A high-density semiconductor memory device may be provided with redundant memory, so that it is capable of repairing defects generated in a normal memory cell array by using a spare memory cell array which has a plurality of sub memory cell arrays, split word line driver blocks and sense amps. The spare memory cell array includes a plurality of unit spare mats, each having a given number of the sub memory cell arrays, split word line driver blocks, spare sense amps, and a corresponding spare column decoder. The spare memory cell array further includes a plurality of spare row decoders. A control unit is provided for controlling the split word line driver blocks included in each of the unit spare mats in response to given address signals.

1. Field of the Invention
The present invention relates to a semiconductor memory device, and more particularly to a redundancy thereof.
2. Description of Background Information
The cost of a semiconductor integrated circuit depends upon the yield in manufacturing. In order to improve manufacturing yield, redundancy memory cells (or spare memory cells) may be provided apart from a fundamental memory cell (or normal memory cell). If a few defective bits (or defective cells) are found in the fundamental memory cell, a redundancy method may be employed to replace the defective cells with the spare memory cells. However, in a high density integrated memory device having a large capacity of more than 256Mb, a stand-by current defect (DC current leakage) and block failures are frequently generated. Stand-by current defects (DC current leakage) are frequently caused during a manufacturing process due to an increase in chip size, and block failures are frequently generated due to a lack of plate margin for manufacturing (e.g., the width of the line becomes narrower).
A stand-by current defect (DC current leakage) causes a stand-by power dissipation due to current leakage from a defective row. A block failure results when there are a plurality of defective word lines or bits lines, which may be generated, for example, due to a short of a word line or a bit line with another word line or bit line adjacent thereto. Accordingly, since a block failure results from more than one defective word line or bit line, it cannot be repaired unless there is a spare row or spare column which can be substituted for the defective word line or bit line. Accordingly, high density integrated semiconductor memory devices present unique defects and failures which require improved strategies to effectively repair defective memory cells of a die.
A recent technique proposed for solving the redundancy problems associated with large capacity, high density semiconductor memory devices is disclosed by M. Asakura et al. and Mitsubishi Electric Corporation in a paper entitled "A 34ns 256Mb DRAM with Boosted Sense-Ground Scheme", ISSCC, pp. 140-141 (1994), the content of which is hereby incorporated herein by reference in its entirety. FIG. 1 illustrates the redundancy method disclosed in this paper. FIG. 1 includes a sub memory cell array 30 which comprises a normal sub memory cell array 320 and a spare sub memory cell array 340. Normal sub memory cell array 320 comprises a plurality of sub blocks, ranging from SUB BLOCK 1 to SUB BLOCK 32; and spare sub memory cell array 340 comprises a plurality of spare sub blocks, ranging from SPARE SUB BLOCK 1 through SPARE SUB BLOCK 32.
A normal row decoder NRD and a spare row decoder SRD are respectively connected to normal sub memory cell array 320 and spare sub memory cell array 340 for decoding rows within the respective arrays. A column decoder CD is shown in FIG. 1 to the right of sub memory cell array 30, and is provided for decoding the columns within either of normal sub memory cell array 320 and spare sub memory cell array 340.
A fuse box 10 is provided and has an output connected to each of a plurality of decoding elements provided within spare row decoder SRD for respective spare sub blocks. Normal row decoder NRD and spare row decoder SRD comprise a common input which receives a voltage signal VWLH, for providing a boosting voltage to a word line of the memory cell. That voltage is coupled to each of the plural row decoding elements through either a fuse 1 or a transistor switch 2.
If a stand-by current defect (i.e., a DC current leakage) is generated in the last sub block (SUB BLOCK 32) included in normal sub memory cell array 320, its corresponding row decoder fuse 1 is blown out, so that the voltage signal VWLH is not provided to the word line corresponding to that sub block. Consequently, the path of the leakage current is severed. In addition, the leakage path of the stand-by current may be formed by a bridge defect between a cell plate and a bit line. When such a bridge defect exists, while a connection is established between plate voltage VCP to each sub block of normal sub memory cell array 320 through a column decoder fuse 3 (or to a spare sub block through the use of a column decoder transistor switch 4), the path of the stand-by leakage current may be severed by turning on a column detector transistor switch 4 connected to the corresponding spare sub block, instead of blowing a column detector fuse 3 of the corresponding normal sub block.
FIG. 1A illustrates a detailed block diagram of the prior art layout. Row decoders "r1" are assigned so as to correspond to each sub block (for example, a set of sixteen 256 Kb unit array has a memory capacity of 4Mb) "sub1," one by one. Column decoders "c1" are assigned so as to correspond to each unit array, each having capacity of 256Kh, one by one. The above unit array is arranged along same column within a plurality of the sub blocks. Thus, the spare memory cell array, SMCA, independently uses the row decoder "sr1" for redundancy, autonomous from the above row decoder "r1" which is assigned to the normal memory cell array NMCA, and uses the column decoder "c1" in common with the normal memory cell array NMCA. In a memory device having a memory capacity of 256Mb, the sub block connected to a row decoder has a memory capacity of 2Mb; whereas, in a memory device having a memory capacity of 1Gb, the sub block connected to a row decoder has a memory capacity of 4Mb as shown in FIG. 1A. For example, therefore, in case that defective cells are detected in five sub blocks "sub 1", in order to carry out a repair operation block by block, space sub memory cell arrays of 10Mb and 20Mb are respectively required in the semiconductor memory devices of 256Mb and 1Gb. Since the spare sub memory cell arrays of 20Mb is required in the memory system as shown in FIG. 1A, five spare sub blocks "rsub 1" are employed to carry out the repair operation. As a result, in the high density integrated semiconductor memory device having a large capacity, the redundancy efficiency becomes significantly low so as to inevitably cause an increase in the chip size.
The illustrated conventional redundancy method, as described above, presents several disadvantages. In order to replace a normal sub block unit in memory cell array 30, a spare sub block must be available which is connected to the same common row decoder. In a semiconductor memory device having a large capacity of more than 256Mb, the sub memory cell array 320 connected to one row decoder will generally have a memory capacity of about 2Mb. In a semiconductor memory device of 1Gb, the sub memory cell array has a memory capacity of 4Mb. Therefore, for example, if five sub memory cell arrays have a stand-by current defect (i.e., a current leakage), in order to repair such a defect, spare sub memory cell arrays of 10Mb and 20Mb are respectively required in each of the above semiconductor devices (of 256Mb and 1Gb). Therefore, the size of the chip will be significantly increased. Another disadvantage occurs when a leakage current is generated in one normal sub block, since the entire sub memory cell array 30 must be replaced by a spare sub memory cell array. Accordingly, redundancy efficiency is significantly low.
A further disadvantage is that the spare sub block shares a column decoder CD with its corresponding normal sub block, and redundancy information based upon the fuse program is not applied to column detector CD. Accordingly, if a defect is generated in two or more normal sub blocks within a common column, it is impossible to replace the defective memory cell array 30 with spare sub blocks which are arranged only according to their row.
In addition, in the conventional redundancy method illustrated in FIG. 1, there is no ability to properly repair leakage current defects generated in parts of the memory circuitry not corresponding to a particular memory cell. Such defects may occur, for example, in: a core circuit area (e.g., an area where there is a sense amp), a row decoder, a column decoder, bit lines, and data input/output lines.
In addition, end differences in peripheral areas of the circuit are lower than such differences where the memory cells are arranged. Accordingly, dirt particles are easily deposited during the manufacturing process, increasing the occurrence of bridge defects.

Semiconductor memory device having redundancy function


A heat sink includes a frame having an opening, the opening extending in a thickness direction of the frame, the opening having a first opening part and a second opening part, the second opening part being larger than the first opening part in a plan view perpendicular to the thickness direction, a wall standing on the frame at an edge of the opening, a groove formed in the frame beside the wall, and a plate member including a first plate disposed in the first opening part and a second plate disposed in the second opening part and larger than the first plate in the plan view, wherein the second opening part is larger than the second plate in the plan view to leave a gap therebetween, and the wall is bent toward the opening to be in contact with an edge along a perimeter of the second plate.

A swage member is fastened at an end thereof to another member by swaging. Such a swage member includes, at the end thereof, a shape retaining part having a shape retaining surface whose shape needs to be retained, a swage part to be swaged, and a groove disposed between the swage part and the shape retaining part to prevent the shape retaining surface from being deformed (see Japanese Patent Application Publication No. 2005-034857, for example).
A conventional swage member has a portion thereof plastically deformed toward a counterpart member to provide a swage engagement so that the swage member partly covers the surface of the counterpart member. With this arrangement, sufficient area size for mounting cannot be secured for the purpose of mounting another member, a device, or the like on such a surface. Such a lack of mounting area size results in a failure to provide sufficient cooling performance when the swage member is used in a heat sink, for example.
Accordingly, it may be desired to provide a heat sink and a semiconductor device that have sufficient area size for mounting and that exhibit sufficient cooling performance.


An externally mounted, reconfigurable machine metering and monitoring apparatus for selectively metering and monitoring operational status of a predetermined type of machine. The reconfigurable machine metering and monitoring apparatus has a data processor, a data input device in communication with the data processor, an algorithmic software directing the data processor, a data storage unit, wherein discrete data associated with the machine operational status is stored and supplied to the data processor such that the data processor, directed by the algorithmic software, can automatically determine and report the current and historical operating status of the metered/monitored machine. The multi-purpose metering and monitoring apparatus is configurable to selectively meter and monitor the operating status of predetermined types of machines including, but not limited to, an injection molding machine, a blow molding machine, a mill insertion machine, a stuffing machine, a vending machine, an office machine, and other like machines.

1. Field of the Invention
The present invention relates generally to metering and monitoring systems, and more particularly to a multi-purpose monitoring apparatus which is externally attachable for selective use with injection molding machines, die stamping machines, blow molding machines, mill insertion and/or stuffing machinery, vending machines, copy machines, facsimile machines, duplicating machines, and the like.
2. Description of the Prior Art
Machine monitoring systems familiar to those skilled in the art are generally dedicated to a specific function or set of functions associated with a single type of machine. For example, one type of machine monitoring system known in the art is specifically dedicated to monitoring office machine data. Other types of machine monitoring systems are dedicated to monitoring injection molding machine functional status. Such dedicated machine monitoring systems have disadvantages however, such as the perpetual necessity to completely redesign the associated hardware, firmware and/or software when it is desired to use the same monitoring system for monitoring the operational status of dissimilar types of machines. It is well known for example, that an injection molding machine monitoring system is generally designed to accommodate specific attributes of the particular injection molding machine being monitored, e.g. communications protocols, physical data input mechanisms and/or devices. Furthermore, such dedicated monitoring systems are not easily reconfigured to accommodate future modifications to the machine(s) being monitored. It is therefore advantageous to have a generic machine metering and monitoring apparatus that is easily externally attachable and adaptable for use with more than a single type of machine where it is necessary or otherwise desirable to continuously meter and/or monitor the operational status of the machine(s).
U.S. Pat. No. 5,611,975, issued Mar. 18, 1997, U.S. Pat. No. 5,539,650, issues Jul. 23, 1996, U.S. Pat. No. 5,518,671, issued May 21, 1996, U.S. Pat. No. 5,309,369, issued May 3, 1994, and U.S. Pat. No. 5,301,120, issued Apr. 5, 1994 each disclose methods and apparatus dedicated to injection machine data collection and/or control. U.S. Pat. No. 5,258,918, issued November 1993, U.S. Pat. No. 5,229,952, issued Jul. 20, 1993, and U.S. Pat. No. 5,216,617, issued Jun. 1, 1993 are specifically directed to control and/or management of injection molding machines. U.S. Pat. No. 5,195,029, issued Mar. 16, 1993 and U.S. Pat. No. 4,965,742, issued Oct. 23, 1990, each disclose control systems suitable for controlling injection-molding machines, but which are not easily and efficiently transportable from one machine of interest to another.
U.S. Pat. No. 5,282,127, issued Jan. 25, 1994, to Mii, entitled Centralized Control System For Terminal Device, discloses a centralized control system comprising interface circuits which are provided in respective terminal devices and communications units for transmitting collected information to a remote control device. The system disclosed by Mii is complex and necessarily requires providing each terminal device with a dedicated interface circuit.
U.S. Pat. No. 5,412,779, issued May 2, 1995, to Motoyama, entitled Method And Apparatus For Controlling And Communicating With Business Office Machines, discloses apparatus dedicated for controlling and communicating with business office devices, such as copiers, facsimiles and/or printers and is not easily adapted for use with other types of machines such as manufacturing equipment, e.g. injection molding machines, die stamping machines, and the like which often requires monitoring analog data in contradistinction with the monitored binary data described in the Motoyama patent.
U.S. Pat. No. 5,084,875, issued Jan. 28, 1992, to Weinberger et al., entitled System For Automatically Monitoring Copiers From A Remote location, discloses a system for remotely monitoring the operational status of one or more copy machines having computers integrated therein. The system disclosed by Weinberger et al. is dedicated to remote monitoring of copy machines and necessarily requires a translator device. Thus, the monitoring system disclosed by Weinberger et al. is similar to the system and apparatus disclosed in the '127 and '779 patents in that it is not easily adapted for use with other types of machines, e.g. manufacturing equipment.
U.S. Pat. No. 4,965,676, issued Oct. 23, 1990, to Ejiri et al., entitled Facsimile Remote Diagnostic System is yet another system dedicated for use with a single type of machine, i.e. facsimile apparatus.
What is needed is a generic type of machine metering and monitoring apparatus that is versatile enough to be easily externally attached and adaptable for use with more than a single type of machine, e.g. office machines, industrial/manufacturing machines, and/or commercially applied machines, where it is necessary or highly desirable to continuously monitor the operational status of the machine(s) of interest.

Multi-purpose machine metering/monitoring apparatus


The present invention relates to a manufacturing process of a sub-module having an electromagnetic shield. Initially, a meta-module having circuitry for two or more sub-modules is formed. An overmold body is placed over the circuitry for all of the sub-modules. The overmold body of the meta-module is sub-diced to expose a metallic layer grid around each of the sub-modules. Next, an electromagnetic shield is applied to the exterior surface of the overmold body of each of the sub-modules and in contact with the metallic layer grid. The meta-module is then singulated to form modules having two or more sub-modules.

Electronic components have become ubiquitous in modern society. The electronics industry proudly, but routinely, announces accelerated clocking speeds and smaller integrated circuit modules. While the benefits of these devices are myriad, smaller and faster electronic devices create problems. In particular, high clock speeds inherently require fast transitions between signal levels. Fast transitions between signal levels create electromagnetic emissions throughout the electromagnetic spectrum. Such emissions are regulated by the Federal Communications Commission (FCC) and other regulatory agencies. Furthermore, fast speed transitions inherently mean higher frequencies. Higher frequencies mean shorter wavelengths, requiring shorter conductive elements to act as antennas to broadcast these electromagnetic emissions. The electromagnetic emissions radiate from a source and may impinge upon other electronic components. If the signal strength of the emission at the impinged upon electronic component is high enough, the emission may interfere with the operation of the impinged upon electronic component. This phenomenon is sometimes called electromagnetic interference (EMI) or crosstalk. Dealing with EMI and crosstalk is sometimes referred to as electromagnetic compatibility (EMC). Other components, such as transceiver modules, inherently have many radiating elements that raise EMI concerns. Thus, even modules that do not have high clock speeds may need to address EMI issues. Furthermore, sub-modules making up a module may need to be shielded from EMI transmissions.
One way to reduce EMI to comply with FCC regulations is to shield the sub-modules. Typically the shield is formed from a grounded conductive material that surrounds the sub-module. When electromagnetic emissions from the sub-module strike the interior surface of the conductive material, the electromagnetic emissions are electrically shorted through the grounded conductive material, thereby reducing emissions. Likewise, when emissions from another radiating element strike the exterior surface of the conductive material, a similar electrical short occurs, and the sub-module does not experience EMI from other sub-modules.
However, as the sub-modules continue to become smaller from miniaturization, creating effective shields that do not materially add to the size of the sub-module becomes more difficult. Thus, there is a need for an electromagnetic shield that is inexpensive to manufacture on a large scale, does not substantially change the size of the sub-module, and effectively deals with EMI concerns.

This patent is subject to a terminal disclaimer.

Sub-module conformal electromagnetic interference shield


The present invention relates to a method of controlling insects on plants. This involves applying a hypersensitive response elicitor polypeptide or protein in a non-infectious form to a plant or plant seed under conditions effective to control insects on the plant or plants produced from the plant seed. Alternatively, transgenic plants or transgenic plant seeds transformed with a DNA molecule encoding a hypersensitive response elicitor polypeptide or protein can be provided and the transgenic plants or plants resulting from the transgenic plant seeds are grown under conditions effective to control insects.

The introduction of synthetic organic pesticides following World War II brought inestimable benefits to humanity and agricultural economic profitability. The widescale deployment of DDT resulted in the complete riddance, from entire countries, of serious public pests such as malaria mosquitoes. The use of DDT, other organochlorines, and, later, organophosphorus and carbamate materials was enthusiastically adopted into control programs despite occasional warnings about the hazard of unilateral approaches to pest control.
The development of new pesticides and the increasing amounts of pesticides used for pest control are closely correlated with the development of pest resistance to chemicals. The number of pesticide resistant species has greatly increased since the adoption of DDT in 1948. As a result, by the 1980s, the number of reports of pesticide resistance for arthropod pests was listed as 281, for plant pathogens 67, and for weeds 17. These numbers have steadily increased to the present day. Thus, the need for biological control agents, especially those with broadbase activity is especially important.
The present invention is directed to overcoming these problems in the art.

Insect control with a hypersensitive response elicitor


A method for the direct analysis of analyte in keratinized structures, e.g., hair, fingernails and toenails, which comprises preparing a mixture containing a low redox potential compound such as dithiothreitol or dithioerythritol, an enzyme suitable for the degradation of the keratin structure and a sample of the keratin structure; permitting the enzyme to at least substantially degrade the sample of keratin structure, and subjecting the mixture to analysis to determine the identity and amount of analyte in the keratin substance sample. To accelerate the method, cupric sulfate or sodium arsenite may be added to the mixture after degradation of the keratin sample. The enzyme may be a peptidase, endopeptidase or proteinase, with papain, chymopapain, and proteinase K being preferred for use in the invention.

In the past, hair analysis techniques for the detection of trace metals were developed that purported to provide information on an individual's nutritional status. One objection to the use of these techniques is the difficulty of distinguishing between trace metals deposited in hair from the bloodstream and metals which have become embedded in hair through external contact with, for example, water and cosmetic agents. Consequently, these techniques are not considered useful by the medical community for diagnosing nutritional problems, and therefore have not been considered sufficiently accurate to determine the level of a particular trace metal consumed by a subject.
The problems with previous hair analysis techniques have caused reliance on urine and blood analysis techniques for the detection of ingested chemicals, e.g., drugs-of-abuse, medications and toxic chemicals, in a subject. However, these techniques are also known to be disadvantageous in that the duration and intensity of use or exposure cannot be ascertained. Urine and blood analysis, at best, can provide short term information concerning ingested drugs or chemicals such as drugs-of-abuse. In addition, there are also problems with the interpretation of such results. For example, the detection of a low level of ingested chemical in the urine could mean that a subject ingested a small amount of the drug or chemical very recently or a larger amount several days earlier. Thus, chronic drug use cannot be determined with these methods without repeated testing.
In response to the problems of establishing a reliable and accurate method that would measure both the duration and intensity of use of drugs-of-abuse, medications, toxic chemicals, etc., work performed by Dr. Werner A. Baumgartner, as reported in "Radioimmunoassay of Hair for Determining Opiate Abuse Histories", J. Nucl Med 20:749-752 (1979), determined that long-term histories of exposure to drugs-of-abuse can be obtained through the analysis of mammalian body hair, since these substances are "trapped" within individual hair fibers during their synthesis. In this respect, hair was shown to act like a tape recorder, i.e., past exposure histories can be evaluated through sectional analysis of hair samples. It was found that heroin, once in the bloodstream, will find its way into hair as it is synthesized.
Thus, it was discovered in this study and confirmed by subsequent studies that a variety of chemicals, such as drugs-of-abuse, medications, toxic chemicals, etc., hereinafter collectively referred to as "analyte", are trapped by hair during its synthesis and that these substances are "locked up" in hair for essentially the duration of the hair. This was found to be true for head and body hair as well as for other keratinized structures such as fingernails. Suzuki et al., Forensic Sci. International, 24:9-16, 1984. These entrapped substances cannot be washed out of hair, and are released only upon complete destruction of the hair fiber.
Prior art methods of extracting an analyte from hair included subjecting the hair to hot methanol solutions (Baumgartner et al., J. Nucl Med 20, 748, 1979) and by overnight incubation of hair in an alkaline or acid medium. D. Valente, et al., Clinical Chemistry, 1952, Vol. 27, No. 11, 1981. Prior methods also include the use of a mortar and pestle to release the entrapped analyte in conjunction with a solvent.
However, solvent extraction procedures suffer from several problems in accurately determining the presence and amount of an ingested analyte. One of these problems is that the solvent extraction methods frequently remove only a small unknown and variable fraction of the total analyte present in the hair sample. Such methods also tend to be time consuming, and generally involve elevated temperatures which may damage the analyte. Another disadvantage is that different analytes require different solvents for extraction. For example, a hair sample containing morphine, phenylcyclindine ("PCP"), cocaine and marijuana has to be extracted sequentially with several different solvents, which is a very time consuming procedure, particularly since the solvents have to be evaporated before analysis can proceed.
Other methods and studies pertaining to the degradation of hair and hair analysis include:
O. Suzuki, et. al., in a publication by Elsevier Scientific Publishers Ireland Ltd., discloses a method for detecting methamphetamine and amphetamine in nail clippings or hair in which the substance was first washed in a mixture of methanol and water and dissolved in sodium hydroxide, followed by analysis of the extracted drug.
A.W. Holmes, in Textile Research Journal, 706-712, August 1964, discloses the degradation of human hair by papain using sodium sulfite as enzyme activator.
Annette M. Baumgartner, et al., in the Journal of Nuclear Medicine, 20:748-752, 1979, discloses the extraction of morphine and heroin from hair by pulverizing hair with a mortar and pestle followed by treatment with methanol.
D. Valente, et al., in Clinical Chemistry, Vol. 27, No. 11, 1981, discloses Dr. Baumgartner's technique of subjecting hair to a treatment of hot methanol to effectuate extraction of drugs of abuse as well as the author's technique of extracting morphine in an acid or alkaline medium.
A.M. Baumgartner, et al., in Journal of Forensic Sciences, p. 576-81, July 1981, discloses the extraction of PCP with mortar and pestle followed by treatment with methanol. The extracted PCP was then analyzed with RIA.
Smith et al., in Journal of Forensic Sciences, Vol. 26, No. 3, July 1981, pp. 582-586, disclose the testing of hair for the presence of phenobarbitol, in which a single head hair was washed, dried, cut in 2 mm lengths and added to 0.2 ml 0.1% SDS/saline solution, and a sample assayed by radioimmunoassay.
W.A. Baumgartner, Black, et al., in J. Nucl Med 23:790-892, 1982, discloses the extraction of cocaine from hair samples by refluxing the hair samples in ethanol followed by RIA analysis.
Ishiyama, et al., in Journal of Forensic Sciences, Vol. 28, No. 2, April 1983, pp. 380-385, disclose a method whereby hair from methamphetamine addicts was dissolved using 1.5N hydrochloric acid at a pH between 1 and 2, followed by analysis using a gas chromatograph and mass spectrometry.
K. Puschel, et al., in Forensic Science International, 21 (1983) 181-186, discloses the dissolving of hair samples by exposure to sodium hydroxide and heat followed by analysis for the presence of morphine by RIA.
O. Suzuki, et al., in Journal of Forensic Sciences, Vol. 29, No. 2, April 1984, pp. 611-617, discloses the detection of methamphetamine and amphetamine in a single human hair by gas chromatography and chemical ionization mass spectrometry. The hair sample was first dissolved in a sodium hydroxide solution to which was added N-methylbenzylamine.
N.J. Haley et al., in Clin. Chem. 31/10, 1598-1600 (1985), discloses the analysis of hair for nicotine and cotinine, in which washed hair samples were dissolved in a buffer solution containing gelatin, sodium chloride, Tris and EDTA, and adjusted to pH 7.4. Samples were then analyzed by radioimmunoassay.
Sramek, Baumgartner, et al., in A.M.J. Psychiatry 142:8, August 1985, discloses the analysis of hair samples of psychiatric patients with methanol extraction and radioimmunoassay.
Baumgartner, et al., in Clinical Nuclear Medicine, vol. 10, September 1985, discloses the benefits of extracting entrapped drugs of abuse from hair followed by RIA analysis.
Gill, et al., in Nature, Vol. 318, p. 577 (1985) discloses the use of an SDS/proteinase k/dithiothreital mixture to extract DNA from whole blood, whole semen, vaginal fluid, hair roots, bloodstains and semen stains. The article states that "no DNA could be isolated from hair shafts".
Smith et al., in J. Forensic Sci. 1986, 31(4), 1269-73, discloses the detection of cocaine in perspiration, menstrual bood stains and hair using RIA.
M. Margio, et al., in "Determination of Morphine and Other Opioids in the Hair of Heroin Addicts by HPLC and MS/MS" at the International Conference, University of Verona, Jun. 25-26, 1986, discloses various methods to assay morphine from hair samples.
M. Marigo, et al., in the Journal of Analytical Toxicology, Vol. 10, July/August 1986, discloses a method for the quantitative determination of morphine contained in the hair of heroin addicts, by means of heat-acid hydrolysis, pre-column dansyl derivatization, straight phase liquid chromatography and fluorescence detection.
Smith, et al., in Journal of Forensic Sciences, Vol. 31, No. 4, October 1986, pp. 1269-1273, disclose a method for the analysis of hair for the presence of drugs whereby hair samples were first washed, cut into small segments, mechanically pulverized for six minutes, refluxed in ethanol and the samples analyzed using radioimmunoassay.
M. Michalodinitrakis, Med.Sci.Law (1987), Vol. 27, No. 1, discloses the detection of cocaine in rats from the analysis of hair samples, which were dissolved upon exposure to 30 1.5 N HCL, which brought the pH value to 1-2, following incubation with 0.01N HCl at 37.degree. C. for one hour.
Pelli, et al., in Biomedical and Environmental Mass Spectrometry, Vol. 14, 63-68 (1987) discloses a procedure for the identification of morphine in the hair of heroin addicts in which hair is treated with diethylether and hydrochloric acid followed by dissolution of the dried extract in methanol.
Higuchi et al., in Nature, Vol. 332, p. 543 (1988) disclose a method for dissolving hair at pH 8 by the action of dithiothreitol, proteinase K, and 2% sodium dodecylsulfate in order to extract DNA from the digest by a complex chemical extraction method.
Also noted is the existence of certain patents, e.g., U.S. Pat. Nos. 3,986,926, 3,966,551, 3,939,040 and 3,623,950, which pertain to depilatory agents for the tanning of hides, and disclose the use of certain enzymes, including papain, in the dehairing process.
However, these and other prior art methods have proven disadvantageous for the reasons noted above and/or because they degrade the analyte probes (e.g., antibodies) of biological analytical methods, thereby preventing the use of such highly sensitive analytical techniques.
Thus, there exists a need for an analyte detection method that can rapidly and completely solubilize a certain analyte from keratinized structures of the body such as hair, fingernails, toenails and skin of a subject and which permits direct analysis of the identity of the analyte and the duration of use of the analyte in, or exposure to, a subject, without destroying the analyte of interest and/or an analyte probe of biological analytical methods.


A memory interface system is operable with a ARINC 629 terminal controller for directing storage of data message received by the terminal controller into a memory device, and associating with each of the words stored in the memory device a tag word which identifies the word type being stored.

1. Field of the Invention
The present invention relates to serial data transmitter/receiver systems, and more particularly to a last word monitor system which cooperates with an ARINC 629 terminal controller.
2. Description of the Related Art
The operation of aircraft relies heavily on many electrical avionic subsystems for successful flight missions. These electrical subsystems include, among others, flight management, navigation, auto-pilot, global positioning systems, landing systems, fuel quantity systems, and the like. Many of these electrical subsystems require communications therebetween, and some sensing subsystems may be located remote from the processing subsystems. Since many of these subsystems may be provided by different manufacturers, standards have been defined for the transfer of data messages on data buses that are wired throughout the aircraft. One such standard is the ARINC (Aeronautical Radio Incorporated) 629 Standard.
The ARINC 629 Standard is such that each data message consists of a plurality of data words of fixed length, i.e., a fixed number of bits. Further, the data message format always consists of a label word, which indicates which subsystem transmitted the data message, followed by one or more data words. The ARINC 629 standard requires that each word be 16 bits and be transmitted at a fixed frequency.
In order to further define some commonality among avionics equipment suppliers, the ARINC 629 standard defines the bus and a Terminal Controller which is coupled to the bus for receiving data messages from the bus or transmitting data messages onto the bus. The ARINC 629 Terminal Controller is configured to have a known set of registers, input/output control signals, read/write control signals, and address/data lines, all of which are clearly defined so that avionic equipment suppliers may work together.

Arinc 629 data receiver system having an interface for providing identification to each of the received data word types


A method and apparatus for providing a read channel having combined parity and non-parity post processing is disclosed. A post-processor combines parity and non-parity post processing to make both parity and non-parity corrections so that error events that cannot be detected by parity may be corrected. Non-parity detectable error events are only kept for consideration if their likelihood is above a set threshold.

1. Field of the Invention
This invention relates in general to signals read from a data storage medium, and more particularly to a method and apparatus for providing a read channel having combined parity and non-parity post processing.
2. Description of Related Art
Recently developed data storage devices, such as magnetic disk drive devices (i.e., hard disk drives), have increased storage capacity and increased data access speed. With these advantages, magnetic disk drive devices have become widely used as auxiliary memory devices for computer systems. More generally, developments in pulse communications related to these improvements in disk drive technology have recently provided increased speed and reliability in a wide range of pulse communications systems.
The primary features of a magnetic disk drive device that affect storage capacity and access speed are the head, the recording medium, the servo mechanism, the signal processing technique used in the read/write channel, and the like. Among these, signal processing techniques utilizing PRML (Partial Response Maximum Likelihood) detection have greatly contributed to the increased storage capacities and high access speeds seen in modern magnetic disk drive devices.
Each read/write head generates or senses electromagnetic fields or magnetic encodings on the magnetic disk as areas of magnetic flux. The presence or absence of flux reversals in the electromagnetic fields represents the data stored on the magnetic disk. A flux reversal is a change in the magnetic flux on contiguous areas of the magnetic disk. The presence or absence of magnetic flux reversals correspond to binary 1's and 0's of a diagnostic input signal.
To "write" data onto a magnetic disk, electronic components receive data from a host device and translate the data into magnetic encodings. The head transfers the magnetic encodings onto a portion of the magnetic disk.
To "read" data from the magnetic disk, the head is positioned adjacent to the portion of the magnetic disk having the desired magnetic encodings. The head senses and transfers the magnetic encodings from the magnetic disk. The electronic components translate the magnetic encodings into the data, which is transferred to the host device. The host device may be a personal computer or other electronic equipment. The electronic components may apply error detection and correction algorithms to ensure accurate storage and retrieval of data from the magnetic disk. To improve data storage densities on disk drives, magneto resistive and inductive read/write heads have been developed with increased sensitivity to sense smaller amplitude magnetic signals and with increased signal discrimination.
The primary function of the disk drive read channel is to reliably recover data from a noise contaminated read back signal. State of the art detection architectures equalize to a fixed length partial response target and then use the Viterbi algorithm for detection. A read channel circuit includes components for initial processing of the analog read signal generated by the read/write head of the device. This processing typically includes automatic gain control (AGC) amplification, filtering, and equalization, as well as analog-to-digital conversion.
It is also common to use some type of post-processing after the Viterbi algorithm to further improve error rate. Post processor algorithms typically generate reliability information for dominant error events and use this information in conjunction with prior knowledge of parity constraints on blocks of the encoded data. In other cases the reliability generation algorithm may be good enough that it does not need to be used in conjunction with parity information. This may be the case, for example, when using a longer partial response target to generate reliability information than was used by the Viterbi algorithm in detection.
Written data bits, when read back, can be thought of as being filtered by some response and corrupted with noise. This signal is then equalized such that the combined effect of filtering and equalization is some desired target response. The Viterbi Algorithm is then used to obtain an estimate of the data sequence. This estimate is then filtered by the target response to obtain a noiseless version of the equalizer output that is then subtracted from the noisy equalizer output and filtered by the time reversed target response.
The time-reversed filter is also referred to as the matched filter. The matched filter output is then input to each of N different error event filters. An offset term specific to each error event filter output is then added to generate a final reliability number associated with each error event. This is done each bit time. The reliabilities are then sent to a selection algorithm block. The selection block uses a specific algorithm for deciding on an error sequence. This error sequence can then be used to improve the reliability of the original decisions made at the Viterbi Algorithm output.
Current selection algorithms generally operate according to two forms. For example, the selection algorithms may incorporate prior knowledge of parity constraints on blocks of the encoded ak data steam or, in the case of a windowed selection algorithm, parity constraints are not relied upon for determining the error sequence.
A codeword size is fixed ahead of time. A typical size is somewhere in the range of 30 to 110 bits. Throughout the processing of each bit in a codeword a list of the predetermined number of most likely error events is kept along with the associated error event type and location. This list is reset at the beginning of each codeword. At the same time the parity syndrome associated with the detected codeword bits is computed and is available at the end of the codeword. At the end of the codeword, a correction is made based on the most likely single or non-overlapping pairs of error events from the final list that fixes parity. If none of these choices fixes the parity no correction is made.
For example, when parity is used to correct error events, a post-processor may determine a next closest pattern, in Euclidian distance, that fixes parity using a list of error events. However, the number of error events that can be corrected in this matter is limited based upon the number of bits of parity that are used. When parity is not used to correct for error events, a post-processor can determine if using an error event will improve an Euclidian distance fit based on using a longer target than the target used in the Viterbi detector. The post-processor biases error event likelihoods based on a number of transitions. Still, each of these two forms of selection algorithms consider only those error events that resulted in a non-zero parity syndrome. Thus, the error rate performance is less than optimal.
It can be seen that there is a need for a method and apparatus for providing a read channel having combined parity and non-parity post processing.

Method and apparatus for providing a read channel having combined parity and non-parity post processing

Hitachi Global Storage Technologies Netherlands B.V.


The present invention entails a method and an apparatus for removing BTX-type gases from a liquid. Herein is disclosed a system where purified water from an oil-water separator is directed into a vacuum chamber. The chamber is closed and a vacuum is pulled on the purified water causing BTX-type gases associated with the water to vaporize and assume a space in the upper portion of the vacuum chamber. The pressure within the vacuum chamber is continuously sensed as well as the liquid level within the chamber. Once the pressure within the vacuum chamber has reached a predetermined level and the level of the purified water is within a certain range within the vacuum chamber, then the BTX-type gases are removed via a vacuum pump and these BTX gases are collected in a collector where they are condensed to form a liquid.

The danger of BTX-type gases which commonly include benzene, tolulene, xylene and other related gases is well-known. Typically, these gases assume a dissolved gaseous state within a liquid such as water.
Presently, the Environmental Protection Agency requires that purified water separated from an oil-water solution be further purified to remove these BTX-type gases. Conventionally, an air stripper is used to remove these gases from water before that water is returned to our lakes and streams. But there is a serious problem with air strippers. It is highly questionable if a basic air stripper is effective in removing BTX-type gases since gases tend to condense and fall back to the Earth.
Therefore, there is and continues to be a need for a method and system for removing BTX-type gases from water that is effective to control and isolate the BTX gases once removed.

Method and apparatus for removing BTX-type gases from a liquid


The present invention provides a single electrode assembly, in which a plurality of negative electrodes and positive electrodes are stacked alternately and repeatedly, and separators are disposed between the plurality of negative electrodes and positive electrodes, the electrode assembly including: a negative electrode tab part formed on one end of the electrode assembly and extending from the plurality of negative electrodes; a positive electrode bus bar spaced apart from the negative electrode tab part on the one end of the electrode assembly and electrically connecting the plurality of the positive electrodes; a positive electrode tab part formed on the other end of the electrode assembly opposite to the one end and extending from the plurality of positive electrodes; and a negative electrode bus bar spaced apart from the positive electrode tab part on the other end of the electrode assembly and electrically connecting the plurality of the negative electrodes.

Batteries (cells) that generate electric energy through physical or chemical reaction of materials to supply power to the outside are used when alternate current (AC) power to be supplied to the building is not obtained, or direct current (DC) power is required according to the living environments surrounded by various electrical/electronic devices.
Among such batteries, primary batteries and secondary batteries, which are chemical cells using chemical reaction, are being generally used. The primary batteries are consumable cells which are collectively referred to as dry cells. Also, the secondary batteries are rechargeable batteries manufactured by using a material in which oxidation and reduction processes between current and a material are capable of being repeated several times. That is, power is recharged when the reduction reaction to the material is performed by the current, power is discharged when the oxidation reaction to the material is performed. Such the recharging and discharging are repeatedly performed to generate electricity.
A lithium ion battery among the secondary batteries is manufactured in such a manner in which: an active material is applied, with a predetermined thickness, to each of a positive electrode conductive foil and a negative electrode conductive foil; a separator is disposed between both the conductive foils so as to be wound several times in an approximate jelly roll or cylindrical shape and thereby to manufacture an electrode assembly; and the electrode assembly is accommodated in a cylindrical or prismatic can, a pouch, or the like to be sealed.
As such a lithium ion battery has been commercialized and widely used, applications thereof also become diverse in vehicles/electronic devices/power tools.
Accordingly, an output of the secondary battery has also been regarded as an important specification.
Recently, in a polymer cell, a positive electrode/a separator/a negative electrode/a separator are stacked sequentially and connected to a tab part, thereby establishing connection between the positive electrodes and between the negative electrodes.
A battery cell having excellent structural safety and insulation resistance is disclosed in Korean Patent Publication No. 10-2008-0038465.
In the pouch type batteries according to the related art, one positive electrode terminal and one negative electrode terminal are being used in a single direction/bi-direction.
However, such a pouch battery according to the related art has a problem in which a size of a tab that is an inlet for electrons is small relative to a gradually increasing electrode area.
Thus, there has been a problem in which a passage through which current flows is small to cause a difference in current density inside an electrode, resulting in an occurrence of deviation in current density.

Electrode assembly and method for manufacturing the same


A position detector which detects the position of a movable member relative to a fixed member includes a signal detector configured to detect periodic signals which respectively indicate predetermined values concerning the position of the movable member relative to the fixed member and change at different periods in accordance with a position change, a signal processor configured to generate displacement signals based on the periodic signals detected by the signal detector and sequentially output the generated displacement signals while switching the signals at a predetermined period, a position calculator configured to calculate a position of the movable member relative to the fixed member based on the displacement signals, and a reliability determining unit configured to determine that the reliability of the position calculated by the position calculator is low, if the displacement amount of the movable member in the predetermined period is larger than a predetermined threshold.

1. Field of the Invention
The present invention relates to a position detection apparatus which detects the position of a movable member relative to a fixed member.
2. Description of the Related Art
Conventionally, as an apparatus for measuring the moving distance of an object, there is known, an absolute encoder which can measure an absolute position as well as an incremental encoder which measures a relative moving distance.
Japanese Patent Application Laid-Open No. H08-304113 discloses a Vernier-type absolute encoder. This encoder is configured to have a main track constituted by lattice patterns with different pitches and at least one sub-track. The encoder performs absolutization in one circulation interval based on the slight shifts between detection signals originating from the pitch differences between the respective tracks.
In addition, Japanese Patent Application Laid-Open No. H05-45151 discloses an invention concerning the timing of absolutization in a Vernier-type absolute encoder. This encoder is configured to have tracks formed with fine coarse pitches. When performing absolutization from these tracks, the encoder performs the absolutization at the timing when the velocity drops to the velocity at which no false detection occurs in incremental measurement with the fine pitch.
However, the absolute encoder disclosed in Japanese Patent Application Laid-Open No. H08-304113 has the following problem. In general, when calculating an absolute position from signals originating from a plurality of tracks, it is necessary to ensure synchronization between the signals originating from the respective tracks of the absolute encoder. This is because of the premise that, signals originating from a plurality of tracks are those obtained when the position of a measurement target object remains the same or within a given allowable range. Assume that the encoder time-divisionally detects signals originating from a plurality of tracks. In this case, if a measurement target object is in a state of movement, the respective signals originating from the plurality of tracks become signals at the different positions of the measurement target object. This breaks the above premise, leading to a problem that the encoder cannot calculate a correct absolute position. In addition, there is also available a method of ensuring synchronization between a plurality of track signals by using a sample/hold circuit and the like. This however raises a problem that the addition of a circuit, will increase the cost and it takes more time to hold signals.
In addition, the absolute encoder disclosed in Japanese Patent Application Laid-Open No. H05-45151 has the following problem. A false detection, in Japanese Patent Application Laid-Open No. H05-45151 is not based on the premise that the encoder time-divisionally detects signals originating from a plurality of tracks, and hence only a false detection occurs in incremental measurement with the fine pitch. In order to calculate a correct, absolution position, however, it is important that each of signals originating from a plurality of tracks is the one at the position of a measurement target object within a given allowable range. Even if, therefore, there is no false detection in incremental measurement with the fine pitch, it cannot be said that the encoder ensures the synchronization between signals originating from a plurality of tracks, and it is not possible to calculate a correct absolute position. That is, if the encoder determines the calculation of an absolute position based on a false detection in incremental measurement with the fine pitch, the encoder calculates a wrong absolute position.

Position detection apparatus having a determining unit to determine the reliability of calculated position of a movable member


A compound of the formula [I]

Calcium receptors sense extracellular Ca2+ concentration and increase intracellular Ca2+, thereby suppressing the production of parathyroid hormone (PTH) involved in the control of Ca2+ metabolism and bone metabolism.
The serum calcium concentration of healthy mammal is strictly maintained at about 9–10 mg/100 ml (ca. 2.5 mM), which is referred to as calcium homeostasis of living organisms. When this value falls to not more than 50%, tetania occurs, and when it increases by 50%, consciousness is clouded, both cases threatening the lives. For maintaining calcium homeostasis, duodenum acts as a Ca2+ uptake organ, bone acts as a Ca2+ storage organ, and kidney acts as a Ca2+ excretory organ. These Ca2+ kinetics are controlled by various hormones generally referred to as "calcium controlling hormone". Representative hormone includes active vitamin D [1α, 25(OH)2D3], PTH, calcitonin, Parathyroid Hormone-Related Protein (PTH-related Protein (PTHrP)) and the like.
Bone plays an important role not only as a supporting framework and motor organ of the body, but also as a storage organ of Ca2+, which is its constituent component. To fulfill such functions, bone tissues repeat formation thereof (osteogenesis) and absorption thereof (bone resorption) throughout the entire life. For osteogenesis, osteoblast derived from mesenchymal cell plays a major role, and for bone resorption, osteoclast derived from hematopoietic cell plays a major role. Osteogenesis is a mechanism including osteoid formation by bone organic matrix (bone matrix proteins such as type I collagen and the like) produced by osteoblast present on the osteogenesis surface, and subsequent calcification. Bone resorption is a mechanism including adhesion of osteoclast to the bone surface, intracellular absorption of Ca2+ via acid secretion and ion transport, and excretion of absorbed Ca2+ to the bone marrow side, thereby releasing Ca2+ into blood. The deficient part of the bone absorbed by osteoclast is repaired by osteogenesis by osteoblast. This series of phenomena are called remodeling of bone, and by the remodeling, old bones are replaced by new bones, thus maintaining the strength of the entire bone while maintaining calcium homeostasis.
PTH is a hormone that plays a key role in maintaining the calcium homeostasis. When blood Ca2+ concentration decreases, secretion of PTH from the parathyroid gland is promoted immediately, which, in the bone, acts on osteoblast (activation of osteoclast by osteoblast, production of bone organic matrix decomposition enzyme and the like) to promote osteoclastic bone resorption, whereby Ca2+ is transferred from the bone into the blood. In kidney, PTH promotes resorption of Ca2+ in the distal convulted tubule, and activates 25(OH) vitamin D3 in the proximal tubule, thereby promoting the production of active vitamin D3 [1α, 25(OH)2D3] having a function of promoting resorption of Ca2+ from the intestine. It also suppresses resorption of phosphorus. As mentioned above, PTH directly or indirectly increases blood Ca2+ concentration.
When blood Ca2+ concentration increases, calcium receptor senses it, immediately suppresses secretion of PTH from the parathyroid gland to decrease the amount of Ca2+ to be supplied into the blood [Brown, E. M., Homeostatic mechanisms regulating extracellular and intracellular calcium metabolism, in the parathyroids, p. 19, (1994), Raven press, New York]. Secretion of PTH is also suppressed by active vitamin D [1α, 25(OH)2D3].
Because PTH is a hormone assuming an important role in controlling Ca2+ metabolism and bone metabolism, attempts have been made to apply PTH to the treatment of osteoporosis. In 1982, Tam et al. found that sustained administration of bovine PTH (1-84) to thyroid/parathyroid gland enucleated rat results in promotion of both osteogenesis and bone resorption of femoral cancellous bone, leading to a decrease in net bone mass, but subcutaneous intermittent administration thereof does not result in promotion of bone resorption but in promotion of osteogenesis alone, leading to an increase in the bone mass [Endocrinology, 110, 506–512 (1982)]. Furthermore, Uzawa et al. compared the actions of sustained administration and intermittent administration of PTH with regard to epiphysial long bone and metaphysial cancellous bone of young rat. As a result, they clarified that sustained administration of PTH results in remarkable increase in bone mass in metaphysial cancellous bone highly susceptible to the effect of enchondral ossification, though associated with abnormal findings such as hyperplasia of epiphysial plate cartilage, fibrous ostitis and the like, and in marked promotion of bone resorption and decrease in bone mass accompanied by rarefaction of cortical bone, in epiphysial cancellous bone where the effect is small [Bone, 16, 477–484 (1995)]. In addition, it has been reported that intermittent administration of PTH results in significant increases in bone mass and bone trabecula in both epiphysial and metaphysial cancellous bones without increase in osteoclast or decrease of cortical bone.
Moreover, Scutt et al. have reported that, in chicken calvaria derived osteoblast, a short time (10–20 min) treatment with PTH promotes cell growth as compared to a long time (18 hr) treatment [Calcif. Tissue Int., 55, 208–215 (1994)]. This suggests that some of the actions of PTH on osteoblast are temporary and that expression of the action by the treatment for an extremely short time may be related to the fact that sustained administration and intermittent administration of PTH in vivo show different actions on bone tissues.
Ishizuya et al. further clarified through investigation of the action of PTH on differentiation of osteoblast using an in vitro experiment system that the action of PTH varies depending on the treatment time. They have reported that sustained action of PTH on osteoblast derived from rat calvaria resulted in strong inhibition of differentiation of osteoblast and nearly complete inhibition of osteogenesis in vitro, but repeated PTH action for the first 6 hr of 48 hr as one cycle resulted in significant promotion of differentiation of osteoblast and promotion of osteogenesis in vitro.
PTH is considered to not only prevent decrease in bone mass of osteoporosis model, but also has a bone mass recovery effect even on an animal already suffering from marked decrease in bone mass. Wronski et al. intermittently administered human PTH (1-34) to 90-day-old SD rat at 4 weeks post-ovariectomy and showing an obvious decrease in cancellous bone, for 15 weeks from 4 weeks post-ovariectomy. As a result, promotion of osteogenesis and inhibition of bone resorption were observed during the period of from week 5 to week 10 after the start of the administration, showing increased bone mass of about twice the bone mass of sham operation group [Endocrinology, 132, 823–831 (1993)]. They have also reported that, in this experiment, estrogen and bisphosphonate prevented decrease in bone mass caused by ovariectomy but did not show increase in bone mass, unlike PTH. They detailedly analyzed the cortical bone of this experiment system and found images showing promoted osteogenesis and bone mass increase on the periost side and endosteum side by intermittent administration of human PTH (1–34), based on which they have clarified that the increase in cancellous bone due to PTH did not accompany decrease in cortical bone [Bone, 15, 51–58 (1994)].
Furthermore, Mosekilde et al. have reported that intermittent administration of human PTH (1-34) or human PTH (1-84) causes not only an increase in bone mass but also a dose-dependent increase in compression strength and bending strength, which are indices of bone substance, of cancellous bone [Endocrinology, 129, 421–428 (1991)] and cortical bone [J. Bone Miner. Res., 8, 1097–1101 (1993)] of rat vertebral bone. As discussed above, since PTH shows an obvious bone mass increasing action in experimental animals, various investigations are ongoing as regards the restrictive conditions expected in actual clinical applications. Mizoguchi studied whether or not a pharmacological effect is observed by intermittent administration of PTH, even when PTH in blood, which is considered to be one of the factors responsible for osteoporosis, has significantly increased, and concluded that the bone mass increased as usual [Journal of Japanese Society of Bone Morphometry, vol. 5, pp. 33–39 (1995)]. Takao et al. have studied the frequency of PTH administration and reported that administration of once a week for 12 weeks to healthy rat scarcely promoted bone absorption but dose-dependently increased the bone mass [Japanese Journal of Bone Metabolism, vol. 12 (Suppl.), p. S343 (1994)], suggesting possible effectiveness of clinically useful low frequency administration. The foregoing achievements suggest the possibility of PTH for making a potent and promising therapeutic drug for the treatment of postmenopausal steoporosis or postovariectomy osteoporosis, which increases one mass and decreases bone fracture rate.
These results clearly indicate that intermittent administration of PTH would enable treatment of osteoporosis. On the other hand, PTH problematically requires injection as an administration route, which is painful for many patients. However, an orally administrable pharmaceutical agent that can intermittently increase PTH concentration in blood is greatly expected to become a therapeutic drug of osteoporosis, which is based on a new action mechanism different from that of the above-mentioned PTH and conventional calcitonin.
Calcium receptor is a G protein coupled receptor, which is cloned as a molecule essential for controlling PTH secretion, and which penetrates cell membrane 7 times. Human calcium receptor consists of 1078 amino acids, and shows 93% amino acid homology with bovine calcium receptor. Human calcium receptor consists of a large N terminal extracellular region consisting of 612 amino acids, a cell membrane penetration region consisting of 250 amino acids and a C terminal intracellular region consisting of 216 amino acids.
Expression of calcium receptor has been found in parathyroid gland, kidney, thyroid C cell, brain and the like, as well as in bone (bone marrow cells).
When calcium receptor is bound with a ligand such as Ca2+ and the like, it activates phospholipase C in conjugation with G protein, causes production of inositol triphosphate and increase in intracellular Ca2+ concentration, and as a result, suppresses secretion of PTH [Nature, 366, 575–580 (1993)].
As mentioned above, a pharmaceutical agent that inhibits activation of calcium receptor, or a pharmaceutical agent that antagonizes calcium receptor, removes suppression of PTH secretion in parathyroid gland cells, and promotes secretion of PTH. If the antagonistic action can increase blood PTH concentration discontinuously and intermittently, its antagonist is expected to show the same effect as provided by intermittent administration of PTH, and a pharmaceutical agent extremely effective for the treatment of osteoporosis is considered to be provided.
As a CaSR antagonist, international publication WO99/51569 describes a compound of the following formula
wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl, or O;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or haloalkyl;    Y3 is a covalent bond or O, S, N—RIV or C1-4 alkylene-O, C1-4 alkylene-S, C1-4 alkylene-N—RIV;    R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is aryl or fused aryl, dihydro or tetrahydro fused aryl, unsubstituted or substituted with any substituents being selected from the group consisting of OH, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2RIV, and O—(CH2)nCO2RIV, wherein n is an integer from 0 to 3 and RIV is selected from the group consisting of H, C1-4 alkyl, and C3-6 cycloalkyl;    or R5 is heteroaryl or fused heteroaryl; wherein the hetero-ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents being selected from the group consisting of OH, OCH3, CH(CH3)2, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2H, (CH2)nCO2RIV, and O—(CH2)nCO2RIV;    G is a covalent bond, CHR6 or C—R6, wherein R6 is H, OH or O (forming a ketone);    R7 is H, OH, or O—C1-4 alkyl;    R8 is H or C0-4 alkyl; or R7 and R8 together form a ketone;    A and B are, independently, selected from the group consisting of a bond, CH2, NH, O, S and C═O, provided that A or B is selected from CH2 and NH; or A and B together form a bond; or the A-B moiety is represented by CH═CH or C≡C;wherein    X1 and X5 are independently selected from the group consisting of H, halogen, CN, NO2, C1-4 alkyl, cycloalkyl, CH2-aryl, and CH2-heteroaryl; provided that either X1 or X5 is H;    X2, X3 and X4 are selected from the group consisting of H, halogen, O—C1-4 alkyl, O-aryl, O-heteroaryl, CH2-aryl, CH2-heteroaryl, alkyl, C(O)aryl, C(O)heteroaryl CH(OH)aryl, CH(OH)heteroaryl and J-K;    J is a covalent bond, alkylene, O-alkylene or alkenylene of up to 5 carbon atoms, unsubstituted or substituted by a substituent selected from the group consisting of C1-4 alkyl, OH, O(forming a ketone), aryl, heteroaryl, and NR′R″, wherein R′ and R″ are independently selected from the group consisting of H, alkyl, aryl, heteroaryl, C(O)alkyl, C(O)aryl, and C(O)heteroaryl;    K is selected from the group consisting of CO2RIV, OH, and CN; and pharmaceutically acceptable salts and complexes thereof.
Particularly, a compound of the formula wherein Y3 is CO1-4 alkylene-O
is suggested, though not directly described. In this case, however, "C1-4 alkylene" means a straight chain, and the branched chain such as in the present invention is not described or suggested.
In addition, international publication WO99/51241 describes, as a CaSR antagonist, a compound of the following formula
wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl or O;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or haloalkyl;    Y3 is covalent bond or selected from the group consisting of O, S, N—RIV, C1-4 alkylene-O, C1-4 alkylene-S, and C1-4 alkylene-N—RIV;    RIV is selected from the group consisting of H, C1-4 alkyl, and C3-6 cycloalkyl;    R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is heteroaryl or fused heteroaryl; wherein the hetero-ring contains N, O or S, and is aromatic, dihydro or tetrahydro, unsubstituted or substituted with any substituents being selected from the group consisting of OH, OCH3, CH(CH3)2, halogen, C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3, CH2CF3, (CH2)nCO2H, (CH2)nCO2RIV, and O—(CH2)nCO2RIV;    n is an integer of from 0 to 3;    G is a covalent bond, CHR6 or C—R6, wherein R6 is H, OH or O (forming a ketone);    R7 is H, OH, or O—C1-4 alkyl;    R8 is H or C1-4 alkyl; or R7 and R8 together form a ketone;    A and B are, independently, selected from the group consisting of a bond, CH2, NH, O, S and C═O, provided that either A or B is selected from CH2 and NH; or A and B together form a bond; or A-B moiety is represented by CH═CH or C≡C;    X is selected from sub formulas (Ia) to (Ie) hereinbelow:
wherein    W is selected from the group consisting of R1, SO2R1, C(O)R1, SO2NR1R1′, C(O)NR1R1′, C(O)OR1, and SO3R1′, wherein R1 and R1′ are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl and aryl C1-4 alkyl; or R1 and R1′ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R, CO2NHR, OH, OR, NH2, halo, CF3, OCF3 and NO2; wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X1 is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2, X3 and X4 are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, provided that either X1 or X3 is H, wherein R′ is C1-4 alkyl or haloalkyl; or X1 and X2 together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3 and X4 independently represent C(O)R1; and    R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl, aryl and aryl-C1-4 alkyl;    X1″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″, X3″ and X4″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, provided that either X1″ or X3″ is H, wherein R′ is C1-4 alkyl or haloalkyl; or X1″ and X2″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″ and X4″ independently represent C(O)R1; and    R1″ and R2″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″ and R2″ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2;    wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    X1″′ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″′, X3″′ and X4″′ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, provided that either X1″′ or X3″′ is H, wherein R′ is C1-4 alkyl or haloalkyl;    or X1″′ and X2″′ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″′ and X4″′ independently represent C(O)R1;    R1″′ and R2″′ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″′ and R2″′ together form a 3 to 7 membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    D is selected from the group consisting of H, CN, NO2, Cl, F, Br, I, R, OR, SR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, C3-6 cycloalkyl, or C1-10 aryl or heteroaryl wherein the heteroatom is selected from N, S and O and substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    n is the integer of 1 or 2;    each E is independently C or N, provided that less than two E moieties is N; further provided that when n is 2, each E is C;    a and b are optionally present bonds;    RIV is selected from the group consisting of (CH2)nCO2R, (CH2)nCO2H, (CH2)nCONR12, (CH2)nCH2OR′, OR′, SR′, CN, NO2, Cl, F, BR, I, H, CF3, OCF3, OSO2R′, R′ and H; wherein R′ is C1-4 alkyl, or C3-6 cycloalkyl;    or R1IV is O, forming a ketone such that YR1IV represents —C═O;    R2IV is selected from the group consisting of hydrogen, CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3, and OSO2R″; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl.    Y is selected from the group consisting of C, CH, O, N and S; provided that when Y is S, R1IV is O or not present; further provided that when Y is O, R1IV is not present;    X′ is CH2, NH, O and S.    R9 is O-alkyl, O—CH2-aryl, and O-aryl;    X1″″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″″, X3″″, and X4″″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR′, CF3, OCF3 and OSO2R′, provided that either X″″1 or X″″3 is H, wherein R′ is C1-4 alkyl or haloalkyl;    or X1″″ and X2″″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″″ and X4″″ independently represent C(O)R1:    and pharmaceutically acceptable salts and complex thereof.
Again, a compound of the formula wherein Y3 is C1-4 alkylene-O
is suggested, though not directly described. In this case, however, "C1-4 alkylene" means a straight chain, and the branched chain such as in the present invention is not described or suggested.
International publication WO98/45255 (EP-A-973730) also describes a compound of the following formula as a CaSR antagonist
wherein    Y1 is a covalent bond, alkylene or alkenylene of up to 4 carbon atoms, unsubstituted or substituted by C1-4 alkyl;    Y2 is methylene, unsubstituted or substituted by C1-4 alkyl or CF3;    Z is selected from the group consisting of a covalent bond, O, S, NH, N—C1-4 alkyl, O(CH2)n, (CH2)nO, NR″′ C═O and C═ONR′″, where R″′ is C1-4 alkyl and n is an integer from 1 to 3,    R3 and R4 are, independently, methyl or ethyl, or, together, form cyclopropyl;    R5 is phenyl or naphthyl, unsubstituted or substituted with one or more substituents selected from the group consisting of OH, C1-4 alkyl CH(CH3)2, halo, halo C1-4 alkyl, C1-4 alkoxy, C3-6 cycloalkyl, OSO2RIV, CN, NO2, OCF3, CF3 and CH2CF3, wherein RIV represents C1-4 alkyl or C3-6 cycloalkyl;    G is a covalent bond or C—R6 wherein R6 is H, OH or O (forming a carbonyl moiety);    R7 is H, OH, or O—C1-4-alkyl;    R8 is H or C1-4 alkyl; or R7 and R8 together form a carbonyl moiety;    the A-B moiety is represented by CH2CH2, a covalent bond, —CH═CH— or —C≡C—; and    X is selected from the group consisting of sub formulae (Ia), (Ib), (Ic), (Id) and (Ie) hereinbelow:
where in    in sub formula (Ia):    W is selected from the group consisting of R1, SO2R1, C(O)R1, SO2NR1R1′, C(O)NR1R1′ and C(O)OR1SO3R1′, wherein R1 and R1′ are independently selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl aryl and aryl C1-4 alkyl; or R1 and R11′ together form a 3- to 7-membered optionally substituted heterocyclic ring; wherein any substituents are selected from the group consisting of CN, aryl, CO2R, CO2NHR, OH, OR, NH2, halo, CF3, OCF3 and NO2; wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X1 is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2, X3 and X4 are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, wherein R″ is C1-4 alkyl or haloalkyl; or X1 and X2 together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3 and X4 independently represent C(O)R1;    provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; also provide that either X1 or X3 is hydrogen; and    R2 is selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl aryl and aryl-C1-4 alkyl; in sub formula (Ib):    X1″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″, X3″ and X4″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ is C1-4 alkyl or haloalkyl; provided that when there are multiple halo substitutions in the haloalkyl, halo represents F, or X1″ and X2″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected form N, S and O and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    or X3″ and X4″ independently represent C(O)R1;    provided that either X1″ or X3″ is hydrogen; and    R1″ and R2″ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″ and R2″ together form a 3 to 7 membered optionally substituted heterocyclic ring; optionally containing an additional heteroatom selected from O, S and N; wherein any substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    in sub formula (Ic):    X1″′ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R, OR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″′, X3″′ and X4″′ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R′, wherein R′ is C1-4 alkyl or haloalkyl; provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; or X1″′ and X2″′ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O and the substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2; or    X3″′ and X4″′ independently represent C(O)R1;    provided that either X1″′ or X3″′ represents H; and    R1″′ and R2″′ are, independently, selected from the group consisting of hydrogen, C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkenyl, C2-5 alkynyl, heterocycloalkyl and aryl; or R1″′ and R2″′ together form a 3 to 7 membered optionally substituted heterocyclic ring optionally containing an additional heteroatom selected from O, S and N; wherein the substituents are selected from the group consisting of CN, aryl, CO2R″, CO2NHR″, OH, OR″, NH2, halo, CF3, OCF3 and NO2; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl;    in sub formula (Id):    D is selected from the group consisting of CN, NO2, Cl, F, Br, I, R, OR, SR, CF3, OCF3 and OSO2R, wherein R represents C1-4 alkyl, C3-6 cycloalkyl, or C1-10 aryl or heteroaryl wherein the heteroatom is selected from N, S and O and substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2—C1-4 alkyl, OSO2—C3-6 cycloalkyl and NO2;    n is the integer of 1 or 2;    each E is independently C or N,    provided that no more than two E moieties are N;    further provided that when n is 2, each E is C;    a and b are optionally present bond;    R1IV is selected from the group consisting of (CH2)nCO2R′, (CH2)nCO2H, (CH2)nCONR′2, (CH2)nCH2OR′, OR′, SR′, CN, NO2, Cl, F, Br, I, CF3, OCF3, OSO2R′, R′ and H; wherein R′ is C1-4 alkyl, or C3-6 cycloalkyl;    or R1IV is O, forming a ketone such that YR1IV represents —C═O;    R2IV is selected from the group consisting of hydrogen, CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3, and OSO2R″; wherein R″ represents C1-4 alkyl, or C3-6 cycloalkyl.    Y is selected from C, CH, O, N and S; provided that when Y is S, R1IV is O; further provided that when Y is O, R1IV is not present;    X′ is CH2, NH, O and S; and attachment is at the carbon atom marked 3; in sub formula (Ie):    X1″″ is selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R′, OR′, CF3, OCF3 and OSO2R″, wherein R′ represents C1-4 alkyl, or C3-6 cycloalkyl;    X2″″, X3″″ and X4″″ are, independently, selected from the group consisting of CN, NO2, Cl, F, Br, I, H, R″, OR″, CF3, OCF3 and OSO2R″, wherein R″ is C1-4 alkyl or haloalkyl; or X1″″ and X2″″ together form an aryl or heteroaryl ring, substituted or unsubstituted; wherein the heteroatom is selected from N, S and O; and any substituents are selected from the group consisting of halo, C1-4 alkyl, OCF3, CF3, OMe, CN, OSO2R′ and NO2; or X3″″ and X4″″ independently represent C(O)R1;    provided that when there are multiple halo substitutions in the haloalkyl, halo represents F; also provided that either X1″″ or X3″″ is hydrogen;    and R9 is O—CH2-alkyl, O—CH2-aryl and O-aryl.
In addition, Japanese Patent Application under PCT laid-open under kohyo No. 2001-501584 (WO97/37967, EP-A-901459, U.S. Pat. No. 6,022,894) also describes a compound of the following formula as a CaSR antagonist.
wherein    R1 is selected from the group consisting of aryl, longer-length alk, and cycloalk;    R2 is selected from the group consisting of lower alk, cycloalk, alkoxy, H, OH, ═O, C(O)OH, C(O)O-lower alk, C(O)NH-lower alk, C(O)N(lower alk)2, SH, S-lower alk, NH2, NH-lower alk, and N(lower alk)2;    R3 and R4 is each independently lower alk or together cyclopropyl;    R5 is either an optionally substituted naphthyl having 1–4 substituents independently selected from the group consisting of methyl, ethyl, isopropyl, methoxy, Cl, F, Br, and lower haloalkoxy, or a substituted phenyl having 1–4 substituents with at least one substituent in a meta or para position selected from the group consisting of lower alkyl, methoxy, Cl, F, Br, and lower haloalkoxy, provided that said substituted phenyl may also have 2 or 3 additional substituents; R6 if present is either hydrogen, lower alkyl or lower alkenyl, wherein R6 is not present if R2 is ═O;    Y1 is either a covalent bond, alkylene or alkenylene;    Y2 is alkylene;    Y3 is alkylene; and    Z is selected from the group consisting of a covalent bond, O, S, NH, N-lower alk, alkylene, alkenylene, and alkynylene, provided that if Z is O, S, NH, or N-lower alk, then Y1 is not a covalent bond; further provided that Y1 and Z may together form a covalent bond;    provided that R1 is not 6-CN-2-pyridyl;    further provided that if R5 is 3,4-dimethoxy-phenyl, then R1 is not CH3(CH2)5O-phenyl; 2-cyclopentyl-phenyl; 2-Cl-phenyl; 2-CN-phenyl; 2-(3-furanyl)phenyl; or 4-(1,2-benzisothiazole);    further provided that if R5 is 4-methoxy-phenyl, then R1 is not 2-cyclopentyl-phenyl; 2-CH3-phenyl; 2-benzyl-phenyl; 3-CH3, 4-CH3SO2-phenyl; 4-(1,2-benzisothiazole);    further provided that if R5 is 4-Cl-phenyl, then R1 is not 2-CH3-phenyl; 5-iso-propyl-phenyl; 2-CH3-phenyl; 4-CH3-phenyl; phenyl; 2-Cl-phenyl; 4-Cl-phenyl; 2-methoxy; 4-CH3CHCH-phenyl; 3,4CH3-phenyl; 2,4CH3-phenyl; 2,3CH3-phenyl; 2-iso-propyl; 5-CH3-phenyl; pyridyl; 1-imidazole; or 4-(1,2-benzisothiazole); and    further provided that if R5 is 3,5-dimethyl, or 4-methoxy-phenyl, then R1 is not 4-CH3, 6-CN-2-pyridyl; or    thiophenecarboxamide; and pharmaceutical acceptable salts and complexes thereof; wherein said compound has an IC50≦10 μM using the Calcium-Receptor Inhibitor Assay.
Maxine Gowen et al. examined the effect of a compound having a CaSR antagonistic action and called NPS-2143
on osteogenesis by orally administering NPS-2143 to OVX rat and measuring the concentration in blood and bone density, and reported the results [J. Clin. Invest., 105, 1595–1604 (2000)].
According to this publication, NPS-2143 significantly promotes release of PTH, but has no direct effect on osteoblast and osteoclast in vitro, as a result of which no bone increase or decrease was found. One of the reasons was considered to be the too long half-life of NPS-2143 in blood. When rat PTH (1-34) was administered to OVX rat at a dose of 5 μg/kg, the PTH concentration in blood shows a peak at about 175 pg/ml in 30 min, and restores its original level in 2 hr. When NPS-2143 was administered at a dose of 100 μmol/kg, PTH concentration kept increasing even after the PTH concentration in blood reached about 115 pg/ml in 30 min, and the concentration was about 140 pg/ml even after 4 hr [see J. Clin. Invest., 105, 1595–1604 (2000), p. 1598, FIG. 3].
At this time, the concentration in blood of NPS-2143 itself remained above 100 ng/ml even at 8 hr after administration and it was only after 24 hr when the concentration became not more than 10 ng/ml and could not be detected.
The reference of the above-mentioned Maxine Gowen et al. suggests that a calcium receptor antagonist having a too long half-life in blood brings about the same results as in sustained administration of PTH and teaches that an increase in the bone mass cannot be expected.
The present invention aims at providing a compound having a calcium receptor antagonistic action. The present invention also aims at providing a pharmaceutical composition comprising said compound, which is effective as an agent for the treatment of a disease showing abnormal calcium homeostasis, namely, osteoporosis, hypoparathyreosis, osteosarcoma, periodontal disease, bone fracture, steoarthrosis, chronic rheumatoid arthritis, Paget's disease, humoral hypercalcemia, autosomal dominant hypocalcemia and the like, particularly as a therapeutic agent for osteoporosis, which is capable of oral administration and intermittent administration. Moreover, the present invention aims at providing a synthetic intermediate for a compound having a calcium receptor antagonistic action.

Abstract: A compound of the formula [I]

Abstract: wherein R1 is optionally substituted aryl group or optionally substituted heteroaryl group; R2 is optionally substituted C1-6 alkyl group, C3-7 cycloalkyl group and the like; R3 is hydrogen atom, C1-6 alkyl group, hydroxyl group and the like; R4 is hydrogen atom, C1-6 alkyl group and the like; R5 and R6 are each C1-6 alkyl group and the like; R7 is optionally substituted aryl group or optionally substituted heteroaryl group; X1, X2 and X3 are each C1-6 alkylene group and the like; and X4 and X5 are each a single bond, methylene group and the like, a salt thereof, a solvate thereof or a prodrug thereof, and a pharmaceutical composition containing the compound, particularly a calcium receptor antagonist and a therapeutic agent for osteoporosis, are provided. The compound of the present invention is useful as a therapeutic drug of diseases accompanied by abnormal calcium homeostasis, or osteoporosis, hypoparathyreosis, osteosarcoma, periodontal disease, bone fracture, steoarthrosis, chronic rheumatoid arthritis, Paget's disease, humoral hypercalcemia, autosomal dominant hypocalcemia and the like.

Abstract: In addition, an intermediate for the compound is provided.


A multifunction apparatus having a plurality of functions, including a copier function, retrieves user identification information from a memory card carried by the user within a detection area, obtains panel angle information that is set for the authenticated user based on the retrieved identification information, and adjusts, by a panel controller, a panel angle of an adjustable panel for the authenticated user according to the information, the panel being provided for inputting various operational instructions.

1. Field of the Invention
The present invention relates to a multifunction apparatus that includes a plurality of functions including a copier function.
2. Description of Related Art
A multifunction apparatus having a plurality of functions such as printer, copier, scanner, facsimile, and e-mail functions has become common. Recent multifunction apparatuses usually include a large-size touch panel to accommodate various functions, the panel displaying various information in an operation screen and selection buttons for the user. (e.g., Related Art 1). The height level for the touch panel is set considering an average height of users, so that the touch panel is easily viewed and operated by the users.                [Related Art 1] Japanese Patent Laid Open Application 2002-7264
However, the above methods have the following shortcomings. Even when the multifunction apparatus is provided at a location for users of wide range of ages (e.g., educational institutions including elementary schools), the position of the touch panel is set at a height for an average adult. Therefore, the position of the touch panel can be too high thus inconvenient for some users having short heights (e.g., children). In addition, when the multifunction apparatus is used by a user having a lower eye-level and/or operation level (e.g., person in a wheelchair), the multifunction apparatus is also inconvenient for such a user to operate on.

Adjusting an angle of an operation panel on a multifunction apparatus

Matsushita Electric Industrial Co., Ltd.


A method and system for minimizing the cycle time when compiling a program in a computer system is disclosed. The program includes a plurality of directories and each of the directories includes a code file. The method and system comprises the steps of providing a master array of directories of the program, wherein the master array lists the dependencies of the directories; providing a code change to the program to provide an updated program; providing associated dependency changes to the master array to provide an updated master array; and compiling the updated program utilizing the updated master array wherein the code files of the directories are compiled in an ordered manner based upon the dependencies of the plurality of directories. Through the use of the method and system in accordance with the present invention, compile cycle time for large programs is significantly reduced. A second advantage is that since the dependencies are updated substantially simultaneously with code changes, there are minimal dependency violations and therefore few deadlocks.

FIG. 1 is a block diagram of a computer system 100 for implementing a complex program. The computer system 100 includes an operating system 102 which controls a plurality of processors 104a–104d. The processors 104a–104d are utilized to compile the program 106. The program could be, for example, an operating system such as an AIX operating system.
Typically, a first version of a complex program such as an operating system has errors therewith. In addition, during the development of the program new features are added. Accordingly, during the development process, typically several changes may be made in the source code related to the complex program.
One way to develop the complex program is to have a single large directory that contains the entire program. However, if a single large directory were utilized to hold data it would require a significant amount of time to make source code changes in the program. The reason why source code changes would take a significant amount of time is that every time a source code change was made in the program, the entire program, no matter where the source code change was made, would have to be accessed up to that source code change. Attempting to manage revisions in this manner would require a significant amount of time.
To more efficiently compile the complex program from version to version in the development process, the program is broken up into a directory structure where discrete files of the code are placed in specific directories or subdirectories. Within each directory are files related to a particular function of the code.
The program is broken up into directories or subdirectories to allow for different entities to be responsible for different functions of the code. The files within the directories that are used in compiling the program can be maintained individually in a program library and accessed as desired. The dependencies of the directories preferably conform to the compile environment conventions of a particular environment, such as Open Software Foundation (OSF) Development Environment.
One way of compiling the code files within each of the directories is to use a MAKE facility. The MAKE facility creates a plurality of make files. In an OSF environment, each make file provides the data that is needed to compile the code files within a particular directory and includes the directory's dependencies on other directories. Breaking the complex program up into code files based upon the directory structure allows for quick access to source code changes and also quick identification of those changes. Typically, the code files within one directory can have a dependency on the code file in one or more other directories. That is, the code files of one directory have to be compiled before the code files of one or more other directories.
In compiling the complex program 106, the change in code within each of the directories is accessed by a processor 104a–104d and scheduled by a scheduler (not shown) for compilation prior to integration into an executable program. For successful compilation of the complex program 106, the code files within each of the directories required must be scheduled for compilation in the correct sequence. Furthermore, logically independent directories must be scheduled for compilation before their dependent directories can be compiled.
Scheduling the compilation of directories when there are no dependencies between the directories is relatively simple. However, the scheduling becomes complex when there are dependencies therebetween. As before mentioned, different entities are typically responsible for a particular portion of the program. The scheduling is complex because each of the directories is maintained independently of each other on an ongoing basis by the entity that is responsible for a particular directory. This may result in a modification to a particular directory, which introduces dependencies on other directories that are unknown to the scheduler.
Accordingly, if a directory that is dependent upon another directory is compiled before that directory, a deadlock occurs. The deadlock can result in a significant delay in compile cycle time. The delay can significantly negatively impact the development process of each program.
Accordingly, what is needed is a system and method for reducing the compile cycle time of a complex program. The solution should be simple, cost effective and capable of being easily adapted to current technology. The present invention addresses such a need.

Method and system for minimizing the cycle time when compiling a program in a processing system

International Business Machines Corporation