocytes (Elliot and Leonard, 1989; Peachell et al, 1989). Studies on whole animals have shown the anti-inflammatory effects of methotrexate to be mediated through adenosine and A2 receptor activation (Asako et al, 1993; Cronstein et al, 1993 and 1994). Adenosine itself, and compounds that raise circulating levels of adenosine also show anti-inflammatory effects in vivo (Green et al, 1991; Rosengren et al, 1995). In addition raised levels of circulating adenosine in man (as a result of adenosine deaminase deficiency) results in immunosuppression (Hirschorn, 1993).
Certain substituted 4xe2x80x2-carboxamido and 4xe2x80x2-thioamido adenosine derivatives which are useful for the treatment of inflammatory diseases are described in international Patent Application Nos. WO94/17090, WO96/02553, WO96/02543 (Glaxo Group). Substituted 4xe2x80x2-carboxamidoadenosine derivatives useful in the treatment of dementia are described in AU 8771946 (Hoechst Japan). Substituted 4xe2x80x2-hydroxymethyl adenosine derivatives which are useful for the treatment of gastrointestinal motility disorders are described in EP-A-423776 and EP-A-423777 (Searle). Substituted 4xe2x80x2-hydroxymethyl adenosine derivatives which are useful as platelet aggregation inhibitors are described in BE-768925 (Takeda). 4xe2x80x2-Hydroxymethyl adenosine derivatives and 4xe2x80x2-esters thereof which are useful as anti-hypertensive agents or have other cardiovascular activity are described in U.S. Pat. No. 4,663,313, EP 139358 and U.S. Pat. No. 4,767,747 (Warner Lambert), U.S. Pat. No. 4,985,409 (Nippon Zoki) and U.S. Pat. No. 5,043,325 (Whitby Research). 4-Hydroxymethyladenosine derivatives useful in the treatment of autoimmune disorders are described in U.S. Pat. No. 5,106,837 (Scripps Research Institute). 4xe2x80x2-Hydroxymethyladenosine derivatives useful as anti-allergic agents are described in U.S. Pat. No. 4,704,381 (Boehringer Mannheim). Certain 4xe2x80x2-tetrazolylalkyl adenosine derivatives which are useful in the treatment of heart and circulatory disorders are generically described in DT-A-2621470 (Pharma-Waldhof). Other 4xe2x80x2-carboxamidoadenosine derivatives useful in the treatment of cardiovascular conditions are described in U.S. Pat. No. 5,219,840, GB 2203149 and GB 2199036 (Sandoz), WO94102497 (US Dept. Health), U.S. Pat. No. 4,968,697 and EP 277917 (Ciba Geigy), U.S. Pat. No. 5,424,297 (Univ. Virginia) and EP 232813 (Warner Lambert). Other 4xe2x80x2-carboxamidoadenosine derivatives lacking substitution on the purine ring in the 2-position are described in DT 2317770, DT 2213180, U.S. Pat. Nos. 4,167,565, 3,864,483 and 3,966,917 (Abbott Labs), DT 2034785 (Boehringer Mannheim), JP 58174322 and JP 58167599 (Tanabe Seiyaku), WO92/05177 and U.S. Pat. No. 5,364,862 (Rhone Poulenc Rorer), EP 66918 (Procter and Gamble), WO86/00310 (Nelson), EP 222330, U.S. Pat. No. 4,962,194, WO88/03147 and WO88/03148 (Warner Lambert) and U.S. Pat. No. 5,219,839, WO95/18817 and WO93/14102 (Lab UPSA). 4xe2x80x2-Hydroxymethyladenosine derivatives lacking substitution on the purine ring in the 2-position are described in WO95/11904 (Univ Florida). 4xe2x80x2-Substituted adenosine derivatives useful as adenosine kinase inhibitors are described in WO94/18215 (Gensia). Other 4xe2x80x2-halomethyl, methyl, thioalkylmethyl or alkoxymethyl adenosine derivatives are described in EP 161128 and EP 181129 (Warner Lambert) and U.S. Pat. No. 3,983,104 (Schering). Other 4xe2x80x2-carboxamidoadenosine derivatives are described in U.S. Pat. No. 7,577,528 (NIH), WO91/13082 (Whitby Research) and WO95/02604 (US Dept Health).
Certain tetrazole containing deoxynucleotides which were found to lack anti-infective activity are described in Baker et al (1974) Tetrahedron 30, 2939-2942. Other tetrazole containing adenosine derivatives which show activity as platelet aggregation inhibitors are described in Mester and Mester (1972) Pathologie-Biologie, 20 (Suppl) 11-14. Certain nitrile containing ribose derivatives are described in Schmidt et al (1974) Liebigs. Ann. Chem. 1856-1863.
Other publications include: WO 98/16539 (Novo Nordisk A/S) which describes adenosine derivatives for the treatment of myocardial and cerebral ischaemia and epilepsy; WO 98/01426 (Rhone-Poulenc Rorer Pharmaceuticals Inc.) which relates to adenosine derivatives possessing antihypertensive, cardioprotective, anti-ischaemic and antilipolytic properties; and WO 98/01459 (Novo Nordisk A/S) which describes N,9-disubstituted adenine derivatives which are substituted in the 4xe2x80x2 position by unsubstituted oxazolyl or isoxazolyl and the use of such compounds for the treatment of disorders involving cytokines in humans. WO 98/28319 (Glaxo Group Limited) was published subsequent to the earliest priority date of this application and describes 4xe2x80x2-substituted tetrazole 2-(purin-9-yl)-tetrahydrofuran-3,4-diol derivatives.
We have now found a novel group of compounds with broad anti-inflammatory properties which inhibit leukocyte recruitment and activation and which are agonists of the adenosine 2a receptor. The compounds are therefore of potential therapeutic benefit in providing protection from leukocyte-induced tissue damage in diseases where leukocytes are implicated at the site of inflammation. The compounds of the invention may also represent a safer alternative to corticosteroids in the treatment of inflammatory diseases, whose uses may be limited by their side-effect profiles.
More particularly, the compounds of this invention may show an improved profile over known A2a-selective agonists in that they generally lack significant agonist activity at the human A3 receptor. This profile can be considered of benefit as A3 receptors are also found on leucocytes (eg eosinophil) and other inflammatory cells (eg mast cell) and activation of these receptors may have pro-inflammatory effects (Kohno et al, 1996; Van Schaick et al 1996). It is even considered that the bronchoconstrictor effects of adenosine in asthmatics may be mediated via the adenosine A3 receptor (Kohno et al, 1996).
Thus, according to the invention we provide compounds of formula (I):
wherein
R1 and R2 independently represent a group selected from:
(i) C3-8cycloalkyl-;
(ii) hydrogen;
(iii) aryl2CHCH2xe2x80x94;
(iv) C3-8cycloalkylC1-6alkyl-;
(v) C1-8alkyl-;
(vi) arylC1-6alkyl-;
(vii) R4R5Nxe2x80x94C1-6alkyl-;
(viii) C1-6alkyl-CH(CH2OH)xe2x80x94;
(ix) arylC1-5alkyl-CH(CH2OH)xe2x80x94;
(x) arylC1-5alkyl-C(CH2OH)2xe2x80x94;
(xi) C3-8cycloalkyl independently substituted by one or more (e.g. 1, 2 or 3) xe2x80x94(CH2)pR6 groups;
(xii) H2NC(xe2x95x90NH)NHC1-6alkyl-;
(xiii) a group of formula
xe2x80x83or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl;
(xiv) xe2x80x94C1-6alkyl-OH;
(xv) xe2x80x94C1-8haloalkyl;
(xvi) a group of formula
(xvii) aryl; and
(xviii) xe2x80x94(CH2)fSO2NHg(C1-4alkyl-)2-g or xe2x80x94(CH2)fSO2NHg(arylC1-4alkyl-)2xe2x80x94g;
R3 represents methyl, ethyl, xe2x80x94CHxe2x95x90CH2, n-propyl, xe2x80x94CH2CHxe2x95x90CH2, xe2x80x94CHxe2x95x90CHCH3, isopropyl, isopropenyl, cyclopropyl, cyclopropenyl, cyclopropylmethyl, cyclopropenylmethyl, cyclobutyl, cyclobutenyl, xe2x80x94(CH2)qhalogen, xe2x80x94(CH2)hY(CH2)iH, xe2x80x94(CH2)hCOOCH3, xe2x80x94(CH2)hOCOCH3, xe2x80x94(CH2)hCON(CH2)mH((CH2)nH), xe2x80x94(CH2)hCO(CH2)oH or xe2x80x94CH2C((CH2)uH)xe2x95x90NO(CH2)vH;
Y represents O, S or N(CH2)j;
a and b independently represent an integer 0 to 4 provided that a+b is in the range 3 to 5;
c, d and e independently represent an integer 0 to 3 provided that c+d+e is in the range 2 to 3;
f represents 2 or 3 and g represents an integer 0 to 2;
p represents 0 or 1;
q represents 2 or 3;
h represents 2 or 3;
i represents an integer 0 to 2 such that h+i is in the range 2 to 4
j represents an integer 0 to 2 such that h+i+j is in the range 2 to 4
m and n independently represent an integer 0 to 2 such that m+n is in the range 0 to 2;
o represents an integer 0 to 2 such that h+o is in the range 2 to 3;
u and v independently represent 0 or 1 such that u+v is in the range 0 to 1;
R4 and R5 independently represent hydrogen, C1-6alkyl, aryl, arylC1-6alkyl- or NR4R5 together may represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or Nxe2x80x94C1-6alkylpiperazinyl.
R6 represents OH, NH2, NHCOCH3 or halogen;
R7 represents hydrogen, C1-6alkyl, C1-6alkylaryl or xe2x80x94COC1-6alkyl;
X represents NR7, O, S, SO or SO2;
provided that when R3 represents methyl, ethyl or isopropyl then R1 and/or R2 independently must represent:
(a) xe2x80x94(CH2)fSO2NHg(C1-4alkyl-)2-g or xe2x80x94(CH2)fSO2NHg(arylC1-4alkyl-)2-g where f is 2 or 3 and g is an integer 0 to 2;
(b) C3-8cycloalkyl independently substituted by one or more xe2x80x94(CH2)pNHCOCH3 groups;
(c) a group of formula
xe2x80x83or such a group in which one methylene carbon atom adjacent to X, or both if such exist, is substituted by methyl;
(d) a group of formula
and salts and solvates thereof.
References to C1-6alkyl include references to an aliphatic hydrocarbon grouping containing 1 to 6 carbon atoms which may be straight chain or branched and may be saturated or unsaturated although will be preferably saturated. References to C1-4alkyl, C1-5alkyl, C2-4alkyl and C1-8alkyl may be interpreted similarly.
References to aryl include references to mono- and bicyclic carbocyclic aromatic rings (e.g. phenyl, naphthyl) and heterocyclic aromatic rings containing 1-3 hetero atoms selected from N, O and S (e.g. pyridinyl, pyrimidinyl, thiophenyl, imidazolyl, quinolinyl, furanyl, pyrrolyl, oxazolyl) all of which may be optionally substituted, e.g. by C1-6alkyl, halogen, hydroxy, nitro, C1-6alkoxy, cyano, amino, SO2NH2or xe2x80x94CH2OH.
Examples of C3-8cycloalkyl for R1 and R2 include monocyclic alkyl groups (e.g. cyclopentyl, cyclohexyl) and bicyclic alkyl groups (e.g. norbornyl such as exo-norborn-2-yl).
Examples of (aryl)2CHCH2xe2x80x94 for R1 and R2 include Ph2CHCH2xe2x80x94 or such a group in which one or both phenyl moieties is substituted, e.g. by halogen or C1-4alkyl. Examples of C3-8cycloalkylC1-6alkyl- for R1 and R2 include ethylcyclohexyl. Examples of C1-8-alkyl for R1 and R2 include xe2x80x94(CH2)2C(Me)3, xe2x80x94CH(Et)2 and CH2xe2x95x90C(Me)CH2CH2xe2x80x94.
Examples of arylC1-6alkyl- for R1 and R2 include xe2x80x94(CH2)2Ph, xe2x80x94CH2Ph or either in which Ph is substituted (one or more times) by halogen (e.g. iodine), amino, methoxy, hydroxy, xe2x80x94CH2OH or SO2NH2; xe2x80x94(CH2)2 pyridinyl (e.g. xe2x80x94(CH2)2pyridin-2-yl) optionally substituted by amino; (CH2)2imidazolyl or this group in which imidazolyl is N-substituted by C1-6alkyl (especially methyl).
Examples of R4R5Nxe2x80x94C1-6alkyl- for R1 and R2 include ethyl-piperidin-1-yl, ethyl-pyrrolidin-1-yl, ethyl-morpholin-1-yl, xe2x80x94(CH2)2NH(pyridin-2-yl) and xe2x80x94(CH2)2NH2. Examples of C1-6alkyl-CH(CH2OH)xe2x80x94 for R1 and R2 include Me2CHCH(CH2OH)xe2x80x94. Examples of arylC1-5alkyl-CH(CH2OH)xe2x80x94 for R1 and R2 include PhCH2CH(CH2OH)xe2x80x94 especially
Examples of aryl C1-5alkyl-C(CH2OH)2xe2x80x94 for R1 and R2 include PhCH2C(CH2OH)2xe2x80x94. Examples of C3-8 cycloalkyl independently substituted by one or more xe2x80x94(CH2)pR6 groups (eg 1, 2 or 3 such groups) for R1 and R2 include 2-hydroxy-cyclopentyl and 4-aminocyclohexyl (especially trans-4-amino-cyclohexyl).
Examples of H2NC(xe2x95x90NH)NHC1-6alkyl for R1 and R2 include H2NC(xe2x95x90NH)NH(CH2)2xe2x80x94.
Examples of groups of formula
for R1 and R2 include pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or a derivative in which the ring nitrogen is substituted by C1-6alkyl (e.g. methyl) or benzyl, tetrahydro-1,1-dioxide thiophen-3-yl, tetrahydropyran-4-yl, tetrahydrothiopyran-4-yl and 1,1-dioxo-hexahydro-1.lamda.6-thiopyran-4-yl.
Examples of xe2x80x94C1-6alkyl-OH groups for R1 and R2 include xe2x80x94CH2CH2OH.
Examples of C1-8haloalkyl for R1 and R2 include xe2x80x94CH2CH2Cl and (CH3)2ClC(CH2)3xe2x80x94.
Examples of groups of formula
for R1 and R2 include 2-oxo-pyrrolidin-4-yl, 2-oxo-pyrrolidin-5-yl or a derivative in which the ring nitrogen is substituted by C1-6alkyl (e.g. methyl) or benzyl.
Examples of aryl for R1 and R2 include phenyl optionally substituted by halogen (e.g. fluorine, especially 4-fluorine).
Examples of C1-6alkyl for R7 include methyl and C1-6alkylaryl for R7 include benzyl. Examples of COC1-6 alkyl for R7 include xe2x80x94COCH3.
Examples of C1-5alkyl for R3 include n-propyl and allyl. An example of C3-4 cycloalkyl for R3 includes cyclobutyl. An example of xe2x80x94(CH2)hO(CH2)iH for R3 includes xe2x80x94(CH2)2OMe. Examples of C2-4alkyl substituted by halogen or hydroxy include xe2x80x94(CH2)2Cl, xe2x80x94(CH2)2OH and xe2x80x94(CH2)3OH.
We prefer that R1 and R2 do not both represent hydrogen.
We prefer R1 to represent aryl2CHCH2xe2x80x94, C1-8alkyl, hydrogen or aryl C1-6alkyl-.
We particularly prefer R1 to represent Ph2CHCH2xe2x80x94, xe2x80x94CH(Et)2, hydrogen or phenylethyl-, especially Ph2CHCH2xe2x80x94.
We prefer R2to represent R4R5Nxe2x80x94C1-6alkyl-, arylC1-6alkyl-, arylC1-5alkylCH(CH2OH)xe2x80x94, aryl C1-6 alkyl or C1-6 alkyl-CH(CH2OH)xe2x80x94.
We particularly prefer R2 to represent (CH2)2(piperidin-1-yl), 2-(1-methyl-1H-imidazol-4yl)ethyl, 1S-hydroxymethyl-2-phenylethyl, phenylethyl or 1S-hydroxymethyl-2-methyl propyl, especially xe2x80x94(CH2)2(piperidin-1-yl).
We prefer R3 to represent C1-3alkyl (including n-propyl and 2-propenyl), cyclobutyl, cyclopropylmethyl, xe2x80x94(CH2)2OCOCH3, xe2x80x94(CH2)2-3OH or xe2x80x94(CH2)2halogen. More preferably R3 represents n-propyl, 2-propenyl, cyclobutyl, cyclopropylmethyl, xe2x80x94(CH2)2OCOCH3, or xe2x80x94(CH2)2-3OH.
We particularly prefer R3 to represent xe2x80x94(CH2)2OCOCH3, xe2x80x94(CH2)2OH or (CH2)3OH, especially xe2x80x94(CH2)2OCOCH3 or xe2x80x94(CH2)2OH, most especially xe2x80x94(CH2)2OH.
We prefer R4 and R5 independently to represent hydrogen, C1-6alkyl or aryl or NR4R5 together to represent pyrrolidinyl, piperidinyl, morpholinyl, azetidinyl, azepinyl, piperazinyl or N-methylpiperazinyl;
We prefer X to represent NR7, O, S or SO2, particularly NR7 or SO2, especially NR7.
We prefer that a and b both represent 2 or that a represents 1 and b represents 2.
We prefer that R7 represents hydrogen.
We prefer that p represents 0. We prefer q to represent 2. We prefer h to represent 2. We prefer i to represent 0 or 1, especially 0. We prefer j to represent 1. We prefer m and n to represent 0 or 1. We prefer o to represent 1.
We prefer u and v to represent 0.
We prefer that R6 represents OH or NH2 especially NH2.
We prefer that c represents 0 and either d represents 2 and e represents 0 or d represents 1 and e represents 1.
The representation of formula (I) indicates the absolute stereochemistry at positions around the tetrahydrofuran ring. When sidechains contain chiral centres the invention extends to mixtures of enantiomers (including racemic mixtures) and diastereoisomers as well as to individual enantiomers. Generally it is preferred to use a compound of formula (I) in the form of a purified single enantiomer.
We also provide a process for preparation of compounds of formula (I) which comprises:
(a) reacting a corresponding compound of formula (II)
wherein L represents a leaving group or a protected derivative thereof with a compound of formula R2NH2 or a protected derivative thereof;
(b) preparing a compound of formula (I) in which R1 represents hydrogen by reducing a compound of formula (III)
xe2x80x83or a protected derivative thereof; or
(c) deprotecting a compound of formula (I) which is protected; and where desired or necessary converting a compound of formula (I) or a salt thereof into another salt thereof.
In process (a) L represents a leaving group such as halogen eg chlorine or fluorine. The reaction of process (a) will generally be carried out on heating the reagents to a temperature of 50xc2x0 C.-150xc2x0 C. in the presence of a solvent such as DMSO. Preferably an organic base, e.g. a trisubstituted organic amine (such as diisopropylethylamine) is also present for the reaction. Under these conditions we particularly prefer that Hal represents fluorine (especially when R1 represents hydrogen) since the reaction has a tendency to proceed rapidly with high efficiency.
In process (b) the reduction reaction may be performed by catalytic hydrogenation, e.g. over Pd/C under standard conditions.
In process (c) examples of protecting groups and the means for their removal can be found in T W Greene xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (J Wiley and Sons, 1991). Suitable hydroxyl protecting groups include alkyl (e.g. methyl), acetal (e.g. acetonide) and acyl (e.g. acetyl or benzoyl) which may be removed by hydrolysis, and arylalkyl (e.g. benzyl) which may be removed by catalytic hydrogenolysis. Suitable amine protecting groups include sulphonyl (e.g. tosyl), acyl e.g. benzyloxycarbonyl or t-butoxycarbonyl) and arylalkyl (e.g. benzyl) which may be removed by hydrolysis or hydrogenolysis as appropriate.
Suitable salts of the compounds of formula (I) include physiologically acceptable salts such as acid addition salts derived from inorganic or organic acids, for example hydrochlorides, hydrobromides, 1-hydroxy-2-naphthoates, mesylates, sulphates, phosphates, acetates, benzoates, citrates, succinates, lactates, tartrates, fumarates and maleates, and if appropriate, inorganic base salts such as alkali metal salts, for example sodium salts. Other salts of the compounds of formula (I) include salts which may not be physiologically acceptable but may be useful in the preparation of compounds of formula (I) and physiologically acceptable salts thereof. Examples of such salts include trifluoroacetates and formates.
Examples of suitable solvates of the compounds of formula (I) include hydrates.
Acid-addition salts of compounds of formula (I) may be obtained by treating a free-base of formula (I) with an appropriate acid.
The compounds of formula (II) or a protected derivative thereof may be prepared by reacting a compound of IV
or a protected derivative thereof with a compound of formula R1NH2. L1 and L2 independently represent a leaving group such as halogen eg chlorine or fluorine. This reaction will preferably be performed in the presence of a base such as an organic amine base (e.g. diisopropyl ethylamine) in a solvate such as an alcohol (e.g. isopropanol) at elevated temperature (e.g. reflux).
Compounds of formula (III) or a protected derivative thereof may be prepared by reacting a compound of formula (IIIA)
wherein L represents a leaving group such as halogen eg chlorine or fluorine, or a protected derivative thereof, with a compound of formula R2NH2 under conventional conditions.
Compounds of formula (IIIA), or a protected derivative thereof, may be prepared by reacting a compound of formula (IV), or a protected derivative thereof, with an azide, e.g. sodium azide under conventional conditions.
The compound of formula (IV) or a protective derivative thereof may be prepared by reacting a compound of formula (V)
wherein L represents a leaving group or a protected derivative thereof with a 2,6,dihalopurine, e.g. 2,6-dichloropurine.
We prefer to use the compound of formula (V) wherein the ribose 2- and 3-hydroxyl groups are protected, e.g. by acetyl. Leaving group L may represent OH but will preferably represent C1-6alkoxy (e.g. methoxy or ethoxy), an ester moiety (e.g. acetyloxy or benzoyloxy) or halogen. The preferred group L is acetyloxy. The reaction may be performed by combining the reactants in an inert solvent such as MeCN in the presence of a Lewis Acid (eg TMSOTf) and DBU and warming to, say, 70-80xc2x0 C.
Compounds of formula (V) may be prepared from a compound of formula (VI)
wherein alk represents C1-6 alkyl eg methyl by treating the compound of formula (VI) with trifluoroacetic acid in water followed by reprotection, e.g. by reaction with acetic anhydride in pyridine.
Compounds of formula (V) in which L represents halogen, may be prepared from the corresponding 1xe2x80x2-alcohol or a 1xe2x80x2-ester such as the acetate. Reaction will generally occur on treatment with anhydrous HCl or HBr. 1xe2x80x2-iodides may be prepared directly on treatment with trimethylsilyliodide and 1xe2x80x2-fluorides may be prepared on treatment with DAST. An inert solvent eg diethylether, DCM, THF or CCI4will generally be suitable.
Compound of formula (VI) may be prepared following Scheme 1:
General conditions for Stages 1-6 will be known to persons skilled in the art. It will also be appreciated that the reagents and conditions set out in Scheme 1 are example conditions and alternative reagents and conditions for achieving the same chemical transformation may be known to persons skilled in the art. For example an alternative alcohol, e.g. a C1-6alkyl alcohol may be used in Stage 1 to give a different C1-6 alkyloxy leaving group in compounds of formula (VII) and (VI). Stage 1 may also be modified in that the use of HCl can be substituted by perchloric acid (HClO4) and 2,2 dimethoxypropane, or alternatively acetyl chloride (which has the advantage that it maintains high yield and avoids use of perchlorate salts). Alternative reaction conditions can be used in Stage 3, which may utilise ethyl acetate, thionyl chloride and gaseous ammonia (which has the advantage that it avoids chlorinated solvent and the synthesis of troublesome ammonium pivaloate impurity). Stage 4 may also be performed using POCl3, TEA, DMF and ethyl acetate in the reaction conditions (which avoids the use of hazardous DMAP). Compounds of formula (VII) wherein a leaving group besides OMe is desired may be prepared by analogy with the method described above for preparation of compounds of formula (V). Alternative groups may be used to protect the 2xe2x80x2 and 3xe2x80x2 hydroxy groups on the ribose in Stage 1. We have also found that Stage 5 may desirably be performed using azidotrimethylsilane and dibutyltin oxide in toluene.
Following stage 6, the impure product may be purified using conventional techniques, and especially using flash chromatography conditions under nitrogen pressure. We have found that satisfactory conditions include loading the impure product in a minimum volume of dichloromethane onto a Keiselgel 60 (Merck 9385) column and eluting using a gradient solvent system with ethyl acetate (10-40%) in cyclohexane.
Compounds of formula (II), and protected derivatives thereof, may also be prepared by reacting a compound of formula (V), or a protected derivative thereof with a compound of formula (VIII)
wherein L represents a leaving group such as halogen, e.g. chlorine or fluorine optionally followed by a deprotection or deprotection and reprotection reaction.
We prefer to use compounds of formula (V) in protected form. In particular we prefer that at least the hydroxy group in the 2-position on the ribose is protected as an ester group, e.g. by acetyl or benzoyl since this has a tendency to result in greater stereoselectivity in the coupling reaction. We prefer that the 2- and 3-position hydroxy groups are protected by acetyl. Suitable leaving groups L are a described previously. The preferred leaving group L is acetyloxy.
This process is particularly preferred when L represents fluorine (and most especially when R1 represents hydrogen) since the reaction is generally fast and efficient and the reaction has a tendency to produce products of high crystallinity.
The product of this reaction may be deprotected if desired under conventional conditions eg on treatment with an alcohol (eg isopropanol) under mild basic conditions (eg in the presence of potassium carbonate).
The reaction of compounds of formula (V) (in protected form) and compounds of formula (VIII) may be performed in the presence of a Lewis Acid (eg TMSOTf) and optionally a silylating agent (eg BSA) in an inert solvent such as acetonitrile followed by work-up eg with water. When L represents halogen the Lewis Acid can generally be omitted when a silylating agent is present.
Certain compounds of formula (VIII) are known. Other compounds of formula (VIII) may be prepared by reaction of a compound of formula (IX)
wherein L1 and L2 independently represent a leaving group such as halogen, e.g. chlorine or fluorine,
with R1NH2 under conventional conditions.
Compounds of formula R1NH2, R2NH2 and IX are either known or may be prepared by conventional methods known per se.
As a further aspect of the invention we also provide new process which may be used to provide compounds of formula (I) without the proviso.
Thus we provide a process for preparation of a compound of formula (I) without the proviso which comprises
(d) reacting a corresponding compound of formula (X)
xe2x80x83with a compound of formula (XI)
R3xe2x80x94Lxe2x80x83xe2x80x83(XI)
wherein L is a leaving group; or
(e) reacting a corresponding compound of formula (XII)
xe2x80x83with a compound of formula (V) or a protected derivative thereof.
Process (d) will generally take place on combining the two reagents in the presence of a mild base e.g. K2CO3 and an inert organic solvent eg DMF. Typical leaving groups L include halogen (e.g. Br).
Process (e) will generally take place in the presence of a Lewis Acid (e.g. TMSOTf) and optionally a silylating agent (e.g. BSA) in an inert solvent such as MeCN followed by work-up e.g. with water. We prefer L to represent acetyloxy and the two hydroxy groups to be protected as the acetyl ester. A deprotection step (using mild base e.g. K2CO3) will then be necessary to generate the compound of formula (I).
Compounds of formula (X) may be prepared by analogous methods to those described above for the preparation of compounds of formula (I). When compounds of formula (X) are prepared via the analogues of compounds of formula (II), (III), (IIIA) and/or (IV) in which R3 is replaced by hydrogen, such compounds are preferably protected in the N2-position of the tetrazole. A suitable protecting group is benzyl which may be incorporated by treating the unprotected tetrazole with a benzyl halide (e.g. benzyl bromide) in the presence of base (e.g. K2CO3). An illustrative process for the preparation of compounds of formula (X) is given in Scheme 2:
Compounds of formula (XI) are known or may be prepared by known methods.
Compounds of formula (XII) may be prepared, for example following Scheme 3:
Processes (d) and (e) are particularly suitable for preparing the compound (2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol and salts and solvates thereof, especially the maleate salt.
We prefer process (e).
The potential for compounds of formula (I) to inhibit leukocyte function may be demonstrated, for example, by their ability to inhibit superoxide (O2xe2x80x94) generation from neutrophils stimulated with chemoattractants such as N-formylmethionyl-leucyl-phenylalanine (fMLP). Accordingly, compounds of formula (I) are of potential therapeutic benefit in providing protection from leukocyte-induced tissue damage in diseases where leukocytes are implicated at the site of inflammation.
Examples of disease states in which the compounds of the invention have potentially beneficial anti-inflammatory effects include diseases of the respiratory tract such as adult respiratory distress syndrome. (ARDS), bronchitis (including chronic bronchitis), cystic fibrosis, asthma (including allergen-induced asthmatic reactions), chronic obstructive pulmonary disease (COPD), emphysema, rhinitis and septic shock. Other relevant disease states include diseases of the gastrointestinal tract such as intestinal inflammatory diseases including inflammatory bowel disease (e.g. Crohn""s disease or ulcerative colitis), Helicobacter-pylori induced gastritis and intestinal inflammatory diseases secondary to radiation exposure or allergen exposure, and non-steroidal anti-inflammatory drug-induced gastropathy. Furthermore, compounds of the invention may be used to treat skin diseases such as psoriasis, allergic dermatitis and hypersensitivity reactions and diseases of the central nervous system which have an inflammatory component eg Alzheimer""s disease and multiple sclerosis.
Further examples of disease states in which compounds of the invention have potentially beneficial effects include cardiac conditions such as peripheral vascular disease, post-ischaemic reperfusion injury and idiopathic hypereosinophilic syndrome.
Compounds of the invention which inhibit lymphocyte function may be useful as immunosuppressive agents and so have use in the treatment of auto-immune diseases such as rheumatoid arthritis and diabetes.
Compounds of the invention may also be useful in inhibiting metastasis.
Diseases of principal interest include asthma and COPD.
It will be appreciated by those skilled in the art that reference herein to treatment extends to prophylaxis as well as the treatment of established conditions.
As mentioned above, compounds of formula (I) are useful in human or veterinary medicine, in particular as anti-inflammatory agents.
There is thus provided as a further aspect of the invention a compound of formula (I) or a physiologically acceptable salt or solvate thereof for use in human or veterinary medicine, particularly in the treatment of patients with inflammatory conditions who are susceptible to leukocyte-induced tissue damage.
According to another aspect of the invention, there is provided the use of a compound of formula (I) or a physiologically acceptable salt or solvate thereof for the manufacture of a medicament for the treatment of patients with inflammatory conditions who are susceptible to leukocyte-induced tissue damage.
In a further or alternative aspect there is provided a method for the treatment of a human or animal subject with an inflammatory condition who is susceptible to leukocyte-induced tissue damage, which method comprises administering to said human or animal subject an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof.
The compounds according to the invention may be formulated for administration in any convenient way, and the invention therefore also includes within its scope pharmaceutical compositions for use in anti-inflammatory therapy, comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together, if desirable, with one or more physiologically acceptable diluents or carriers.
There is also provided a process for preparing such a pharmaceutical formulation which comprises mixing the ingredients.
The compounds according to the invention may, for example, be formulated for oral, buccal, parenteral, topical or rectal administration, preferably for parenteral or topical (e.g. by aerosol) administration.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch, cellulose or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycollate; or wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid. The preparations may also contain buffer salts, flavouring, colouring and/or sweetening agents (e.g. mannitol) as appropriate.
For buccal administration the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds may also be formulated as suppositories, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.
The compounds according to the invention may also be formulated for parenteral administration by bolus injection or continuous infusion and may be presented in unit dose form, for instance as ampoules, vials, small volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions, or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as anti-oxidants, buffers, antimicrobial agents and/or tonicity adjusting agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use. The dry solid presentation may be prepared by filling a sterile powder aseptically into individual sterile containers or by filling a sterile solution aseptically into each container and freeze-drying.
By topical administration as used herein, we include administration by insufflation and inhalation. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, pessaries, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator, solutions for nebulisation or drops (e.g. eye or nose drops).
Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents and/or solvents. Such bases may thus, for example, include water and/or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil or a solvent such as a polyethylene glycol. Thickening agents which may be used include soft paraffin, aluminium stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax.
Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents or thickening agents.
Powders for external application may be formed with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilising agents or suspending agents.
Spray compositions may be formulated, for example, as aqueous solutions or suspensions or as aerosols delivered from pressurised packs, with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra-fluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, 1,1,1,2-tetrafluoroethane, carbon dioxide or other suitable gas.
Intranasal sprays may be formulated with aqueous or non-aqueous vehicles with the addition of agents such as thickening agents, buffer salts or acid or alkali to adjust the pH, isotonicity adjusting agents or anti-oxidants.
Capsules and cartridges of for example gelatin, or blisters of for example laminated aluminium foil, for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
Solutions for inhalation by nebulation may be formulated with an aqueous vehicle with the addition of agents such as acid or alkali, buffer salts, isotonicity adjusting agents or antimicrobials. They may be sterilised by filtration or heating in an autoclave, or presented as a non-sterile product.
The pharmaceutical compositions according to the invention may also be used in combination with other therapeutic agents, for example anti-inflammatory agents (such as corticosteroids (eg fluticasone propionate, beclomethasone dipropionate, mometasone furoate, triamcinolone acetonide or budesonide) or NSAIDs (eg sodium cromoglycate)) or beta adrenergic agents (such as salmeterol, salbutamol, formoterol, fenoterol or terbutaline and salts thereof) or antiinfective agents (eg antibiotics, antivirals).
The invention thus provides, in a further aspect, a combination comprising a compound of formula (I) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent, for example an anti-inflammatory agent such as a corticosteroid or NSAID.
The combination referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a physiologically acceptable diluent or carrier thereof represent a further aspect of the invention.
The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations. Appropriate doses of known therapeutic agents will be readily appreciated by those skilled in the art.
Compounds of the invention may conveniently be administered in amounts of, for example, 0.01 to 500 mg/kg body weight, preferably 0.01 to 100 mg/kg body weight, 1 to 4 times daily. The precise dose will of course depend on the age and condition of the patient and the particular route of administration chosen.
The compounds of the invention have the advantage that they may be more efficacious, show greater selectivity, have fewer side effects, have a longer duration of action, be more bioavailable by the preferred route, show less systemic activity when administered by inhalation or have other more desirable properties than similar known compounds.
In particular the compounds of the invention have the advantage that they may show greater selectivity for the adenosine 2a receptor subtype over other adenosine receptor subtypes (especially the A1 and A3 receptor subtypes) than hitherto known compounds.
As a further aspect of the invention we provide certain compounds as new and useful intermediates.
Compounds of the invention may be tested for in vitro and in vivo biological activity in accordance with the following screens:
(1) Agonist activity against adenosine 2a, adenosine 1 and adenosine 3 receptor subtypes.
Agonist selectivity of compounds against other human adenosine receptors is determined using Chinese hamster ovary (CHO) cells transfected with the gene for the relevant human adenosine receptor following a method based on that of Castanon and Spevak, 1994. The CHO cells are also transfected with cyclic AMP response elements promoting the gene for secreted placental alkaline phosphatase (SPAP) (Wood, 1995). The effect of test compounds is determined by their effects on basal levels of cAMP (A2a ) or on forskolin-enhanced cAMP (A1 and A3) as reflected by changes in levels of SPAP. EC50 values for compounds are then determined as a ratio to that of the non-selective agonist N-ethyl carboxamide adenosine (NECA).
(2) Antigen-induced lung eosinophil accumulation in sensitised guinea pigs.
Ovalbumin sensitised guinea pigs are dosed with mepyramine (1 mg/kg ip) to protect against anaphylactic bronchospasm. A compound of the invention is then given by the inhaled route (30 min breathing of an aerosol of the compound) immediately prior to ovalbumin challenge (30 min breathing of an aerosol generated from a 50 ug/ml solution of ovalbumin). Twenty four hours after challenge, the guinea pigs are killed and the lungs lavaged. Total and differential leukocyte counts are then obtained for the bronchoalveolar lavage fluid and the dose of test compound giving a 50% reduction in eosinophil accumulation (ED50) is determined (Sanjar et al. 1992).
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A high-performance stainless steel sheet which has a high strength which is optimal for a gasket for use in high-performance engines of automobiles and motorcycles and which also has excellent workability and fatigue properties and a method for its manufacture are provided.

An engine gasket for an automobile or a motorcycle is an important sealing member which is inserted between a cylinder head and a cylinder block and which prevents leakage of combustion gas, engine cooling water, and oil from between them (through the gap). The majority of gaskets used today have a structure comprising a plurality of stainless steel sheets which are stacked on each other. As can be seen from the test piece 10 shown in FIG. 1(a) which simulates a gasket, a projection called a bead 14 is formed in the shape of a ring in the periphery of a bore (a hole) 12 corresponding to the combustion chamber of an engine. FIG. 1(b) shows the cross-sectional shape and dimensions of the bead 14. Due to the contact (spring-back) force of this bead, it performs sealing of high pressure combustion gas and the like against repeated increases and decreases of the gap occurred during combustion. The cylinder head and the cylinder block are secured to each other by bolts.
In the past, materials such as JIS SUS301, 304, and 301L which are metastable austenite (γ) stainless steels specified by JIS G 4305 were widely used for gaskets. These steels are generally used after undergoing cold rolling (temper rolling) performed to adjust strength. A high strength can be obtained relatively easily due to a large amount of hardening caused by deformation-induced transformation into martensite (α′). As a result of this large amount of hardening, deformation of undeformed portions having a small value of (strength×cross-sectional area) compared to deformed portions is promoted and the material is deformed as a whole with suppressed local deformation due to the so-called TRIP effect. A steel of this type is distinguished among stainless steels as having excellent workability. In addition, it exhibits the necessary corrosion resistance when contacted by cooling water.
However, in recent engines, due to environmental problems and the like, there has come to be a demand for both (i) higher compression ratios of fuel/gas mixtures and (ii) decreases in weight (reductions in size and higher densities) necessary to improve fuel consumption. There has also been a demand for both of these properties from users desiring an increase in output. In order to realize these demands, high strength and excellent ability to be worked into complicated shapes are simultaneously demanded of a gasket material.
However, even in stainless steels like those described above, in the same manner as with other metal materials, a degradation in workability accompanying an increase in strength is unavoidable, and at present it is not possible to adequately achieve both high strength and workability.
In the course of working to form a gasket, during bead formation, there was the problem that wrinkles, cracks (minute splits in the sheet surface), and the like occurred, and fatigue resistance ended up greatly decreasing. This will result in an engine, in which at the time of repeated increases and decreases in the gap between the cylinder head and the cylinder block due to combustion, the bead portion of the gasket undergoes fatigue failure at an early stage with the above-described defects as starting points, and the fatigue failure becomes a cause of problems such as the sealing ability becoming inadequate, a decrease in fuel efficiency and output, and pollution of the atmosphere. In the worst case, the fatigue failure may become a cause of engine failure or damage.
Patent Documents 1, 2, 3, and 4 disclose materials having improved fatigue properties and methods for their manufacture. According to these materials and methods, the crystal grain diameter of a gasket material is refined to greatly inhibit the formation of defects which are thought to be formed primarily at crystal grain boundaries at the time of bead formation while maintaining a high strength equal to that of earlier materials. Such conventional materials refine the crystal grains by final annealing and thereby aim at an increase in strength, and they achieve the necessary strength by a synergistic effect of work hardening during temper rolling which is subsequently carried out. Namely, with such conventional materials, after final annealing is carried out to refine the crystal grains in the above manner, temper rolling is further carried out to form a product sheet, and then the product sheet is worked to form a gasket.
However, since annealing to be carried out for refining crystal grains must be carried out at a relatively low temperature and in a narrow temperature range, compared to conventional high temperature annealing having the primary object of softening, it has the problems that it is difficult to obtain a stable structure and that control is difficult.
Patent Document 1: Japanese Published Unexamined Patent Application Hei 4-214841
Patent Document 2: Japanese Published Unexamined Patent Application Hei 5-279802
Patent Document 3: Japanese Published Unexamined Patent Application Hei 5-117813
Patent Document 4: WO 00/14292

Abstract: At least in a region from the surface of the sheet up to 3 μm in the thickness direction, nitrogen compounds of at least 10 nm and at most 200 nm are present in an amount of at least 200 per 100 μm2. The number of nitrogen compounds of at least 10 nm and at most 200 nm in a region from the sheet surface up to 3 μm in the thickness direction of the sheet is at least 2 times the number of nitrogen compounds of this size in the central portion of the sheet thickness.