In a chromatographic quantitative assay device and a manufacturing method thereof according to the present invention, as shown in FIG. 1, there are provided a non-moistenable reaction layer carrier support 1, a sample addition portion 2 for adding a liquid sample, a marker reagent holding portion 3 for holding a marker reagent, a antibody fixing portion 5 where specific protein is fixed on the region of a reaction layer 4, and a absorption portion 6 for absorbing the liquid sample. These portions are formed above the carrier support 1, and the reaction layer carrier support 1 is covered by close adhesion with the liquid-impermeable sheet member 7 except the portion for adding a liquid sample.

1. Technical Field
The present invention relates to a chromatographic quantitative assay device for assaying an analyte utilizing antigen-antibody reaction and, more particularly, a chromatographic quantitative assay device including a liquid-impermeable sheet member, and a manufacturing method thereof.
2. Background Art
Conventionally, an assay method by immunochromatography utilizing antigen-antibody reaction is universally taken as an implementation method for chemical or clinical examination of a liquid sample, such as water analysis or urinalysis. Generally, chromatography refers to a method for separating mixtures in accordance with their components, and a specimen used for chromatography comprises a plurality of portions as follows: a portion for adding a liquid sample, a portion for holding a marker reagent which can migrate by infiltration of the liquid sample, a portion that performs binding reaction with the marker reagent containing a substance capable of being bound specifically to a flowing-down analyte, and a portion for absorbing a flowing-down sample. According to this assay method of a chromatographic assay device, chemical reaction which causes coloration or discoloration by color reaction is performed after a predetermined period of time from when the liquid sample was added on the specimen, whereby determination based on visual observation is possible.
Measurement principle by immunochromatography is based on an assay method for identifying antigen or antibody utilizing the specificity of antigen-antibody reaction. The process is as follows: adding a liquid sample to an immunochromatographic specimen, a marker reagent dissolved by the liquid sample extends in infiltration direction and then a substance capable of being bound specifically to an analyte in the liquid sample is fixed, consequently coloration generates in a measurement range. Further, since the result of immunochromatographic analysis is determined by color reaction, it is recorded by the visual observation. In other words, since determination of the result of analysis is extremely easy, the range of use expands.
Such measurement by immunochromatography can be adopted for examinations of various analytes. In some cases with some analytes, however, only semi-quantitative result, at the most, is derived by this method when quantitative result is also required besides qualitative examination. Therefore, advent of any means to lead to more quantitative result of analysis has been desired.
To improve the above-mentioned problems, there is disclosed an immunochromatographic specimen in Japanese Published Patent Application Hei.8-240591. In an assaying method with this immunochromatographic specimen, after a sample was added to this specimen and reaction was done, a coloration degree detected on the specimen is measured as signals of absorption and reflection on the color-reacted portion, by using a detecting instrument. Further, Japanese Published Patent Application Hei.8-334511 discloses a quantitative assay method by immunochromatography using an immunochromatographic specimen, which is performed by taking a coloration degree given by analytic processing of a gradated image of the specimen previously converted after image-capturing by an image sensor.
However, in the case of the quantitative assay method using an immunochromatographic specimen as in the embodiments of the Japanese Published Patent Applications Hei.8-240591 and Hei.8-334511, the quantitative assay method is performed by adopting a suitable detecting instrument in accordance with the degree or level of coloration involved in color reaction. Conventionally, because an immunochromatographic specimen used in general can not be controlled artificially without mechanical control, infiltration rate of liquid sample is dominated by the permeability of the specimen. For example, owing to vaporization of liquid sample from side surfaces of the specimen, the amounts of analyte flowing out toward the measurement range sometimes become heterogeneity. Moreover, in each immunochromatographic specimen used for every measurement, the amount of liquid sample to be added and marker reagent to be added are not always fixed. Accordingly, there is a problem that these causes increase the dispersion of quantitative assay values that appear after a predetermined time.
Additionally, although an assay method by immunochromatography using immunochromatographic specimen is performed after a liquid sample is added and a predetermined period of time has passed, the marker reagent which permeates at this time can begin to dissolve simultaneously, and sometimes remains on the reaction layer as a background. If the value of this background is included in the coloration degree, the detecting instrument executes the measurement including such error. Therefore, quantitative measurement in short time with immunochromatographic specimen is hard to execute. Furthermore, residual amount of the marker reagent flowing out to the reaction layer is inconstant, and is different for every measurement or specimen to use, and thus obtained coloration degree at this time attributed in the error of the reading value greatly.
From the above-mentioned problem, performance of immunochromatographic quantitative assay was extremely close to semi-quantitative due to various standards for specimen and the dispersion of the added liquid sample, or the errors derived from background. Accordingly, the performance improvement of the specimen has been strongly required to enable more accurate measurement.
Further, when carrying out assay of a liquid sample including cell components such as whole blood or bacterial solution, using conventional immunochromatographic specimen, viscosity of the liquid sample and the presence of cell components cause clogging in a reaction layer carrier. Consequently, it takes much time for measurement, and desiccation of the liquid sample during measurement, if any, causes lack of reaction precision and quantitative efficiency. Thereby, simple and easy-handling immunochromatographic quantitative assay device has been strongly required for examination of whole blood, bacterial solution, or the like.
The present invention is made to solve the above-mentioned problems and has for its object to provide an immunochromatographic quantitative assay device and a manufacturing method thereof, which enables precise measurement without influenced by the character of the added liquid sample, accurate reading of coloration degree as a result of reaction of a liquid sample as an analyte and a marker reagent, and results in no influence in the residual amounts of the marker reagent by the background.
According to a first aspect of the present invention, there is provided a chromatographic quantitative assay device comprising: a non-moistenable reaction layer carrier support and a moistenable layer which is formed above the support and consists of one or arbitrary number of member portions, the moistenable layer comprising a portion for adding a liquid sample, a portion for holding a migratable marker reagent, a portion that performs binding reaction with a marker reagent which is provided with a substance capable of being bound specifically to an analyte in the liquid sample, and a portion for absorbing the liquid sample; and a liquid-impermeable sheet member which is provided being adhered to the upper surface and side surfaces except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration.
According to a second aspect of the present invention, there is provided a chromatographic quantitative assay device comprising: a non-moistenable reaction layer carrier support and a moistenable layer which is formed above the support and consists of one or arbitrary number of member portions, the moistenable layer comprising a portion for adding a liquid sample, a portion for holding a constant quantity of migratable combination reagent which is previously prepared consisting of an analyte and a marker reagent, a portion that performs competitive binding reaction between an analyte in the liquid sample and the combination reagent provided with a substance capable of being bound specifically to the analyte in the liquid sample, and a portion for absorbing the liquid sample; and a liquid-impermeable sheet member which is provided being adhered to the upper surface and side surfaces except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration.
According to a third aspect of the present invention, there is provided a chromatographic quantitative assay device comprising: a non-moistenable reaction layer carrier support and a moistenable layer which is formed above the support and consists of one or arbitrary number of member portions, the moistenable layer comprising a portion for adding a liquid sample where a substance for destroying cell components in the liquid sample is held, a portion for holding a migratable marker reagent, a portion that performs binding reaction with the marker reagent provided with a substance capable of being bound specifically to an analyte in the liquid sample, and a portion for absorbing the liquid sample; and a liquid-impermeable sheet member which is provided being adhered to the upper surface and side surfaces except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration state of the liquid sample uniform by destroying cell components in the liquid sample, and to control the quantity of the sample and marker reagent which flow out in a constant time.
According to a fourth aspect of the present invention, there is provided a chromatographic quantitative assay device comprising: a non-moistenable reaction layer carrier support and a moistenable layer which is formed above the support and consists of one or arbitrary number of member portions, the moistenable layer comprising a portion for adding a liquid sample where a substance for destroying cell components in the liquid sample is held, a portion for holding a constant quantity of a migratable combination reagent which is previously prepared consisting of an analyte and a marker reagent, a portion that performs competitive binding reaction between an analyte in the liquid sample and the combination reagent provided with a substance capable of being bound specifically to the analyte in the liquid sample, and a portion for absorbing the liquid sample; and a liquid-impermeable sheet member which is provided being adhered to the upper surface and side surfaces except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration state of the liquid sample uniform, and to control the quantity of the sample and combination reagent which flow out in a constant time.
According to a fifth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member which is provided being adhered to the upper surface, or from the upper surface to the back surface, except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, and to make the infiltration state of the liquid sample uniform. Furthermore, it is possible to make the marker reagent flow out at uniform concentration, and to restrain the affection of background values added on the values of color-reacted portions.
According to a sixth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the reaction layer carrier support is removed; and the liquid-impermeable sheet member is provided on the periphery except the portion for adding a liquid sample.
Therefore, in this chromatographic quantitative assay device, it is possible to reduce the number of materials. Further, it is possible to make the infiltration state of the liquid sample uniform and to control the quantity of the sample and marker reagent which flow out in a constant time. Moreover, the liquid sample never leaks out of the gap, and the liquid sample never intrudes from the outside except a portion for adding the sample.
According to a seventh aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the vertical side surfaces of the liquid-impermeable sheet member is opened in the direction where the liquid sample infiltrates.
Therefore, in this chromatographic quantitative assay device, the air-releasing path at infiltration of liquid is restricted in only the infiltration direction, whereby it is possible that liquid sample and marker reagent flow out at uniform concentration.
According to an eighth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the end of the liquid-impermeable sheet member is opened at an arbitrary position at the end of the chromatographic quantitative assay device in the direction where the liquid sample infiltrates.
Therefore, in this chromatographic quantitative assay device, the air-releasing path at infiltration of liquid is restricted in only the infiltration direction, whereby it is possible that liquid sample and marker reagent flow out at uniform concentration.
According to a ninth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member is adhered by an adhesive made of an arbitrary adhesive.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample.
According to a tenth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member is adhered by an arbitrary adhesive which hardens after adhesion.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened after adhesion, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby the performance of the chromatographic quantitative assay device can be maintained over a long period.
According to an eleventh aspect of the present invention, in a chromatographic quantitative assay device of the ninth aspect discussed above, the adhesive applied to the liquid-impermeable sheet member is made of thermoplastic resin.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the water, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened by cooling after adhesion, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby the performance of the chromatographic quantitative assay device can be maintained over a long period.
Here, the thermoplastic resin is a resin having the property that it is in a solid state at normal temperature, softens when heated to be processed, and solidifies when cooled thereafter. That is, it has the property that the plasticity is held reversibly by repetition of cooling and heating. The thermoplastic resin of this kind includes polyethylene, polypropylene, polychlorinated vinyl, polystyrene, polychlorinated vinylidene, fluororesin, methyl polymethacrylate, polyamide, polyester, polycarbonate, polyphenylene oxide, polyurethane, polyacetal, or the like.
According to a twelfth aspect of the present invention, in a chromatographic quantitative assay device of the ninth aspect discussed above, the adhesive applied to the liquid-impermeable sheet member is made of thermosetting resin.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened after adhesion and is not melted, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby the performance of a chromatographic quantitative assay device can be maintained over a long period.
Here, the thermosetting resin is a resin having the property that it softens when heated to be processed, but hardens by further heating and thus does not soften thereafter. The thermosetting resin of this kind includes urea resin, melamine resin, phenol resin, or the like.
According to a thirteenth aspect of the present invention, in a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member is made of an arbitrary transparent or semi-transparent liquid-impermeable material.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to enable visual detection when measuring the results on the detection region from the outside, whereby it is easy to perform the measurement.
According to fourteenth aspect of the present invention, a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member is made of an arbitrary semi-transparent or opaque liquid-impermeable material, and a transparent window is provided at the detection region.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to enable visual detection when measuring the results on the detection region from the outside, whereby it is easy to perform the measurement.
According to a fifteenth aspect of the present invention, in a chromatographic quantitative assay device of the third or fourth aspects discussed above, the substance for destroying cell components held at the portion for adding a liquid sample is a surfactant.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to avoid clogging to be caused by cell components in a liquid sample such as whole blood or bacterial solution, thereby to make the infiltration state uniform, resulting in more precise quantitative measurement in a short time.
According to a sixteenth aspect of the present invention, in a chromatographic quantitative assay device of the third or fourth aspects discussed above, the substance for destroying cell components held at the portion for adding a liquid sample is composed of chloride such as sodium chloride, potassium chloride.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to avoid clogging to be caused by cell components in a liquid sample such as whole blood or bacterial solution, thereby to make the infiltration state uniform, resulting in more precise quantitative measurement in a short time without inhibition of binding reaction.
According to a seventeenth aspect of the present invention, in a chromatographic quantitative assay device of the third or fourth aspect discussed above, the substance for destroying cell components held at the portion for adding a liquid sample is saponin series.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to avoid clogging to be caused by cell components in a liquid sample such as whole blood or bacterial solution, thereby to make the infiltration state uniform, resulting in more precise quantitative measurement in a short time.
According to an eighteenth aspect of the present invention, in a chromatographic quantitative assay device of the third or fourth aspects discussed above, the substance for destroying cell components held at the portion for adding a liquid sample is a substance having bacteriolytic effect such as lysozyme.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to avoid clogging to be caused by cell components in a liquid sample such as bacterial solution or thereby to make the infiltration state uniform, resulting in more precise quantitative measurement in a short time without inhibition of binding reaction.
According to a nineteenth aspect of the present invention, a manufacturing method of a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member, which is previously treated by performing aging at an arbitrary temperature, is adhered closely to the upper surface and side surfaces of the chromatographic quantitative assay device.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to accelerate the volatilization of organic solvent which brings adverse effects on the protein contained in the adhesive for the liquid-impermeable sheet member or on the reaction layer by performing aging, whereby preservation stability over a longer period is realized.
Here, the aging means leaving the liquid-impermeable sheet member for an arbitrary period of time under arbitrary and constant environment.
According to a twentieth aspect of the present invention, a manufacturing method of a chromatographic quantitative assay device of any of the first to fourth aspects discussed above, the liquid-impermeable sheet member is adhered closely to the upper surface and side surfaces of the chromatographic quantitative assay device by applying of an arbitrary pressure to the liquid-impermeable sheet member at an arbitrary temperature.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to adhere the liquid-impermeable sheet member onto the front surface and the side surfaces of the chromatographic quantitative assay device more solidly.
Here, the liquid-impermeable sheet member means e.g. an adhesive sheet material of heat seal type, therefore adhesion of a sheet material by laminating processing as seen in thermocompression bonding or the like is enabled.
According to a twenty-first aspect of the present invention, in a manufacturing method of a chromatographic quantitative assay device of the nineteenth or twentieth aspects discussed above, the adhesive applied to the liquid-impermeable sheet member has a characteristic of being melted and taking on stickiness at the temperature higher than normal temperatures and is hardened after adhesion.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened after adhesion, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby a manufacturing method of specimen that can keep the performance of the chromatographic quantitative assay device over a long period is provided.
Here, the adhesive is an adhesive having the property that it softens when heated and hardens when cooled after adhesion and, preferably, an adhesive having a low melting point as not to soften at normal temperature and to melt at lower temperature.
According to a twenty-second aspect of the present invention, a manufacturing method of a chromatographic quantitative assay device of the twenty-first aspect discussed above, the adhesive applied to the liquid-impermeable sheet member is made of thermoplastic resin.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened by cooling after adhesion, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby the performance of the chromatographic quantitative assay device can be maintained over a long period.
According to a twenty-third aspect of the present invention, a manufacturing method of a chromatographic quantitative assay device of the twenty-first aspect discussed above, the adhesive applied to the liquid-impermeable sheet member is made of thermosetting resin.
Therefore, in this chromatographic quantitative assay device, it is possible to prevent the vaporization of the moisture, to make the infiltration direction and infiltration state of the liquid sample uniform, and to make the liquid sample and marker reagent, which flow out in a constant time, flow out at uniform concentration, as well as, to prevent the liquid-impermeable sheet member from exfoliation by infiltration of the liquid sample. Further, because the adhesive is hardened after adhesion and is not melted, it is possible to prevent attachment of the paste to a cutter when the sensor is cut. Moreover, it is possible to facilitate mass production, as well as, to prevent transition of paste to reaction layer, thereby preventing transformation of reaction layer carrier or specific protein, whereby the performance of a chromatographic quantitative assay device can be maintained over a long period.

Quantitative chromatographic measuring device and method for manufacturing the same

Matsushita Electric Industrial Co., Ltd.


A plurality of cutting tools are attached to a pair of axles on a frame for chopping crop residue in a direction parallel to the direction of travel. A plurality of transverse knives are attached to the cutting tools for simultaneously chopping the crop residue in a direction perpendicular to the direction of travel. The transverse knives are attached to the circumferential edges of the cutting tools and extend away from the cutting tool edges. The outer edges of the transverse knives are sharp and are angled radially outward from the cutting tools.

1. Field of the Invention
This invention relates in general to farm machinery. In particular, the invention relates to machinery for chopping crop residue left after harvesting.
2. Description of the Prior Art
After a crop, such as corn or wheat, has been harvested, a certain amount of crop residue, consisting of corn stalks, wheat stubble, or the like, is left behind. Prudent farming techniques and government regulations require that the crop residue be chopped into small pieces, and that a large amount of the chopped residue be left lying on top of the ground. This action prepares the soil for the next crop and helps to minimize soil erosion and pollution of air and water.
Prior art choppers include rolling choppers for chopping the crop residue in a direction perpendicular to the direction of travel. Other choppers have colters to chop the crop residue in a direction parallel to the direction of travel. The disadvantages to both of these types of machines is that the residue may lie in a particular orientation that causes the residue to be missed by the prior art chopper.
U.S. Pat. No. 4,884,391, issued Dec. 5, 1989, to Cosson, discloses a stalk cutting apparatus that has both a cutter wheel for cutting the stalks perpendicular to the direction of travel, and colters for cutting the stalks parallel to the direction of travel. The cutting wheel is mounted on one axle, and the colters are mounted on several axles located behind the cutting wheel. Thus, as the apparatus is pulled across a field, the crop residue is first chopped perpendicular to the direction of travel, and then parallel to the direction of travel.


Aerosol solution formulations for use in an aerosol inhaler which comprise 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]-ethyl]-2(1H)-quinolinone or a salt thereof, in particular the hydrochloride salt (TA 2005), as an active ingredient, a propellant containing a hydrofluoroalkane, and a cosolvent, stabilized by addition of a specific small amount of a high concentrated phosphoric acid exhibit improved shelf life. The formulation may be optionally contained in a can having part or all of its internal metallic surfaces lined with an inert organic coating.

1. Field of the Invention
The present invention relates to stable pharmaceutical solution formulations to be used with pressurized metered dose inhalers (MDIs) suitable for aerosol administration. In particular, the present invention relates to solutions to be used with pressurized metered dose inhalers (MDIs), which are suitable for aerosol administration, which contain a β2-agonist, and which are stable at room temperature for a pharmaceutically acceptable shelf-life.
2. Discussion of the Background
Pressurized metered dose inhalers are well known devices for administering pharmaceutical products to the respiratory tract by inhalation.
Drugs commonly delivered by inhalation include bronchodilators such as β2-agonists and anticholinergics, corticosteroids, anti-leukotrienes, anti-allergics, and other materials that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
MDIs use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract as an aerosol. Formulations for aerosol administration via MDIs can be solutions or suspensions. Solution formulations offer the advantage of being homogeneous with the active ingredient and excipients completely dissolved in the propellant vehicle or its mixture with suitable co-solvents such as ethanol. Solution formulations also obviate physical stability problems associated with suspension formulations so assuring more consistent uniform dosage administration.
For many years the preferred propellants used in aerosols for pharmaceutical use have been a group of chlorofluorocarbons which are commonly called Freons or CFCs, such as CCl3F (Freon 11 or CFC-11), CCl2F2 (Freon 12 or CFC-12), and CClF2—CClF2 (Freon 114 or CFC-114).
Recently, the chlorofluorocarbon (CFC) propellants such as Freon 11 and Freon 12 have been implicated in the destruction of the ozone layer and their production is being phased out.
Hydrofluoroalkanes ((HFAs) known also as hydro-fluoro-carbons (HFCs)) contain no chlorine and are considered less destructive to ozone and these are proposed as substitutes for CFCs.
HFAs and in particular 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) have been acknowledged to be the best candidates for non-CFC propellants and a number of medicinal aerosol formulations using such HFA propellant systems have been disclosed.
Due to the higher polarity of the HFA propellants, in particular of HFA 134a (dielectric constant D≧9.5), with respect to CFC vehicles (D≦2.3), HFA solution formulations may suffer to a greater extent from chemical stability problems with respect to the corresponding CFC formulations.
Preparation of stable HFA solution formulations is even more critical when bronchodilator β2-agonists belonging to the class of the phenylalkylamino derivatives are concerned. Said drugs, like formoterol, 8-hydroxy-5-[(1R)-1-hydroxy-2-[[(1R)-2-(4-methoxyphenyl)-1-methylethyl]amino]ethyl]-2(1H)-quinolinone hydrochloride (hereinafter referred as TA 2005), salbutamol (albuterol) and others, may suffer from inherent chemical stability problems due to their susceptibility to oxidative conditions. Moreover, in view of the presence of some functional groups like formamide, a higher polarity of the vehicle may accelerate the rate of solvolysis reactions.
As for formoterol, the currently marketed CFC solution formulation (Foradil®) exhibits a limited shelf life, i.e., 12 months at refrigerator temperature, 4±2° C., and only 3 months at room temperature.
As for salbutamol, no formulation as an HFA solution for aerosol administration is currently on the market.
In the case of TA 2005, no formulation at all is currently available for aerosol administration.
In consideration of the problems outlined above, it would be highly advantageous to provide formulations in the form of HFA solutions to be administered by MDIs which afford pharmaceutical doses of β2-agonists characterized by having an adequate shelf-life.

Stable pharmaceutical solution formulations for pressurized metered dose inhalers


A coupler includes a main body that has an inner bore. The inner bore has a non-circular profile and a longitudinal axis. The coupler includes a cross aperture disposed in the main body. The cross aperture has an axis that is nonintersecting with the longitudinal axis of the main body.

Dual drill rod drilling systems ("dual rod") for use in directional drilling having an inner rod and an outer rod are known. A typical dual rod drilling system is generally configured to drive into the ground a series of drill rods joined end-to-end to form a drill string. At the end of the drill string is a rotating drilling tool or drill bit. A dual rod drilling system typically includes a first drive mechanism that controls rotation of a drill bit and a second drive mechanism that controls rotation of a steering element. When a straight hole is drilled with a dual rod drilling system, the first and second drive mechanisms are concurrently operated such that both the drill bit and the steering element are rotated as the drill string is thrust into the ground. When a directional change is needed, because the steering element is axially misaligned with the drill string, the drive mechanism that controls the steering element is stopped and the drill string is thrust further into the ground while the drive mechanism that controls the drill bit is rotated. This causes the drill bit to deviate from a straight path and follow the direction dictated by the steering element.
Dual rod drilling systems also use drilling fluid that is passed internally within the drill rods for cooling of the drill bit and also for transporting cuttings within the drill hole. Therefore, to ensure proper operation, it is important to reduce obstructions within the drilling fluid flow path. However, this can be difficult due to the unavoidable relative longitudinal offsets between inner and outer drill rods within the drill string.
Further, the inner and outer drill rods of each drill rod assembly can have variations in length resulting from manufacturing tolerances. Because of the length variations, drill rod assemblies are designed such that the overall length of interconnected inner drill rods are never longer than the overall length of interconnected outer drill rods. If the interconnected inner drill rods were longer than the outer drill rods, the inner rods would collide while the outer drill rods were being coupled together, causing damage to one or both of the inner and outer drill rods. Accordingly, by design, the length of interconnected inner drill rods is slightly less than the length of interconnected outer drill rods. However, this design requirement results in a situation where certain portions of the drill string, e.g., the inner drill rods, contact the outer drill rods and obstruct the fluid flow path. This results in being able to send less drilling fluid to the drill head and/or possible damage to portions of the drill string. Therefore, improvements in maintaining an open drilling fluid flow path are needed.
To drive the drill bit with the first drive mechanism, flexible and/or bent drive shafts have been used in order to allow steering and still facilitate torque transfer. Other designs have used a coupling (sometimes referred to as a "transmission") so as to allow misalignment between a straight drill bit shaft and a straight drive shaft. However, such a coupling, or transmission, has traditionally included several components and required separate lubrication and isolation from the drilling fluid, thus complicating manufacture and maintenance. Therefore, improvements to the drill head of a dual rod drilling system are needed.
To drive the rotation of the drill string, a gearbox having a plurality of motors has traditionally been used. The gearbox can include a gear arrangement that transfers power from the plurality of motors to the inner and out drill rods of the dual rod drilling system. Drilling fluid has also been traditionally introduced at the gearbox to the drill string; however, isolating the drilling fluid from the internal components of the gearbox can be difficult. Further, should a malfunction occur and drilling fluid be introduced to the interior of the gearbox, due to the internal positioning of the gearbox components, it is difficult for an operator to realize this before the components of the gearbox are damaged. Therefore, improvements to the gearbox of a dual rod drilling system are needed.


An elongated element having at least one electrical and/or optical conductor, and at least one additional element allocated to the elongated element. This additional element has at least one function that stores messages and/or that processes messages.

1. Field of the Invention
The present invention relates generally to the field of electromagnetic transmission devices such as optical or electrical transmission devices. More particularly, the present invention relates to an elongated element having at least one electrical and/or optical conductor and at least one additional element.
2. Description of the Related Art
Previously, communication networks have been organized in such a way that "intelligent" terminal devices are located at discrete locations. This may be, for example, at desks in offices, in computing centers, at service providers, in switching offices, etc. Discrete memories are then also located here in the form of hard disks, memory chips, magnetic cards, solid-state memories or similar devices. As a rule, lines are laid between these terminal devices to connect the devices. Various structures can thereby be used such as, for example, a star, tree, mesh or bus. Devices and amplifiers necessary for signal transmission or conversion are located at discrete locations between the terminal devices, depending on topology. The connections themselves are passive, consisting generally as a rule of copper wires, glass fibers or plastic fibers. The connection thereby respectively serves only as an end in itself.
It is for example known to insert amplifiers into the route of a line or of a cable. The cable is thereby interrupted in the region of the amplifier, and amplification is carried out in a separate structure (e.g., amplifier housing). Subsequently, a new cable piece is connected to the output of the amplifier, etc.
It is also known (WO 90/10879) to employ optical cables, which, in contrast to electrical cables, are very difficult to locate from the outside when buried. Externally permanent magnets may be attached at determined spacings, in order to locate the cables with a magnetic probe.
From DE 43 33 121 C2, a locating device is known having a magnetometer to locate magnetic objects in the ground. During a measurement, a person carrying out the measurement guides a magnetometer probe over the measurement path along a cord, whereby the measurement signals are retained by an electronic measurement device, taking into account the speed of the person carrying out the measurement. A plurality of detectable spaced emitters are provided on the cord, which respectively emit a path signal to the measurement device if the sensor passes over a spaced emitter of this type during the measurement. The emitters can also be realized in the form of electronic components in a chip, containing both the active electronic components and memory devices. When a spaced emitter is inserted, the cord is interrupted, and is led through a corresponding bore at the end side in the form of a loop.
From U.S. Pat. No. 5,045,368, a tube line (e.g., a gas line) is known for passing a flowing medium in which, for location in the buried state, marking means are arranged on the tube line in the form of passive electrical circuits which are tuned to a specific frequency. The marking means can be arranged in a predetermined pattern in order to obtain additional items of information. The individual marking means can be attached either to the line tube or can be successively strung on a cord.


This invention provides a matching point extracting method and an apparatus therefor, for extracting the matching points among plural images based on the template matching method. The method consists of forming mutually different plural templates from an arbitrary one of plural images, and determining the matching points in the plural images, in an image area showing a specified condition, by utilizing one of thus formed plural templates, thereby enabling highly prescise extraction of the matching points over the entire image area, without difference between the object and the background in the image.

1. Field of the Invention
The present invention relates to a matching point extracting method, in determining distance information on an object based on plural images of such an object taken from mutually different positions, for extracting mutually matching points in such images.
2. Related Background Art
Such an apparatus for extracting the matching points of the images has conventionally been utilized, for example, in producing a control program for a moving robot or cutting out the image data of a predetermined object from image data of a phototaken image.
In such a matching point extracting apparatus, for determining the distance to the object in the image, there are known, for example, a method shown in FIG. 1A of employing two or more cameras 133a, 133b for taking the images of the object 131 from different viewing points and utilizing the parallax between the images obtained by such cameras 133a, 133b, and a method shown in FIG. 1B of employing one camera 134, and moving such a camera 134 for taking the images of the object 132 from different viewing points and utilizing the parallax between the time-sequentially obtained images. In these methods shown in FIGS. 1A and 1B, the extraction of the matching points is executed for obtaining the parallax required in the determination of the object distance.
More specifically, in the method shown in FIG. 1A, the matching points are determined in all the points (pixels) in the image data of the image obtained by the left-side camera 133a and in those of the image obtained in synchronization by the right-side camera 133b. Also in the method shown in FIG. 1B, the matching points are determined in all the points (pixels) in the image data of an image obtained at a certain position and in those of another image obtained at a position after movement. The determination is made in all the pixels (points) of the image data because the area of the object within the image is not known.
Among the representative methods for such a matching point extraction, there is known a template matching method. In this method, around a point P for which a matching point is to be determined, in FIG. 2A, a template (template image) 143 is prepared as shown in FIG. 2A and is moved over the entire area of a searched image 142 as shown in FIG. 2B, with a calculation of the similarity at every point and a point showing the highest similarity is determined as the matching point.
As the evaluation function for determining the similarity, there can be employed a following function (1) utilizing the difference in the luminance (pixel values) or a following function (2) utilizing the correlation of the luminance (pixel values):                               E                                (                          x              ,              y                        )                          =                              ∑            i                                          xe2x80x83                                                        ∑              j                                                                  [                                                      F                                                              (                                              i                        ,                        j                                            )                                                        -                                      A                                                              (                                                                        i                          -                          x                                                ,                                                  j                          -                          y                                                                    )                                                                      ]                            2                                                          (        1        )                                          σ                                (                          x              ,              y                        )                          =                                            ∑              i                                                  xe2x80x83                                                                  ∑                j                                                          {                                                      (                                          i                      ,                      j                                        )                                    -                                      A                                                              (                                                                        i                          -                          x                                                ,                                                  j                          -                          y                                                                    )                                                                      }                                                                                ∑                  i                                                                  xe2x80x83                                                                                ∑                    j                                                                                F                      2                                                                                (                                              i                        ,                        j                                            )                                                                                xe2x80x83                        ·                          xe2x80x83                                                                                ∑                  i                                                                  xe2x80x83                                                                                ∑                    j                                                                                A                      2                                                                                (                                              i                        ,                        j                                            )                                                                                (        2        )
In the foregoing equations (1) and (2), F(i, j) indicates the luminance value of the pixel at a coordinate (i, j) on the template image, and A(i, j) indicates the luminance value of the pixel at a coordinate (i-x, i-y) on the image to be searched (hereinafter, called a search image). Thus, the function (1) or (2) represents the similarity when the position of the template image is moved by (x, y) on the search image.
With the function (1), the matching point is indicated at a point where E(x, y) reaches a minimum, which can theoretically reach 0 at a minimum. With the function (2), the matching point is indicated at a point where "sgr"(x, y) reaches a maximum, which can theoretically reach 1 at a maximum.
For determining the similarity there is also known the following other evaluation function (3). It determines the number of pixels, within the entire template, for which the difference between the luminance value (pixel value) of such a pixel and the luminance value of a pixel in the search image is within a predetermined threshold value xcex5, namely it determines the numbers of the pixels in the template, having differences in the luminance value within a predetermined value from each pixel of the search image, and a point on the search images showing the largest number of such pixels is defined as the matching point to the center point of the template:                     kij        =                  {                                                                                1                                                                    (                                                                              "LeftDoubleBracketingBar"                                                                                F                                                                                (                                                                      i                                    ,                                    j                                                                    )                                                                                -                                                              A                                                                                (                                                                                i                                      -                                      x                                                                        ,                                                                          j                                      -                                      y                                                                                )                                                                                "RightDoubleBracketingBar"                                                                                xe2x80x83                                                     less than                                                       xe2x80x83                                                                              ϵ                                                )                                                                                0                                                                    (                                                                              "LeftDoubleBracketingBar"                                                                                F                                                                                (                                                                      i                                    ,                                    j                                                                    )                                                                                -                                                              A                                                                                (                                                                                i                                      -                                      x                                                                        ,                                                                          j                                      -                                      y                                                                                )                                                                                "RightDoubleBracketingBar"                                                                                xe2x80x83                                                    ≥                                                      xe2x80x83                                                                              ϵ                                                )
                                                          C                                                  (                                      x                    ,                    y                                    )                                                      =                                          ∑                i                                                          xe2x80x83                                                                            ∑                  j                                                kij                                                                        (        3        )
With this function (3), the matching point is indicated at a point where C(x, y) reaches a maximum, which can theoretically reach the number of all the pixels in the template at a maximum.
Conventionally, the object distance is determined from the images, by extracting the matching points from the images, determining the amount of parallax in each point of the image, and effecting trigonometry based on such amount of parallax, focal length and positional information of the camera.
Such a template matching method, however, in extracting the matching points between the images that have recorded an object at a finite distance from the cameras, has been associated with a drawback that the precision of extraction becomes significantly deteriorated at a certain portion of the object.
Such a drawback will be explained with reference to FIGS. 3A to 3C, which show images having recorded a car as the main object, by the two cameras 133a, 133b shown in FIG. 1A, wherein FIG. 3A shows an image obtained by the left-side camera 133a while FIGS. 3B and 3C show images obtained by the right-side camera 133b. For the convenience of explanation, the car is considered as the main object while the house and the tree are considered as the background and are assumed to be distant from the car and positioned in the back of the scene.
Now, there is considered a case of cutting out a template (template image) from the image shown in FIG. 3A, taken as a reference image. In this operation, a certain size is required for the template.
This is because the area of a point A in the sky or a point B in the door of the car in the image shown in FIG. 3A shows little change in the luminance, lacking conspicuous features and having similar luminance values therearound. Also, the area of superposed leaves of the tree at a point C has the area of similar luminance distribution therearound, and, for the extraction of exact matching points in such areas A, B and C, the template needs a certain size for detecting the variation in the distribution of the luminance.
For example, if the template is defined in the illustrated size around the point B in FIG. 3A, the template 151 contains a type in addition to the door of the car, thus showing a large variation in the luminance and allowing an exact determination of the matching point.
Now, let us consider a point D at an end of the car, which is the main object in the image shown in FIG. 3A. If the template 152 is prepared around the point D, with a same size as around the point B, the template 152 includes the house in the background, in addition to the car constituting the main object. The matching point extraction with such a template 512 results as shown in FIG. 3C, in an erroneous matching point F instead of the correct matching point E.
Such an erroneous matching results from a fact that, in the calculation of the evaluation function (similarity) in the example shown in FIGS. 3A to 3C, with respect to a point E of the search image, an area corresponding to the car in the template image shows a high similarity because the image remains the same in the template image and in the search image and an area corresponding to the background of the template image shows a low similarity because of the change in the image, whereby the point E is judged as not the matching point, whereas, with respect to a point F of the search image, the area corresponding to the background of the template image shows a high similarity because the image remains the same in the template image and the search image and the area corresponding to the car of the template image also shows a high similarity because of an eventually high proportion of the area of similar luminance values despite the change in the image, whereby the point F is finally judged as the matching point.
Such an erroneous matching is a phenomenon generally resulting from a fact that the car constituting the main object is positioned in front of the house and the tree constituting the background, thus providing a difference in the parallax. Thus, in the case of taking an object at a finite distance as the main object, the accuracy of the matching point extraction is deteriorated in an area close to the boundary between the main object and the background, or, if the main object contains a portion showing a significant change in the object distance, in an area close to the boundary of such a portion.
As explained in the foregoing, in employing the conventional template matching method for the matching point extraction, the template is required to have a certain size, but the template of such a certain size results in a deterioration in the accuracy of matching point extraction in an area close to the boundary between the main object and the background.
On the other hand, the evaluation function (3) is effective, to a certain extent, for preventing the above-mentioned deterioration of the accuracy of the matching point extraction in the area close to the boundary between the main object and the background.
However, for example, when the background occupies a major portion of the template, the number of pixels in the template showing differences in luminance within the threshold value xcex5 from a pixel in the search image becomes larger in a portion corresponding to the main object in the template image than in a portion corresponding to the background, whereby the accuracy of matching point extraction becomes deteriorated.
Another drawback lies in a fact that an occlusion area, which exists in the images prepared as shown in FIGS. 1A and 1B and which does not have the matching point, is difficult to detect.
Such a drawback will be explained with reference to FIGS. 4A and 4B, showing images obtained by the two cameras 133a, 133b shown in FIG. 1A.
As an example, the matching point for a point I in the image shown in FIG. 4A is hidden by the car in the image shown in FIG. 4B and does not exist, therefore, in this image. Such an area is called an occlusion area, and does not contain the matching point, so that the matching point extraction should be inhibited even if the similarity is evaluated as high.
For identifying such an occlusion area, there is known a method of at first preparing a template image around a point in the reference image, then searching, on the search image, a candidate matching point for a certain point (center point of the template image) of the reference image, preparing a new template image around the thus obtained candidate matching point in the search image, and searching a candidate matching point on the reference image which is now taken as a search image, utilizing the thus prepared new template image around the first-mentioned candidate matching point. If the candidate matching point searched in the reference image coincides with the center point of the initially prepared template, the candidate matching point in the search image is identified as the matching point for the center point of the initially prepared template image, but, in the case of absence of coincidence, it is identified that the matching point does not exist.
However, such a method has a drawback of possibility of erroneous matching, for example, in the case a point J in the reference image shown in FIG. 4A erroneously extracts a candidate matching point K in the search image shown in FIG. 4B because of a window in the background and the template image prepared around the point K again erroneously extracts the point J in the reference image as a candidate matching point, namely in the case of doubled erroneous extractions, or in case a point L in the reference image shown in FIG. 4A correctly extracts a point M in the search image in FIG. 4B, but such a point M erroneously extracts a candidate matching point N in the reference image shown in FIG. 4A because of the tree and the ground in the background.
An object of the present invention is to provide a matching point extracting method capable of resolving the above-mentioned drawbacks, and an apparatus therefor.
Another object of the present invention is to provide a matching point extracting method, enabling highly precise matching point extraction in the entire area of the image to be used, without distinction of the object and the background therein, and an apparatus therefor.
The above-mentioned objects can be attained, according to an embodiment of the present invention, by a matching point extracting method and an apparatus therefor for determining matching points between plural images based on the template matching method, comprising:
a template formation step of preparing mutually different plural templates from an arbitrary one of the plural images; and
a matching point determination step of determining the matching points of the plural images, utilizing, in an image area showing a specified condition, one of the plural templates prepared in the template formation step.
Still another object of the present invention is to provide a matching point extracting method, enabling matching point extraction within a short time in the entire area of the image to be used, without distinction of the object and the background therein, and an apparatus therefor.
The above-mentioned object can be attained, according to an embodiment of the present invention, by a matching point extracting method and an apparatus therefor for determining matching points between plural images based on the template matching method, comprising:
a first template formation step of preparing an initial template from one of plural input images;
a similarity operation step of determining a similarity utilizing the pixel value of each pixel in the template prepared in the first template formation step and the pixel value of each pixel in another of the input images;
a decision step of judging a specified condition based on the similarity determined in the similarity operation step; and
a second template formation step of preparing another template based on the result of a judgment in the judgment step.
Still another object of the present invention is to provide a matching point extracting method and an apparatus therefor capable of precisely determining an occlusion area or an area containing a large change in the distance in the image to be used, thereby enabling highly precise matching point extraction.
The above-mentioned object can be attained, according to an embodiment of the present invention, by a method for extracting, in synthesizing plural images, matching points of such plural images and an apparatus therefor, comprising:
a template image data formation step of entering plural sets of image data each corresponding to an image of an image frame, taking an image represented by the image data corresponding to an image frame among the thus entered image data of plural image frames as a reference image, extracting the image data, corresponding to a partial area in such a reference image, as a template image and outputting the template image data corresponding to the thus extracted template image;
a matching candidate extracting step of comparing the values of the pixel data constituting the template image data outputted by the template image data formation step with the pixel data constituting the image data corresponding to each of search images which are the images, other than the reference image, of the image data of the plural image frames entered in the template image data formation step, determining the number of pixel data showing differences smaller than a predetermined value, calculating the similarity of such a search image to the template image according to such a number of pixel data, extracting the search image showing a maximum similarity as a matching candidate for such a template image, and outputting such a matching candidate together with such a similarity;
a decision step of judging, based on the similarity data outputted by the matching candidate extraction step, whether the pixel data constituting the template image satisfy a predetermined condition; and
a template image changing step of, when the decision step identifies that the pixel data constituting the template image satisfy such a specified condition, changing the shape of the template image represented by the template image data outputted by the template image formation step and outputting such a changed template image to the matching candidate extraction step.
Still other objects of the present invention, and the features thereof, will become fully apparent from the following detailed description of the embodiments, to be taken in conjunction with the attached drawings.

Matching point extracting method and apparatus therefor


New pyridine compounds are provided along with their method of preparation. The compounds are useful as intermediates in preparing new anticancer agents. A few of the pyridine compounds are also useful for treating cancer.

The present invention relates to certain novel pyridine compounds. The compounds of the present invention are especially useful for producing new acyl derivatives of 4-demethylpenclomedine (also referred to herein as DM PEN). The acyl derivatives, in turn, exhibit anticancer activity, and are the subject of U.S. patent application Ser. No. 60/116,675 filed Jan. 21, 1999 and entitled xe2x80x9cAcyl Derivatives of 4-Demethylpenclomedine, Use and Preparation Thereofxe2x80x9d, the entire disclosure of which is incorporated herein by reference. Certain of the pyridine compounds of the present invention also exhibit anticancer activity. Accordingly, the present invention also relates to pharmaceutical compositions comprising those particular pyridine compounds, as well as a method of using them in treating cancer in a mammal. The present invention also relates to a method for producing the compounds of the present invention and to a method for producing the acyl derivatives of 4-demethylpenclomedine from the pyridine compounds of the present invention.
Even though significant advances have occurred in treatment of cancer, it still remains a major health concern. It has been reported that cancer is the cause of death of up to one of every four Americans.
Included among the known chemotherapeutic drugs are carmustine, doxorubicin, methotrexate, TAXOL(copyright), nitrogen mustard, procarbazine, and vinblastine, to name only a few. However, many chemotherapeutic drugs also produce undesirable side effects in the patient. For example, U.S. Pat. No. 4,717,726 reportedly discloses a compound suitable for inhibiting the growth of certain types of malignant neoplasms in mammals. See also Plowman et al., Cancer Res., 49 (1989), 1909-1915. The disclosed compound, 3,5-dichloro-2,4-dimethoxy-6-(trichloromethyl)pyridine, also known as penclomedine, is not satisfactory as a chemotherapeutic, however, because it is known to produce certain undesirable side effects especially in the central nervous system.
For example, neurological and hematological toxicities of penclomedine have been reported in preclinical and early clinical studies. Dose related neurotoxicity, consisting of muscle tremors, incoordination, convulsions and reduced activity, has been observed in rats. Neurotoxicity appears to be related to peak plasma drug concentrations, as it developed during or immediately after infusion and could be ameliorated by decreasing the rate of drug administration. In dogs, severe emesis and seizures have been associated with plasma penclomedine levels above 30 xcexcM. Neurotoxicity, consisting of dysmetria, ataxia, and vertigo, was also the principal dose limiting toxicity of penclomedine administered as a one hour infusion for 5 consecutive days in patients with advanced solid tumors. The presence of these toxicities, at much lower peak plasma concentrations compared to those reported in preclinical studies, may preclude the administration of higher doses of penclomedine and the achievement of concentrations associated with optimal antitumor activity. Berlin et al., Proc. Amer. Assoc. Cancer Res., 36, 238 (1005); O""Reilly et al., Proc. Amer. Soc. Clin. Oncol., 14, 471 (1995).
Some relevant background art can be found in O""Reilley et al., Clinical Cancer Research, 2 (March 1996), 541-548. This reference describes a study to assess the distribution of 14C-penclomedine in the tissues and tumors of tumor-bearing rats. The study found that the predominant radioactive species in the brain was penclomedine, which may explain the observed neurotoxicity of the drug.
More recently, 3,5-dichloro-2-methoxy-4-hydroxy-6-(trichloromethyl)pyridine or 4-demethylpenclomedine has been suggested as a compound for treating cancer. See WO 97/46531 to Hartman et al.
Notwithstanding the advances in cancer treatment that have been made, there still remains room for improved drugs that are effective in treating cancer, while at the same time exhibit reduced adverse side effects.
The present invention relates to new pyridine compounds that find especial utility as precursors for producing certain acyl derivatives of 4-demethylpenclomedine which, in turn, possess anticancer activity as will be discussed hereinbelow.
The compounds of the present invention are represented by the following formulae:
wherein
each R1 is independently an alkyl group provided that at least one R1 is an alkyl group containing at least two carbon atoms; and
each R2 is independently H, acyl or an alkyl group having at least two carbon atoms or R2 can be methyl in position 4 provided that R2 is acyl in position 6.
The present invention also relates to a process for preparing compounds of formula I by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base to produce the corresponding 3,5-dichloro-4,6-dialkoxy-2-(trichloromethyl)pyridine of formula I.
The compound according to formula II wherein both R2 are H can be prepared by reacting the compound of formula I with a dealkylating agent such as anhydrous aluminum chloride to produce didemethylpenclomedine.
The compounds according to formula II wherein at least one of R2 is acyl can be prepared by reacting didemethylpenclomedine with an acylating agent to form a corresponding acyl compound of formula II.
The acyl compound of formula II can then be reacted with an alkylating agent such as (trimethylsilyl)diazomethane or diazomethane to produce the acyl derivatives of 4-demethylpenclomedine.
These novel acyl derivatives of 4-demethylpenclomedine compounds are represented by the formula:
Pharmaceutically acceptable salts thereof can also be provided.
The present invention also relates to compounds represented by the formula
wherein one of R3 or R4 is Cl and the other of R3 or R4 is O-alkyl.
A further aspect of the present invention is concerned with producing compounds of formula IV. The compounds of formula IV can be produced by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base and separating the desired compound from the reaction mixture.
Another aspect of the present invention relates to an alternative method for producing a compound of formula I above by reacting a compound of the formula IV
wherein one of R3 or R4 is Cl and the other of R3 or R4 is O-alkyl with an alcohol in the presence of a base.
In addition, compounds of formula I above can be produced by reacting a compound of the formula
wherein R1 is an alkyl group having at least two carbon atoms with an alkylating agent.
A still further aspect of the present invention is directed to producing a compound of formula II above wherein R2 in position 4 is H and R2 in position 6 is an alkyl which comprises reacting a compound represented by the formula I
wherein each R1 is independently an alkyl group with R1 in position 4 having at least two carbon atoms with a dealkylating agent to selectively dealkylate said compound in position 4.
Compounds of the present invention wherein the R1 group located at position 4 is ethyl show anticancer activity. Accordingly, the present invention also relates to pharmaceutical compositions containing these compounds wherein the R1 group located at position 4 is ethyl, and to methods of using such compounds in treating cancer in a mammal.
Still other objects and advantages of the present invention will become readily apparent by those skilled in the art from the following detailed description, wherein it is shown and described only the preferred embodiments of the invention, simply by way of illustration of the best mode contemplated of carrying out the invention. As will be realized, the invention is capable of other and different embodiments, and its several details are capable of modifications in various obvious respects, without departing from the invention. Accordingly, the description is to be regarded as illustrative in nature and not as restrictive.
The present invention is concerned with pyridine compounds represented by the following formulae:
wherein
each R1 is independently an alkyl group provided that at least one R1 is an alkyl group containing at least two carbon atoms; and
each R2 is independently H, acyl or an alkyl group having at least two carbon atoms or R2 can be methyl in position 4 provided that R2 is acyl in position 6.
The alkyl group typically contains 1 to 22 carbon atoms and preferably 2 to 22 carbon atoms.
The R2 acyl groups can be straight or branched chained, can be unsubstituted or substituted such as with halogen such as Cl, Br and I, and/or include 5 and 6 membered rings. The ring moiety can be a carbocycle or a heterocycle including a hetero atom such as O, S or N. Typically, the acyl group contains 1-12 carbon atoms.
The present invention is also directed to compounds represented by the formula
wherein one of R3 or R4 is Cl and the other of R3 or R4 is O-alkyl.
The alkyl group typically contains 1 to 22 carbon atoms. Preferably R3 is O-alkyl and R4 is Cl.
The compounds of formula IV can be produced by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base and separating said compound from the reaction mixture. A typical base is NaOH. This process is preferably carried out under reflux with a typical alcohol being methanol.
Although many of the above precursor compounds do not exhibit any appreciable anti-cancer activity, it has been observed that at least a few of the precursor compounds show active anti-cancer activity. These compounds have the structure wherein at least the R1 group located at position 4 is ethyl and include 3,5-dichloro-4,6-diethoxy-2-(trichloromethyl)pyridine and 3,5-dichloro-4-ethoxy-6-methoxy-2-(trichloromethyl)pyridine. Therefore, those compounds wherein at least the R, group at position 4 is ethyl or pharmaceutically acceptable salts thereof can be used in treating cancer in a mammal. However, these compounds are not as active as the acyl derivatives of 4-demethylpenclomedine according to copending U.S. patent application Ser. No. 60/116,675 filed Jan. 21, 1999 and entitled Acyl Derivatives of 4-Demethylpenclomedine, Use and Preparation Thereof, the entire disclosure of which is incorporated herein by reference, and also exhibit higher toxicity as compared to these acyl derivatives of DM-PEN.
These novel acyl derivatives of 4-demethylpenclomedine compounds are represented by the formula:
and pharmaceutically acceptable salts thereof.
The acyl groups can be straight or branched chained, can be unsubstituted or substituted such as with halogen such as Cl, Br and I, and/or include 5 and 6 membered rings. The ring moiety can be a carbocycle or a heterocycle including a hetero atom such as O, S or N. Typically, the acyl group contains 1-12 carbon atoms.
Examples of such suitable acyl groups are the following, each of which has been evaluated for activity according to the present invention, and each has been characterized by mass spectroscopy:
Examples of pharmaceutically acceptable acid addition salts include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulfonic, for example p-toluenesulfonic acid.
It has been found that the acyl compounds of formula III are surprisingly and advantageously useful in treating mammalian cancer, especially human cancer. These compounds have been shown to exhibit generally superior activity in comparison to 4-demethylpenclomedine and penclomedine. Moreover, these are believed to possess reduced toxicity in comparison to both demethylpenclomedine and penclomedine (PEN).
It is further noted, as will be discussed below, that the acyl compounds of formula III are not considered to be prodrug forms of DM-PEN. Both penclomedine (PEN) and DM-PEN are inactive as cytotoxic agents in vitro but must be metabolized to produce cytotoxicity, as demonstrated by their anticancer activity in vivo, which indicates that DM-PEN, as well as PEN, is a prodrug of the ultimate activated metabolite. The proposed mechanism by which PEN and DM-PEN exhibit cytotoxicity in vivo is shown in Scheme 1 and indicates that PEN and DM-PEN are on the same metabolic activation pathway, which includes a non-acylated, free radical activated for DNA crosslinking. In contrast, it is believed (Scheme 2) that the acyl derivatives (DM-ACYL-PEN) are converted via the liver to an acylated free radical (rather than a non-acylated free radical) and, as such, are not fully activated for DNA crosslinking but remain in a prodrug form as they exit the liver and enter the circulation. The partially activated acylated free radical is transported to cells via circulation and forms an adduct with nuclear DNA. Subsequently, the adduct is deacylated by general cellular esterases particularly in the tumor cell, which allows for in situ, full activation and possibly reduced generalized host toxicity in comparison to PEN and DM-PEN, both of which are fully activated in the liver for DNA adduction and crosslinking before being transported via circulation to tumor and non-tumor cells. Deacylation generates a 4-hydroxy moiety on the pyridine nucleus, which then tautomerizes via the enol-keto mechanism to produce an alpha-haloketo moiety at the 4,5-positions in which the 5-chloro function is activated for displacement by a nucleophilic moiety on the DNA for completion of a DNA crosslink, as shown in Scheme 2. This mechanism is further supported by the generally superior activity of the acyl derivatives in comparison to DM-PEN vs. both subcutaneously (s.c.)- and intracerebrally (i.c.)-implanted human MX-1 mammary tumor xenograft, s.c.-implanted human U251 CNS tumor xenograft, and both parent, and particularly, cyclophosphamide (CPA)-resistant lines of P388 leukemia, as shown in Tables 1-4 below.
The acyl derivatives of DM-PEN can be synthesized by the following route that employs the pyridine compounds of the present invention.
As illustrated above, the acyl derivatives of DM-PEN can be produced by reacting 3,4,5,6-tetrachloro-2-(trichloromethyl)pyridine with an alcohol in the presence of a base to produce the corresponding 3,5-dichloro-4,6-dialkoxy-2-(trichloromethyl)pyridine (i.e. compound of formula I); which in turn is reacted with a dealkylating agent such as anhydrous aluminum chloride to produce didemethylpenclomedine. (Compound of formula II wherein each R2 is H.)
Of course, other dealkylating agents can be used if desired. The didemethylpenclomedine is then reacted with an acylating agent to form the corresponding acyl derivatives of demethylpenclomedine (i.e. compound of formula II wherein at least one R2 is acyl), which is then reacted with an alkylating agent such as (trimethylsilyl)diazomethane to produce the acyl derivatives of DM-PEN.
It is understood that other acylating agents and alkylating agents can be used. Moreover, various reaction parameters such as temperature, relative amounts, and pressure can be selected by those skilled in the art once aware of the present disclosure.
In addition, compounds of formula I disclosed above can be produced by reacting a compound of the formula
wherein one of R3 and R4 is Cl and the other of R3 and R4 is O-alkyl with an alcohol in the presence of a base.
A typical base is NaOH, and the reaction is typically carried out under reflux.
Moreover, compounds of formula I disclosed above can be produced by reacting a compound of the formula
wherein R1 is an alkyl group having at least two carbon atoms with an alkylating agent such as (trimethylsilyl)diazomethane.
R1 typically has 2-22 carbon atoms.
Compounds of formula II disclosed above wherein R2 in position 4 is H and R2 in position 6 is an alkyl can also be prepared by reacting a compound represented by the formula
wherein each R1 is independently an alkyl group with R1 in position 4 having at least two carbon atoms with a dealkylating agent to selectively dealkylate said compound in position 4.
A typical dealkylating agent is dimethyl sulfoxide.
The reaction is typically carried out under elevated temperatures such as about 140 to about 160xc2x0 C., an example of which is about 150xc2x0 C.
The alkyl group in the 4 position typically contains 2-22 carbon atoms, and preferably 2-6 carbon atoms, examples of which are ethyl and n-butyl. The alkyl group is preferably straight chained. For instance under the conditions employed in Example 3 below, using isopropyl did not achieve the desired result.
The above process is suitable for producing 4-demethylpenclomedine which in turn can be used to produce the above disclosed acyl derivatives of 4-demethylpenclomedine.
Novel precursors for producing the acyl derivatives of the present invention are represented by the following formulae:
wherein
each R1 is independently an alkyl group provided that at least one R1 is an alkyl group containing at least two carbon atoms; and
each R2 is independently H, acyl or alkyl having at least two carbon atoms or R2 can be methyl in position 4 provided that R2 is acyl in position 6.
The alkyl group typically contains 1 to 22 carbon atoms and preferably 2 to 22 carbon atoms.
The R2 acyl groups can be straight or branched chained, can be unsubstituted or substituted such as with halogen such as Cl, Br and I, and/or include 5 and 6 membered rings. The ring moiety can be a carbocycle or a heterocycle including a hetero atom such as O, S or N. Typically, the acyl group contains 1-12 carbon atoms.
Although many of the above precursor compounds do not exhibit any appreciable anti-cancer activity, it has been observed that at least a few of the precursor compounds show active anti-cancer activity. These compounds have the structure wherein at least the R1 group located at position 4 is ethyl and include 3,5-dichloro-4,6-diethoxy-2-(trichloromethyl)pyridine and 3,5-dichloro-4-ethoxy-6-methoxy-2-(trichloromethyl)pyridine. Therefore, those compounds wherein at least the R, group at position 4 is ethyl or pharmaceutically acceptable salts thereof can be used in treating cancer in a mammal. However, these precursor compounds are not as active as the acyl compounds of the present invention and also exhibit higher toxicity as compared to acyl compounds of the present invention.

Pyridine compounds, use and preparation thereof


Methods, systems, and devices for wireless communications are described. An antenna structure for wideband coverage may include a first bowtie antenna disposed in a first plane. The first bowtie antenna may be, for example, an elliptical bowtie antenna or a triangular bowtie antenna. The antenna structure may also include a plurality of additional bowtie antennas, each of the plurality of additional bowtie antennas disposed in a different plane parallel to the first plane. The first bowtie antenna and the plurality of additional bowtie antennas may be stacked in a first direction perpendicular to the first plane to form a bowtie antenna stack. The antenna structure may include a plurality of bowtie antenna stacks. The antenna structure may also include a staggered conductive wall.

The following relates generally to wireless communication, and more specifically to multilayer bowtie antenna structures.
Wireless communications systems are widely deployed to provide various types of communication content such as voice, video, packet data, messaging, broadcast, and so on. A wireless multiple-access communications system may include a number of base stations or network access nodes, each simultaneously supporting communication for multiple communication devices, which may be otherwise known as user equipment (UE).
Base stations, UEs, and other wireless communications devices may use antennas to transmit and receive signals on a wireless medium. The design of the antenna in a particular device may impact whether and how well the device may transmit and receive signals having a certain frequency. Different types of systems may operate at different frequencies, and therefore the antennas for different types of systems may be designed based on the operating parameters required for those systems. For example, fifth generation (5G) networks in the United States operate in the 28 GHz band, and accordingly antennas for 5G devices in the United States may be designed to operate at that frequency.


Provided is a method of manufacturing an ornament inlaid with mother-of-pearl, which makes the ornament inlaid with mother-of-pearl look more beautiful by harmoniously forming the ornament inlaid with mother-of-pearl on a corresponding surface. The method includes: applying an acrylic polymer onto a surface to be inlaid with mother-of-pearl to enable subsequent painting to be smoothly performed; painting the surface applied with the acrylic polymer with colors; drawing a picture on the surface painted with the colors; adding and boiling each of the mother-of-pearl and salt in water having a dyeing color dissolved therein for each color, and bonding the mother-of-pearl dyed with each color onto a corresponding portion of the surface of the picture by using an adhesive, followed by drying; and applying paint onto the entire surface, followed by drying.

In Korean Patent Application Laid-Open No. 10-2004-0023144 (Laid-Open Date: Mar. 18, 2004) entitled "Decorating Member using Mother-of-Pearl and Manufacturing Method and Using Method thereof" related to the present invention, the decorating member is a decorating member for nail art or a decorating member for decorating an appearance of a mobile phone, and is characterized in that the decorating member includes mother-of-pearl having several natural colors, a plurality of elongated grooves is formed in the decorating member in a width direction thereof so that the decorating member is in close contact with a surface of an object to be attached with the decorating member at the time of attaching the decorating member, and the decorating member is integrated with the mother-of-pearl.
However, according to the related art, even though the mother-of-pearl used in the decorating member has several natural colors and is integrated with the decorating member, there is a limitation in harmoniously forming an ornament inlaid with mother-of-pearl.

Method of manufacturing ornament inlaid with mother-of-pearl


In a multi-electrode welding torch, electrodes (2) are configured into a shape that has an arc-shaped curved surface area (R) in at least a portion of a cross-section thereof that is orthogonal to the longitudinal direction thereof. Collets (4) are each provided with a groove portion (4a) in which an electrode (2) is fitted, and whose inner wall surfaces (4b) come into contact in a plurality of locations with the curved surface area (R) when viewed in the longitudinal direction of the electrode (2).

In Patent document 1, for example, a multi-electrode type of welding torch that is able to achieve high-speed welding when performing TIG welding is disclosed.
As is shown in Patent document 1, this type of multi-electrode welding torch is provided with a pair of electrodes that are placed opposite each other on either side of an insulating material, and a collet or the like that fixes these electrodes in position.
In addition, in Patent document 1, in order to weld an even narrower groove, a system in which the electrodes are formed in a thin plate shape, and the distal ends of the electrodes are formed as pointed tips is employed.