An image reading apparatus in which a contact type image sensor (CIS) is pressed by springs to cause abutment members to abut the lower surface of an original support glass, wherein the abutment members are arranged within the main scanning reading range of the CIS and, more specifically, at positions where the deflection amount of the original support glass with respect to the end portions of the main scanning reading range is approximately ½ of the maximum deflection amount. Thus, when the original support glass is deflected, the CIS is pressed down against the spring force by approximately ½ of the maximum deflection amount in the main scanning reading range of the original support glass from the position where the original table has no deflection, whereby the optimum focal position of the CIS is downwardly shifted and as a result, the upper surface of the original support glass constituting the original surface is retained within the effective focus range of the CIS over the entire main scanning reading range, thereby making it possible to perform high quality image reading.

1. Field of the Invention
The present invention relates to a stationary-original-table type image reading apparatus using a contact type image sensor.
2. Related Background Art
In an image reading apparatus, a charge-coupled device (CCD) image sensor or a contact image sensor or a contact image sensor (hereinafter referred to as CIS) is used. As compared with the CCD image sensor, the CIS has many advantages. For example, it allows a reduction in apparatus size, and its driving system is substantially simplified, so that there is practically no need for adjustment. Further, no image distortion due to the reduction in optical system is generated.
On the other hand, due to the construction of the CIS in which reflected light from the original surface is focused onto a photoreceptor by means of a SELFOC lens array, the CIS has a problem in that the focal depth is rather small and thus the image is likely to be out of focus unless the support structure for the CIS has sufficient accuracy. In view of this problem, Japanese Patent Application Laid-Open No. 07-193689 and U.S. Pat. No. 5,801,851, etc. disclose a method according to which an image is read with the distance between the CIS and the original surface being kept constant by causing rollers, slide members or the like provided at the end portions of the upper surface of the CIS to abut the lower surface of the original support glass, whereby an out-of-focus state is prevented.
In a so-called book scan type image reading apparatus, which reads original image information with the original being fixed onto the original support glass, downward deflection of the original support glass can be generated when a thick original such as a book or a dictionary is placed on the original support glass and pressed by a presser plate. The deflection amount of the original support glass in the main scanning direction is maximum substantially in the central portion between the back end and the front end supports of the original support glass.
In all of the above-mentioned examples, the rollers, slide members or the like are caused to abut the lower surface of the original support glass outside the image reading range at the both ends of the CIS. Thus, of the image reading range of the CIS, the distance between the CIS and the original surface is maintained with accuracy near the both ends of the CIS, whereas in the central portion, an out-of-focus state is likely to be brought about when the original surface comes too close to the CIS beyond the optimum focal position.
FIG. 11 is a side sectional view of a conventional image reading apparatus. FIG. 12 shows how deflection is generated in an original support glass 3 by placing a thick original thereon and pressing it with a presser plate 8. The focal depth of the SELFOC lens mounted to a CIS 1 is ±0.5 mm, and a range of 1 mm across the optimum focal position is the effective focus range. The deflection amount of the original support glass 3 is maximum in the central portion between the end portions of the main scanning reading range of the CIS 1; in this case, it is assumed to be a downward deflection of 0.6 mm.
In the conventional image reading apparatus, abutment members 2 are arranged outside the main scanning reading range. Thus, as shown in FIG. 12, when the deflection amount of the original support glass 3 in the main scanning direction exceeds the effective focus range of the CIS 1, the portion of the upper surface of the original support glass 3 constituting the original surface is deviated from the effective focus range in the vicinity of the central portion of the main scanning reading range, so that an out-of-focus state is caused in this portion, resulting in a deterioration in image quality.


A closure device for connecting two parts is provided. The closure device includes a connector, a housing which includes a connector receptacle, into which the connector can be inserted in a closing direction for closing the closure device, a slide shiftably arranged at the housing, which for opening the closure device is shiftable along an opening direction different from the closing direction, a detent spring element which in a closed position of the closure device latchingly holds the connector at the housing and for opening the closure device can be moved out of engagement with the connector by shifting the slide in the opening direction, in order to release the connector from the housing, so that in an open position of the closure device the connector is separated from the housing, and at least one guide element which guides the connector on insertion into the connector receptacle for closing the closure device along the closing direction into the closed position and supports the connector against tilting relative to the closing direction when the slide is shifted for opening the closure device.

Field of the Invention
This invention relates to a closure device for connecting two parts.
Description of Related Art
Such closure device includes a connector and a housing with a connector receptacle, into which the connector can be inserted in a closing direction for closing the closure device. On the housing, a slide is arranged in a shiftable way, which for opening the closure device can be shifted along an opening direction different from the closing direction.
Such closure devices for example serve for connecting two belts, as closure for a bag, a backpack, a suitcase or a box, as closing mechanism for other lids, for example a glove box, or as closure for connecting any other parts. One part here is to be connected with the connector and another part with the housing, so that by arranging the connector in the connector receptacle of the housing a connection of the parts can be established.
In a closed position of the closure device the connector is mechanically held at the housing. For opening the closure device, the slide can be shifted along the opening direction and the connector thereby can be released from the housing, so that in an open position of the closure device the connector is separated from the housing.
By the fact that the opening direction is different from the closing direction it is to be understood here that the opening direction does not point along the closing direction, i.e. is not directed inversely to the closing direction. The opening direction thus includes an angle to the closing direction which differs from 0° and 180°.
The closure device includes a detent spring element which in a closed position of the closure device latchingly holds the connector at the housing and for opening the closure device can be moved out of engagement with the connector by shifting the slide in the opening direction, in order to release the connector from the housing, so that in an open position of the closure device the connector is separated from the housing. For opening the closure device, the slide thus is moved in the opening direction and the detent spring element, which in the closed position mechanically holds the connector at the housing, is moved thereby.
In principle, a movement of the slide relative to the housing and to the connector thus is effected for opening, which effects that the mechanical hold of the connector at the housing is eliminated. During the opening movement of the slide an action of force on the connector, for example due to friction, also can occur, which connector thus is loaded relative to the housing and possibly may cant in the connector receptacle of the housing. Separating the connector from the housing therefore can become difficult or even impossible, and the operability of the closure device thus can be impaired.
In a closure device known from WO 2008/006357 A2 a latching mechanism is provided for mechanically holding a connector at a housing, which is formed by a spring locking element at the one of connector and housing and a blocking piece at the other one of connector and housing. For opening the closure device the connector for example can be rotated relative to the housing, so as to bring the latching mechanism out of its latching engagement, so that the connector can be removed from the housing. In addition, a magnet-armature construction is provided, which effects a force of magnetic attraction between the connector and the housing for supporting the closing operation of the closure device.


Disclosed are a source drive integrated circuit (IC), a method of manufacturing the same, and a display apparatus including the source drive IC. The source drive IC includes a core portion, a first channel portion disposed outside one side of the core portion, a second channel portion disposed outside the other side of the core portion, a first resistor string provided inward from the one side of the core portion to generate a plurality of gamma voltages, a first resistance corrector provided between the first resistor string and the first channel portion, and a first connection line extending from the first resistor string to each of the first channel portion and the second channel portion and transferring the plurality of gamma voltages to the first channel portion and the second channel portion. The first connection line extends to the first channel portion via the first resistance corrector.

With the advancement of information-oriented society, various requirements for display apparatuses for displaying an image are increasing. Various display apparatuses such as liquid crystal display (LCD) apparatuses and organic light emitting display apparatuses are being practically used as display apparatuses.
Display apparatuses each include a display panel including a plurality of pixels defined by a plurality of gate lines and a plurality of data lines, a gate driving circuit which supplies a gate signal to the gate lines, and a data driving circuit which supplies data voltages to the data lines.
The data driving circuit includes a plurality of source drive integrated circuits (ICs). Each of the source drive ICs converts data, corresponding to a digital image signal received from a timing controller, into a data voltage corresponding to an analog image signal and outputs the data voltage to a corresponding data line.
The source drive IC includes a plurality of driving circuits and a plurality of lines for connecting the driving circuits. In this case, a length difference between the plurality of lines may occur, and due to this, a resistance deviation between the lines may occur due to the length difference. When a resistance deviation occurs between the plurality of lines, the delay or distortion of a driving signal occurs, causing the degradation in image quality.

Source drive integrated circuit, method of manufacturing the same, and display apparatus including the source drive integrated circuit


According to the present invention, a light guidance system for adapted illumination in emergency or power cut situations is provided, wherein the light guidance system is connected to an auxiliary power supply system (101) and comprises at least one light unit (103) adapted to emit light for illuminating surroundings and a control unit adapted to increase a light level of the light unit (103) according to a presence signal indicating the presence of a person, wherein the increasing of the light level is adjusted to enable a mandatory lighting period and a mandatory light level by considering a power value of the auxiliary power supply system (101).

Conventional light guidance systems in an underground car park or public subways employ movement detectors in order to reduce power consumption by switching on light sources only, when a person passes by. In a situation of restricted power supply, however, switching on all light sources of the whole system will soon result in a supply shortfall. Therefore, in many of these systems, the intensity level of emitted light is lower than in a standard illumination for saving energy, although a higher light level would ameliorate the ability of orientation and the feeling of ease and comfort. Normally, these light guidance systems are powered by an external power supply system and the light sources are emitting at a low mandatory intensity level. For power cut situations, the light guidance systems and in particular emergency lighting systems are often provided with a backup power system so that the illumination can be kept up.
U.S. Pat. No. 7,355,349 B2 describes an emergency lighting system adjusting the emergency lighting level according to a detected luminance of surroundings and a detected motion of a person. However, if battery level is low and power is cut, a high-intensity illumination will lead to a decreased time period of illumination, possibly contradicting the norm standards.

Light guiding system and a method for controlling the same


A video system and method of operation are described that compensate for low-light conditions. The video system includes a light source that adjusts. In one example the light source is controlled to either shine more light upon the user's face or less dependent upon the ambient conditions. In another example, the color of the light is changed to improve image quality. The light source may also be directly or indirectly controlled by a switch mounted onto the video telephone. Various configurations of light sources may also be implemented into the video system.

Video telephones provide for a highly interactive communication experience. People can now hear and speak to each other along with seeing the facial expressions that are an important part of human communications.
One problem with video processing devices, including video telephones, is the proper lighting of the user's face. Due to the image processing at both the transmitter and receiver ends, poor lighting conditions at the transmission side can result in the user's face being heavily shadowed and distorted at the receiver side. In addition, under poor lighting conditions, image sensors tend to be noisy, and this added noise in the signal degrades the quality of the video encoding for a given bit rate, further degrading the overall video telephony experience.


The present invention provides novel disulfone compounds and methods of preparing and using those compounds to further prepare biologically relevant gem-disulfone analogs of natural enzyme substrates. Methods of using a variety of disulfone compounds as reagents capable of forming symmetrical and non-symmetrical xcex1, xcex2 unsaturated gem-disulfones are also provided. There is also provided a disulfone reagent which reacts with both aromatic and aliphatic aldehydes in good to moderate yield to give exclusively the trans isomer. In accordance with further aspects of the present invention, a methodology for stereospecifically preparing potential gem-disulfone enzyme inhibitors is provided. A synthetic design which allows easy substitution of functional groups so that a number of substrate analogs can be synthesized readily is also provided. In addition, there is provided a new class of compounds which are potential glycosyl transferase inhibitors having characteristics which can inhibit the incorporation of sialic acid and/or fucose into glycoconjugates present at the surface of certain cancer cells. Additionally, a class of potent disulfone-linked catechol-based enzyme inhibitors, such as HIV-1 integrase inhibitors, is provided.

The present invention relates generally to sulfone phosphonate compounds and their use in organic synthesis and, more particularly, to disulfone bis-phosphonates and their preparation and use as reagents in the synthesis of biologically relevant disulfones.
Enzymes are biological catalysts which mediate the great majority of biochemical reactions that occur in living organisms Enzymatically catalyzed reactions typically result in higher reaction rates, under milder reaction conditions, with much greater reaction specificity than other chemical reactions. The specific geometric configuration and identity of the chemical elements that create the reacting group of a reactant or substrate for a particular enzyme are important factors affecting whether that enzyme can catalyze a given reaction Typically, the amino acids which constitute the enzyme""s substrate-binding site form a pocket, or cleft, in the surface of the enzyme which is geometrically and electronically complementary to the particular shape and charge distribution of the substrate""s functional groups. Thus, a substrate having the wrong charge distribution, stereochemistry, chirality, et cetera will not fit into the enzymatic binding site.
The highly specific nature of enzyme-substrate binding renders enzymatic reactions particularly susceptible to influence by other substances. Compounds that can combine with an enzyme and/or its substrate may affect either substrate binding or the enzyme""s turnover rate A compound which reduces enzymatic activity by either of these methods is referred to as an inhibitor. In many cases, enzyme inhibitors structurally resemble an enzyme""s natural substrate in at least some respects, but the reaction catalyzed by the enzyme when it is bound to its natural substrate either cannot achieve its normal product or will do so at a considerably reduced rate, Such inhibitors are frequently referred to as analogs. Inhibitors can act through several mechanisms, two of which are competitive inhibition and noncompetitive inhibition.
A compound can be a competitive inhibitor of an enzyme if that compound competes directly with a natural substrate for an enzyme""s binding site. Structurally, this type of inhibitor usually is sufficiently similar to the normal or natural substrate to enable binding to the enzyme active site, but the inhibitor differs from the natural substrate in that it is comparatively unreactive when bound to the enzyme. Since most competitive inhibitors reversibly bind their target enzyme, such compounds tend to reduce the cellular concentrations of free enzyme available for natural substrate binding, thereby inhibiting productive enzymatic activity and reducing the availability of enzyme reaction products. Inhibitors which irreversibly bind an enzyme active site are referred to as inactivators, or suicide inhibitors, and their effects on free enzyme concentration levels are much longer lived.
A substance may be deemed a noncompetitive inhibitor of an enzyme if the substance can bind the enzyme-substrate complex directly but cannot bind the free enzyme. This inhibitory mechanism likely functions by distorting the structure of the active site and rendering the enzyme incapable of catalyzing the reaction with the substrate. A noncompetitive inhibitor need not resemble the substrate at all, for it has no affect on an enzyme""s ability to bind the natural substrate As such, the noncompetitive inhibitor acts by interfering with an enzyme""s catalytic function, not its ability to bind its natural substrate. Since substrate binding is relatively unaffected, this type of inhibition is thought to occur more frequently in the case of multisubstrate enzymes, such as transferase enzymes which catalyze reactions that transfer a specific functional group from one substrate to another.
As enzymatic reactions often play an important role in a variety of biocbemical pathways that affect biological systems, enzymes frequently are good targets for strategic efforts to affect disease processes, such as cancer, or viral invasions of a host system, such as by the human immunodeficiency virus (HIV). For example, small cell lung cancer (SCLC), a highly malignant carcinoma that is prevalent in cigarette smokers, has been found to be particularly sensitive to chemotherapy, and there are a number of combination therapies currently in clinical use. Chemotherapeutic agents currently under investigation include camptothecan derivatives, which have been found to inhibit DNA topoisomerase I, and taxol, which is an antitubular agent. While these therapies generally are thought to hold promise for inhibiting cancer cell growth and proliferation in a particular tissue or organ, they do not speak to the issue of cancer metastasis. Metastasis is the, mechanism by which cancer cells travel or spread from one area of the body to other, often unrelated, areas, thereby resulting in the development of malignant tumors throughout the body. Tumor metastasis is believed to be one or the leading causes of cancer-related mortality. Since SCLC is a form of cancer that is characterized by early onset of metastatic spread, making it a very difficult cancer to cure, the development of new chemotherapeutics which target invasion and metastasis of malignant cells is a particularly important strategy for combating this type of cancer.
Generally, cancer develops in four principle stages: (1) initiation; (2) promotion of cell growth; (3) invasion and metastasis; and (4) death of the host. Initiation is characterized by hyperproliferation of cells which then continues during the growth stage. During invasion and metastasis, tumors form and the cancer spreads to other tissues. Different forms of cancer respond differently to the variety of treatment protocols, depending upon the type and developmental stage of the cancer. In the case of SCLC, for example, the three primary methods of treatment include surgical removal of cancerous tissue, radiation therapy, and chemotherapy.
Sialyl Lewis X is a cell surface glycoconjugate that serves as a recognition element in cancer metastasis. Structurally, sialyl Lewis X is a tetrasaccharide consisting of N-acetyl neuraminic acid (NeuAc) xcex1-(2xe2x86x923) linked to galactose, which in turn is xcex2-(1xe2x86x924) linked to a glucosamine bearing an xcex1-(1xe2x86x923) linked fucose residue. Sialyl Lewis X is synthesized in the Golgi apparatus, which is located in the cytoplasm of the cell. As illustrated by the following Reaction Equation,
preparation of sialyl Lewis X begins when an activated sialyl residue (CMP-NeuAc) is transferred to lactosamine using a 2xe2x86x923-sialyl transferase enzyme. Subsequently, activated fucose (GDP-fucose) is transferred to the molecule by a fucosyl transferase enzyme The resultant tetrasaccharide is then transported out of the Golgi and to the cell surface. Once at the cell surface, sialyl Lewis X serves as a cell recognition element for other molecules, such as selectin proteins (P-selectins), which are on the surface of other cells. Thus, cells having P-selectins at their surface, for example, are able to recognize and adhere to cells which have sialyl Lewis X on their surface. Studies have shown that selectin recognition of sialyl Lewis X at the cell surface is most efficient when both the fucosyl and sialyl residues are present on the sialyl Lewis X molecule. (See eg., Einhorn L. H, Bond W. H., Hornback N., and Joe B. T. xe2x80x9cLong-Term Results in Combined-Modality Treatment of Small Cell Carcinoma of the Lung.xe2x80x9d Sem. Oncol. 1978, 5, 309-313; Bolscher J., Bruyneel E., Rooy H., Schallier D., Marcel M., and Smets L. xe2x80x9cDecreased Fucose Incorporation in Cell Surface Carbohydrates is Associated with Inhibition of Invasion.xe2x80x9d Clinical and Experimental Metastasis. 1989, 7(5), 557-569; Yamada N., Chung Y. S., Takatsuka S., Arimoto Y., Sawada T., Dohi T., and Sowa M. xe2x80x9cIncreased Sialyl Lewis A Expression and Fucosyl Transferase Activity with Acquisition of a High Metastatic Capacity in a Colon Cancer Cell Line.xe2x80x9d British J. of Cancer 1997, 76(5), 582-587).
An abundance of evidence links the presence of fucosyl and sialyl residues at the surface of cancer cells to both metastatic potential and patient survival. (See e.g., Izumi, Y., Nemoto Y.; Kawamura Y., Nakatsugawa S., Dohi T., Oshima M., Irimura T. xe2x80x9cCorrelation of Cell Surface Sialyl-LeX, Fucosyltransferase Activity and Experimental Liver Metastasis of Human Colon Carcinoma Cellsxe2x80x9d Sixth International Congress of the Metastasis Research Society, Gent, Belgium, Sep. 8-11, 1996. Clinical and Experimental Metastasis 1996, 14(supplement I), 94-95.) This evidence serves to highlight the significance of sialyl- and fucosyl-transferases, the enzymes which mediate the transfer of these residues to cell surface glycoconjugates, as key targets for chemotherapeutic intervention.
Generally, tumor metastasis is facilitated by cell-cell adhesion and communication, which is accomplished through interactions between molecules expressed on the cells"" surface, For example, studies have shown that, during metastasis, many carcinoma cells interact with certain proteins, such as the P-selectins, found on the surface of blood platelets (thrombocytes). (See e.g., Handa K., White T., Ito K., Fang H., Wang S-S., Hakomori S-I. xe2x80x9cP-Selectin-Dependent Adhesion of Human Cancer Cells: Requirement For Co-Expression of a xe2x80x98PSGL-1-Likexe2x80x99 Core Protein and the Glycosylation Process for Sialosyl-Lex or Sialosyl-Leaxe2x80x9d Int. J. Oncol. 1995, 6, 773-81 and references cited therein; Stone J. P., and Wagner D. D. xe2x80x9cP-Selectin Mediates Adhesion of Platelets to Neuroblastoma and Small Cell Lung Cancerxe2x80x9d J. Clin. Invest. 1993, 92, 804xe2x80x9413). This evidence suggests that the ability of malignant cells to bind particular proteins, such as the selectins, mediates the transport of those cells through the body. Thus, if selectin binding by cancer cells can be inhibited or prevented, it is likely that metastasis of malignant cells can be slowed or eliminated. Since the presence of fucose and/or sialic acid on sialyl Lewis X has been shown to facilitate selectin recognition at the cell surface, and since selectin binding has been demonstrated to mediate metastasis, it is highly likely that fucose and/or sialic acid are important recognition elements in tumor metastasis. Thus, if either fucose or sialic acid is prevented from being incorporated into cancer cell surface glycoconjugates, P-selectin binding can be inhibited, and tumor metastasis can be slowed or prevented entirely. Cumulatively, this research indicates that the development of enzyme substrate analogs designed to target and effectively inhibit the transferase enzymes that facilitate the incorporation of either fucose or sialic acid into cancer cell-surface glycoconjugates is a viable strategy for impeding or eliminating these important metastatic pathways.
Enzyme inhibitors also can be used to affect undesirable biochemical processes in the context of human immunodeficiency virus (HIV) infection. The lifecycle of HIV has seven distinct phases: (1) viral binding to host cell receptors; (2) entry of the viral core into host cells; (3) shedding of the viral core; (4) reverse transcription of viral RNA into viral DNA; (5) integration of viral DNA into host DNA; (6) viral DNA replication and protein synthesis; and (7) budding of new viral cores. Current drug therapies for the treatment of HIV focus on two of these phases by inhibiting to key enzymes, HIV-reverse transcriptase (HIV-RT) and HIV-protease.
HIV-RT is an enzyme endogenous to retroviruses that has two known catalytic duties. It functions as an RNA or DNA dependent DNA polymerase and as a ribonuclease H. Currently, only the polymerase activity has been targeted for enzyme inhibition. HIV-RT inhibitors block the transcription of viral RNA into viral DNA These inhibitors were the first HIV inhibitors approved by the FDA, but viral resistance to their activity tends to develop over time, thereby limiting their use as a sole therapy. The first drug approved for treatment of HIV infection was AZT (3xe2x80x2-azido-3xe2x80x2deoxythymidine), a compound in which the natural 3xe2x80x2-OH of thymidine is substituted with an azide. This azide functionality eliminates the possibility of covalent elongation of a growing DNA strand by functioning as a chain terminating inhibitor. Since the active form of AZT includes a 5xe2x80x2-triphosphate, which is synthesized and added in vivo by endogenous host enzymes after the uncharged form of the compound has been transported across the cell membrane, AZT is properly characterized as a prodrug.
One of the major drawbacks of currently available chain terminating nucleoside inhibitors is the high mutation rate of HIV-RT, which promotes viral resistance to the available inhibitor therapies. A recent study by Harrison and Verdine (Huang H., Chopra R., Verdine G., Harrison S. C. xe2x80x9cStructure of a Covalently Trapped Catalytic complex of HIV-1 Reverse Transcriptase: Implications for Drug Resistancexe2x80x9d Science 1998, 282, 1669-1674) demonstrated that the binding pocket of the catalytic complex of HIV-RT is a 3xe2x80x2-binding pocket and that this pocket incorporates point mutations in those enzymes that are resistant to AZT as well as other nucleoside analog inhibitors. Although extensive research has focused on the use of various 3xe2x80x2-analogs of nucleosides, much less attention has focused on altering the 5xe2x80x2-triphosphate moiety of the natural nucleoside triphosphate substrates.
Another class of approved compounds is HIV-protease inhibitors, which interfere with the processing of viral proteins. Combination therapy of protease inhibitors and RT-inhibitors has proven promising in some cases; however, the search for less toxic and more potent candidates in both of these classes continues. As combination therapy is the most promising approach to HIV treatment to date, identification of other key enzymes that can be targeted for chemotherapeutic intervention is needed.
One of the most recently targeted enzymes for anti-HIV therapy has been the HIV integrase HIV-IN) enzyme. This enzyme integrates newly formed viral DNA into host DNA by inserting the viral DNA product of the reverse transciptase and viral RNA reaction into the host""s chromosomes. As no cellular counterpart to this enzyme has been identified, it is an attractive target for chemotherapeutic intervention because compounds directed at its inhibition are unlikely to interfere with or affect the functioning of the host system. Catechol-based analogs, which may be exemplified by the following Formula,
comprise one class of compounds that have been identified as having potent anti-HIV-IN activity. Recent studies based on a large number of these HIV-IN inhibitors have shown that catechol-based inhibitors have several general structural features in common: (1) the presence of two aryl units, (2) separated by a central linker, (3) with at least one aryl ring having an ortho bis-hydroxylation pattern (Zhao i., Neamati N., Mazumder A., Sunder S., Pommier Y., ad Burke T. xe2x80x9cArylamide Inhibitors of HIV-1 Integrasexe2x80x9d J. Med. Chem. 1997, 40, 1186-1194) The inhibitory potency of compounds in this general class has been demonstrated repeatedly, and development of improved catechol-based HIV-IN inhibitors holds promise for chemotherapeutic intervention in the progression of HIV infection (Zhao H., Neamati N., Mazumder A., Sunder S., Pommier Y., ad Burke T. xe2x80x9cArylamide inhibitors of HIV-1 Integrasexe2x80x9d J. Med. Chem. 1997, 40, 1186-1194; Lin Z., Neamati N., Zhao H., et al. xe2x80x9cChicoric Acid Analogues as HIV-1 Integrase Inhibitorsxe2x80x9d J. Med. Chem. 1999, 42, 1401-1414). Thus, in the field of HIV research as well as cancer research, the successful development of enzyme substrate analogs to inhibit particular target enzymes is a viable strategy for either elating or slowing the progression of the disease.
A well-designed substrate analog or competitive inhibitor should be capable of passing through the cell membrane, being recognized by the target enzyme, binding the enzyme successfully, not reacting in a manner that will yield the undesirable biochemical product, and riot degrading or hydrolyzing within the environment of the cell. For example, in the case of targeting SCLC tumor metastasis when developing successful competitive inhibitors of sialyl transferase or fucosyl transferase, the inhibitor or analog should structurally resemble the relevant nucleotide sugar substrate in many respects. A nucleotide sugar is the glycosyl or sugar donor in biosynthetic reactions catalyzed by glycosyl transferases. Nucleotide sugar substrates consist of the relevant carbohydrate residue (sialic acid for sialyl transferase and fucose for fucosyl transferase) linked to the relevant activating nucleoside mono- or diphosphate (cytidine and guanosine, respectively). In most cases, the link between the carbohydrate residue and the nucleoside phosphate is either a mono- or a diphosphate linkage, which, in either case, results in the sugar being linked to the other components via at least one phosphodiester bond. Additionally, the 5-bond distance between the sugar and the 5xe2x80x2-nucleoside residue must be maintained, since this distance has been shown to be critical for achieving enzyme-substrate binding. These basic components, that is, the carbohydrate residue, the nucleoside phosphate, and the linking group need to be present in the inhibitor, otherwise the inhibitor cannot be recognized and bound by the target enzyme. However, because the phosphodiester bond connecting the sugar to the nucleoside is a highly labile bond, replacing the oxygen atom linkage in that bond with a carbon atom linkage, creating what is known as a C-glycoside, rather than the natural O-glycoside, often tends to create a more robust analog under physiological conditions. However, incorporation of the carbon atom presents its own set of constraints. In order for a C-glycoside to fit into the enzyme active site, the carbon atom must be incorporated in an equatorial rather than an axial position so that the molecule maintains the appropriate stereochemistry needed for complexation with the enzyme. The challenge, therefore, lies in designing and implementing chemical substitutions within the natural substrate molecule to impart all the above-noted characteristics to an inhibitor.
There are several prior art examples of glycosyl transferase inhibitors, including tunicamycin, a naturally occurring antibiotic which is an isosteric analog of nucleoside diphosphates. However, because tunicamycin is highly toxic, researchers have sought alternative isosteres of this compound. One design strategy has been to produce analogs with a more stable functionality than the extremely labile diphosphate linkage, while still retaining the critical 5-bond distance between the sugar and the 5xe2x80x2-nucleoside residue. To date, both O-linked and C-linked glycosidic analogs of the nucleoside diphosphates have been developed. However, while the prior art glycosyl transferase analogs have been shown to actively inhibit the target enzyme, they have proved to be unsatisfactory in vivo in several regards. First, as with tunicamycin, toxicity may present a problem. Second, the oxygen atom linkages comprised by the molecules frequently result in enzymatic cleavage of the molecule within the cellular environment. Finally, the presence of a formal charge on the molecule often precludes its successful transport across the cell membrane.
In the light of the known disadvantages of prior art substrate analogs, phosphate linkages present in many enzyme substrates have been recognized as likely sites for altering the chemistry of the natural substrate in a manner which would result in a successful inhibitor compound. Depending on the targeted enzyme substrate, these phosphate linkages may be mono-, di-, or triphosphate linkages. Among the reasons for identifying the phosphate linkage as a site for chemical substitution is that the phosphate moiety itself is unsuitable in a substrate analog inhibitor because it is easily hydrolyzed or cleaved by other enzymes present within the cell and, as an ionic or charged moiety, it generally has difficulty in crossing cell membranes, which are lipophilic.
Sulfones have been recognized in the literature as substitutes for phosphate moieties, such as biological phosphodiesters, in a variety of contexts. (Castro A. and Spencer T. A. xe2x80x9cFormation and Alkylation of Anions of Bis(methylsulfonyl)methane.xe2x80x9d J. Org. Chem. 1992, 57, 3996-3499) In particular, the disulfone moiety has been recognized as a good potential surrogate for the diphosphate group present in a variety of natural enzyme substrates for several reasons: (1) the disulfone moiety is not readily hydrolyzed; (2) disulfones presumably have less difficulty in crossing the cell membrane due to tbeir electrical neutrality; (3) disulfones are generally similar in size and shape to the corresponding diphosphates; and (4) disulfones likely are sufficiently polar to bind the enzyme active site in the place of an ionic diphosphate moiety. (Id) Despite recognition of the usefulness of disulfones, prior art disulfone reagents and methods of preparing substrate analogs for certain enzymes have been generally unsatisfactory, as the design and preparation of a suitable disulfone reagent capable of being used to synthesize stereospecific substrate analogs in an acceptable yield has proved elusive. For example, the use of gem-disulfones as pyrophosphate analogs was initially investigated by Spencer in his attempt to produce farnesyl transferase inhibitors (Castro A. and Spencer T. A. xe2x80x9cFormation and Alkylation of Anions of Bis(methylsulfonyl)methane.xe2x80x9d J. Org. Chem. 1992, 57, 3996-3499). However, the highly basic di- and tri-anion chemistry employed in Spencer""s syntheses resulted in low yields and produced compounds with no resultant biological activity. Thus, an important reason for the reported unacceptable yields of disulfone analogs is that known reagents and reaction sequences require strongly basic conditions which ultimately degrade the target molecule over the course of the reaction.
However, the disulfone moiety is extremely versatile, and its application in the synthesis of relevant enzyme inhibitors goes beyond its ability to substitute for the phosphate moiety frequently present in natural substrates. For example, in the case of HIV-1 inhibition, the disulfone moiety can be used to synthesize effective HIV-integrase inhibitors by serving as the central linker between the two aryl units of a catechol derivative. Many catechol-based inhibitors have been shown to inhibit HIV-IN effectively in cell-free assays. However, many of these inhibitors exhibit collateral cellular toxicity, which is thought to be caused by either their oxidation to reactive quinone species or, perhaps, catabolism to cytotoxic metabolites. Other catechol inhibitors may be characterized as prodrugs, since they would rely on host enzymes to convert them to their active inhibitory form after they have been transported across the cell membrane in an electrically neutral, inactive form. Still other catechol derivatives would exhibit a short half-life, metabolizing very quickly and affecting free enzyme concentrations for only limited periods of time.
In view of the foregoing, a need exists for suitable reagents and methods of preparing biologically relevant enzyme inhibitors which overcome the shortcomings of the prior art.
In accordance with the principles of the present invention, a disulfone compound is provided, Methods of preparing various disulfone compounds are also provided. Methods of using a variety of disulfone compounds as reagents capable of forming symmetrical and non-symmetrical xcex1, xcex2 unsaturated gem-disulfones are also provided. There is also provided a disulfone reagent which reacts with both aromatic and aliphatic aldehydes in good to moderate yield to give exclusively the trans isomer.
In accordance with further aspects of the present invention, a methodology for stereospecifically preparing potential gem-disulfone enzyme inhibitors is provided. A synthetic design which allows easy substitution of functional groups so that a number of substrate analogs can be synthesized readily is also provided. In this regard, a reagent which is capable of incorporating a disulfone moiety into a sugar nucleoside so that a suitable substrate analog can be synthesized is also provided. Inhibitors of diphosphate-dependent enzymes, such as enzymes which catalyze the metastatic pathways of certain cancers like small cell lung cancer are also provided. In addition, there is provided a new class of compounds which are potential glycosyl transferase inhibitors. Potential chemotherapeutics which will inhibit the incorporation of sialic acid and/or fucose into glycoconjugates present at the surface of certain cancer cells are also provided. Additionally, a class of potent catechol-based enzyme inhibitors, such as HIV-1 integrase inhibitors, is provided.
Other objects, features, and advantages of the present invention will become apparent to those skilled in the art from the following detailed description. It should be understood, however, that the detailed description and specific examples, while indicating exemplary embodiments of the present invention, are given for purposes of illustration only and not of limitation. Many changes and modifications within the scope of the instant invention may be made without departing from the spirit thereof, and the invention includes all such modifications.
In accordance with one embodiment, the present invention provides novel disulfone compounds and methods of preparing and using those compounds to further prepare biologically relevant gem-disulfone analogs of natural enzyme substrates. In accordance with one aspect of this embodiment of the present invention, a disulfone Compound 10 is provided that may be represented by the follows Formula:
In Compound 10, n is preferably 0, 2, or 3. Preferably, R1 represents a carbon atom or a nitrogen atom. Preferably, R2 may be the same or different and represents any suitable chemical element or chemical group, such as hydrogen; an alkyl group of from about 1 to 4 carbons (for example, methyl, ethyl, isopropyl, and tert-butyl); or an arylalkyl group, such as a benzyl group, which can be a substituted arylalkyl group, such as a mono-, di-, tn-, tetra-, or pentasubstituted benzyl group. Preferably, R3 may be the same or different and represents any suitable chemical element or chemical group, such as hydrogen, a double bonded oxygen atom, a fluorine atom, a hydroxyl group, or an epoxide ring. No particular double bond geometry (for example, cis or trans) is intended by the structure of Compound 10 nor by any of the other compounds referenced below, unless specifically stated herein.
As illustrated by the following Reaction Equation A,
an exemplary embodiment of the novel disulfone compound in accordance with this aspect of the instant invention can be synthesized from commercially available diisopropylphosphite 12. The sodium ion of diisopropylphosphite 12 can be condensed with carbon disulfide and followed by methylation to give the dithioester 14. Selective reduction of the dithioester 14 gives the sodium thiolate which is reacted in situ with diiodomethane to give the bis-sulfide 16. Oxidation of the bis-sulfide 16 with meta-chloroperbenzoic acid (mCPBA) affords the bis-sulfone bis-pbosphonate of Compound 10. Alternatively, as illustrated by the following Reaction Equation B,
oxidation of the bis-sulfide 16 with OXONE (namely, a compound whose active ingredient is potassium peroxymonosulfate, available from DuPont under the OXONE trademark) also affords the bis-sulfone bis-phosphonate of Compound 10. Various other methods, as now known or hereafter devised, also may be utilized to produce the bis-sulfone bis-phosphonate of Compound 10.
It should be understood that the disulfone compounds of the subject invention may be modified, and, as a result, a variety of derivatives are possible and also come within the scope of the present invention. For example, derivatives of the inventive bis-sulfone bis-phosphonate compound may include a bis-sulfone carbonyl analog, represented by the formula of Compound 10, where n is 0, R1 is a carbon atom, and R3 is a double bonded oxygen atom and a fluorinated bis-sulfone analog, represented by the formula of Compound 10, where n is 3, R1 is a carbon atom, and R3 is preferably hydrogen or fluorine.
As illustrated by Reaction Equation C below, a bis-sulfone carbonyl analog can be prepared by selective reduction of 18 followed by reaction with carbonyl diimidazole to give 20 and oxidation to form the carbonylated derivative of Compound 10.
As illustrated by Reaction Equation D below, a fluorinated derivative of Compound 10 can be prepared by reacting the inventive bis-sulfone bis-phosphonate Compound 10 with hexamethyldisilazane (HMDS) and N-fluoro-O-benzendisulfonimide to form a mono-fluorinated derivative of Compound 10.
These and other derivatives of Compound 10 may be synthesized, as may be necessary, in accordance with conventional techniques.
In accordance with one embodiment of the present invention, Compound 10 may be used to synthesize biologically relevant gem-disulfones, such as analogs of target enzyme substrates for example. While the disulfone compounds of the instant invention may be modified in any number of ways for a variety of uses, the present inventors have found that the inventive compounds are particularly useful as reagents in the Homer-Emmons-Wittig reaction. In accordance with this embodiment, the bis-sulfone moiety of Compound 10 is capable of undergoing selective condensation with any suitable aldehyde, thereby producing a highly efficient route for synthesizing particular molecules of interest. For example, reacting Compound 10 with a suitably protected reducing sugar and subsequent condensation with a 5xe2x80x2-guanosyl aldehyde derivative gives the target differentially functionalized gem-disulfone. Alternatively, as illustrated in Table 1 below, condensation of Compound 10 with a variety of simple aromatic aldehydes and carbohydrate-based aldehydes occurs readily, and either mono- or bis-addition can be achieved, depending upon the quantity of aldehyde employed, to produce both mono- and bis-substituted xcex1,xcex2 unsaturated gem-disulfones.
The novel disulfones of the various embodiments of the present invention can be used in a variety of ways and for a variety of purposes now known or hereafter devised by those skilled in the art. However, in accordance with one embodiment of the present invention, the novel disulfones have been found to be useful as Horner-Emmons-Wittig (HEW) reagents. In this regard, the term HEW reagent refers to the use of the novel disulfones as reagents in the Horner-Emmons-Wittig reaction (also known as the Horner-Emmons reaction) with all types of aldehyde compounds. As used herein, the term Horner-Emmons-Wittig reaction generally refers to types of condensation reactions used in organic synthesis to generate carbon-carbon bonds, producing olefins as products. In accordance with this embodiment, use of the novel disulfones as HEW reagents produces high reaction rates, good to moderate yields, and high stereoselectivities (e.g., no Z isomers were formed). As illustrated in Table 2 below (see next page), both activated and deactivated aromatic aldehydes are well-tolerated, Aliphatic substrates also undergo the condensation reaction, rendering this an efficient method for the incorporation of gem-disulfones into a variety of molecules. In this regard, the reaction conditions may be varied in any conventional manner now known or hereafter devised by those skilled in the art. For example, other bases and/or solvents as are now known or hereafter devised may be utilized. Preferred bases include, but are not limited to, the following: NaH, t-BuOLi, DIEA-LiBr, and/or suitable mixtures thereof. Preferred solvents include, but are not limited to, the following: i-PrOH, t-BuOH, THF, and/or suitable mixtures thereof.
While the novel disulfones of the present invention can be used in accordance with the various embodiments described herein to produce numerous types of compounds, the present inventors have found that use of the novel disulfones as HEW reagents yields compounds which are or may be useful due to, inter alia, their enzyme inhibition characteristics. In accordance with the instant invention design considerations for the synthesis of effective enzyme inhibitors include, but are not limited to, the following: First, inhibitors of cellular enzymes should be able to cross the cell membrane and be readily absorbed by cells; secondly, they should be stable to degradation by host enzymes so that cellular inhibitor concentrations can be maintained for a suitable period of time; and, finally, once the inhibitors bind the target enzymes, the inhibitors should effectively compete with the natural substrate without reacting and subsequently being converted to product. These criteria are illustrative only and not intended to be restrictive, as those skilled in the art will appreciate in view of the variety of modifications of these criteria that are possible, all of which are intended to be within the scope of the present invention, as hereinafter more fully described.
In the light of these criteria, the present inventors have found that the various HEW reactions which can be carried out in accordance with the embodiments of the present invention are particularly well-suited to the synthesis of enzyme inhibitors, Those reactions which are capable of synthesizing either C-glycoside disulfone analogs of glycosyl transferase substrates or disulfone-linked catechol-based inhibitors of HIV-1 integrase are especially preferred.
In accordance with the present invention, these reactions generally proceed by reacting a novel disulfone HEW reagent with a selected aldehyde under mildly basic conditions to obtain a desired end product. In certain applications, suitable protection strategies preferably are employed to render certain functional groups on the selected aldehyde and/or other reactants unreactive. In this manner, normally reactive functional groups are less likely to undergo undesirable reactions as the condensation reaction proceeds. In such cases, generally, once the reaction produces the desired intermediate, suitable deprotection strategies are employed, as may be required, to achieve the desired end product. The specific protection and deprotection strategies employed during a given synthetic reaction sequence will depend upon, inter alia, the particular reactants used, and such strategies can be effected by any means known and practiced by those of ordinary skill in the art. Likewise, the preferred mildly basic reaction conditions can be created by any means known and practiced by those skilled in the art; however, in accordance with various aspects of the present invention, such conditions are preferably created by utilizing a source of lithium cations, such as lithium chloride or lithium bromide for example, and a suitable amine base, such as diisopropylethyl amine (DIEA), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, any suitable base having a pKa of about 15 or higher can be used. (See e.g., xe2x80x9cHorner-Wadsworth-Emmons Reaction: Use of lithium chloride and an amine for base-sensitive compoundsxe2x80x9d Tetrahedron Letters, 1984, 25(21), 2183-2186). As will be appreciated by one skilled in the art, various changes and modifications to the above-described method for using novel disulfone reagents can be implemented, and the method thus modified will still come within the scope and spirit of the present invention.
In the case of synthesizing C-glycoside disulfone analogs of glycosyl transferase substrates in accordance with preferred aspects of this embodiment of the present invention, the novel disulfone reagent and a suitably selected and, in many cases, suitably protected sugar-based aldehyde are caused to undergo condensation preferably under mildly basic conditions to produce an intermediate compound. Then, this intermediate compound and a suitably selected and, in most cases, suitably protected 5xe2x80x2-furanosyl aldehyde sugar also are caused to undergo condensation, preferably under mildly basic conditions, and preferably followed by global deprotection, if applicable, to yield the targeted enzyme substrate analog. In its general design the synthetic strategy thus employed conserves the five bond distance between the carbohydrate and the nucleoside. The present inventors believe this to be an important factor in maintaining the spatial requirements of the glycosyl transferase enzyme""s active site. Further, as discussed in greater detail above, the O-glycoside linkage between the carbohydrate and the nucleoside preferably is substituted with a C-glycoside linkage to prevent potential cellular degradation, and the phosphate linkages are substituted with the non-labile sulfone functionalities.
Using the novel disulfone reagent of the present invention, compounds for inhibiting the incorporation of a carbohydrate residue, such as an xcex1-L-fucose for example, into cell surface glycoconjugates have been designed and synthesized. Since sugar-based aldehydes are in equilibrium with their corresponding closed pyranose forms, excess base typically is required to achieve efficient conversion. However, since the use of excess base frequently leads to undesirable elimination, in accordance with various aspects of the present invention, deprotonation of the disulfone HEW reagent under mild conditions in the presence of lithium cations is preferably employed in the condensation reaction. For example, as illustrated by the Reaction Equation E below, utilization of either lithium chloride or lithium bromide and an amine base has been found to create tie preferred mildly basic conditions and prevent undesirable elimination resulting from possible internal deprotonation by the alkoxide formed at C-5. If an unprotected sugar 22 is employed, the allylic proton in 24 should be relatively less acidic, since the allylic hydroxyl also may be deprotonated. It should be noted, however, that in cases where the fully deprotected sugar 22 is utilized, care should be taken to ensure the formation of the desired pyranose using upon conjugate addition rather than the furanose
ring. Preferably, the disulfone reagent is reacted with 3,4-isopropylidene-D-fucose 26 under mildly basic conditions to afford 28, an exemplary protected fucosyl-C-glycoside bis-sulfone phosphonate, which can then undergo condensation with a suitably protected nucleotide sugar, such as 5xe2x80x2-guanosyl aldehyde for example. Under the reversible conditions of the reaction, the xcex2-C-glycoside will form, as demonstrated by Davidson and co-workers. (See, Davidson A. H., Hughes L. R, Qureshi S. S., and Wright B. xe2x80x9cWittig Reactions of Unprotected Aldohexoses: Formation of Optically Active Tetrahydrofurans and Tetrahydropyransxe2x80x9d Tetrahedron Lett. 1988, 29, 693-696).
As illustrated by the following Reaction Equation F,
the feasibility of this transformation has been demonstrated, and 30 has been produced in an unoptimized 17% yield.
As illustrated by the following Reaction Equation G,
a protected form of guanosine, the 5xe2x80x2-furanosyl aldehyde sugar that serves as the activating nucleoside for GDP-Fucose, has been prepared by reacting 32 with N,N-dimethylformamide dibenzyl acetal in DMF for 3 h at 80xc2x0 C. Dess-Martin oxidation affords 33, which then can be condensed with a suitable fucosyl-C-glycoside bis-sulfone phosphonate 30 yielding 36. Global deprotection of 36 gives the targeted enzyme substrate analog 38 both with and without a double bond, depending on the deprotection strategy. Various deprotection strategies can be used but, in general, such strategies should proceed in a manner such as shown in Reaction Equation G above.
As seen in Reaction Equation H below, an alternative strategy for selective condensation involves stepwise addition employing reagent 42, which can be prepared by the reaction of 40 with potassium permanganate. Deprotonation of 42 with LiBr/DBU can give a single anion that can be condensed with a suitably protected fucose derivative 26. Subsequent oxidation of intermediate 44 then can give the bis-sulfone 46, which then can be reacted with 34 to yield 36.
Sulfonimide analogs, represented by Compound 10, where n preferably is 0, R1 preferably is a nitrogen atom, and preferably R3 is R2, also have been synthesized as fucosyl transferase inhibitors. These compounds preferably are prepared by reacting an amine with methane sulfonyl chloride to give 48, as illustrated by the following Reaction Equation I:
Reactant 48 can be treated with three equivalents of base and reacted with diethyl chlorophosphate to generate 50, a derivative of Compound 10. Compound 50 behaves similarly to other derivatives of Compound 10 and can undergo condensation with fucose to give 52, which then can be reacted with 34 to afford 54.
In accordance with still other aspects of these embodiments of the present invention, monosulfones which exhibit inhibitory properties can be synthesized. For example, the synthesis of the C-glycoside monosulfone of N-acetyl neuraminic acid (NeuAc) is suitably illustrated by the following Reaction Equation J:
As shown above, the bis-phosphonate sulfide reagent 56 preferably is prepared by the reaction of commercially available diethyl iodomethylphosphonate 55 with disodium sulfide. Subsequent oxidation with OXONE (namely, a compound whose active ingredient is potassium peroxymonosulfate, available from DuPont under the OXONE trademark) can provide the sulfone 58. Selective reaction of a suitably protected NeuAc derivative 60 with 58 yields 62. Condensation of 62 with the aldehyde 64 forms 66, which upon deprotection can provide the target molecule 68. Suitable selectivity can be achieved by using two equivalents of base, one equivalent of NeuAc 60, and one equivalent of 58. As illustrated by Reaction Equation K below, the phosphonate anion 58 attacks the ketone of NeuAc 60 and, in the presence of an xcex1,xcex2 unsaturated sulfone capable of undergoing Michael addition, undergoes elimination of diethyl phosphate, thereby yielding the desired product. While bis-addition is possible, single addition can be achieved by limiting the ratios of reagent to carbonyl compound to about 1:1. The intermediate Michael acceptor can undergo either a 6-exo-trig 62 or a 7-endo-trig 70 cyclization and both are favored according to Baldwin""s rules. However, six-membered ring-formation may be kinetically favored. If the axial sulfone phosphonate does not form preferentially, then modification of the NeuAc ester R group may be one means for gaining stereochemical control of the anomeric center.
It should be appreciated that while the foregoing examples are illustrative of various mechanisms and reactions by which suitable C-glycoside sulfone isosteres of GDP-fucose and CMP-NeuAc can be prepared, these are merely exemplary embodiments of the present invention. The novel reagents of various aspects of the present invention may be utilized in a variety of ways, and the subject sulfone isosteres and analogs prepared in other manners, as may be now known or hereafter devised by those skilled in the art.
In addition to providing an efficient means for synthesizing C-glycosidic substrate analogs targeting enzymes involved in tumor metastasis, the novel disulfone reagents of the instant invention also provide a rapid synthetic sequence into diverse classes of compounds that target inhibition of various other enzymes, such as enzymes used by the human imnmunodeficiency virus (HIV), by acting as analogs of the natural enzyme substrates. These classes of compounds include, but are not limited to, the following: (1) symmetrical and/or unsymmetrical disulfones based on the known catechol inhibitors of certain enzymes, such as HIV integrase (HIV-IN); and (2) non-nucleoside inhibitors of other enzymes, as shown in Table 3 below.
In the case of synthesizing disulfone-linked catechol-based inhibitors of particular enzymes, such as HIV-1 integrase for example, a novel disulfone reagent and a suitably selected and, in most cases, suitably protected benzaldehyde are caused to undergo condensation, preferably under mildly basic conditions, and preferably followed by deprotection, if applicable, to yield the target catechol-based enzyme inhibitor, such as an inhibitor of HIV integrase. Any suitable protection and deprotection strategies may be employed to render particular functional groups present on the selected benzaldehyde unreactive during the condensation reaction. Preferably, protection of the benzaldehyde is accomplished through acetylation or methylation, and deprotection is consequently achieved through deacetylation or demethylation. As described above, the preferred mildly basic reaction conditions can be created by any means known and practiced by those skilled in the art; however, in accordance with various aspects of the present invention, such conditions are preferably created by utilizing a source of lithium cations, such as lithium chloride or lithium bromide for example, and a suitable amine base, such as diisopropylethyl amine (DIEA), or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Alternatively, any suitable base having a pKa of about 15 or higher can be used.
Synthesis of disulfone-linked catechol-based enzyme inhibitors, such as inhibitors of HIV integrase for example, can be accomplished in a one step (symmetrical) or two step (unsymmetrical) synthesis followed by deprotection, if applicable, as illustrated by Equation L below. In accordance with various aspects of the present invention, an HEW condensation reaction of a novel disulfone reagent with an excess amount of a suitably selected aldehyde and a suitable base can produce symmetrical catechol-base inhibitors of such enzymes as HIV-IN. An HEW reaction of an aldehyde with an excess amount of a novel disulfone reagent and a suitable base can produce mono-substituted analogs which, when reacted with another suitably selected aldehyde, can produce unsymmetrical catechol-based inhibitors of enzymes such as HIV-IN.
In accordance with various aspects of this embodiment of tile present invention, a novel disulfone reagent can be used to synthesize disulfone-linked catechol-based inhibitors of certain enzymes, such as HIV integrase for example, as illustrated by the following Reaction Equation M:
Preferably, the synthesis of catechol-based inhibitors of enzymes such as HIV-IN begins by selecting a suitable benzaldehyde, such as the commercially available 3,4-dihydroxy benzaldehyde 72 for example, and implementing a suitable protection strategy, such as acetylation of the hydroxyl groups on 3,4-dihydroxy benzaldehyde 72 with acetic anhydride in pyridine to form 74. Preferably, a Horner-Emmons-Wittig olefination reaction is carried out, which is then preferably followed by a suitable deprotection strategy, such as deacetylation, if applicable, to generate the target disulfone-linked catechol derivative, such as 76 and/or 78.

Disulfone reagents and methods of preparing and using same

The Arizona Disease Control Research Commission


A waste solution discharging apparatus for waterless lithographic printing plates which is used in a waterless lithographic printing plate developing apparatus, in which a waterless lithographic printing plate is developed while processing solution inside an accommodating tank is pumped out by a circulating pump, supplied to the waterless lithographic printing plate, and recovered in the accommodating tank, and a replenishing solution is replenished periodically. The waste solution discharging apparatus for waterless lithographic printing plates discharges the processing solution, which is within the accommodating tank and which contains scrapings generated after development, as waste solution. In the waste solution discharging apparatus for waterless lithographic printing plates, a processing solution inflow opening of a discharge pipe, which discharges the processing solution in the processing tank along with the scrapings, is formed of a material having low surface tension, and/or the waste solution discharging apparatus is provided with a guide member which guides the scrapings to the processing solution inflow opening. Accordingly, the processing solution which includes the scrapings smoothly flows into the discharge pipe.

1. Field of the Invention
The present invention relates to a waste solution discharging apparatus for waterless lithographic printing plates which is used to discharge waste solution including scrapings which are generated after developing.
2. Description of the Related Art
Various waterless PS plates in which a silicone layer is used as an ink-resistant layer have been proposed. A waterless PS plate in which a light-soluble or a light-insoluble photosensitive layer and a silicone rubber layer are laminated on a base is disclosed in Japanese Patent Application Publication Nos. 44-23042 and 46-16044. Japanese Patent Application Laid-Open Nos. 48-94504 and 50-50102 disclose a waterless PS plate in which a light-adhesive photosensitive layer and a silicone rubber layer are laminated on a base. With these plates, several tens of thousands of prints can be printed without the use of dampening water.
The above-mentioned waterless PS plates are formed by laminating a photosensitive layer and a silicone rubber layer on a supporting body made of aluminum or the like. The top surfaces of these layers are laminated with a protective film so that the surfaces are protected. When an image is printed onto the waterless PS plate, the photosensitive layer hardens in accordance with the amount of exposure, and further adheres to the silicone rubber layer. In this state, when developer is supplied to the surface, the photosensitive layer swells due to the developer as much as unexposed portions and portions where there is little amount of exposure, and the silicone rubber layer is peeled off. These scrapings of the peeled off silicone rubber layer are recovered in the developer recovery tank along with the excess developer. The recovered developing solution is returned by the circulating pump to a developing solution supplying portion, and is supplied to the waterless lithographic printing plate.
There are various developers used in developing processing, including the following examples:
______________________________________ Developer 1 diethylene glycol-mono-n-hexyl ether 15 part by weight diethylene glycol-mono-ethyl ether 17 part by weight pure water 68 part by weight Developer 2 diethylene glycol-mono-hexyl ether 10 part by weight Newcol B4SN (60% aqueous solution) 4.5 weight % pure water 85.5 part by weight ______________________________________
For waterless development, use of a processing solution containing no organic matter (hereinafter called developing solution) has been proposed (see Japanese Patent Application No. 3-9558, Publication No. 1). This improves the quality of the PS plate itself by making processing without use of organic matter possible. As a result, tap water can be used, and there is no need to dispose of organic matter. There is therefore no environmental pollution.
However, when water being used as developing solution is used repeatedly in order to conserve resources, the scrapings in the developing solution, which are mainly silicone rubber, are recovered to the developing solution recovery tank. The scrapings adhere to the interior of the developing solution resupplying tank, thereby dirtying the developing solution resupplying tank. As a result, it is necessary to periodically clean the developing solution resupplying tank, and the maintenance thereof is complex.
Efforts have been made to place a filter in the circulating path, which supplies the developing solution from the developing solution recovery tank to the developing tank, in order to remove the scrapings from the developing solution circulating in the developing tank, the developing recovery tank and the circulating path. However, in this case, the filter gradually becomes blocked so that the predetermined amount of developer cannot circulate. As a result, the filter must be periodically changed, which requires labor.
In order to solve the above drawback, the following method has been proposed. The surface portion of the developing solution within the developing solution resupplying tank, in which the scrapings are floating, is recovered to a separate tank (collection tank) so that the developing solution remaining in the developing solution recovery tank (the developing solution other than the surface portion) is separated. The separated surface portion of the developing solution, which includes the scrapings, flows into a conduit of a discharge pipe, whose opening is in a vicinity of the surface of the solution, and is discharged as so-called waste solution. The remaining developing solution is circulated and used. Discharge of only the waste solution containing many scrapings is thereby effected.
Further, the discharge pipe is formed from a vinyl chloride pipe such that the cost is low and the manufacturing is easy.
However, scrapings which should flow into the discharge pipe may remain due to contact resistance with the discharge pipe such that the scrapings may not flow smoothly into the discharge pipe.
FIG. 6 illustrates the relationship between the processed amount of the waterless PS plate and the residual rate of the scrapings (silicone scrapings). Even if a vinyl chloride pipe is used as the discharge pipe to discharge the scrapings from the developing solution recovery tank, the residual rate is 5% for a 10 m.sup.2 amount to be processed, 40% for a 20 m.sup.2 amount, and 50% for a 30 m.sup.2 amount. The residual rate of the scrapings rises steeply in accordance with an increase in the processed amount.
A cause of this phenomenon is that the wettability of the material of the discharge pipe greatly effects the residual rate. Wettability is exhibited in the surface tension of a solid body. Namely, as mentioned above, vinyl chloride is used as a material for conventional discharge pipes. The surface tension of vinyl chloride is 41.9 mN/m(dyn/cm). As the value of the surface tension increases, the contact resistance of the floating scrapings to the periphery of the discharge pipe increases, and it is easier for the scrapings to remain thereat.
Further, another cause is that the opening end portion of a conventional discharge pipe is cut in a direction perpendicular to the axis. Therefore, the opening surface faces straight up. Namely, because the scrapings have certain thicknesses, the undersides thereof encounter resistance when the scrapings cross over the angled portion of the outermost periphery of the opening portion end surface. This increases the likelihood of the scrapings remaining thereat.

Waste solution discharging apparatus for waterless lithographic printing plates


The invention relates to a method and an apparatus for the manufacture of a poly-V-pulley, particularly with a toothed reference mark sensor. The method uses per se known spin forming and combines in one setting on a spinning machine with tool changers, the method steps of upsetting, profiling and gear cutting. The method according to the invention is preferably based on a tilted circular metal blank, which has a bevelled or angled marginal area with a clearly defined length and wall thickness. From the tilted or upset blank is formed a cup-shaped preform with an asymmetrically reinforced, cylindrical area with the aid of a spinning roll and subsequently in a radial setting is infed a spinning roll with a recess and an axially limited diameter reduction and material accumulation are obtained. This is followed by preprofiling, profiling of the thickened area and a gear cutting on a simultaneously constructed reference mark sensor of an outer flange.

A method of the aforementioned type is described in DE 30 42 312 C2. From a metal sheet is punched a circular blank and a cup-shaped preform is produced, e.g. by deep-drawing or spinning. The cup-shaped preform with a radial hub area and a cylindrical area virtually perpendicular thereto and coaxial to a longitudinal axis has a uniform wall thickness. The preform is fixed in a spinning device and the cylindrical area is exposed to an axial pressure, while supported on a centrally mounted block, in order to bring about a "partial collapse" i.e. a radial outward bulging from the inside to the outside. A sought material accumulation for forming a grooved bed is consequently possible through a shortening of the cylindrical area. The circular blank or the cylindrical area of the cup-shaped preform must therefore be constructed with a corresponding length.
The radial bulging out is to be obtained by rolling of a pair of rollers, which are movable axially to one another and when in engagement define an approximately arcuate recess. In the case of an axial compression, the material of the cylindrical area collapses into said recess. With the aid of correspondingly constructed support areas before or during the axial compression and collapse, an inner flange is formed between the hub area and cylindrical area, as well as an outer flange on the free end of the cylindrical area and are directed radially outwards.
The collapsed, cylindrical area is then flattened, leading to a material thickening. With the aid of a profile roller and a central support block, as well as limiting chuck and spinning mandrel halves, a V-shaped profiling of the thickened area is carried out.
This method is particularly complicated from the machinery standpoint and leads to corresponding manufacturing costs.
In a method described in EP 0 343 314 B1, a bordering roll is radially infed directly onto a circular metal blank without forming a cup-shaped preform. The bordering or curling roll has a semicircular recess and brings about a corresponding rolling in of the blank edge. Subsequently, using a spinning roll, from the bordering is formed a cylindrical wall area with a wall thickness greater than that of the hub area. In this method an inner flange and an outer flange can only be constructed after flattening. The production of poly-V-pulleys with a toothed reference mark sensor on an outer flange is not possible.
The journal "Machinery and production engineering" of 26 Jan., 1977 discloses a method for the manufacture of a toothing on the end face of a rotationally symmetrical body. A circular blank is fixed in a spinning device and is frontally upset with radially infeedable spinning rolls. The spinning rolls are provided with a depression, which has an arcuate base surface between parallel walls. The material of the end region of the circular blank is forced into the depressions of the spinning rolls. The material displacement leads to a terminal thickening, which can be symmetrical, i.e. projecting uniformly to either side of the blank, or asymmetrical, i.e. projecting only to one side. A toothing is then performed on the thickened area.

Method and apparatus for the manufacture of a poly-V-pulley


Systems and methods for a robust underwater vehicle are described herein. A robust underwater vehicle may include a force-limiting coupler connecting an actuation system to an actuation fin. The force-limiting coupler may be configured to break away from the actuation system upon receiving a threshold force. The robust underwater vehicle may also comprise hull sections connected by a threaded turnbuckle. Carbon-fiber axial strength members may mate with the threaded turnbuckle to pull the hull sections together to a specified preload tension. The robust underwater vehicle may also include a blazed sonar array protected by a carbon fiber bow including a plurality of slits. The plurality of slits may provide significant protection to the sonar array while simultaneously allowing one or more transducers to transmit sonar signals in a two-dimensional plane.

Underwater vehicles are typically controlled using actuated fins that protrude from the vehicle into the flow field around the hull. If the fins on the vehicle come into contact with a foreign object moving with a different velocity than the vehicle, the inertia of the vehicle can cause extremely high forces to develop on the fin, coupling, and actuation system. In order to prevent transmission of these forces into the structure of the vehicle and limit damage to the actuators driving the fins, there exists a need for a force limiting coupler between the actuation system and the fin.
Furthermore, the hull of an underwater vehicle is typically designed and manufactured in separate sections. The separate hull sections typically are joined by metal rings that are bonded to the hull by adhesives or fasteners. However, hull sections made out of composite materials generally cannot accommodate sharp angles as well as metal, making it difficult to use trapezoidal cross section band clamps typically used on torpedoes. Moreover, since underwater vehicles are generally engineered to be similar in density to water, any saved weight can translate to greater buoyancy, greater payload volume, and lower manufacturing and operating costs. Thus, these hull interfaces present an opportunity to design a robust underwater vehicle with a joint geometry that is light, low cost, strong, and relatively rigid.
Forward looking sonar arrays also present an opportunity to increase robustness of underwater vehicles. Most forward looking sonars are precariously placed in the front of a vehicle and are often destroyed in the event of a collision. Furthermore, a front-mounted sonar array typically results in a planar-shaped bow section, which may expose the sonar to damage. Moreover, the hydrodynamics of the vehicle are often disrupted due to the planar bow shape and the constraints of the sonar (planar boxes to accommodate planar arrays, etc). Thus, there exists a need to design a robust underwater vehicle with improved protection for forward-facing sonar arrays.


A coil unit and coil assembly for iron-less liar motor and the coil unit includes two vertical function sides and two axial non-function sides. The multiple units are alternatively connected to each other by inserting the vertical function side of one coil unit into the hollow portion of the adjacent coil unit so as to form a coil assembly. The width of the vertical function side is D1 and the distance between two respective insides of the two vertical function sides is D2. D2=m×D1+ΔL, wherein m representing the number of the vertical function sides of other coil units received in the vertical direction of the hollow portion. The ΔL is the width of the gap which receives a separation plate between the two adjacent vertical function sides to increase the efficiency of dissipating heat or insulation when current passes through the coil assembly.

The conventional iron-less linear motor is disclosed in FIGS. 17 and 18 and comprises a stator X and a coil assembly Y which moves along the rail of the stator X. The stator X is composed of multiple permanent magnets M which are arranged in alternative pattern with gaps located there between so as to form the U-shaped rail having alternating N and S polarities. The coil assembly Y has multiple coil loops which are arranged to form the coil unit and the current with multiple phases is input, such as the well known three-phase coil unit. The coil unit has a resin package layer Z mounted thereto and installed in the recess of the board W.
Taiwan Patent Application No. 201126875 discloses a coil unit of a linear motor wherein the coil unit comprises multiple adjacent coil units, a base and a resin package layer. These coil loops form two linear function sides, a first non-function side and a second non-function side. The coil loops form multiple first bent sections which are alternative to each other on the first non-function side, and multiple conductive lines on the second non-function side. These conductive lines are connected to the exterior cables located outside of the coil unit. The base has a slot whose cross section is correspondent to the cross section of the first bent section. The coil loops are inserted in the slot. The resin package layer encloses the coil loops and seals the slot, thereby increasing the contact area between the coil loops and the insides of the slot and the efficiency for dissipating heat. The two linear function sides are alternative to each other to reduce the volume required for the coil unit.
U.S. Pat. No. 5,998,890 discloses a linear motor wherein the coil unit defines the shape of the coil loop which has two vertical function sides and two axial non-function sides. The relationship between the coil inside width (CIW) of the vertical function sides, the coil side width (CSW) and the number of phases of the current (#Φ) is expressed by the equation:CIW=CSW×(#Φ−1).Because of the shape, the coil loops can be overlapped tightly to reduce the space occupied by the coil unit.
However, along with the demands of higher output and speed for the linear motors, higher current and voltage are input into the linear motor and which generate higher heat and reduce the efficiency of the motor. The coil loops are arranged close to each other so that the heat is difficult to be dissipated and the risk of circuit short becomes high. The specific relationship of CIW=CSW×(#Φ−1) cannot provide extra room for the heat dissipating members or insulation members.
The present invention intends to provide a coil unit for linear motors and improves the shortcomings of the conventional ones.

Coil assembly having separation plates for iron less linear motor


Provided is a blowing device including a blower that sends air, a blower pipe having an inlet that takes in the air sent from the blower, an outlet that is formed in an elongated opening shape parallel to the portion of the target structure in the longitudinal direction, and a body portion that connects the inlet and the outlet and to cause the air to flow therethrough, and plural flow dividing plates, each of the flow dividing plates having a distributing portion and a changing portion.

(i) Technical Field
The present invention relates to a blowing device, and an image forming apparatus.
(ii) Related Art
In image forming apparatuses that form an image constituted by a developer on a recording sheet, for example, there is an image forming apparatus using a corona discharge device that performs corona discharge in the process of charging a latent image holding body, such as a photoconductor, or the process of neutralization, the process of transferring an unfixed image to the recording sheet, or the like.
Additionally, in the corona discharge device, in order to prevent unnecessary substances, such as paper debris or a discharge product, from adhering to component parts, such as a discharging wire or a grid electrode, a blowing device that blows air against component parts may be provided together. The blowing device in this case is generally constituted by a blower that sends air, and a duct (blower pipe) that guides and sends out the air sent from the blower up to a target structure, such as a corona discharge device.
In the related art, various improvements for enabling air to be uniformly blown in the longitudinal direction of the component parts, such as a discharging wire, are performed on the blowing device or the like. Particularly, as such a blowing device or the like, there are proposed the following blowing devices that adopt a configuration in which the shape of a passage space of a duct through which air flows is formed in a special shape or a configuration in which a straightening plate or the like that adjusts a direction in which air flows is disposed in the passage space of the duct, or the like.

Blowing device, and image forming apparatus


Embodiments of the present disclosure include a two piece modular draw stop system for an archery bow cam including a positioner piece and an abutment piece. The positioner piece defines a groove for a power cable of the archery bow and is arranged on the cam to present the power cable toward the abutment piece upon rotation of the cam. The abutment piece is configured to abut the power cable to impede further rotation of the cam. The abutment piece may be reversible to allow different draw lengths of the bowstring at a selected mounting location.

The present invention deals primarily with compound archery bows, generally including a bow frame and a cable system on the frame mounted to at least two rotational elements such as wheels or cams. The draw length of a bow can be controlled by positioning a "stop" which prevents drawing of the bow past a certain point. The stop is typically a portion of the cam which abuts the cable arrangement at a certain rotational point and prevents further rotation. The draw length of the bow can be adjusted by adjusting the position of the stop on the cam. Certain prior bows use one-piece modules of different sizes or a pivotal module to set the draw length.
An improved bow and cam stop arrangement is desired.


Provided are a method and a system, wherein optical beams of a plurality of wavelengths are directed through a plurality of optical devices, wherein waveguides comprising the optical devices have different fabrication errors, and wherein the waveguides have a plurality of waveguide lengths and a plurality of waveguide widths. Optical phase errors corresponding to the waveguides are measured by the optical devices. A determination is made of the components of the optical phase errors for the waveguides from the measured phase errors.

A waveguide is a material medium that confines and guides a propagating electromagnetic wave. An optical waveguide may comprise a filament of a light conducting medium, where the light conducting medium may include silicon dioxide (SiO2), silicon, compound semiconductors, etc. The filament of the light conducting medium may be referred to as a core, and the core may be surrounded by a cladding. The cross section of the optical waveguide may be circular or rectangular. The refractive index of the core is higher than that of the cladding for the light to be guided by the optical fiber.
An arrayed waveguide grating may be comprised of circuitry in which optical waveguides comprising a silica-based cladding and core are fabricated on a substrate of silicon. Crosstalk may affect the performance characteristics of an arrayed waveguide grating. Optical phase errors in the waveguides that comprise the arrayed waveguide grating may contribute to the crosstalk. The optical phase error in a waveguide, ∂ø, may be caused by imperfections in the waveguide as a result of fabrication processes. The imperfections may be caused by fluctuations in waveguide parameters, such as, the spatial core size error, ∂w, the refractive index error of the core, ∂n core, the refractive index error of the cladding, ∂nclad, and the actual waveguide length error, ∂L.
The ability to identify and extract the optical phase errors in a waveguide may assist in debugging the design of waveguides and in improving the fabrication process of waveguides. The optical performance of arrayed waveguide gratings and other devices, such as, devices based on Mach-Zehnder interferometers, may also be improved, where the performance of the arrayed waveguide gratings and the other devices are affected by the optical phase errors of waveguides.
Details of the theory of waveguides are described in the book "Integrated Optics: Design and Modeling" by Reinhard Marz, published by Artech House, Inc., 1995. Certain techniques for extracting optical phase errors in waveguides and interferometers are described in the publication entitled "Estimation of Waveguide Phase Error in Silica-Based Wavelengths" by T. Goh, S. Suzuki, and A. Sugita, published in the Journal of Lightwave Technology, Vol. 15, No. 11, November 1997, pages 2107–2113.


A stylus provided in the present invention is utilized to input accompanying with a capacitive touch panel. The stylus includes a housing, a magnetic core and a pen tip. The magnetic core is disposed inside the housing. The magnetic core has an axial through hole which defines a bore diameter. The pen tip is disposed at an end of the housing, and the pen tip is made of conductor. The pen tip has a rod portion and a contacting portion. The rod portion is inserted into the axial through hole, and the contacting portion protrudes from the pen shell. The contacting portion has a cylindrical surface and a part spherical surface. The cylindrical surface defines a first diameter; the part spherical surface defines a second diameter. The first diameter is less than the second diameter, and the first diameter is greater than or equal to the bore diameter.

A capacitive touch panel is a substrate on which transparent electrode patterns are coated. When a finger is closes to or contacts the touch panel, a coupling capacitor is formed between the finger and the transparent electrode patterns because the finger is a conductor and has static electricity. Meanwhile, electrical capacitance of the electrode positioned at a touch point on the touch panel will change, thus making voltage or current on the electrode change. And then by comparing the voltage difference between the electrode and adjacent electrodes, a position of the touch point can be calculated.
However, although the touch input by the fingers is convenient, it is obviously difficult to achieve the following requirements of depicting lines with various thicknesses on a touchscreen, or realizing touch recognition for fine locations by the fingers. Therefore, in order to increase the accuracy of the touch, a solution by using a stylus has been proposed. The principle of the conventional capacitive stylus is mostly to disposed conductive rubber or foam on an end of a metal tube of the stylus. Although it can achieve a more accurate input with respect to the finger input, the capacitive stylus can not show the lines with the various thicknesses on the screen corresponding to force that exerts to the stylus, still having the shortcoming for the usage.
Therefore, in order to realize pressure sensing of the pen tip, an electromagnetic stylus has been proposed. The conventional electromagnetic stylus interacts with an electromagnetic sensor board behind the touchscreen. When the electromagnetic stylus is close to the touchscreen, the electromagnetic sensor board behind the touchscreen will sense an electromagnetic signal emitted from the stylus so as to obtain x and y coordinates of the position of the stylus. In addition, the electromagnetic stylus is equipped with a longitudinal pressure sensor. When a user is writing with the stylus causing the pen tip to be given a force, the pressure is transmitted to the pressure sensor via a pen core. A change of the pressure leads to a variation in the electromagnetic signal emitted from the stylus, and thus the electromagnetic sensor board can appear various pressure-sensitive values according to the signal.
However, the above-mentioned solution for achieving the pressure sensing requires disposing the electromagnetic sensor board behind the touchscreen. It will significantly increase costs.

Stylus for use with capacitive touch panel


A synthetic resin bottle with a handle of this invention comprises a biaxially drawn and blow-molded PET bottle and a handle, an injection-molded product of the same PET resin, which is fitted firmly to the bottle as an insert. The up-and-down property of the surfaces of the handle inserts, which come in contact with the PET bottle, is adjusted in response to the softening and drawing state of the PET preform that is deformed and molded into the bottle. This adjustment causes the friction resistance to be reduced between the handle inserts and the blow-molded PET bottle. The finely textured up-and-down pattern can be easily formed through the tests and adjustments by the surface treatment inside the mold cavity used for the injection molding of the handle. Thus, the optimum surface properties can be obtained in response to the bottle sizes and the handle shapes. Therefore, this invention requires no separate process, such as thermal crystallization. Bottles, which fully get around the handle inserts, have high fitting strength but no abrasion, can be provided at a low cost.

As a large-size bottle, which is easy to handle, there is known a synthetic resin bottle with a handle, in which the handle has been previously injection-molded into a certain shape and is used as an insert, and in which the PET bottle is biaxially drawn and blow-molded. However, it is desired that the handle is made of the same PET as used in the bottle, rather than a polyethylene resin or a polypropylene resin, so that the bottles can be separated and disposed easily at the time of waste disposal.
As conventional art that can meet this demand, Japanese Patent Application (OPI) No. 1994-298253 discloses that the fitting portions of the handle coming in contact with the bottle are crystallized to a degree of crystallinity of 10% or more. This makes it possible for the handle to be made of PET just as the bottle is made of PET. When the PET handle is fitted, usually the bottle tends to be ruptured because slide gets worse, but the crystallization prevents the bottle from rupturing during the drawing and deformation.
However, in the above-described conventional art, a dedicated operation is required for the crystallization treatment (typically, thermo-crystallization treatment) of the fitting portion, which is a specified portion of the handle. A problem arose here that it takes more time and labor to mold a bottle.
When the fitting portions of the handle are heated for crystallization, it is necessary to control the heat precisely, without giving any adverse effect thermally on the nearby portions. In practice, therefore, this requires high technological expertise, thus causing a problem that the operation cannot be conducted easily.
A technical problem of this invention is to improve the low slide between bottle and handle made of the same PET. An object of this invention is to obtain a biaxially drawn, blow-molded PET bottle, in which the PET handle is firmly fitted to the bottle as the insert, merely by an ordinary biaxial drawing and blow molding process, without requiring any dedicated operation.
As the handles to be used with this type of synthetic resin bottles with a handle, there are another disclosed in Japanese patent No. 2998820 and Japanese Patent Application (OPI) No. 2001-328636, which is an improvement from the above patent. A lot of these handles are in common use because stable and firm fitting can be secured and because handling of the inserts is easy.
The handle disclosed in the Japanese Patent Application (OPI) No. 2001-328636 is as shown in FIG. 16 and FIGS. 24–27. The handle comprises a grip plate 11′ in a vertical strip shape, embedded projecting pieces 14′ disposed on the front end faces at the extended end of this grip plate 11′, a pair of engaging ridges 15′ in a vertical ridge shape disposed on the sides facing each other, a pair of embedded fitting portions K′ that serve as strong undercut fittings to the bottle 1′, a pair of fitting beams 12′ in a vertical rod shape, and a pair of connecting arms 12a′ in the curved rod shape, which connect between the pair of fitting beams 12′ at both the upper and lower ends of the grip plate 11′.
In the case of this handle 10′ shown in these drawings, a vertical projecting wall 5′ is held tight by the pair of fitting beams 12′ when the wall 5′ is formed at the bottom 4′ of the recession 3′ of the bottle 1′. Therefore, the handle 10′ is stably and firmly fitted to the bottle 1′.
The afore-mentioned bottle with a handle can be obtained when injection-molded PET perform P′ is blow-molded into the bottle 1′. At that time, the previously injection-molded PET handle 10′ is fitted to the bottom of the handle-fitting recession 3′ at the rear of the body 2′ of the bottle 1′ by means of simultaneous insert molding.
During the process of afore-mentioned insert molding, the heated and softened PET preform P′ is smoothly deformed as its shape follows the shapes of the embedded projecting pieces 14′ and the engaging ridges 15′, which are the inserts of the handle 10′ and are fitted firmly to the bottle 1′. High fitting strength between the handle 10′ and the bottle 1′ is obtained by allowing the PET bottle wall portion to get around smoothly and tightly the peripheries of the handle inserts.
However, in the field of alcoholic beverages, juices and other soft drinks, there has lately been an increasing need for larger containers. Even if the bottles have a larger capacity, the neck does not have a large diameter, but has the same diameter as that of small-size bottles in many cases. As a result, it is required that thick-wall preform is drawn at a high magnification and that the biaxial drawing and blow molding operation has to be conducted at a high air-blow pressure.
Therefore, when the PET preform is drawn, a strong force pushes a portion of the expanding bottle wall against the surfaces of the inserts of the handle 10′, i.e., the surfaces of the connecting arms 12a′, the fitting beams 12′, and the embedded projecting portions. At that time, the PET bottle gets abrasions on the clear bottle wall, especially at places near the connecting arms 12a′. The problem of resultant bad appearance of the bottle has to be solved.
Another technical problem of this invention is to prevent abrasions from occurring at the inserts during the biaxial drawing and blow molding operation under a high blowing pressure. Another object of this invention is to provide a synthetic resin bottle with a handle, which has high safety, easy handling ability, and good appearance even in the case of large-size bottles reaching a capacity of a few liters.