The present invention provides 2-piperidone compounds or pharmaceutically acceptable salts thereof, which have a potent activity of inhibiting the proliferation of tumor cells and thus are useful as medicaments, as well as antitumor agents containing these compounds. The 2-piperidone compound is represented by the following formula (I):

This invention relates to a pharmaceutical composition comprising as an active ingredient a 2-piperidone compound which has antitumor activity and is useful as a medicament such as an antitumor agent.
Although studies have been widely made on antitumor agents efficacious on solid tumors, there are only few antitumor agents having low toxicity. The present inventors investigated antitumor agents efficacious on solid tumors and, as a result, found that certain 2-piperidone compounds are efficacious on solid tumors while showing low toxicity, thus completing the present invention.
4,6-Diphenyl-5-nitro-2-piperidone has been known as an intermediate for the synthesis of 3-aminopiperidine derivatives (U.S. Pat. No. 5,232,929). However, no pharmacological activity of this compound has been known. Also, 5-nitro-6-phenyl-1-(2-phenylethyl)-2-piperidone has been known (Synthesis, 615-616 (1976)) but its pharmacological activity is also unknown.
An object of the present invention is to provide 2-piperidone compounds which have an activity of inhibiting the proliferation of solid tumor cells and are useful as excellent antitumor agents.
The present invention relates to a 2-piperidone compound represented by the following formula (I) or a pharmaceutically acceptable salt thereof:
wherein
R1 represents xe2x80x94(CH2)nR1a {wherein n is an integer of from 0 to 5, and R1a represents amino, lower alkylamino, di(lower alkyl)amino, substituted or unsubstituted aryl, or a substituted or unsubstituted heterocyclic group}, and
R2 and R3 independently represent lower alkyl which may be substituted by lower alkoxycarboyl; lower alkenyl, aralkyl or lower alkynyl which may be substituted by substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group; substituted or unsubstituted aryl; or a substituted or unsubstituted heterocyclic group. Among the compounds of the formula (I), the compounds wherein R1a represents a substituted or unsubstituted heterocyclic group and R2 and R3 independently represent substituted or unsubstituted aryl or pharmaceutically acceptable salts thereof are preferable, and the compounds wherein R1a represents a heterocyclic group, and R2 and R3 independently represent substituted aryl or pharmaceutically acceptable salts thereof are further preferable. The present invention also relates to a pharmaceutical composition which comprises as an active ingredient the aforementioned 2-piperidone compound or a pharmaceutically acceptable salt thereof. The present invention further relates to an antitumor agent which comprises as an active ingredient the aforementioned 2-piperidone compound or a pharmaceutically acceptable salt thereof.
The present invention further relates to a pharmaceutical composition which comprises the 2-piperidone compound of the formula (I) or a pharmaceutically acceptable salt thereof; an antitumor agent which comprises the 2-piperidone compound of the formula (I) or a pharmaceutically acceptable salt thereof; a method for preventing or treating a patient having tumor, which comprises administering to the patient an effective amount of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof; and use of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof for the production of a pharmaceutical composition which is effective in preventing or treating a patient having tumor; use of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof for the prevention or treatment of a patient having tumor; and a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of any one of the 2-piperidone compounds of the formula (I) or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable dosage form.
Hereinafter, the compounds represented by the above formula (I) will be referred to as Compounds (I), and the same will apply to compounds represented by other formula numbers.
In the definition of each group given in the formula (I), the term xe2x80x9carylxe2x80x9d stands for a mono- to tricycle of 3- to 7-membered carbon rings wherein at least one of the rings is an aromatic ring. Examples thereof include phenyl, naphthyl, anthracenyl, tetrahydronaphthyl, indanyl and phenanthrenyl.
Examples of the heterocyclic group include azepinyl, benzimidazolyl, benzofurazanyl, benzopyranyl, benzothiopyranyl, benzofuryl, benzothiazolyl, benzothiadiazolyl, benzothienyl, benzoxazolyl, 1,4-benzodioxanyl, chromanyl, cinnolinyl, dihydrobenzofuryl, dihydrobenzothienyl, dihydrobenzothiopyranyl, furyl, imidazolidinyl, imidazolyl, imidazothiazolyl, indolinyl, indolyl, isochromanyl, isoindolyl, 1,3-dioxolanyl, 1,3-dithiolanyl, isoxazolyl, isoquinolyl, isothiazolyl, isothiazolidinyl, morpholinyl, naphthyridinyl, oxadiazolyl, oxazolyl, 2-oxoazepinyl, 2-oxopiperazinyl, 2-oxopyrrolidinyl, piperidyl, piperazinyl, pyridyl, pyridyl N-oxide, pyrazinyl, pyrazolinyl, pyrazolyl, pyrimidinyl, pyrrolidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinoxalinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydroquinolyl, tetrahydropyranyl, tetrazolyl, thiadiazolyl, thiazolyl, thiazolinyl, thienofuryl, thienothienyl, thienyl, triazolyl and pyridonyl.
Examples of the aralkyl include C7-20 aralkyl such as benzyl, phenethyl, benzhydryl, naphthylmethyl and trityl.
The lower alkyl and the lower alkyl moieties in the lower alkylamino, di(lower alkyl)amino and lower alkoxycarbonyl include linear, branched or cyclic C1-10 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and adamantyl.
The lower alkenyl includes linear, branched or cyclic C2-10 alkenyl such as vinyl, allyl, crotyl, 1-propenyl, prenyl, isopropenyl, 2-methyl-2-butenyl, pentenyl, hexenyl, heptenyl, 2,6-dimethyl-5-heptenyl, cyclobutenyl, cyclopentenyl, and cyclohexenyl.
The lower alkynyl includes linear or branched C2-10 alkynyl such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, and octynyl.
Substituents on the aryl or heterocyclic group may be the same or different 1 to 3 substituents, and examples thereof include hydroxy; halogen; nitro; amino; carboxy; lower alkyl optionally substituted by 1 to 3 halogen, lower alkoxycarbonyl or hydroxy; lower alkoxy optionally substituted by 1 to 3 halogen or lower alkoxy; lower alkoxycarbonyl; lower alkylthio; lower alkenyl optionally substituted by 1 to 3 lower alkoxy, lower alkoxycarbonyl or a heterocyclic group; lower alkynyl; aryl optionally substituted by 1 to 3 halogen atoms; aryloxy; aryloxy(lower alkyl); aroyloxy; lower alkylamino optionally substituted by a heterocyclic group; hydroxyamino; formyl; lower alkanoyl; lower alkanoyloxy; amino substituted by lower alkanoyloxy or lower alkanoyl; di(lower alkyl)amino; di(lower alkyl)aminocarbonyloxy; lower alkanoylamino; lower alkylsulfonylamino; lower alkoxycarbonylamino; aralkylamino; sulfamylamino (aminosulfonylamino); ureido (carbamoylamino); cyano; aralkyl; aralkyloxy; arylsulfonyl; a heterocyclic group; a heterocyclic group-carbonyloxy; camphanoyloxy; methylenedioxy; ethylenedioxy; B(OH)2 and SO3H. The term xe2x80x9chalogenxe2x80x9d stands for fluorine, chlorine, bromine and iodine atoms. The aralkyl and the aralkyl moieties in the aralkylamino and the aralkyloxy are each as defined above. The lower alkyl and the lower alkyl moieties in the lower alkoxy, lower alkoxycarbonyl, aryloxy(lower alkyl), lower alkanoyl, lower alkylthio, lower alkylamino, lower alkanoyloxy, di(lower alkyl)amino, di(lower alkyl)aminocarbonyloxy, lower alkanoylamino, lower alkylsulfonylamino and lower alkoxycarbonylamino are each as defined above. The aryl and the aryl moieties in the aryloxy, aryloxy(lower alkyl), arylsulfonyl and aroyloxy are each as defined above. The heterocyclic group and the heterocyclic group moiety in the heterocyclic group-carbonyloxy are each as defined above. The lower alkenyl and the lower alkynyl are each as defined above.
Examples of the pharmaceutically acceptable salt of Compounds (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and amino acid addition salts thereof. Examples of the acid addition salt include inorganic acid addition salts such as hydrochlorides, hydrobromides, sulfates, phosphates and nitrates, and organic acid addition salts such as formates, acetates, propionates, benzoates, maleates, fumarates, succinates, tartrates, citrates, oxalates, methanesulfonates, p-toluenesulfonates, aspartates and glutamates. Examples of the metal salt include alkali metal salts such as lithium salts, sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, and zinc salts. Examples of the ammonium salt include ammonium salts and tetramethylammonium salts. Examples of the organic amine addition salt include addition salts with morpholine and piperidine. Examples of the amino acid addition salt include addition salts with glycine, phenylalanine, glutamic acid and lysine.
Next, a process for producing Compounds (I) will be explained.
In the following process, when a group defined therein changes under the employed conditions or the group is inappropriate for carrying out the process, the object compound can be obtained by using the method of introducing and eliminating protective group(s) commonly used in the field of synthetic organic chemistry [see, for example, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, T. W. Greene, John Wiley and Sons, Inc. (1981)]. If necessary, the order of the reaction steps of, for example, introducing substituents may be appropriately changed.
Production Process
Compound (I) can be synthesized starting with Compound (II), which are known compounds or which can easily produce by a known process, via Compound (III) by, for example, the following steps.
In the formula, R1, R2 and R3 are each as defined above.
(Step 1)
Compound (III) can be synthesized by reacting Compound (II) with 1 to 100 equivalents of nitromethane in an inert solvent (e.g., acetonitrile, dimethylformamide) in the presence of 0.01 to 10 equivalents of a base [e.g., 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)] in accordance with a method reported in Synthesis, 226 (1984). The reaction is usually carried out at xe2x88x9230 to 100xc2x0 C. and completed within 1 to 72 hours. In this process, nitromethane can be employed also as the solvent.
(Step 2)
Compound (I) can be synthesized by reacting Compound (III) in a solvent (e.g., ethanol, methanol) with Compound (IV) represented by the following formula:
R3xe2x80x94CHOxe2x80x83xe2x80x83(IV)
wherein R3 is as defined above;
and Compound (V) represented by the following formula:
R1xe2x80x94NH2xe2x80x83xe2x80x83(V)
wherein R1 is as defined above. Usually, Compound (IV) and Compound (V) are used each in an amount of 1 to 5 equivalents based upon that of Compound (III). Also, an acid addition salt (e.g., acetate) of Compound (V) can be used instead of Compound (V). The reaction is usually carried out at 0 to 100xc2x0 C. and completed within 1 to 72 hours.
In the production of Compound (I), the conversion of the functional groups R1, R2 and R3 may be carried out by using a method for converting functional groups commonly employed in synthetic organic chemistry [see, for example, xe2x80x9cComprehensive Organic Transformationsxe2x80x9d, R. C. Larock (1989)].
In the above production process, the product can be isolated and purified by using an appropriately combination of techniques commonly employed in organic synthesis (e.g., filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography).
Some of Compounds (I) can exist in the form of various stereoisomers such as enantiomers or diastereomers. All of the possible isomers and mixtures thereof including the above-mentioned ones fall within the scope of the present invention.
Compounds (I) and their pharmaceutically acceptable salts may exist in the form of adducts with water or various solvents. The above adducts can also be used as the treating agents according to the present invention.
Tables 1 to 6 show the structures and physical data of typical examples of Compound (I).
(wherein, R2a, R2b and R2c, and R3a, R3b and R3c respectively mean the substituents of the substituted phenyl groups as R2 and R3)
Next, the pharmacological activities of Compound (I) will be illustrated by reference to Test Examples.
Proliferation Inhibition Test on Human Colonic Cancer DLD-1 Cell
On a 96-well microtiter plate (Nunc #167008), 1,000/well of human colonic cancer DLD-1 cells were supplied, which were then pre-incubated in RPMI1640 medium containing 5% or 10% fetal calf serum (FCS) in a 5% carbon dioxide gas incubator at 37xc2x0 C. for 24 hours. Subsequently, a 10 mmol/L solution of each test compound in dimethylsulfoxide (DMSO) was diluted with the incubation medium and then further diluted 3-fold stepwise. The incubation was performed for additional 72 hours. After the completion of the incubation, the medium was discarded followed by the addition of 50 xcexcl/well of a solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma, hereinafter referred to simply as MTT) in the incubation medium (final concentration: 1 mg/ml). After maintaining the plate at 37xc2x0 C. in a 5% carbon dioxide gas incubator for 4 hours, the MTT solution was discarded and 150 xcexcl/well of DMSO was added. After completely dissolving the MTT-formazane crystals by vigorously stirring with the use of a plate mixer, the difference in the absorbances at 550 nM and 630 nM was measured by using a microplate reader SPECTRAmax 250 (Wako Pure Chemical Industries, Ltd.) The 50% inhibitory concentration (IC50) showing the proliferation inhibitory activity was calculated by using 4-parameter logistic curves of the included software SOFTmaxPRO.
Anti-tumor Activity Test on Human Colonic Cancer DLD-1 Solid Tumor Transplanted in Nude Mouse
Fragments (2 mmxc3x972 mm) were excised from well-proliferating parts of human colonic cancer cell DLD-1 tumor masses which had been subcultured in male nude mice (BALB/c-nu/nu mice, Clea Japan). Then, these fragments were subcutaneously transplanted into the abdominal region of 7-week-old male nude mice by using trocars. When the tumor volume (see, Formula-1) attained 50 to 70 mm3, the mice were divided into groups each having 5 animals. Next, each test compound was dissolved in physiological saline containing polyoxyethyelne sorbitan monooleate and the resulting solution was intraperitoneally administered to the mice twice a day continuously for 10 days. The value T/C (%) of each test compound was determined by measuring the tumor volume before the administration (V0) and that after the administration (V) and calculating the ratio (V/V0), as Formula-2 shows. The results are given in Table 8.
Tumor volume (mm3)={major diameter (mm)xc3x97(minor diameter (mm))2}xc3x971/2xe2x80x83xe2x80x83Formula-1
T/C (%)=((V/V0 of test group)/(V/V0 of control group))xc3x97100.xe2x80x83xe2x80x83Formula-2
Proliferation Inhibition Test on Human Pancreatic Cancer MIA-PaCa2 Cell
On a 96-well microtiter plate (Nunc #167008), 2,000/well of human pancreatic cancer MIA-PaCa2 cells were supplied, which were then preincubated in RPMI1640 medium containing 10% fetal calf serum (FCS) in a 5% carbon dioxide gas incubator at 37xc2x0 C. for 24 hours. Subsequently, a 10 mmol/L solution of each test compound in dimethyl sulfoxide (DMSO) was diluted with the incubation medium and then further diluted 3-fold stepwise. The incubation was performed for additional 72 hours. After the completion of the incubation, the medium was discarded, followed by the addition of 50 xcexcl/well of a solution of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (Sigma, hereinafter referred to simply as MTT) in the incubation medium (final concentration: 1 mg/ml). After maintaining the plate at 37xc2x0 C. in a 5% carbon dioxide gas incubator for 4 hours, the MTT solution was discarded and 150 xcexcl/well of DMSO was added. After completely dissolving the MTT-formazane crystals by vigorously stirring with the use of a plate mixer, the difference in the absorbances at 550 nM and 630 nM was measured by using a microplate reader SPECTRAmax 250 (Wako Pure Chemical Industries, Ltd.). The 50% inhibitory concentration (IC50) showing the proliferation inhibitory activity was calculated by using 4-parameter logistic curves of the included software SOFTmaxPRO.
The above Compound (I) have an effect of inhibiting the proliferation of human colonic cancer DLD-1 cells and human pancreatic cancer MIA-PaCa2 cells and, therefore, are useful as the active ingredient of medicaments, preferably antitumor agents. The first embodiment of the pharmaceutical composition of the present invention is characterized by containing as the active ingredient substances selected from the group consisting of Compound (I), pharmaceutically acceptable salts thereof, and hydrates and solvates of the same. The pharmaceutical compositions of the present invention are useful as antitumor agents in treating non-solid cancers such as leukemia, malignant lymphoma and myeloma and solid cancers such as gastric cancer, esophageal cancer, intestinal cancer, rectum cancer, pancreatic cancer, hepatic cancer, renal cancer, bladder cancer, pulmonary cancer, uterus cancer, ovarian cancer, mammary cancer, prostatic cancer, skin cancer and brain tumor.
For the medicaments of the present invention, the above-mentioned substances as such may be administered as the active ingredient. However, it is generally preferable to administer them in the form of pharmaceutical compositions comprising the above substances together with one or more pharmaceutical additives. These pharmaceutical compositions can be produced by using methods which are well known or have been conventionally employed in the field of pharmaceutics. The medicaments of the present invention in the form of such pharmaceutical compositions may contain one or more other pharmaceutically active ingredients. The medicaments of the present invention are applicable to mammals including humans.
The medicaments of the present invention may be administered via an arbitrary route without restriction, and the most suitable administration route may be selected from oral and parenteral routes depending on the purpose of treatment and/or prevention. Examples of the parenteral administration route include tracheobronchial, rectal, subcutaneous, intramuscular and intravenous routes. Examples of the preparation appropriate for oral administration include tablets, granules, fine granules, powders, syrups, solutions, capsules and suspensions, while examples of the preparation appropriate for parenteral administration include injections, drips, inhalants, sprays, suppositories, transdermal absorption preparations and mucosal absorption preparations.
To prepare liquid preparations appropriate for oral administration, pharmaceutical additives such as water; saccharides (e.g., sucrose, sorbitol, fructose); glycols (e.g., polyethylene glycol, propylene glycol); oils (e.g., sesame oil, olive oil, soybean oil); preservatives (e.g., p-hydroxybenzoates); and the like can be used. To prepare solid preparations such as capsules, tablets or granules, excipients (e.g., lactose, glucose, sucrose, mannitol); disintegrating agents (e.g., starch, sodium alginate); lubricating agents (e.g., magnesium stearate, talc); binders (e.g., polyvinyl alcohol, hydroxypropylcellulose, gelatin); surfactants (e.g., fatty acid esters); and plasticizers (e.g., glycerol); and the like may be used.
Among the preparations appropriate for parenteral administration, those for intravascular administration (e.g., injections, drips) may be prepared preferably with the use of aqueous media isotonic to human blood. For example, injections may be prepared with the use of aqueous media selected from salt solutions, glucose solutions and saline/glucose solution mixtures in accordance with a conventional manner by using appropriate adjuvants to give solutions, suspensions or dispersions. Suppositories for rectal administration may be prepared by using carriers such as cacao fat, hydrogenated fats or hydrogenated carboxylic acids. Sprays may be prepared by using carriers which can promote the dispersion of the above-mentioned substances serving as the active ingredient in the form of fine particles and the absorption thereof without irritating human oral cavity or respiratory mucosa. As such a carrier, lactose, glycerol, or the like may be used. These preparations may be in the form of aerosols, dry powders, etc. depending on the properties of the above-mentioned substances serving as the active ingredient as well as the properties of the carriers selected. To produce preparations for parenteral administration, one or more pharmaceutical additives selected from diluents, flavors, preservatives, excipients, disintegrating agents, lubricating agents, binders, surfactants, plasticizers, and the like may be used. The dosage forms and production processes of the medicaments of the present invention are not restricted to those described above in detail.
The dose and administration frequency of the medicaments of the present invention are not particularly restricted but can be appropriately determined depending on various factors, for example, the type of the above-described substance as the active ingredient, the type of the cancer to be treated, the administration route, the age and body weight of the patient, and the conditions and severity of the disease. For example, about 0.01 to 500 mg/kg/day may be administered to an adult at a frequency of once to 5 times in a day or once in several days to several weeks, though neither the dose nor the administration frequency is restricted thereto. The medicament of the present invention can be used together with other antitumor agents. It is generally favorable to combine the medicament of the present invention with several antitumor agents differing in the functional mechanism.
Hereinafter, Examples and Production Examples of the present invention will be given.
Tablet
A tablet of the following composition is prepared in a conventional manner:
Capsule
A capsule of the following composition is prepared in a conventional manner:
The above components are mixed and packed into a gelatin capsule.
Injection
An injection of the following composition is prepared in a conventional manner:

Abstract: wherein


In a portable terminal, a character string clipping section clips an image of a character string from image data photographed by a screen image pickup device. A character recognition section recognizes the clipped image of the character string and acquires a character code string corresponding to the clipped character string. A character string tracking section sets the acquired character code string as a tracking object character string when the tracking object character string extends beyond the photographable area as well as tracking the tracking object character string or a marker character string ultimately used as an input character string while repeatedly updating the marker character string. A display section highlights the tracking object character string when the tracking object character string extends beyond the photographable area of the image pickup device and displays an arrow showing the relative direction.

1. Field of the Invention
The present invention generally relates to a portable terminal, for example, a cellular phone, a Personal Handyphone System (PHS), a Personal Digital Assistant (PDA), etc. More particularly, the present invention relates to a portable terminal equipped with a camera comprising a photography function and a character reading method together with a character reading program using a portable terminal.
2. Description of the Related Art
Recently, in portable terminals, such as a cellular phone, PHS, etc., the occasions for inputting character data in a portable terminal has been increasing. Most occasions include creating and sending E-mail messages, inputting a Uniform Resource Locator (URL) to access the Internet and inputting a keyword term to use a search engine site on the Internet.
However, because of a portable terminal's compact size, only a small number of keys can be installed, which makes it difficult to mount a QWERTY arranged keyboard (QWERTY refers to the order of the top row of letters) suitable for inputting characters widely used on a personal computer (PC).
Therefore, in a portable terminal, commonly a plurality of characters (a letter, number or other symbol) is assigned to one key and the character inputted changes by the number of times the assigned key is depressed. However, in the previously mentioned portable terminal in which a plurality of characters is assigned to one key and the character inputted changes by the number of times the assigned key is depressed, many successive key depressions are required for inputting a character which makes manipulation complicated and takes time to accomplish.
Accordingly, in the conventional prior art (for example, refer to Japanese Laid-Open (Kokai) Patent Application No. 2002-111841 titled "PORTABLE COMMUNICATION TERMINAL AND CHARACTER READER"), technology has been proposed which uses an image of a character photographed (optically read) by a screen image pickup device and supplied by acquiring the corresponding character code.
However, in the conventional prior art mentioned above, in order to photograph a character using the portable terminal equipped with an imaging device, the portable terminal must be placed considerably close to the character and any slight movement of the portable terminal greatly influences the photography. Particularly, when inputting consecutive characters, since the portable terminal must shift after recording a character, there is a problem of easily losing sight of the immediately preceding photographed characters.

Portable terminal and character reading method using a portable terminal

Casio Hitachi Mobile Communications Co., Ltd.


The present invention provides an optical semiconductor device including a semiconductor thin film (4) having photoconductivity and a pair of electrodes (5) and (10) for applying an electric field to an inside of the semiconductor thin film (4) in a direction approximately vertical to a surface of the semiconductor thin film (4), wherein the semiconductor thin film (4) generates an electromagnetic wave when light is applied to a region thereof to which the electric field is applied. The electrodes are provided to a front surface and a back surface of the semiconductor thin film (4) with the semiconductor thin film interposed therebetween.

In recent years, there has been developed a nondestructive sensing technique using an electromagnetic wave (30 GHz to 30 THz) ranging from a millimeter wave to a terahertz (THz) wave. Techniques under development in the application field of the electromagnetic wave having this frequency band include a technique for carrying out imaging using a safe radioscopic inspection system in place of an X-ray system, a spectroscopic technique for obtaining an absorption spectrum or a complex dielectric constant of the inside of a substance to evaluate a coupling state of atoms, a technique for analyzing a biomolecular, and a technique for evaluating concentration or mobility of carriers.
JP10-104171A discloses a THz generating means suitably employing a photoconductive element in which an antenna also serving as an electrode is provided on a photoconductive film deposited on a substrate. A detector 132 is shown in FIG. 10 as an exemplary structure of the photoconductive element. A substrate 30 has, for example, a silicon-on-sapphire structure treated with radiation, in which a silicon film as a photoconductive material is deposited on a sapphire substrate. Generally, LT-GaAs grown at a low temperature on a GaAs substrate is also often used as a photoconductive film. A dipole antenna 138 formed on a surface includes a pair of dipole feed lines 138a and 138b and a pair of dipole arm portions 139a and 139b. An optical pulse is condensed at a gap 133. When a voltage is applied across the gap, a THz pulse is generated. When photocurrent is detected without applying a voltage, a THz pulse can be detected. A substrate lens 136 serves to couple a slab mode (substrate mode) of an electromagnetic wave confined in a substrate 130 to a free-space radiation mode and also serves to control an angle of radiation in the electromagnetic wave space-propagation mode.
The foregoing illustrates by way of example that a photoconductive element is used alone to propagate an electromagnetic wave into space. On the other hand, Applied Physics Letters, vol. 80, no. 1, Jan. 7, 2002, pp. 154-156 and Applied Physics Letters, vol. 84, no. 12, Mar. 22, 2004, pp. 2049-2051 disclose a small functional device in which a semiconductor film functioning as a photoconductive element and a transmission path for transmitting a generated electromagnetic wave are integrated on a single substrate. This device has such a structure that a thin film of only an epitaxial layer of a photoconductive element made of LT-GaAs is transferred on a portion of a high frequency transmission path formed on a substrate. According to Applied Physics Letters, vol. 80, no. 1, Jan. 7, 2002, pp. 154-156, a microstrip line is formed on an Si substrate with an insulator resin interposed. A gap is formed at a portion of the line. An LT-GaAs thin film is arranged only at the bottom of the gap. On the other hand, according to Applied Physics Letters, vol. 84, no. 12, Mar. 22, 2004, pp. 2049-2051, coplanar strip lines are formed on a quartz substrate. An LT-GaAs thin film is partially arranged to extend across a gap between the two lines.
Each device performs driving so that a laser beam is applied, through spatial propagation, to the gap of the metal line from the surface side of the substrate to allow a generated THz electromagnetic wave to propagate through the line.

Optical semiconductor device in which an electromagnetic wave is generated in a region of an applied electric field


An electrical connector for a camera provided on a camera body, an interchangeable lens and accessories for the electrical connection thereof comprises an upper contact holding member having an engagement portion and a fitting portion, a lower contact holding member having an engagement portion and a fitting portion corresponding to the engagement portion and fitting portion of the upper contact holding member, a plurality of contact springs, and a flexible print distributing panel having a pattern for conduction on the surface of contact thereof with the contact springs, the plurality of contact springs and the flexible print distributing panel being appropriately disposed between the upper contact holding member and the lower contact holding member, the engagement portion and fitting portion of the upper contact holding member being engaged with and fitted to the engagement portion and fitting portion of the lower contact holding member.

1. Field of the Invention
This invention relates to the structure of electrical connectors provided on a camera body, an interchangeable lens and accessories for the electrical connection thereof.
2. Related Background Art
In an interchangeable lens type camera system using a rotation mounting and dismounting type bayonet mount for coupling or separating a camera body, an interchangeable lens and accessories by clockwisely or counter-clockwisely rotating the mounts thereof, there are provided electrical connectors having electric circuits, respectively, and adapted to effect the giving and receiving of various kinds of information such as information for automatic exposure control and information for automatic focus adjustment, and having a number of contacts near the mounts.
FIG. 1 of the accompanying drawings shows an electrical connector for a camera according to the prior art. For example, Japanese Utility Model Publication No. 4-10582 discloses the electrical connector for a camera.
The reference numeral 1 designates an interchangeable lens, the reference character 1a denotes a lens side bayonet mount, the reference numeral 2 designates a camera body, and the reference character 2a denotes a camera side bayonet mount.
The reference numeral 3 designates the upper contact holding member of a lens side electrical connector which is formed of plastic.
The reference numeral 4 denotes a lower contact holding member which is also formed of plastics.
The reference numeral 5 designates a required number of contact springs.
The reference numeral 6 denotes a lens side flexible print distributing panel (hereinafter referred to as FPC) having a conducting pattern (not shown) provided on the surface of contact thereof with the contact springs.
The contact springs 5 and lens side FPC 6 are superposed one upon the other and are sandwiched by and between the upper contact holding member 3 and the lower contact holding member 4, and ultrasonic vibration is imparted thereto to thereby heat and weld the surfaces of contact between the upper contact holding member 3 and the lower contact holding member 4.
Rearwardly of the camera side bayonet mount 2a, a camera side contact holding member 7 formed of plastic is secured to the inner peripheral surface of the camera body 2. A contact 8 is insert-formed in the camera side contact holding member 7, and a camera side FPC 9 is soldered to the contact 8.
In such a lens side electrical connector, the spring force of the contact springs 5 always acts to keep the upper contact holding member 3 and the lower contact holding member 4 away from each other and therefore, where a plurality of contact springs 5 are provided in the circumferential direction, their combined spring force acts, and if the number of the contact springs 5 becomes great, the spring force thereof will exceed the welding force between the upper contact holding member 3 and the lower contact holding member 4, and this has led to the problem that the welding work becomes difficult or the welded portions are peeled by a change with time. If the welded portions are peeled during photographing, unsatisfactory conduction will take place and the giving and receiving of an electrical signal will become impossible, and automatic exposure control and automatic focus adjustment will become impossible. Also, when the camera is to be repaired, there will be no alternative but to interchange the entire electrical connector, and since electric circuit parts are usually soldered to the lens side FPC 6, the repair will become costly.


A telephony system for completing conference calls includes a premise-based network having a local controller coupled to local endpoints, a proxy, and a conference bridge. The telephony system includes a public telephone network coupled to the premise-based network. A request call is initiated to the proxy for setting up the conference call. The request call is routed to the conference bridge. A plurality of local endpoints for participation in the conference call is provided to the proxy via the request call. The local controller contacts the plurality of local endpoints and routes successful connections to the conference bridge. The request call and the successful connections are then bridged at the conference bridge.

The present invention relates in general to telephonic conference calling, and, more specifically, to a local conference bridge in a premise-based network for extending the number of participants in a conference call.
Telephone conference calls are a widely available service for connecting three or more different telephone terminals for the mutual exchange of voice and/or video communication signals. In a typical arrangement using the public telephone system, each of the separate conference call participants are connected to a conference bridge. The cost and complexity of maintaining a conference bridge is proportional to the particular number of ports provided in the bridge allowing participants to connect to a particular conference call. Thus, there are practical limits to the number participants to any particular conference call under control of a single conference bridge.
In addition to requiring separate ports for each participant, prior art conference calling utilizes individual dedicated circuits between the terminal of each conference call participant and the conference bridge. When multiple participants of a conference call are located in close proximity (e.g., separate telephone terminals within a building served by a private branch exchange or terminals served by the same telephone company central office), then the multiple individual circuits to the conference bridge may result in an inefficient use of the telephone switching circuits and communication channels.
Privately owned enterprise systems such as a private branch exchange (PBX) or a wireless local area network (WLAN) are becoming widely used because of their reduced cost and increased availability of various calling features. These systems are especially useful in the context of enterprise communication systems (e.g., telephony systems for business or governmental organizations) involving large numbers of coworkers, associates, and colleagues wherein many conference calls may be conducted involving participants and different endpoints or terminals within the enterprise system. This increases the likelihood of inefficient utilization of conference bridge and telephone circuit resources when establishing conference calls.


A current detection circuit according to one embodiment includes a low-pass filter, a voltage-to-current converter circuit, and a comparator. The low-pass filter has a first terminal connected to a signal input terminal to which a signal current is input. The voltage-to-current converter circuit has a first terminal connected to a second terminal of the low-pass filter and has a second terminal connected to the signal input terminal. The comparator has a first input terminal and a second input terminal and outputs a signal according to a difference between a signal input through the first input terminal and a signal input through the second input terminal, the first input terminal being connected to the second terminal of the low-pass filter, and the second input terminal being connected to the second terminal of the voltage-to-current converter circuit.

Conventionally, there is known a current detection circuit that detects an input signal current. The current detection circuit uses, for example, a method of detecting a signal current by comparing an input signal generated from the signal current with a predetermined reference signal. The reference signal is normally set according to the direct-current component of the signal current. However, when the signal current is input on an irregular basis, the direct-current component of the signal current changes according to the frequency of input. Thus, it is difficult to accurately detect a signal current even if an input signal is compared with a predetermined reference signal.
To solve such a problem, there is proposed a method of detecting a signal current by comparing a reference signal with an input signal to which the signal current is converted with the direct-current component of the signal current removed. However, the method requires a plurality of amplifier circuits, which may cause an increase in the power consumption of the current detection circuit.

Current detection circuit and pile-up detection circuit


A chair base includes a leg assembly having a plurality of radially-extending legs, and a leg cover adapted to cover the legs. The tubular legs have a top surface divided by a center line and have apertures offset from the center line. The leg covers are adapted to cover the legs, and the leg covers including downwardly extending off-centered bosses for engaging the apertures. Each of the tubular legs have an end with aligned vertical holes therein. A sleeve-like pintle retainer is located in the aligned vertical holes and flared at its top and bottom to hold the pintle retainer in the tubular legs. The leg assembly includes a tubular center hub. The plurality of radially extending tubular legs each have a top wall, a bottom wall and opposing side walls, the top and bottom walls each having an arcuately shaped end engaging the center hub. A pair of ring welds extend continuously circumferentially around the center hub for welding the arcuately shaped ends of the top and bottom walls to the center hub. In a modified form the covers include a plurality of flat-topped intermediate retainers shaped for attachment to a top of the legs, and a plurality of aesthetic flat-bottomed trim pieces shaped for mating adhering attachment to the top of the retainers.

The present invention relates to chair bases, and more particularly to chair bases constructed to improve manufactureability and reduce cost while maintaining aesthetics.
Chairs often include bases with radially extending legs with casters on their ends for movably supporting the chairs. The legs must be structurally sound for supporting the weight of the chair and a person seated in the chair. The legs must also be visually attractive since at least a portion of the legs are visible when looking down at the chair from a few feet away. This can be problematic since materials strong enough to provide the structural strength desired may be difficult to aesthetically cover. Also, some legs have peculiar cross sectional shapes that are difficult to uniformly paint or coat. For example, some customers desire chrome plated legs on their chairs. However, chrome plating processes have severe limitations concerning the type of materials that can be plated and the depth that the chrome plating material can be thrown. Another problem is that many coatings unacceptably show through surface defects, such as weld marks, scuff marks, and any other surface inconsistencies. Still another problem is that people often put their feet on the legs while seated in the chair, thus tending to scratch and scuff the top of the legs. A chair base construction is desired having reduced manufacturing costs, but that allows use of coating materials having high wear resistance and an attractive appearance.
Many chair bases include a sleeve-like central hub and radially extending legs with casters on their outer ends. The legs undergo considerable stress based on their cantilevered construction, and for this reason must be attached to the central hub repeatably, consistently, and securely. However, it can be difficult to weld the legs to the central hub since the legs interfere with clear access to the area of the joint when welding 360.degree. around the joint. Further, the legs must be accurately welded, since the casters on the ends of the legs must all touch the floor. Thus, it has been difficult to automate the leg-to-hub joining process, and also difficult to consistently make a high quality joint.
Accordingly, a chair base solving the aforementioned problems is desired.


The invention is a process for repairing a coating having a precise thickness damaged in a specific area. In detail, the process includes the steps of: 1) removing the damaged coating from the specific area; 2) placing a scrim material having a thickness equal to the required thickness of the coating in the specific; and 3) filling the specific area with coating material to the thickness of the scrim material.

1. Field of the Invention
The invention relates to the field of coating applicator processes and, in particular, to a coating process for repairing coating requiring a very precise thickness.
2. Description of Related Art
In most instances, the thickness of a painted coating is not critical; the principle issue is complete covering of the surface. Thus repair is a simple matter; one need only clean up the repair and re-coat with a brush or roller. However, if the coating thickness is critical, then such repairs become difficult, especially in the field. For example, Radar Absorbing Material (RAM) coatings are held to a precise thickness in order to insure that radar signals of a particular frequency of interest are absorbed. These coating are applied by spray guns in order to insure that the proper thickness is applied. Often, several passes are made, requiring the testing of absorption properties between each pass.
Thus it is obvious that repair of such RAM coatings in the field is a difficult process. While portable handheld RAM coating testing apparatus is available, spray-coating equipment may not be readily available. Proper thickness has been obtained using rollers or paintbrushes, but is a time consuming process involving a lot of trial and error. This is because the required ratio of solvent to resin is significantly different when using a roller in stead of a spraying machine.
Thus, it is a primary object of the invention to provide a process for repairing coatings having a precise thickness.
It is another primary object of the invention to provide a process for repairing coatings having a precise thickness using scapulas and rollers.
It is a further object of the invention to provide a process for repairing RAM coatings having a precise thickness that does not effect the radar absorbing properties of the coating.

Process for repairing coatings having a critical thickness


A method for providing time information comprises sending time information to at least one communications device and receiving information indicating error in received time information from at least one of said at least one communications device, said error in received time information having been determined in a communications device. In a communications device, first time information from a communications system is received and second time information with respect to an external time frame is determined. Thereafter an error in first time information based on at least said second time information is determined, and information indicating said error in said first time information is sent to said communications system. A communications device, a communications system and a network element for a communications system are also discussed.

1. Field of the Invention
The present invention relates to providing time information to a communications device.
2. Description of the Related Art
Positioning services have become very popular in the recent years. Positioning refers here to determining the location of a receiver device. The receiver device may be capable of determining its position based on signals it receives. The signals can be sent either from a specific positioning system or, for example, from a cellular communications system. Alternatively, the receiver device may act as a measurement device and send measurement results to a further unit, which then determines the location of the receiver device.
The most widely used positioning system is the Global Positioning System (GPS). GPS positioning is based on measuring relative time of arrival of signals sent simultaneously from GPS satellites. The locations of the GPS satellites at the time of sending the signal can be determined. It is possible to determine the location of the GPS receiver by determining the distance between GPS satellites and the GPS receiver using time of arrival measurement results together with the exact GPS time.
In theory, three time of arrival measurements would be enough to calculate the GPS receiver's position and also the velocity, if the exact GPS time is known to the GPS receiver. In practice, a GPS receiver has low-cost, low-accuracy local oscillator as a local clock. Therefore a fourth time of arrival measurement is typically needed to determine the difference between the local time and the GPS time. This means that for successfully locating a GPS receiver, it typically needs to receive signals simultaneously from at least four GPS satellites.
Each signal transmitted by a GPS positioning satellite carries a navigation message, which includes both data unique to the transmitting satellite and data common to all satellites. The navigation message contains time information, satellite clock correction data, ephemeris (precise orbital parameters), almanac (coarse orbital parameters), health data for all satellites, coefficients for the ionospheric delay model and coefficients to calculate the Universal Coordinated Time (UTC) from the GPS system time. The navigation message consists of 25 frames, and the frames are organized in such a way that a GPS receiver is able to obtain satellite-specific data (ephemeris) for exact position calculation within 30 seconds. This 30 seconds is the minimum time-to-first-fix (TTFF) of GPS in the general case. It takes 12.5 minutes to receive all the 25 frames completely.
As mentioned above, GPS positioning is dependent on obtaining accurate GPS time and navigation data and on performing distance measurements. For carrying out GPS positioning successfully, signals from three or four GPS satellites need to be received properly for demodulating navigation data needed for the distance measurements. GPS provides accurate positioning results especially in rural areas, where a GPS receiver can have a line-of-sight with the needed number GPS satellites. In urban areas, where buildings may cause attenuation of the GPS signals and reflections to the signal propagation paths, especially the reception of the navigation data may not be successful.
The distance measurements need to be performed at the GPS receiver, but the GPS time and navigation data may be provided to the GPS receiver also via another system. In Assisted GPS (AGPS), at least part of the GPS time and/or navigation data is provided as location assistance data to a GPS receiver by means of some other signals than by the GPS satellite signals. By providing navigation data and/or exact GPS time as location assistance information, the availability and the response time of GPS positioning can be enhanced. For example, the Time-To-First-Fix can be shortened. By obtaining location assistance information, a GPS receiver can perform distance measurements and optionally also calculate its position even when the GPS signals the GPS receiver receives are so weak that the navigation message cannot be properly demodulated. If the GPS time can be transferred to a GPS receiver with better accuracy than 2-3 seconds, it already helps in positioning. The best assistance is obtained with better than 10 microseconds accuracy.
A communications system, for example a cellular communications system, may be used for transmitting the location assistance information. The communications system may be equipped with a plurality of reference GPS receivers for obtaining and determining the location assistance information. Typically each reference GPS receiver is associated with a serving area. The location assistance information sent to GPS receivers within a serving area typically includes information relating to those GPS satellites, from which the reference GPS receiver of the respective serving area is able to successfully receive GPS signals. The GPS receivers, to which location assistance information is transmitted using a cellular telecommunications network, are typically integrated to a communication device capable of supporting communication via the communications system.
There are at least two alternatives for providing to a communication device information about a reference time for positioning. The first alternative is to tie the reference time of the positioning system to an event or events in the communications network. For example, the reference time may be tied to a start of a certain frame transmitted from a certain network element. For this purpose, time differences between base stations of a communication network typically need to be measured. A Location Measurement Unit is defined in the 3GPP (Third Generation Partnership Project), and it is responsible, for example, for measuring time differences between base stations and reporting them to a serving mobile location center. From the measurements the serving mobile location center defines the time correspondence between the reference time and GSM frames. Using this first alternative it is possible to deliver accurate reference time to a communications device. The accuracy may be better than 10 microseconds.
A second alternative is to estimate the current time of the positioning system in the communications system and send this information to the communications device. A GPS clock or receiver connected to the communication system may be used for determining current GPS time. This second alternative means, in practice, delivery of less accurate reference time. Providing reference time information without reference to external events in location assistance data is an example of this second alternative. When information about the reference time is sent to a communications device, there is a delay between the time instant when the reference time of the positioning system is determined and when the communications device receives the reference time information.
Especially if it is desired to provide a user-plane based positioning solution, the first alternative for providing reference time is not likely, as it would require a connection between a location measurement unit or a corresponding unit and a user-plane application.
To provide more accurate time information about the positioning system, it is possible to try to take into account the transfer delay. For example, for packet data transfer using IP (Internet Protocol) connections, a ping procedure may be used to measure the transfer delay. It is, however, possible that ping or similar procedures cannot be used due to data channel characteristics or standards support problems. As an example, ping assumes the existence of Internet Control Message Protocol (ICMP) in the communications device. The ICMP is part of the TCP/IP (Transfer Control Protocol/Internet Protocol) protocol suite. Ping therefore does not work if the communications device does not have a proper protocol stack. Moreover, depending on the settings and configurations of the network operator, the ICMP data packets that are used by ping, may not be able to reach the communications device. For example, the communications device does not have data connection subscription or some intermediate network element (such as a firewall or a proxy) blocks the IP packets carrying ICMP messages.
It is appreciated that although problems relating to providing accurate time information relating to GPS are discussed above, similar problems may arise in connection with delivering time information for other purposes.
Embodiments of the present invention aim to provide a feasible solution for providing time information accurately to a communications device.


In a PPP terminating equipment 100 connected with a switch fabric and terminating PPP link, the PPP terminating equipment 100 has an LCP echo requirement detecting section 20 detecting whether or not a received packet is the LCP echo requirement packet, and an LCP echo response producing section 40 producing a response packet to the LCP echo requirement by rewriting the LCP header of the received LCP echo requirement packet. The PPP terminating equipment 100 thereby produces and returns the response packet to the LCP echo requirement.

The present invention relates to a PPP terminating equipment, and a network equipment, such as a router, and the like, in particular to the PPP terminating equipment and the network equipment both capable of rapidly processing a response to an LCP echo requirement, and a method of responding to the LCP echo requirement.
Conventionally, a PPP (Point-to-Point Protocol) terminating equipment has been mainly used, when a network equipment, such as a router, and the like is connected by the use of a PPP link.
Numbers of the PPP link terminals required for the PPP terminating equipment correspond to numbers of lines by 1 to 1 in a case of a non-multiple interface, such as POS (Packet over SONET), or the like. On the other hand, the PPP link can be established per each VPI/VCI (virtual path identifier/virtual channel identifier) or per each channel, in a case that a multiple interface, such as ATM (Asynchronous Transfer Mode), a channelized interface, or the like is contained. As a result, it becomes necessary that several thousands to several ten thousands number of the PPP links can be terminated by a single PPP terminating equipment.
Processing required for the PPP terminating equipment are divided into two major processing, namely, a processing of establishing a link and a processing of maintaining the link. The former, namely, the processing of establishing the link is such a processing that negotiates with the object of the link and decides and admits parameters required for connection of PPP.
On the other hand, the latter, namely, the processing of maintaining the link is, for example, a processing of response to LCP (Link Control Protocol) echo requirement packet transmitted and received at intervals of several seconds to confirm normality of the link, mainly after the PPP link has been established. An equipment that transmitted the LCP echo requirement judges the link to be invalid and disconnects the link, if any responses were not received from the opposite PPP terminating equipment during a predetermined certain time. Consequently, if the LCP echo requirement has been received, the PPP terminating equipment must give a response to the LCP echo requirement during the predetermined certain time by all means. Herein, numbers of the received LCP echo requirements are increased, when numbers of the links are many. Accordingly, a processing of responding to the LCP echo requirement is a large load on a processor.
In a conventional technique, the above-mentioned processing of responding to the LCP echo requirement is processed mainly by the use of a general purpose microprocessor. However, load on the general purpose microprocessor is increased, as numbers of connection of PPP are increased. For example, in the above-mentioned processing of establishing a link, it takes a longer time to finish the connection of all the links. In addition, even if the link has been established, only the PPP links of numbers corresponding to numbers of the LCP echo requirements capable of being processed by the general purpose microprocessor can be maintained Thus, in the conventional technique, it is possible only to obtain the performance of processing far inferior to numbers of connection of PPP capable of being established in an actual multiple interface.

PPP terminating equipment, network equipment and method of responding to LCP echo requirement


The present invention provides methods and materials that enhance a plant""s resistance to certain pathogens. A novel pathway is described and has been designated with the acronym, SI-SAR pathway, for salicylic acid-independent systemic acquired resistance. DNA constructs and methodologies are provided that facilitate the identification of compounds that activate this pathway. Methods are provided to enable the identification of novel genes and signaling components that are expressed when the SI-SAR pathway is activated. Transgenic plants with altered expression of these novel genes or signaling components of the pathway are expected to have enhanced resistance to plant pathogens. Also provided is a novel, pathogen-induced epoxide hydrolase that is inducible in the absence of SA.

The present invention pertains to the fields of plant molecular biology. More specifically, the invention relates to induction of systemic acquired disease resistance in plants involving a novel salicylic acid-independent signal transduction pathway whose activation is associated with enhancement of a plant""s ability to resist microbial infection.
Several publications are referenced in this application in parentheses in order to more fully describe the state of the art to which this invention pertains. Full citations for these references are found at the end of the specification. The disclosure of each of these publications is incorporated by reference herein.
In plants, resistance to environmental challenges, e.g. pathogens, insects and stresses, enables them to better survive in nature, Resistance to pathogen attack is often associated with the hypersensitive response (HR), in which rapid, local cell death occurs at the infection site. The formation of these necrotic lesions is associated with the restriction of pathogen multiplication and spread. In the tobacco/tobacco mosaic virus (TMV) system, a typical HR develops on TMV-inoculated leaves of the tobacco cultivar Xanthi nc, which contains the N resistance gene. By contrast, when the TMV-susceptible cultivar Xanthi is infected, the virus spreads throughout the plant and causes disease symptoms. Several days after HR formation, systemic acquired resistance (SAR) develops throughout the plant (Ross, 1961a, 1961b; Ryals et al., 1994, 1996). SAR confers enhanced resistance not only to a secondary challenge by the initial infecting pathogen, but also to a broad range of other pathogens. Therefore, plant disease resistance is associated with both local (HR) and systemic (SAR) responses.
Activation of resistance responses is associated with the induction of a large number of defense genes and the synthesis of many secondary compounds. The former include genes encoding peroxidases, glucanases, chitinases, and other pathogenesis-related (PR) proteins while the latter include phytoalexins, phenolic compounds and lignin (Bowles, 1990; Cutt and Klessig, 1992). Phytoalexins are low molecular weight antimicrobial compounds that are synthesized by the plant and accumulate at the site of infection. While most phytoalexins are synthesized via the phenylpropanoid pathway, some are synthesized by the isoprenoid biosynthetic pathway (Ebel, 1986). Phenylalanine ammonia-lyase (PAL) is the first enzyme in the phenylpropanoid pathway and it regulates the biosynthesis of flavonoids, phytoalexins and lignins (Hahlbrock and Scheel, 1989; Dixon and Lamb, 1990). Levels of PAL mRNA and enzymatic activity increase in the inoculated tissue of resistant plants after pathogen infection. In addition, when tobacco plants are treated with a fungal elicitor, PAL mRNA accumulates in stem tissues (Pellegrini et al., 1994).
Plants resisting pathogen attack also synthesize a variety of PR proteins (Linthorst, 1991; Cutt and Klessig, 1992). In tobacco, at least five families of PR genes have been identified. They are induced in both the TMV-infected leaves and the upper uninoculated leaves of resistant cultivars (Ward et al., 1991). The function of some PR proteins is still unclear; however, several have been shown to have antimicrobial activities either in vivo or in vitro (Dempsey and Klessig, 1995).
Increases in salicylic acid (SA) levels also correlate with resistance to pathogen attack (Malamy et al., 1990; Metraux et al., 1990; Rasmussen et al., 1991). In tobacco resisting TMV infection, endogenous SA levels increase in both inoculated and uninoculated leaves. These increases correlate with the HR and SAR and precede the induction of PR genes (Malamy et al., 1990). A correlation between SA accumulation and resistance to pathogen attack has also been shown in other plants, e.g. cucumber and Arabidopsis (Metraux et al., 1990; Rasmussen et al., 1991; Uknes et al., 1993; Lawton et al., 1994; Summermatter et al., 1995; Dempsey et al., 1997). In addition, exogenously applied SA enhances resistance and induces nine gene families whose expression is associated with SAR in TMV-inoculated tobacco (Ward et al., 1991). Elevated SA levels also correlate with the activation of plant defenses in temperature shifted tobacco. At temperatures above 28xc2x0 C., development of resistance to TMV is blocked and tobacco plants become systemically infected (Kassanis, 1952). At this elevated temperature, there is no detectable increase in SA levels, no PR protein synthesis and no HER after TMV infection (Gianinazzi, 1970; Yalpani et al., 1991; Malamy et al., 1992). However, when these infected tobacco plants are shifted to lower temperatures, resistance to TMV is restored. Moreover, a rapid and dramatic increase in SA levels precedes both PR gene expression and the appearance of a HR (Malamy et al., 1992).
Mutant analysis in Arabidopsis also provides support for SA""s importance in disease resistance. Several mutants (e.g. npr1, nim1, and sai1), have been isolated which are unable to activate PR gene expression after treatment with SA or INA (2,6-dichloroisonicotinic acid, a synthetic functional analog of SA; Conrath et al., 1995; Durner and Klessig, 1995; Vernooij et al., 1995; Malamy et al., 1996). These mutants show greater susceptibility to bacterial and fungal pathogens (Cao et al., 1994; Delaney et al., 1995; Shah et al., 1997). conversely, mutants with elevated levels of SA, including the lesion mimic mutants acd2 and the 1sd series (Dietrich et al., 1994; Greenberg et al., 1994), as well as cpr1 (Bowling et al., 1994) and cep1 (Klessig et al., 1996), constitutively express these PR genes and exhibit enhanced resistance to pathogens.
Some of the strongest evidence supporting a signaling role for SA comes from the analysis of transgenic tobacco and Arabidopsis plants that contain the bacterial nahG gene encoding salicylate hydroxylase. Since salicylate hydroxylase degrades SA, these transgenic NahG plants are unable to accumulate SA. Following inoculation with TMV, NahG tobacco plants exhibit substantially reduced induction of PR gene expression and fail to develop SAR. Furthermore, they show enhanced susceptibility to infection with both virulent and avirulent pathogens (Gaffney et al., 1993; Delaney et al., 1994; Vernooij et al., 1994). Thus, SA appears to be required for an effective resistance response.
While SA mediates resistance to certain pathogens, other signal transduction pathways also appear to be involved in plant defense response. Both ethylene and jasmonates have been implicated as signal molecules that induce PR proteins during plant defense responses (Boller et al., 1983; Boller, 1991; Xu et al., 1994). Furthermore, several recent reports have shown that induction of a number of defense genes by pathogens, elicitors or abiotic agents (soluble sugars) is mediated by a SA-independent pathway(s) (Herbers et al., 1996; Penninckx et al., 1996; Pieterse et al., 1996; Vidal et al., 1997).
Compositions and methods that enhance disease resistance in plants are agronomically important and highly desirable. While SA is a key component in a plant""s capacity to withstand environmental stresses, mounting evidence suggests that a second pathway leading to systemic acquired disease resistance exists. Thus, a need exists to identify and characterize the genes and encoded proteins involved in this novel, second pathway.
The present invention relates to a new signal transduction pathway in plants which is associated with and leads to the development of systemic acquired resistance (SAR). Activation of this pathway results in the induction of a diverse group of genes which are expressed in both uninfected and infected tissues in a salicylic acid (SA)-independent manner. These genes are termed SIS for SA-independent systemically induced.
According to one aspect of the invention, a method for identifying SIS genes is provided. The method uses the following steps: (a) providing pairs of plants, each pair being of of equivalent species and variety, wherein one of the pair (the xe2x80x9cSA+xe2x80x9d plant) accumulates endogenous SA, and the other of the pair (the xe2x80x9cSA-xe2x80x9d plant) does not accumulate endogenous SA; (b) inoculating one pair of plants with a plant pathogen to which the plant variety responds by exhibiting SAR; (c) mock-inoculating another pair of plants; (d) identifying defense-related genes in the plants by detecting genes that are expressed in the inoculated plants but not in the mock-inoculated plants (the defense-related genes indentified in this manner include the SIS genes as well as other defense-related genes); and (e) identifying the SIS genes by detecting the defense-related genes expressed in the inoculated SA+ plant and the defense-related genes expressed in the inoculated SAxe2x88x92 plant, the SIS genes being expressed in both the inoculated SA and SA plants, the other defense-related genes being expressed only in the inoculated SA+ plant. In a preferred embodiment, the pair of plants are tobacco of the variety Xanthi nc and the pathogen is TMV. The plant not accumulating SA expresses a nahG gene, resulting in conversion of SA to catechol.
According to another aspect of the invention, a method is provided for identifying compounds that activate an SI-SAR pathway in plants. The method has the following steps: (a) providing a first DNA construct in which a first reporter gene is operably linked to a SIS gene promoter; (b) providing a second DNA construct in which a second reporter gene is operably linked to a SA-inducible gene promoter, such as a PR-1 gene promoter; (c) transforming a plant with the first and second DNA constructs; (d) administering to the plant a test compound suspected of activating the SI-SAR pathway; and (e) detecting expression of the first and second reporter genes, expression of the first reporter gene and lack of expression of the second reporter gene being indicative of activation of the SI-SAR pathway by the test compound.
Another method for identifying compounds that activate an SI-SAR pathway in plants comprises the following steps: (a) providing a plant that does not accumulate endogenous SA; (b) transforming the plant with a DNA construct in which a reporter gene is operably linked to a SIS gene promoter; (c) administering to the plant a test compound suspected of activating the SI-SAR pathway; and (d) detecting expression of the reporter gene, the expression of the reporter gene being indicative of activation of the SI-SAR pathway by the test compound.
According to another aspect of the invention, a method is provided for enhancing SA-independent resistance of a plant to infection by a plant pathogen. The method comprises transforming the plant with a DNA construct having a coding region of at least one SIS gene operably linked to a constitutive promoter, causing the transformed plant to constitutively express the SIS gene, thereby conferring the enhanced resistance to the plant pathogen.
In another aspect of the invention, a method for isolating signaling components of the SI-SAR pathway in plants is provided. The method comprises: (a) transforming a plant with a DNA construct having a reporter gene coding sequence operably linked to a SIS gene promoter; (b) producing progeny of the transgenic plant that are homozygous for the transgene; (c) mutagenizing seeds of the progeny; (d) producing M2 progeny from the mutagenized seeds; (e) selecting individuals of the M2 progeny that desplay altered expression of the reporter transgene as compared with non-mutagenized plants; and (f) identifying mutations in the selected mutagenized plants that confer the altered expression of the reporter transgene, the mutations being associated with genes that: encode signaling components of the SA-SAR pathway.
According to another aspect of the present invention, an isolated nucleic acid molecule is provided that includes an open reading frame encoding a plant pathogen-inducible epoxide hydrolase (piEH). This nucleic acid represents one of the SIS genes identified in accordance with the invention. In a preferred embodiment, the nucleic acid encodes a piEH that is inducible in the absence of SA. In various embodiments of the invention, the nucleic acid is DNA, either cDNA or genomic DNA. In other embodiments, it is RNA. In a preferred embodiment, the nucleic acid encodes a tobacco piEH, preferably having an amino acid sequence which is greater than 40% homologous with Sequence I.D. No. 2, and most preferably comprises Sequence I.D. No. 2.
According to another aspect of the invention, an isolated nucleic acid molecule is provided, which has a sequence selected from the group consisting of: (a) Sequence I.D. No. 1; (b) an allelic variant of Sequence I.D. No. 1; (c) a natural mutant of Sequence I.D. No. 1; (d) a sequence hybridizing with part or all of a sequence complementary to Sequence I.D. No. 1 and encoding a polypeptide substantially the same as part or all of a polypeptide encoded by sequence I.D. No. 1; and (e) a sequence encoding part or all of a polypeptide having amino acid sequence I.D. No. 2.
Also provided in accordance with the invention are recombinant DNA molecules comprising the aforementioned nucleic acid molecules, operably linked to vectors for transforming plant cells. Also provided are plant cells transformed with those recombinant DNA molecules, and transgenic plants comprising those recombinant DNA molecules.
According to another aspect of the invention, an isolated plant pathogen-inducible epoxide hydrolase (piEH) is provided, the expression of which is inducible by inoculation of the plant with a pathogen, in the absence of salicylic acid. In a preferred embodiment, the piEH is of tobacco origin and is inducible by inoculation of tobacco with TMV. In preferred embodiments, the piEH has an amino acid sequence greater than 40% homologous to Sequence I.D. No. 2, and most preferably comprises Sequence I.D. No. 2.
According to another aspect of the invention, a polypeptide is provided, which is produced by expression of an isolated nucleic acid sequence selected from the group consisting of: (a) Sequence I.D. No. 1; (b) an allelic variant of Sequence I.D. No. 1; (c) a natural mutant of Sequence I.D. No. 1; (d) a sequence hybridizing with part or all of a sequence complementary to Sequence I.D. No. 1 and encoding a polypeptide substantially the same as part or all of a polypeptide encoded by sequence I.D. No. 1; and (e) a sequence encoding part or all of a polypeptide having amino acid sequence I.D. No. 2.
In another aspect of the invention, antibodies immunologically specific for part or all of the aforementioned proteins are provided.
Other aspects and advantages of the invention will be understood by reference to the detailed description of the invention and examples set forth below.

Methods and compositions for improving salicylic acid-independent systemic acquired disease resistance in plants

Rutgers, The State University of New Jersey


A device for working of glass panes (1) has a support (5) for the glass panes (1) and a nozzle (2) from which a water jet emerges for cutting the glass panes (1). The nozzle (2) can be moved on a guide (8) parallel to the plane of the support (5). The tool (12) for working of the cut edges of the material plates (1) can likewise be moved on the guide (8) of the nozzle (2) and is preferably mounted on the same carriage (9) which can be moved on the guide (8), as the nozzle (2). This simplifies not only the technical structure of the device, but also shortens the working time, since the glass pane (1) need not be transported to another device for finishing. Moreover, essentially the same control program as for the water jet cutting can be used for finishing.

Such a device is known for example from DE 100 51 942 A1. The cut edges of the material plates or glass panes must then be further worked, especially ground and polished, for which they are conveyed to another workstation. In this other workstation the glass panes must be exactly positioned relative to the tool so that this finishing can be precisely carried out. This is associated not only with high technical cost, but also lost time, since the glass pane must not only be moved to another workstation, but must also be positioned there.


A peripheral switch (62) is electrically interposed between a peripheral device (10) and a plurality of computing devices respectively coupled to host computer ports (70a)–(70N). The peripheral switch (62) includes host computer port state sensing means (110) for determining a state of each host computer port (70a)–(70N) and providing a communication path to the peripheral device (10) from a host computer port (70a)–(70N) at a state indicative of a server computer being coupled thereto. The peripheral switch (62) further includes local handshaking means (120) for simulating communications from a server computer to peripheral device (10) if none of host computer ports (70a)–(70N) are determined to be coupled to a server computer.

1. Field of the Invention
The invention described herein is related to switching devices for sharing a peripheral device among a plurality of computing devices. More specifically, the present invention selectively connects a peripheral device to one of a plurality of computing devices that presents a predetermined state at a communication port thereof and for simulating an active communication link between a computing device and the peripheral device when a computing device at the predetermined state is not available among the plurality of computing devices.
2. Description of the Prior Art
Referring to FIG. 1, there is shown an exemplary network architecture found in, for example, tactical military environments. The network consists of a plurality of computing devices, such as single board computer (SBCs) 50a–50h electrically coupled to back plane 40 and mechanically secured within chassis 30. Each computing device 50a–50h is electrically coupled to a corresponding peripheral device, such as precision lightweight global positioning system receivers (PLGRs) 10a–10h. Each peripheral device 10a–10h is coupled to a corresponding chassis port 20a–20h via communications cable 15a–15h, respectively. Individual communication paths are separately maintained between the peripheral device 10a–10h and its corresponding computing device 50a–50h. The electrical connection between the peripheral port 20a–20h and its corresponding computing device 50a–50h may be hard-wired directly or may be distributed in conductors along the back plane 40.
It is apparent from FIG. 1 that the redundancy of the components of the depicted network can be extremely costly. For example, each PLGR 10a–10h of the network may cost hundreds, if not thousands, of dollars. However, in some applications, the parallel structure, i.e., each single board computer 50a–50hcoupled to its own PLGR 10a–10h, respectively, may be necessary or unavoidable. For example, each single board computer 50a–50h may be dedicated to a specific application and may be executing the program code therefore under separate and distinct operating systems. Each of the single applications being executed on the single board computers 50a–50h may require its own set of global positioning system (GPS) data and, therefore, requires a dedicated PLGR.
One alternative to the redundancy of peripheral devices is to interpose a peripheral switch 60 between a single peripheral device 10 and the plurality of computing devices 50a–50h, as is illustrated in FIG. 2. Through peripheral switch 60, a single communication path may be selectively established between the peripheral device 10, coupled at peripheral port 80, and each of the single board computers 50a–50h, coupled at host computer ports 70a–70h of peripheral switch 60 and computer chassis ports 20a–20h of computer chassis 30.
Peripheral sharing switches are well-known in the art. U.S. Pat. No. 4,608,663 to Gordon discloses a computer network incorporating a switch by which more than one computer shares a common peripheral. The switch searches for hosts with an active request line. Hosts gain access to the peripheral based upon a predetermined search sequence and upon the discovery, in the predetermined search sequence, of an active request line. Such switches may be useful for simple networks, but may not be used for distributing the functionality of the peripheral to a number of differently configured computer systems, each requiring a unique communication protocol. Moreover, the peripheral switch of Gordon cannot be effectively utilized to establish a communication between a peripheral requiring a particular host computer signature and a particular computing device in possession of the host computer signature. Such is the case of PLGR 10 of FIG. 2, which requires a host computer configured as a server computer having a particular state in order to connect therewith. Such a server computer may be connected at any of the host computer ports 70a–70h and the switch of Gordon is not equipped to locate the server computer at any given instant of time so that communication with the PLGR 10 can be established.
Another peripheral switch of the prior art is disclosed in U.S. Pat. No. 5,307,462 to Hastings. The peripheral sharing device of Hastings allows multiple hosts to share a single peripheral such as a printer or a fax machine. The switch relies on stored peripheral state information to restore the peripheral to a previous configuration when one host is finished with the peripheral. It is assumed that the peripheral changes state when the host requires it and that the peripheral has no requirements as to the state of the host. However, if the peripheral were such that it would change state depending on the availability and operating status of a host (e.g., going into a "sleep" state when a host does not require it), a network incorporating the switch of Hastings would behave erratically when the peripheral automatically changed its operating mode and a host was expecting a "ready" peripheral with which to connect.
Another approach to peripheral sharing is disclosed in U.S. Pat. No. 6,308,239 to Osakada, et al., which utilizes features of the universal serial bus architecture and communication protocol. The switch of Osakada, et al. allows flexible means for connecting a peripheral to a host computer, however, the host must request the switching action. Thus, the switch disclosed by Osakada, et al. has limited applicability when the peripheral actively searches its connection for a specific host signature. Further, the switch of Osakada, et al. does not provide means for preventing the peripheral from reverting to a secondary mode of operation should there be a failure to find a host of the specified signature.
In light of the foregoing discussion, there exists a need in the field of peripheral sharing for a peripheral switch that shares the functionality of a single peripheral among a plurality of distinctly configured computers. There is a further need for a peripheral switch which provides a default communication with the peripheral when a server computer, or a computer with a particular configuration, cannot be found. Furthermore, there is the need for the peripheral switch to be programmable to accommodate various network changes.


A coating agent, which comprises a cellulose derivative, an isocyanate group-containing 1,2-polybutadiene, a synthetic wax having a softening point of 100°-150° C., a fatty acid amide having a softening point of 60°-170° C., and graphite, can satisfy desired performances, when applied to rubbery elastomers, etc. such as prevention of sticking, adhesion and blocking, and improvement of abrasion resistance, and also can serve as a surface-treating agent for vulcanized rubber without peeling of coating films due to adhesion under high-temperature compression or friction-abrasion under high specific pressure.

Coating films of graphite, or coating films of metal salts or amides of fatty acids, wax such as paraffin, etc., silicone oil, etc. have been so far formed on the surfaces of rubbery elastomers, such as gaskets made from rubber-coated metal, bearing seals, oil seals, O rings, etc. to prevent sticking and blocking, and to improve the abrasion resistance, etc., or coating films containing ethyl cellulose, phenol resin, silicone resin, or the like as a binder have been so far formed thereon. In spite of the formation of such coating films in the case of engine gaskets, etc., the rubber coating layers on the surfaces of gaskets undergo abrasion, when used under service conditions of high specific pressure, high temperatures, and further subjected to engine vibrations, sometimes resulting in gas leakage. In the case of bearing seals, oil seals, etc., the rubber coating layers at the sliding positions of rubber elastomers undergo abrasion due to repeated sliding actions, sometimes resulting in oil leakage.
In view of such a problem, the present applicant has so far proposed coating agents for rubbery elastomers capable of forming effective gaskets, etc., while maintaining a sealability, substantially free from any phenomena of abrasion or damages to the rubber coating layers on the gasket surfaces even under severe service conditions of high specific pressure, high temperatures and further under applied vibration as in the engine gasket service circumstances, that is, a coating agent for rubbery elastomers, which comprises a hydroxyl group-containing compound of liquid 1,2-polybutadiene, an isocyanate group-containing 1,2-polybutadinene as a curing agent, and a polyolefin resin (Patent Literatures 1 and 2), and also a coating agent, which comprises an isocyanate group-containing 1,2-polybutadiene resin, a wax, and a fluororesin (Patent Literature 3).
[Patent Literature 1] Japanese Patent No. 2,827,402
[Patent Literature 2] Japanese Patent No. 3,316,993
[Patent Literature 3] Japanese Patent No. 3,893,985
However, these coating agents for the rubbery elastomers have suffered from such phenomena that the polybutadiene derivative resins, one component of the coating agents, become tacky at elevated temperatures, resulting in a decrease in the friction abrasion resistance. Thus, in some cases, the coating agent layer still has a problem in the resistance at elevated temperatures.


A method and apparatus for supplying molten metal to a die-casting machine. Metal is received from a smelter in a road-going vessel. A burner is lowered into an opening in the road-going vessel to direct heat into the road-going vessel to maintain the molten metal within the road-going vessel at a suitable temperature. Molten metal is transferred from the road-going vessel to a die-casting machine without substantial re-refining. Preferably the molten metal is transferred directly to a die-casting machine using a covered launder system connectable to the road-going vessel to shield the molten metal from atmospheric contact.

Metal die-casting is a process in which molten metal, such as aluminum or magnesium is injected into a metal mold to produce a molded article. The molten metal is usually introduced into a shot sleeve which uses a piston or plunger to force the molten metal at pressure into the mold.
The properties of the molded article depend to a large extent on the quality of the molten metal introduced into the mold. Molten metal quality is adversely affected by contaminants such as dissolved hydrogen and oxide impurities. Impurities may be introduced in the molten metal in the smelting process and by exposure to atmosphere.
According to the traditional process, which is still used by many die-casting facilities, metal is initially refined by a metal smelter and cast into ingots. A die caster purchases ingots from the smelter and melts the ingots in a furnace, usually adding scrap metal from the die-casting process. As some refining is carried out in the remelting, ingot metal quality is often not as high as it should be for high quality die cast articles. Some loss of metal occurs through oxide formation on the ingot surface and hydrogen dissolution may occur in the melting process.
A significant amount of energy is wasted in re-melting an ingot as metal which has already been melted to form the ingot has to be re-melted. Typically using a conventional reverbatory furnace, this requires an energy input on the order of 2,500 BTU per pound in the case of aluminum.
Another problem associated with having a die-casting facility melt and at least partially refine its own metal arises when an increase in capacity is required. To add more die-casting equipment it is necessary to increase the ability to melt metal. This requires both capital and space to increase furnace size or the number of furnaces.
One method that has been previously used to enhance furnace capacity is to obtain molten metal from a metal smelter and pour the molten metal directly into the furnace. Molten aluminum is transportable for considerable distances (up to approximately 200 miles) using road-going vessels. Road-going vessels are in essence covered, insulated containers which may be carried on a suitably modified flat-bed trailer.
Having molten metal delivered assists in reducing the amount of furnace capacity and energy required. As molten metal is poured into the furnace, impurities are introduced through contact with the atmosphere therefore requiring at least some further refining before use. Although molten metal delivery maximizes furnace capacity, increasing production would still eventually require increasing the size or number of furnaces.

Method and apparatus for supplying molten metal


A method (300), system (400), base station (500), head-end unit (600), and subscriber unit (700) provide for efficient resource hopping in a communication system or group of communication systems supporting a plurality of communication units, where different communication units may have varying resource size requirements. The method includes the steps of: assigning a communication unit of the plurality of communication units to a resource slot within a level of a plurality of levels of a hierarchical representation of a resource region, assigning an available resource hopping pattern and associated initial resource location within the resource slot to the communication unit, and hopping, by the communication unit in accordance with a predetermined hierarchical resource hopping scheme.

Hopping methods are known to provide performance benefits in wireless communication systems. For example, frequency hopping methods can significantly improve communication system performance by providing a frequency diversity mechanism and an interferer diversity mechanism. Similarly, time hopping methods can also improve communication system performance by providing a time diversity mechanism and an interferer diversity mechanism. Furthermore, both frequency hopping methods and time hopping methods can improve performance in fixed access or low-mobility communication systems by providing nearly independent fading from hop-to-hop in an environment that would otherwise be very slowly fading. In this latter case, the independent fading from hop-to-hop improves the effectiveness of forward error correction coding.
It is straightforward to implement a resource hopping method for a communication system which supports a plurality of communication units with uniform resource size requirements. Uniform resource size requirements imply that each communication unit operates with the same bandwidth, time-slot length, or more generally the same amount of any of the radio signal resources known in the art. In the case where the resource being hopped is the frequency of a signal, the available spectrum is divided into equal-width frequency slots, with the width of each slot being equal to the communication unit signal bandwidth. A communication unit is then able to transmit or receive within one of the available frequency slots. Frequency hopping in the communication system is facilitated by having the active communication units switch frequency slot assignments according to a set of predefined frequency hopping patterns. Switching frequency slot assignments may also be described as the changing of the center frequency of a signal to the center of a different frequency slot.
Generating frequency hopping patterns for a communication system that uses uniform bandwidth frequency slots is well known in the art. Similarly, generating time hopping patterns for communication systems with uniform sized time slots is also well known in the art. However, the prior art hopping methods are not applicable to a communication system or group of communication systems which support multiple resource sizes. Therefore, a need exists for a method, system, base station, head-end unit, and subscriber unit that provide for efficient resource hopping in a communication system or group of communication systems supporting a plurality of communication units, where different communication units may have different or varying resource size requirements.

Hierarchical resource hopping method, system, base station, head-end unit, and subscriber unit for variable resource size communication systems


Methods are described for removing aluminum from a solution using novel di- and tripodal compounds as chelators.

A chelator or chelating agent is a polydentate ligand that bonds to more than one coordination site of a metal ion. Chelating agents have long been known in the art to be useful in chemical analysis, in environmental remediation and in medicine. In chelation therapy, a chelating agent is employed to bind a poisonous metal agent such as mercury, arsenic, iron, lead or aluminum in order to displace the ion from biological ligands such as proteins and convert the metal ion into a less toxic form that can be excreted without further interaction with the body.
The present invention relates to (1) novel chelating agents or compounds, (2) novel immobilized, tethered chelators comprising the novel chelating compounds linked to immobilized supports and (3) methods of employing the novel compounds and chelators to remove trivalent metals such as Al3+ from aqueous systems in situ, in vivo and in vitro.
There have been previous studies of tripodal, trihydroxamic acids. Most of these ligands are based on tripodal platforms of tris(2-aminethyl)amine (tren) (Matsumoto et al., Chem. Commun. 2001, 978-979; Matsumoto et al., Inorg. Chem., 2001, 40: 190-191; Matsumoto et al., Inorg. Chem. 2004, 43: 8538-8546; Ng et al., Inorg. Chem. 1989, 28: 2062-2066), tris(3-aminopropyl)amine (Matsumoto et al., Eur. J. Inorg. Chem. 2001, 2481-2484); or nitrilotriacetic acid (nta) (Lee et al, J. Med. Chem. 1985, 28: 317-323; Hara et al., Inorg. Chem. 2000, 39: 5074-5082). These studies teach that such ligands form Fe3+ with binding constants in the range of 1028 to 1033, so long as there are five or six atoms connecting the bridgehead atom of the platform and the first atom of the hydroxamate functional group on the sidearm (Matsumoto et al., Eur. J. Inorg. Chem. 2001, 2481-2484; Matsumoto et al., Inorg. Chem. 2001, 40: 190-191; Ng et al., Inorg. Chem. 1989, 28: 2062-2066). These ligands include amide functional groups in the sidearms, and the iron complexes appear to be stabilized by intramolecular hydrogen bonding between the amide functional groups (Matsumoto et al., Inorg. Chem. 2001, 40:190-191).
The common feature of all the above ligands is that the bridgehead atom is a tertiary nitrogen. To attach these ligands to a solid support via this nitrogen would require the formation of a quaternary ammonium group. This is expected to have an adverse effect on the chelating ability of the ligand. It will introduce a permanent positive charge on the ligand, resulting in electrostatic repulsion of the target metal ion. In some cases, it will also require a change in the conformation of the metal complex.
A few tripodal tris(hydroxamate) ligands have been prepared in which the bridgehead atom is a carbon, rather than a nitrogen. These ligands are built on tripodal bases of either 1,1,1-tris(hydroxymethyl)ethane (Motekaitis et al., Inorg. Chem. 1991, 30: 1554-1556) or 1,1,1-tris(hydroxymethyl)propane (Dayan et al., Inorg. Chem. 1993, 32: 1467-1475). Hydroxamate groups were added to these tripodal bases through ether linkages. These studies teach that one needs 4 or 5 atoms between the bridgehead carbon and the first atom of the hydroxamate functional group for strong metal binding. The Fe3+ of these ligands have binding constants of 1026 to 1028. However, it is not possible to link these ligands to a polymeric support through the quaternary carbon bridgehead atom.
The current invention is based in the use of hydroxyalkylaminomethanes, especially the common buffer tris(1,1,1-tris(hydroxymethyl)aminomethane), as the tripodal base. The use of hydroxylalkylaminomethanes allows us to construct tripodal chelating functional groups that will mimic the high metal binding affinities of the ligands already in the literature, but it also provides a free amine group that can be used to easily attach the ligands to a variety of solid support.

Removing aluminum from solution using chelating compounds and immobilized tethered chelators

University of Kentucky Research Foundation