Improved performance of counter-rotating turbo machines and compressors. An increase in the thermodynamic efficiency of the compression process is obtained by removing the boundary layer in locations where separation is likely to occur.

1. Field of the Invention
The invention relates to the field of turbomachines and compressors. More particularly, the invention relates to improving the pressure ratio obtainable by a turbomachine or compressor having a given blade speed and number of stages of compression and to increasing the thermodynamic efficiency of the turbomachine or compressor.
2. Prior Art
Thought about fluid dynamics and invention pertaining thereto has existed for a substantial period of time. So too has man's interest in creating power persevered. One of the arts in which substantial and powerful thought has been devoted to is that of compressors and turbomachines. One of the most important areas driving such research is aeronautics and astronautics for both the commercial interests of high speed transportation and military interests for defense and the exploration of space. Some important issues with respect to the advance of compressors and turbomachines is the pressure ratio attainable and the efficiency of the machines.
Reissue U.S. Pat. No. 23,108 to E. A. Stalker discloses the provision of slots located well rearward on the blade to increase the effectiveness of the blade. This is taught in order to control the boundary layer on the blades of blowers and compressors to better enable the machine to run at lower than optimal speeds.
J. R. Irwin, U.S. Pat. No. 2,720,356 imposes continuous boundary layer control for compressors by moving the boundary layer through porous surfaces. The teaching recommends to then reintroduce the viscous interactive flow to the main flow of the compressor at a later stage.
U.S. Pat. No. 2,749,025 to Stalker focuses primarily on providing blades of later stages in a compressor with progressively larger radii rounded leading edges. This reduces losses associated with the flow angle into these blades which would normally be experienced at below optimum speeds. The substantially semi-circular nose cross-section is professed to be able to smooth the flow and avoid burbling when the approach vectors are far from optimum. A further step to assist the machine in these conditions is to remove the boundary layer in this area.
U.S. Pat. No. 3,694,102 to Conrad teaches use of suction slots in stator blades to prevent separation of the boundary layer in supersonic blading. Conrad, however, fails to recognize the benefit of removing the boundary layer permanently from a compressor. This is evidenced by equating bleeding of the boundary layer to atmosphere to reintroducing the boundary layer into the compressor at another stage.
U.S. Pat. No. 3,993,414 to Meauze discloses an axial supersonic compressor comprising a casing and a hub rotating in the casing and carrying blades. On each of the suction surfaces of the blades is formed a zone in which the curvative changes and which corresponds to a supersonic subsonic shock wave. A channel formed in each blade and opening in the zone is connected to a boundary layer aspiration means.
U.S. Pat No. 3,897,168 to Amos and U.S. Pat No. 4,595,339 to Naudet both disclose the recapture of energy from a withdrawn boundary layer to avoid losses.
U.S. Pat No. 3,385,509 to Garnier discloses an engine with counter-rotating compressor blades and counter-rotating turbine blades. Nozzle flow area of the turbines is adjusted to control the boundary layer by either moving the stators or by blowing through slots in their surfaces. Gamier is silent however on removing the boundary layer from the flow permanently.
None of the prior art discussed provides insight to the thermodynamic benefits of fluid removal from the flow path. In fact, many of skill in the prior art believed that reintroducing the fluid of the viscous interaction to the flow path at another compressor stage was beneficial to the functioning of the machine.
It is well known in the prior art to construct compressors and turbomachines having counter-rotating blades. However, counter-rotating machines have never been as useful as they should be in view of the better compression attainable with counter-rotating blades as opposed to alternating rotating and stator blades because of mechanical factors which limited the total attainable pressure to levels not commercially viable. Unfortunately, mechanical arrangements do not exist to enable the use of more than two counter-rotating blade rows, all with high blade speeds. Prior conceptions of counter-rotating compressors have had one set of rotating blades mounted on a rotating casing, rather than a hub. This limits their blade speed. Therefore, the machines have been disappointing. Providing a means to make these machines function better would be an important advance to the industry primarily because they are less expensive to manufacture and weigh less than conventional machines.

Counter-rotating compressors with control of boundary layers by fluid removal


Electrically conductive films comprising a flexible support, an extensible metal or metal alloy layer, and a crosslinked polymeric protective layer have at least one permanently deformed curved region. The films can be light transmissive and can have regions of compound curvature, and the metal or metal alloy layer can be substantially continuous. The films have reduced susceptibility to fracture or corrosion compared to commercially available electromagnetic interference (EMI) shielding films.

EMI shielding films block the transmission of unwanted electromagnetic energy into or out of electronic equipment. A variety of conductive materials can be used for this purpose. For applications in which it is necessary to see through the shielding (e.g., to view a display), windows containing fine wire mesh and specialized transparent films have been used. Transparent EMI shields are also described in U.S. Pat. Nos. 4,910,090 and 5,489,489 and in European Patent Application No. EP 810452. Commercially available transparent EMI shielding films typically employ a polymer substrate such as PET coated with a conductive oxide film (e.g., indium tin oxide) or with alternating coated layers of metal (e.g., silver) and conductive oxide. Representative commercially available transparent EMI shielding films include AgHT™-4 and AgHT™-8 films (CP Films, Inc.), ALTAIR™ M and XIR™ transparent conductive film (Southwall Technologies) and WIN-SHIELD™ AgF8 film (Chomerics Division of Parker Hannifin Corporation).
Current commercially available EMI shielding films lack adequate durability, contamination resistance or corrosion resistance. For example, the handling guidelines for film-based shields supplied by CP Films, Inc. recommend that workers wear non-dusted latex gloves and face masks when handling shielding films; caution that the conductive film coating is susceptible to attack by inorganic ions such as sodium, potassium and chloride, all of which are present on human fingers and in saliva; and recommend that if the film does become contaminated, its surface should be cleaned with a non-linting clean room wipe dampened in isopropyl alcohol. These handling guidelines also caution against excess rubbing when wiping the coating, since it is very thin and somewhat fragile.


An electrically actuated weapon system is provided, which may be mounted in a robotic vehicle or device, and controlled remotely by a user. In particular, the electrically actuated weapon system is composed of an electrically actuated weapon, a weapon control means connected thereto, and a controller means remotely located therefrom. The controller means is in wireless communication with the weapon control means, which is operable to control three linear actuators which cycle the weapon. These linear actuator means are controlled electronically, based on communications received from the controller means. Accordingly, if the weapon is stolen, lost, or captured by an enemy combatant during combat, the weapon will cease to be functional. Further, the weapon can be reliably operated from remote locations, as the cycling of the weapon is not dependent upon recoil forces.

Automatic guns can be generally classified, according to their mode of operation, as either self-powered or externally powered. Self-powered automatic guns utilize recoil or high pressure barrel gasses caused by firing to cycle operating mechanisms which load and fire the gun. In particular, a mechanically actuated firing pin strikes a primer cap at the rear of the weapon cartridge, to thereby ignite the propellant for the projectile. The bolt is driven rearward by the propellant gases shortly after the firearm is fired. This action, i.e., "cycling" of the weapon, pulls the spent cartridge from the chamber and ejects the empty shell. Once the bolt reaches the end of travel, the bolt suddenly stops. A spring then provides forward bias to drive the bolt forward and pushes a new cartridge in the chamber.
Self-powered automatic guns are inherently more portable or mobile than externally-powered guns, in which operating mechanisms of externally-powered guns are driven by actuators or motors independently of firing forces, are, therefore, usually preferred for small arms, machine guns and light cannons. However, for larger cannons, external powered actuators are sometimes needed to operate the weapon systems, including loading, cycling, and gun aiming movement. Since such larger guns are difficult to implement as self-powered guns, because of shell size, weight and size of moving operational gun parts, larger guns have typically been constructed to be contrast.
However, automation of guns in general, and large guns in particular, such as those used in tanks and armored vehicles in particular, has heretofore usually been limited to the automation of a single operational function. For example, an actuator has been used for opening and closing the breech, or loading shells into an open breech. A human operator has ordinarily functioned to operationally bridge the separately automated functions. Firing rates of such guns, in which an operator performs the key role as system integrator, have thus been limited by the operator's skill and ability in perceiving the operational status of the automated gun hardware and in deciding when the operating commands should be given to initiate each successive automated operation.
Many problems encountered in mechanizing (automating) large guns are attributable to the fact that the guns were not originally designed for automatic operation. Thus, design of such guns has principally involved adaptations of pre-existing, manually operated guns. As a consequence, their automation has usually consisted of little more than the retrofitting of existing gun hardware. Although some limited success has been achieved through such retrofitting, the resulting gun systems have, at best, been awkward and non-optimal in terms of gun operating speeds and firing rates, and also in terms of system cost and reliability.
Moreover, control systems for previously automated large caliber guns have controlled only a few sequential steps, and have been implemented by simple and/or logic elements, flip-flop circuits typically being used to control actuating motors, or solenoids. Further, the progression from one separately automated step to another has heretofore been sequenced by pre-set timers, so that gun operation proceeds in accordance with a fixed time schedule. Reliance upon such timing schedules, however, can cause serious problems because operating times may, in fact, vary widely in the same gun according to conditions. For example, the time required to advance shells to the gun typically varies according to the number, and hence the mass, of shells which must be advanced.
Operating times also depend upon such factors as how clean or how well lubricated the gun is, the extent of gun wear and the operating temperatures. If the gun design does not take such time-affecting variables into consideration, one operating step may be initiated before a preceding step is completed, with potentially disastrous consequences. A particular event which is difficult to provide for in a fixed timing schedule is shell firing time. Typically shells fire within a few milliseconds after firing impact or, as the case may be, electrical contacting. Propellant combustion ordinarily occurs within the next few milliseconds and casing pressure is typically reduced to a safe casing extraction level in several more milliseconds. Thus, only about 10 to 20 milliseconds of firing "dwell time" is ordinarily required.
However, in system use, a few shells, presumably due to manufacturing defects, do not fire as expected. Instead, there is a brief delay after impact or electrical contact before ignition occurs. This phenomenon is commonly referred to as a "hang fire" condition. If a hang fire causes a shell to fire after a timed casing extraction has begun, the gun may be destroyed and operating personnel may be injured. On the other hand, if worst case hang fires are considered in establishing the gun operating time schedule, gun performance will be compromised. If the timing schedule also takes into account all other possible worst case conditions affecting gun operating times, the firing rate will be drastically reduced over that possible under most operating conditions. As a result, the automatic operation of a gun on a fixed timing schedule is generally unsatisfactory.
Further, currently, robotic devices have begun to be commonly used in police and military applications. Systems for mounting firearms on such robotic devices have been recently developed. These systems for mounting firearms on robotic devices are designed, however, to utilize conventional gas-powered (self-powered) weapons. In particular, the weapon, such as a conventional shotgun or an M-4, is removably mounted in the system, wherein the system allows a user to wirelessly control mechanical mechanisms to release the weapon safety switch and pull the trigger.
However, such conventional systems for mounting firearms on robotic devices have several drawbacks. First, an enemy can disable the robotic device, remove the firearm from the mounting system, and utilize the firearm against the controller of the robotic device and/or friendly forces. Second, as discussed above, self-powered weapons tend to periodically jam, and require human interaction to clear the jam when same occurs, placing the operator in a potentially fatal situation. Third, by requiring placement of a conventional weapon in the mounting system, a soldier usually must place his weapon into the mounting system of the robotic device during operation thereof, which personally places the operator in a vulnerable position during operation of the robotic device.
It is, therefore, an object of the present invention to provide an externally-powered, electrically actuated weapon, in which all firing operations of the weapon can be remotely externally operated.
It is another object of the present invention is to provide an externally-powered, electrically actuated weapon which, if removed from the device upon which the weapon is mounted, such as a robotic device, is inoperable.
A further object of the present invention is to provide an externally-powered electrically actuated weapon which operates on a strict logic basis, rather than on a fixed timing schedule, which stops operating if pre-established logic conditions are not met, and which provides status and malfunction information to the gun operator.
Another object of the present invention is to provide an externally-powered, electrically actuated weapon in which initiation of each operational step is conditioned on specific moving parts of the gun being in specific positions.

The United States of America as represented by the Secretary of the Army


The present invention provides methods for determining a level of methotrexate polyglutamates (MTXPGs) in an individual undergoing methotrexate (MTX) therapy and for optimizing dose efficacy of MTX therapy in an individual by genotyping the individual at a polymorphic site in at least one folate pathway gene (e.g., a reduced folate carrier (RFC-1) gene, a gamma glutamyl hydrolase (GGH) gene, etc.). Methods are also provided for determining a level of MTXPGs in an individual undergoing MTX therapy and for optimizing dose efficacy of MTX therapy in an individual by generating a pharmacogenetic index based upon the genotype of the individual at a polymorphic site in an RFC-1 gene and/or a GGH gene.

Folate (folic acid) is a vitamin that is essential for the life-sustaining processes of DNA synthesis, replication, and repair. Folate is also important for protein biosynthesis, another process that is central to cell viability. The pteridine compound, methotrexate (MTX), is structurally similar to folate and as a result can bind to the active sites of a number of enzymes that normally use folate as a coenzyme for biosynthesis of purine and pyrimidine nucleotide precursors of DNA and for interconversion of amino acids during protein biosynthesis. Despite its structural similarity to folic acid, methotrexate cannot be used as a cofactor by enzymes that require folate, and instead competes with the folate cofactor for enzyme binding sites, thereby inhibiting protein and DNA biosynthesis and, hence, cell division.
The ability of the folate antagonist methotrexate to inhibit cell division has been exploited in the treatment of a number of diseases and conditions that are characterized by rapid or aberrant cell growth. For example, methotrexate is currently one of the most widely prescribed drugs for the treatment of rheumatoid arthritis, psoriasis, and cancer (Weinblatt et al., Eng. J. Med., 312:818-822 (1985); Kremer and Lee, Arthritis Rheum., 29:822-831 (1986)). Although methotrexate is among the best tolerated of the disease-modifying anti-rheumatic drugs, a major drawback of methotrexate therapy is a troublesome inter-patient variability in the clinical response and an unpredictable appearance of side-effects including gastrointestinal disturbances, alopecia, elevation of liver enzymes, and bone marrow suppression (Weinblatt et al., Arthritis Rheum., 37:1492-1498 (1994); Walker et al., Arthritis Rheum., 36:329-335 (1993)). Several studies in well-controlled clinical trials have demonstrated that methotrexate is effective at decreasing functional disability, with the maximum effect occurring after about six months of therapy. However, recent findings from retrospective studies on a large cohort of patients with rheumatoid arthritis have suggested that methotrexate dosage may be suboptimal in some patients (Ortendahl et al., J. Rheumatol., 29:2084-2091 (2002)). Thus, the lack of efficient therapeutic drug monitoring of methotrexate therapy and difficulty of rapidly individualizing methotrexate dose-maximizing response hampers effective patient treatment.
Methotrexate enters cells through the reduced folate carrier (RFC-1) and is intracellularly activated by folylpolyglutamate synthase to methotrexate polyglutamates (MTXPGs) (Chabner et al., J. Clin. Invest., 76:907-912 (1985)). The γ-linked sequential addition of glutamic acid residues enhances intracellular retention of methotrexate (Allegra et al., Proc. Natl. Acad. Sci. USA, 82:4881-4885 (1985)). The polyglutamation process is in competition with deconjugation by gamma glutamyl hydrolase (GGH) (Rhee et al., Mol. Pharmacol., 53:1040-1046 (1998); Yao et al., Proc. Natl. Acad. Sci. USA, 93:10134-10138 (1996); Panetta et al., Clin. Cancer Res., 8:2423-2429 (2002)), a lysosomal enzyme having high affinity towards long chain polyglutamates. (Masson et al., J. Clin. Invest., 97:73-80 (1996)).
The accumulation of MTXPGs is critical to the pharmacological effects of methotrexate. In vivo, the concentration of MTXPGs in lymphoblasts and erythrocytes appear to correlate with the therapeutic response to methotrexate in patients with leukemia (Dervieux et al., Blood, 100:1240-1247 (2002); Dervieux et al., Arthritis Rheum., in press, (2004)) or rheumatoid arthritis (Angelis-Stoforidis et al., Clin. Exp. Rheumatol., 17:313-320 (1999); Allegra et al., Proc. Natl. Acad. Sci. USA, 82:4881-4885 (1985)). Polyglutamation of methotrexate is thought to promote the sustained inhibition of de novo purine synthesis by 5-aminoimidazole carboxamide-ribonucleotide transformylase (ATIC) (Dervieux et al., Blood, 100:1240-1247 (2002); Allegra et al., supra, (1985)), thereby promoting the build-up of adenosine, a potent anti-inflammatory agent (Baggott et al., Biochem. J., 236:193-200 (1986); Morabito et al., J. Clin. Invest., 101:295-300 (1998); Montesinos et al., Arthritis, 48:240-247 (2003); Cronstein et al., J. Clin. Invest., 92:2675-2682 (1993)). Furthermore, MTXPGs are inhibitors of thymidylate synthase (TS) (Allegra et al., J. Biol. Chem., 260:9720-9726 (1985)). TS methylates deoxyuridine monophosphate to produce deoxythymidylate, providing a unique de novo source of thymidylate.
Part of the large inter-individual variability in the response to methotrexate is related to common polymorphisms in genes implicated in methotrexate pharmacokinetics or pharmacodynamics (Relling and Dervieux, Nat. Rev. Cancer, 1:99-108 (2001)). Recently, a G to A transition in exon 1 (position 80) of RFC-1, resulting in an arginine to histidine substitution at codon 27, was identified (Chango et al., Mol. Genet. Metab., 70:310-315 (2000)). However, the functional consequence of this polymorphism on methotrexate transport has remained unclear (Whetstine et al., Clin. Cancer Res., 7:3416-3422 (2001); Laverdiere et al., Blood, 100:3832-3834 (2002)). Moreover, a recent study of children with acute lymphoblastic leukemia has suggested that the A variant may be associated with poor clinical outcomes as compared with patients having the G/G genotype; individuals carrying the A/A genotype presented higher plasma concentrations of methotrexate compared to those with the G/G or G/A genotypes (Laverdiere et al., supra, (2002)).
Because individual differences in pharmacokinetic and pharmacodynamic parameters can be difficult to predict and because patient genotype affects these parameters, methotrexate treatment can be rendered safer and more effective through patient genotyping. Thus, there exists a need for novel correlations between patient genotypes and efficacy of methotrexate therapy. There also exists a need for new methods of determining or optimizing the efficacy of methotrexate therapy by determining MTXPG levels in a patient through genotyping. The present invention satisfies these needs and provides related advantages as well.

Methods for predicting methotrexate polyglutamate levels using pharmacogenetics


A fuel cell includes a membrane electrode assembly and first and second metal separators sandwiching the membrane electrode assembly. A first cell voltage terminal for detecting a voltage generated in the membrane electrode assembly is formed integrally with an outer region of the first metal separator. The first cell voltage terminal extends outwardly from the first metal separator. A first seal member covers the outer region of the first metal separator, and includes a first extension seal which covers the first cell voltage terminal to a position near a tip end of the first cell voltage terminal.

1. Field of the Invention
The present invention relates to a fuel cell including a membrane electrode assembly and separators sandwiching the membrane electrode assembly. The membrane electrode assembly includes a pair of electrodes and an electrolyte membrane interposed between the electrodes.
2. Description of the Related Art
For example, a solid polymer fuel cell employs a polymer ion exchange membrane as a solid polymer electrolyte membrane. The solid polymer electrolyte membrane is interposed between an anode and a cathode to form a membrane electrode assembly. Each of the anode and the cathode is made of electrode catalyst and porous carbon. The membrane electrode assembly is sandwiched between separators (bipolar plates) to form the fuel cell.
In the fuel cell, a fuel gas such as a gas chiefly containing hydrogen (hereinafter also referred to as the hydrogen-containing gas) is supplied to the anode. The air or the like (hereinafter also referred to as the oxygen-containing gas) is supplied to the cathode. The catalyst of the anode induces a chemical reaction of the fuel gas to split the hydrogen molecule into hydrogen ions and electrons. The hydrogen ions move toward the cathode through the electrolyte membrane, and the electrons flow through an external circuit to the cathode, creating a DC electrical energy.
In operation of the fuel cell, typically, a voltage detection device is used to detect a cell voltage at the time of power generation for detecting whether the desired power generation performance is achieved or not. In relation to this operation, Japanese Laid-Open Patent Publication No. 11-339828 discloses a fuel cell stack equipped with a cell voltage measuring terminal.
According to the disclosure of Japanese Laid-Open Patent Publication No. 11-339828, the fuel cell stack includes a metal separator 1 as shown in FIG. 6. The separator 1 has an air supply passage 2a, a cooling water passage 3, a hydrogen supply passage 4a, an air discharge passage 2b, and a hydrogen discharge passage 4b. For example, a pin shaped voltage measuring terminal 6 is welded to one end surface 5 of the separator 1 by projection welding.
However, in the fuel cell stack of Japanese Laid-Open Patent Publication No. 11-339828, the pin shaped voltage measuring terminal 6 protrudes from the end surface 5 of the separator 1. Therefore, at the time of assembling the fuel cell or the fuel cell stack, the voltage measuring terminal 6 is deformed easily. Thus, the quality of the separator 1 lowered, and the number of processes required for the assembling operation is large. In particular, when the separator 1 is thin, the diameter of the voltage measuring terminal 6 is significantly small. The voltage measuring terminal 6 is deformed easily, and may be damaged (broken) undesirably.


The present invention concerns an antibody which specifically binds to an abnormal superoxide dismutase 1 (SOD1), and which neutralizes its pathologic effect when administered to an animal such as a human. The antibody of the invention is a monoclonal antibody produced by hybridoma cell lines deposited with the International Depositary Authority of Canada on Aug. 29, 2006 under accession numbers ADI-290806-01, ADI-290806-02 and ADS-290806-03. The present invention also concerns the use of the antibody of the invention in the treatment, prevention and diagnosis of neurodegenerative diseases such as Amyotrophic lateral sclerosis, Parkinson and Alzheimer in an animal such as a human.

A neurodegenerative disease is a disorder caused by the deterioration of certain nerve cells. Changes in these cells cause them to function abnormally, eventually bringing about their death.
Neurodegenerative diseases include familial and sporadic amyotrophic lateral sclerosis (FALS and ALS, respectively), familial and sporadic Parkinson's disease, Huntington's disease, familial and sporadic Alzheimer's disease, olivopontocerebellar atrophy, multiple system atrophy, progressive supranuclear palsy, diffuse lewy body disease, corticodentatonigral degeneration, progressive familial myoclonic epilepsy, strionigral degeneration, torsion dystonia, familial tremor, Gilles de la Tourette syndrome, and Hallervorden-Spatz disease. Most of the diseases are typified by onset during the middle adult years and lead to rapid degeneration of specific subsets of neurons within the neural system, ultimately resulting in premature death. There is no known cure nor is there an effective therapy to slow the progression for any of the stated diseases.
Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease characterized by progressive muscle weakness during adulthood. Pathological hallmarks are represented by the massive loss of motor neurons together with astrocytosis and microgliosis in the motor cortex, brainstem and spinal cord. Generally, the onset is between the third and sixth decade, typically in the sixth decade. ALS is uniformly fatal, typically within five years. ALS may only be diagnosed when the patient begins to experience asymmetric limb weakness and fatigue, localized fasciculation in the upper limbs and/or spasticity in the legs which typifies onset.
In ALS, the neurons of the cerebral cortex and anterior horns of the spinal cord, together with their homologues in some of the motor nuclei of the brain stem, are affected. The class of neurons affected is highly specific; motor neurons for ocular motility and sphincteric motor neurons of the spinal cord remain unaffected until very late in the disease. Although death occasionally results shortly after the onset of the symptomatic disease, the disease generally ends with respiratory failure secondary to profound generalized and diaphragmatic weakness.
Approximately 10% of ALS cases are family related, the remainder ALS cases being diagnosed as sporadic (90%). The discovery a decade ago by Rosen et al. (1993, Nature, 362, 59-62) of missense mutations in the gene coding for the Cu/Zn superoxide dismutase 1 (SOD1) in subsets of familial cases directed most ALS research to elucidating the mechanism of SOD1-mediated disease. To date, 114 different mutations have been discovered in the SOD1 gene that account for ˜20% of familial ALS cases.
The enzyme superoxide dismutase (SOD), catalyzes the dismutation of superoxide into oxygen and hydrogen peroxide. As such, it is an important antioxidant defense in nearly all cells exposed to oxygen. SOD is widely distributed in a living body of animals, plants or microorganisms. More specifically SOD1 is an abundant and ubiquitously expressed protein. Because of its normal function in catalyzing the conversion of superoxide anions to hydrogen peroxide, it was first thought that the toxicity of different SOD1 mutants could result from decreased free-radicals scavenging activity. However, different SOD1 mutants showed a remarkable degree of variation with respect to enzymatic activity. Mice expressing mutants SOD1 G93A (glycine substituted to alanine at position 93) or SOD1 G37R developed motor neuron disease despite elevation in SOD1 activity levels (Cleveland et al., 2001, Nat Rev Neurosc, 2, 806-819). Moreover, SOD1 knockout mice did not develop motor neuron disease (Reaume et al., 1996, Nat Genet, 13, 43-47). Gene disruption for the copper chaperone for SOD1 (CCS) that delivers copper to SOD1 catalytic site had no effect on disease progression in mutant SOD1 transgenic mice (Subramanian et al., 2002, Nat Neurosci, 5, 301-307). Finally, transgenic mice overexpressing a mutant form of SOD1 lacking two of the four histidine residues coordinating the binding of the Cu at the catalytic site still developed motor neurodegeneration despite a marked reduction in SOD1 activity (Wang et al., 2002, Neurobiol Dis, 10, 128-138). Overall, these studies with genetically altered mice indicate that SOD1 mutants cause motor neuron disease through the gain of new toxic properties that is independent of the enzymatic activity involving the copper catalytic site.
The most prevailing view is that the toxicity of SOD1 mutants is related to the propensity of mutant SOD1 to form noxious misfolded protein species and aggregates. Moreover, unlike wild type (WT) SOD1, extracellular mutant SOD1 proteins activate microglia and induce motor neuron death in culture (Urushitani et al., 2006, Nat Neurosci, 9, 108-118), a pathogenic pathway that would be in line with the notion that motor neuron death in mutant SOD1-linked ALS is not strictly cell-autonomous (Boillee et al., 2006, Science, 312, 1389-1392). Interestingly, the oxidation of WT SOD1 is a phenomenon that may promote its aggregation (Furukawa, et al., 2006, PNAS USA, 103, 7148-7153). Considering evidence of oxidative damage in sporadic ALS patients (Ihara et al., 2005, Neurol Res, 27, 105-108) and the abundance of SOD1 protein in cells, it seems plausible that SOD1 molecules might constitute targets of oxidative damage in sporadic ALS.
Since the discovery of genetic mutations in superoxide dismutase 1 (SOD1) in 20% of familial ALS patients and the development of excellent mouse models based on overexpression of ALS-linked SOD1 mutants, many pathogenic pathways to motor neuron death have been elucidated including protein misfolding and aggregation, proteasome impairment, inflammation, reactive oxygen species, excitotoxicity and mitochondrial dysfunction. Based on these hypotheses, multiple approaches for treatment have been tested in the ALS mice including pharmacological approaches and virus-mediated delivery of molecules.
U.S. Pat. No. 5,762,929 reports a pharmaceutical agent that may alleviate symptoms of motor neurons diseases such as amyotrophic lateral sclerosis by oral or parenteral administration. U.S. Pat. No. 5,780,489 reports a method for treating and alleviating the symptoms of amyotrophic lateral sclerosis by administering to a patient an effective amount of a non-cysteine glutathione precursor or a glutathione derivative. U.S. Pat. No. 6,420,429 reports the use of antioxidants for the treatment of diseases such as amyotrophic lateral sclerosis. U.S. Pat. No. 5,843,641; U.S. Pat. No. 5,849,290 and U.S. Pat. No. 6,723,893 report the use of an effective amount of SOD protein or DNA encoding an SOD protein to treat neurodegenerative diseases, specifically amyotrophic lateral sclerosis (ALS). They also report a method of diagnosis of amyotrophic lateral sclerosis using the DNA encoding an SOD protein or a fragment thereof in a PCR reaction.
Although it is well known that SOD1 is a cytosolic protein without specific translocation sequence, there is emerging evidence that both normal and mutant SOD1 can be secreted through secretory pathways (Urushitani, et al., 2006, Nature Neurosci, 9, 108-118). Furthermore, Urushitani, et al. (2006) discovered that extracellular SOD1 mutant can trigger microgliosis and death of motor neurons in culture suggesting a pathogenic mechanism based on toxicity of secreted SOD1 mutant proteins.
There is thus need for new agents, such as monoclonal antibodies which are efficient for the treatment, prevention and/or diagnosis of diseases associated with SOD1 abnormalities.

Antibodies and their use in the treatment, prevention and diagnosis of a disease associated with SOD1 abnormalities


A method for making an indole compound includes transition metal-catalyzed arylation of a hydrazone to form an aryl hydrazone, hydrolysis of the aryl hydrazone to form an aryl hydrazine, and acid catalyzed cyclization of the aryl hydrazine to form the indole compound.

This invention relates to methods for making aryl hydrazines and substituted indoles, which are useful intermediates and end products in pharmaceutical and agricultural applications.
Certain 3,5-disubstituted indole compounds have been found to be selective agonists which act on 5-hydroxytryptamine receptors and to be useful in the treatment of migrane and other medical conditions, see U.S. Pat. No. 5,607,960.
Syntheses of such indole compounds have typically been based on the approach of functionalizing an existing indole nucleus, necessitating a large number of processing steps and reduced theoretical efficiency for the sequence of steps, see for example, U.S. Pat. No. 5,998,438, which discloses synthesis of 5-(1-Aza-1-methylcyclohex-3-en-4-yl)-3-[2-(N,N-dimethylamino)ethyl]-1-H-indole. The route desclosed in the ""438 patent also requires use of a toxic reagent, that is, 4-tributylstannyl-1-aza-1-tertbutoxycarbonylcyclohex-3-ene, and the use of a hazardous reagent, LAH.
There is an interest in development of a simplified synthetic route to such indole compounds.
In a first aspect, the present invention is directed to a method for making an aryl hydrazine, comprising:
(a) reacting a substrate aromatic compound, said substrate aromatic compound bearing an activated carbon atom, and a hydrazone in the presence of a transition metal catalyst under conditions suitable to form an aryl hydrazone having a new carbon-nitrogen bond between the activated carbon of the substrate aromatic compound and a nitrogen atom of the hydrazone, and
(b) hydrolyzing the aryl hydrazone to form the aryl hydrazine.
The method of the present invention for making an aryl hydrazine provides a simple, two step linear synthesis of substituted aryl hydrazine compounds and does not require the use of toxic or hazardous reagents.
In a second aspect, the present invention is directed to a method for making an indole compound, comprising:
(a) reacting a substrate aromatic compound, said substrate aromatic compound bearing an activated carbon atom, and a hydrazone in the presence of a transition metal catalyst under conditions suitable to form an aryl hydrazone having a new carbon-nitrogen bond between the activated carbon of the substrate aromatic compound and a nitrogen atom of the hydrazone,
(b) hydrolyzing the aryl hydrazone to form an aryl hydrazine, and
(c) cyclizing the aryl hydrazine in the presence of an aldehyde or ketone and acid catalyst to form the substituted indole compound.
The method of the present invention for making an indole compound provides a simple, three step linear synthesis of substituted indole compounds and does not require the use of toxic or hazardous reagents.
In a preferred embodiment, a substrate aromatic compound and a hydrazone are coupled to form a hydrazone according to reaction scheme 1:
wherein:
Ar is aryl and may, optionally, be further substituted beyond X,
X is a leaving group that is capable of being replaced by a nucleophilic nitrogen in a transition metal-catalyzed arylation reaction, and
R1 is H, substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted alkynyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl, and
each R2 is independently H, substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted alkynyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl, or, alternatively, the R2 groups are fused to form, together within the carbon atom to which they are each attached, a substituted or unsubstituted monocyclic cycloalkyl, cycloalkenyl, aryl or heterocyclyl ring.
As used herein, the term xe2x80x9csubstitutedxe2x80x9d denotes the conceptual replacement of a hydrogen atom of a given organic moiety with a substituent group other than a hydrogen atom and includes all permissible substituent groups, including acyclic hydrocarbon groups, alicyclic hydrocarbon groups, monocyclic aromatic hydrocarbon groups, polycyclic aromatic hydrocarbon groups, heteroacyclic groups, heterocyclic groups, fused ring systems and bridged ring systems, of which the substituents specifically described below are illustrative examples.
As used herein the term xe2x80x9cheteroatomxe2x80x9d means an element other than carbon, such as for example, oxygen, nitrogen and sulfur.
xe2x80x9cAlkylxe2x80x9d refers to a linear, branched or cyclic saturated hydrocarbon group, preferably a (C1-C30) linear, branched or cyclic saturated hydrocarbon group that may, optionally, contain one or more heteroatoms, such as, for example, methyl, ethyl, propyl, n-butyl, isobutyl, t-butyl, neopentyl, cyclopentyl, hexyl, cyclohexyl, decyl, stearyl, eicosyl, methoxy, triacontyl, 2,5,7-trioxanonanyl, 2,5,8-triazadecenyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, alkyl, alkenyl, alkynyl, aryl, heterocyclyl, halo, hydroxy, sulfhydryl, hydroperoxy, carbonyl-containing groups (including, for example, carboxy, ketone, ester and aldehyde groups), alkyloxy, alkyldioxy, amino, amido, imino, hydrazino, nitro, cyanato, thiocyanato, mercapto, thiocarbonyl-containing groups (including, for example, thioketone groups, thioester groups and thioaldehyde groups), sulfonyl-containing groups (including, for example, sulfate, sulfonate and sulfamoyl groups), silyl, siloxy and phosphoruscontaining substituent groups (including, for example, phosphoranyl, phosphinyl, phosphinothioyl, phosphinimyl). Such substituent groups may themselves be further substituted with, for example, any of the groups described above as suitable substituents for alkyl groups, to form compound substituent groups, such as, for example, aralkyl, aminoalkyl, haloalkyl, heterocyclylalkyl.
xe2x80x9cAlkenylxe2x80x9d refers to a linear, branched or cyclic hydrocarbon group, preferably a (C2-C20) linear, branched or cyclic hydrocarbon group, that contains one or more carbon-carbon double bonds per group and that may, optionally, contain one or more heteroatoms, such as, for example, ethenyl, propenyl, allyl, isopropenyl, ethenylidenyl, cyclopentyl, cyclohexadienyl, azanonenyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
xe2x80x9cAlkynylxe2x80x9d refers to a linear, branched or cyclic unsaturated hydrocarbon group, preferably a (C2-C20) unsaturated hydrocarbon group, that contains one or more carbon-carbon triple bonds per group and that may, optionally, contain one or more heteroatoms, such as, for example, ethynyl, propynyl, thianonynyl, and that may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
xe2x80x9cArylxe2x80x9d refers to an unsaturated hydrocarbon group that contains one or more six membered rings in each of which the unsaturation may be represented by three conjugated carbon-carbon double bonds, including monocyclic and polycyclic ring systems, such as, for example, phenyl, naphthyl, anthryl, phenanthryl, indenyl, fluorenyl, which may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
xe2x80x9cHeterocyclylxe2x80x9d refers to a saturated or unsaturated organic group that contains one or more rings in which one or more ring members is a heteroatom, preferably a nitrogen, sulfur or oxygen heteroatom, such as, for example, thiacyclopentadienyl, thiaindenyl, thianthrenyl, oxacyclopentadienyl, oxaindenyl, isobenzylfuranyl, pyranyl, azacyclopentadienyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolinyl, quinolinyl, isoquinolinyl, phthalazinyl, cinnolinyl, azafluorenyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenarsazinyl, isothiazolyl, isoxazolyl, phenoxazinyl, pyrrolidinyl, pyrimadinyl, imidazolidinyl, piperidinyl, piperizinyl, oxathiaanthracenyl, isoxazolyl, oxaazaanthracenyl, isothiazolyl, morpholinyl, and which may, optionally, be substituted at one or more positions with other moieties, such as, for example, any of the possible substituents described above in respect to alkyl groups.
As used herein, xe2x80x9chaloxe2x80x9d means fluoro, chloro, bromo or iodo, xe2x80x9chydroxyxe2x80x9d means xe2x80x94OH, xe2x80x9csulfhydrylxe2x80x9d means xe2x80x94SH, xe2x80x9chydroperoxyxe2x80x9d means xe2x80x94OOH, xe2x80x9ccarbonylxe2x80x9d means xe2x80x94C(O)xe2x80x94, xe2x80x9ccarboxyxe2x80x9d means xe2x80x94COOH, a ketone group is a group containing a carbonyl moiety that is attached to two carbon atoms, an ester group is a group containing a xe2x80x94C(O)OR moiety, an aldehyde group is a group containing a xe2x80x94CHO moiety, xe2x80x9calkyloxyxe2x80x9d means xe2x80x94ORxe2x80x2, xe2x80x9calkyldioxyxe2x80x9d means xe2x80x94OORxe2x80x2, xe2x80x9caminoxe2x80x9d is conceptually a derivative of NH3 in which one or more hydrogen atoms are replaced by nonacyl organic groups and includes primary, secondary and tertiary amines, xe2x80x9camidoxe2x80x9d includes, for example, xe2x80x94C(O)NRxe2x80x32, xe2x80x9ciminoxe2x80x9d means xe2x95x90NH, xe2x80x9chydrazinoxe2x80x9d includes, for example, xe2x80x94HNNRxe2x80x32, xe2x80x9cnitroxe2x80x9d is xe2x80x94NO2, xe2x80x9ccyanatoxe2x80x9d is xe2x80x94OCN, xe2x80x9cthiocyanatoxe2x80x9d is xe2x80x94SCN, xe2x80x9cmercaptoxe2x80x9d is xe2x80x94SH, xe2x80x9cthiocarbonylxe2x80x9d is xe2x80x94C(S)xe2x80x94, a xe2x80x9cthioketone groupxe2x80x9d is a group containing a thiocarbonyl moiety that is attached to two carbon atoms, a xe2x80x9cthioester groupxe2x80x9d is xe2x80x94C(S)OR, a xe2x80x9cthioaldehydexe2x80x9d group is a group containing a xe2x80x94CHS moiety, xe2x80x9csulfonylxe2x80x9d is xe2x80x94SO2xe2x80x94, xe2x80x9csulfatexe2x80x9d includes, for example, xe2x80x94OSO2ORxe2x80x3, xe2x80x9csulfonatexe2x80x9d includes, for example, xe2x80x94O2SORxe2x80x3, xe2x80x9csulfamoylxe2x80x9d includes, for example, xe2x80x94O2SNRxe2x80x32, xe2x80x9csilylxe2x80x9d is xe2x80x94SiRxe2x80x33, xe2x80x9csiloxyxe2x80x9d is xe2x80x94OSiRxe2x80x33, xe2x80x9cphosphinoxe2x80x9d includes xe2x80x94PRxe2x80x32, xe2x80x9cphosphoranylxe2x80x9d includes, for example, xe2x80x94PRxe2x80x34,xe2x80x9cphosphinylxe2x80x9d includes, for example, xe2x80x94P(O)Rxe2x80x32, xe2x80x9cphosphinothioylxe2x80x9d includes, for example, xe2x80x94P(S)Rxe2x80x32, xe2x80x9cphosphinimylxe2x80x9d includes, for example, xe2x80x94P(NH)Rxe2x80x32, xe2x80x9caralkylxe2x80x9d means an alkyl group substituted with an aryl group, such as, for example, benzyl, xe2x80x9caminoalkylxe2x80x9d means an alkyl group substituted with an amino group, such as, for example, dimethylaminoethyl, xe2x80x9chaloalkylxe2x80x9d means an alkyl group substituted with a halogen atom, such as, for example, chloromethyl, xe2x80x9cheterocyclylalkylxe2x80x9d means an alkyl group substituted with a heterocyclyl group, such as, for example, pyrrolidinylethyl, wherein, as used above in this paragraph, R is an organic group, Rxe2x80x2 is alkyl and Rxe2x80x3 is H, alkyl or aryl.
The substrate aromatic compound ArX contains an electrophilic atom bonded to leaving group X that is susceptible to the above cross-coupling reaction. As used herein, the term xe2x80x9cnucleophilicxe2x80x9d refers to a chemical moiety having a reactive pair of electrons and the term xe2x80x9celectrophilicxe2x80x9d refers to a chemical moiety that can accept a pair of electrons from a nucleophile.
In a preferred embodiment, Ar comprises a phenyl ring that is substituted on one or more carbons of the ring, wherein each such substituent group is independently selected from substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted alkynyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl.
In a more highly preferred embodiment, each of the substituent groups on the phenyl ring of the Ar moiety is independently selected from alkyl, alkenyl, sulfonyl-containing groups, acyclic groups that contain one or more nitrogen heteroatoms per group and heterocyclic groups that contain one 5- or 6-membered heterocyclic ring per group, wherein the heterocyclic ring contains one or two heteroatoms, each independently selected from nitrogen, oxygen and sulfur, per ring and wherein the heterocyclic group may, optionally, be substituted on one or more atoms of the heterocyclic ring. Suitable sulfonyl-containing groups include, for example, alkylsulfate, alkylsulfonate and alkylsulfamoyl. Suitable nitrogen-containing heteroacyclic groups include, for example, cyano, thiocyano, isocyano, alkylthiocyano, alkylcyano, and xe2x80x94(CH2)nxe2x80x94NR3R4, wherein n is a number from 0 to 6, and R3 and R4 are each independently H or (C1-C6)alkyl. Suitable nitroge-containing heterocyclic groups include, for example, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, each of which may be substituted or nonsubstituted. Suitable oxygen-containing groups include, for example, pyranyl, furanyl, oxacyclopentyl, oxacyclohexyl, each of which may be substituted or nonsubstituted. Suitable sulfur-containing heterocyclic groups include, for example, thiophenyl, thiacyclohexyl, each of which may be substituted or nonsubstituted. Suitable hereocyclic groups containing two different heteroatoms include, for example, isothiaolyl, isooxazolyl, furazanyl, morpholinyl.
In a more highly preferred embodiment, at least one of the carbon atoms of the phenyl ring of the Ar moiety is substituted with a group selected from (C1-C10)alkyl, cyclo(C4-C6)alkyl, (C2-C6)alkenyl, cyclo(C4-C10) alkenyl and 5- or 6-membered heterocyclic rings that contain one nitrogen heteroatom, each of which may connected to the carbon atom of the phenyl ring via an alkylene bridging group and each of which may be nonsubstituted or substituted, for example, with one or more groups selected from hydroxy, (C1-C6)alkyl (C1-C6)alkoxy and (C1-C6)alkoxycarbonyl.
In a preferred embodiment, X is a halo, sulfonate or phosphonate group, more preferably halo. Preferred sulfonate groups are those according to the general formula:
wherein R5 is alkyl, aryl, fluoroalkyl, preferably trifluoromethyl, perfluoroalkyl.
Preferred phosphonate groups are those according to the general formula:
wherein each R6 is independently alkyl or aryl.
The preferred halo group is chloro.
Suitable substrate aromatic compounds include, for example, 4-chloro-N-methylbenzenemethanesulfonamide, 1-bromo-3-cyclohexylbenzene, 4-(2,3-dihydropyran-2-yl)-1-trifluoromethanesulfonatobenzene,1-chloro-2-(2-pyridyl)benzene, 1-chloro-4-[2-(N,N-dimethylamino)ethyl]benzene, 4-chlorobenzonitrile, 1-bromo-4-cyanomethylbenzene,1-chloro-3-(3-hydroxy-1-butyl)benzene, 1-chloro-4-[2-(1-hydroxycyclopentyl)ethyl)benzene, 1-bromo-4-(1-hydroxybut-3-enyl)benzene and 1-methyl-4-hydroxy-(4xe2x80x2-chlorophenyl)-piperidine, 4-(1-aza-methylcyclohex-3-en-4-yl)-1-chlorobenzene. In a highly preferred embodiment, the substrate aromatic compound is 1-methyl-4-hydroxy-(4xe2x80x2-chlorophenyl)-piperidine.
Suitable substrate aromatic compounds are made by known synthetic methods. The substituents on the substrate aromatic compound are selected based on structure of the desired indole product.
In a preferred embodiment, R1 is H, alkyl or aryl, more preferably H.
In a preferred embodiment, each R2 is independently monocyclic cycloalkyl, monocyclic cycloalkenyl or monocyclic aryl, more preferably, phenyl, or, alternatively, the R2 groups are fused to form, together with the carbon atom to which they are each attached, a monocyclic 5- or 6-membered cycloalkyl, cycloalkenyl or aryl ring.
Suitable hydrazones include, for example, benzophenone hydrazone, benzaldehyde hydrazone and cyclohexanone hydrazone. In a highly preferred embodiment, the hydrazone is benzophenone hydrazone.
In a preferred embodiment, reaction of the substrate aromatic compound and the hydrazone is run with an excess of from about 4:1 to about 1.01:1, more preferably from about 2:1 to about 1.05:1, of either the substrate aromatic compound or the hydrazone. In a highly preferred embodiment the reaction of the substrate aromatic compound and the hydrazone is run with an excess of from about 1.5:1 to about 1.1:1 of the hydrazone.
In a preferred embodiment, reaction of the substrate aromatic compound and hydrazone is conducted in the presence of a transition metal catalyst and a base according to the method for transition metal-catalyzed arylation disclosed in U.S. Pat. No. 6,235,936 xe2x80x9cMETAL-CATALYZED ARYLATION OF HYDRAZINES, HYDRAZONES, AND RELATED SUBSTRATESxe2x80x9d to Buchwald et. al., the disclosure of which is hereby incorporated herein by reference.
Suitable transition metal catalysts include, for example, soluble or insoluble complexes of platinum, palladium or nickel, more preferably palladium. Suitable palladium catalysts include, for example, PdCl2, Pd(OAc)2, (CH3CN)2PdCl2, Pd(P(C6H5)3)4, Pd2(dba)3 or Pd(dba)2, wherein xe2x80x9cdbaxe2x80x9d is dibenzylideneacetone, as well as supported palladium, such as palladium on carbon. In a preferred embodiment, the catalyst comprises Pd(OAc)2.
In a preferred embodiment, the catalyst is provided in the reaction mixture as a metal-ligand complex wherein the transition metal catalyst is bound to a supporting ligand. In a preferred embodiment, the ligand is a monodentate alkyl or aryl phosphine or a hybrid thereof, or a chelating ligand, such as for example, alkyl and aryl derivatives of phosphines, biphosphines, amines, diamines, imines, arsines and hybrids thereof.
In a more highly preferred embodiment, the ligand is a phosphine ligand. Suitable phosphine ligands include monodentate phosphine ligands, such as, for example, trimethylphosphine, tripropylphosphine, trisobutylphosphine, tricyclohexylphosphine, trimethyl phosphite, triphenylphosphine. tri-t-butylphosphine, 2-(di-t-butyl-phosphino)biphenyl, 2-(dicyclohexylphosphino)biphenyl, 2-methyl-2xe2x80x2-dicyclohexylphosphinobiphenyl, 2-dimethylamino-2xe2x80x2-dicyclohexylphosphinobiphenyl and 2-dimethylamino-2xe2x80x2-di-t-butylphosphinobiphenyl, and bidentate ligands such as 2,2xe2x80x2-bis(diphenylphosphino)-1,1xe2x80x2-binaphthyl; (xe2x80x9cBINAPxe2x80x9d), 2,2xe2x80x2-bis(dicyclohexylphosphino)-1,1xe2x80x2-binaphthyl, 1,2-dimethylphosphino)ethane, 1,3bis(dicyclohexylphosphino)propane. In a highly preferred embodiment, the ligand is 2-(di-t-butyl-phosphino)biphenyl.
The metal catalyst and ligand may be added to the reaction mixture as separate compounds. Alternatively, a metal ligand complex may be formed prior to addition to the reaction mixture and then added to the reaction mixture as the metal-ligand complex.
In a preferred embodiment, the coupling reaction is run in the presence of a catalytic amount of catalyst. Typically, the amount of catalyst ranges from about 0.0001 to about 20 mole %, more preferably from about 0.05 to about 5 mole %, based on the amount of limiting reactant.
In a preferred embodiment, the reaction mixture includes from about 1 to about 3 equivalents, based on the amount of hydrazone, of a base. Suitable bases include, for example, NaH, LiH, alkoxides such as sodium t-butoxide, sodium 2-methyl-2-butoxide, alkyl metal amides such as sodium amide, alkali metal bis(trialkylsilyl)amides such as lithium bis(trimethylsilyl)amide, tertiary amines such as triethylamine, 4-(dimethylamino)pyridine, alkaline earth carbonates, bicarbonates, hydroxides and phosphates, such as, for example, magnesium bicarbonate, calcium carbonate, potassium carbonate, cesium carbonate and potassium phosphate.
In a preferred embodiment, the reaction of the substrate aromatic compound and the hydrazone is conducted in a liquid reaction medium. The reaction may be run without solvent or, alternatively, may be run in a solvent that is inert under the reaction conditions. Preferably, the solvent is one in which the reaction ingredients, including the catalyst, are soluble. Suitable solvents include aliphatic or aromatic hydrocarbon solvents such as pentane, hexane, benzene, xylene and toluene, ethers such as diethyl ether and t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, esters such as ethylacetate, polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide, dimethylacetamide and 1-methyl-2-pyrrolidinone, halogenated solvents such as dichloromethane, as well as mixtures of two or more solvents. In a highly preferred embodiment, the solvent is an aromatic hydrocarbon or an ether.
In general, the coupling reaction is run under mild conditions that will not adversely affect the reactants, catalyst or product. In a preferred embodiment, the coupling reaction is run at a temperature of from about 25xc2x0 C. to about 300xc2x0 C., more preferably from about 25xc2x0 C. to about 150xc2x0 C.
In a preferred embodiment, the coupling reaction is run in an inert atmosphere, such as, for example, under an argon purge or a nitrogen atmosphere.
In a preferred embodiment, the aryl hydrazone formed in the coupling step is hydrolyzed to form an aryl hydrazine salt according to reaction scheme 2.
wherein
Ar, R1 and R2 are each defined as in scheme 1 above,
Xxe2x80x2 is halo, acetate, trifluoroacetate, sulfate or phosphate, and
n is a number of from 1 to 5.
In a preferred embodiment, Xxe2x80x2 is halo.
In a preferred embodiment, the hydrolysis is run in a liquid reaction medium comprising water, an alcohol and an acid.
Suitable alcohols include, for example, methanol, ethanol isopropanol or t-butanol. In a preferred embodiment, the alcohol is methanol or ethanol.
Suitable acids include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, trifluoroacetic acid or phosphoric acid. In a preferred embodiment the acid is hydrochloric acid or sulfuric acid.
In a preferred embodiment, the hydrolysis is run in the presence of from about 2 to about 5 equivalents, based on the amount of hydrazone, of the acid.
In general, the hydrolysis is run under mild conditions that will not adversely affect the reactants or product. In a preferred embodiment, the hydrolysis is run at a temperature of from about 25xc2x0 C. to about 300xc2x0 C., more preferably from about 25xc2x0 C. to about 150xc2x0 C.
In a highly preferred embodiment, the aryl hydrazone is treated with a mixture of water, ethanol and hydrochloric acid at reflux to yield the hydrochloric acid salt of the desired hydrazine.
In a preferred embodiment, the substituted indole compound is formed by an acid catalyzed reaction of the aryl hydrazone with a ketone or an aldehyde.
In a highly preferred embodiment, the substituted indole compound formed from the aryl hydrazine via an acid-catalyzed Fischer indole cyclization reaction according to reaction scheme 3:
wherein:
Ar, R1 and Xxe2x80x2 are each defined as in scheme 1 above,
R7 is substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl,
R8 is H, substituted or nonsubstituted alkyl, substituted or nonsubstituted alkenyl, substituted or nonsubstituted aryl or substituted or nonsubstituted heterocyclyl, and
nxe2x80x2 is a number of from 1 to 5.
In a preferred embodiment, R7 is substituted or nonsubstituted nitrogen-containing heteroacyclic group, more preferably a group according to xe2x80x94(CH2)nxe2x80x94NR3R4, wherein n, R3 and R4 are each as described above, or a heterocyclic moiety according to:
xe2x80x94(CH2)mxe2x80x94A
wherein:
m is a number from 0 to 6, and
A is a nitrogen-containing heterocyclic group that contains one 5- or 6-membered heterocyclic ring per group, wherein the heterocyclic ring contains one or two nitrogen heteroatoms per ring and wherein the heterocyclic group may, optionally, be substituted on one or more atoms of the heterocyclic ring, with for example, (C1-C6)alkyl.
In a more highly preferred embodiment, R7 is aminoalkyl such as aminoethyl, alkylaminoethyl such as methylaminoethyl, dialkylaminoalkyl, such as dimethylaminoethyl, pyrrolidinyl, pyrrolidinylalkyl such as pyrrolidinylethyl, alkylpyrrolidinylalkyl such as methylpyrrolidinylmethyl, pyridyl, alkylpyridyl such as methylpyridyl, piperidinyl, piperidinylalkyl such as piperidinylmethyl or alkylpiperidinyalkyl such as methylpiperidinylmethyl.
Suitable ketones include, for example, phenylacetone, cyclohexanone, ethyl pyruvate, 2-nonanone, and acetophenone.
Suitable aldehydes include, for example, 4-chlorobutyraldehyde, ethyl glyoxalate, hept-5-en-1-al, 4-piperidinylacetaldehyde, 3-cyclohexylpropionaldehyde, phenylacetaldehyde, 3-(2-N-methylpyrrolidinyl)propionaldehyde, 4-(1-pyrrolidinyl)butyraldehyde, and 4-(N,N-dimethylamino)butyraldehyde, and may be formed in situ from an aldehyde precursor, such as, for example, an acetal or bisulfite adduct. Suitable acetals include, for example, acetals such as 4-(N,N-dimethylamino)butyraldehyde diethyl acetal or 4-(N,N-dimethylamino)butyraldehyde dimethyl acetal. Suitable bisulfite adducts include, for example, 4-chloro-1-hydroxybutanesulphonic acid sodium salt.
In a preferred embodiment, dimethylaminobutyraldehyde is formed in situ from 4-(N,N-dimethylamino)butyraldehyde diethyl acetal or 4-(N,N-dimethylamino)butyraldehyde dimethyl acetal.
In a preferred embodiment, the indole synthesis reaction is run in the presence of from about 1 to about 5 equivalents, more preferably from about 1 to about 2 equivalents, aldehyde or aldehyde precursor, based on the amount of hydrazine.
Suitable acids include hydrochloric, hydrobromic acid, sulfuric acid, trifluoroacetic acid and phosphoric acid. In a preferred embodiment, the acid is sulfuric acid or phosphoric acid. In a preferred embodiment, the indole cyclization reaction is run in the presence of from about 0.5 to about 2 equivalents, more preferably from about 0.8 to about 1.2 equivalents acid, based on the amount of hydrazine.
In a preferred embodiment, the indole cyclization reaction is run in a liquid reaction medium. In a preferred embodiment, the indole synthesis reaction is conducted in a suitable solvent, such as water, alcohol or a mixture thereof.
In a preferred embodiment, the indole cyclization reaction is run under mild conditions that will not adversely affect the reactants, catalyst or product. In a preferred embodiment, the coupling reaction is run at a temperature of from about 25xc2x0 C. to about 250xc2x0 C., more preferably from about 25xc2x0 C. to about 150xc2x0 C.
The indole product may then be isolated and purified by known techniques.
In a highly preferred embodiment, a substituted aryl halide is made via a Grignard reaction and metal-catalyzed arylation of benzophenone hydrazone with the substituted aryl halide is followed by hydrolysis to give to give a substituted aryl hydrazine. The aryl hydrazine then undergoes acid-catalyzed Fischer indole synthesis to give the 5-(1-Aza-1-methylcyclohex-3-en-4-yl)-3-[2-(N,N-dimethylamino)ethyl)]-1H-indole product.
The method of the present invention is useful for making a wide variety of substituted indole compounds, such as for example, those substituted indole compounds which have been found to act on 5-HT1-like receptors and to be useful in the treatment of certain medical conditions, as disclosed, for example, in U.S. Pat. No. 5,607,960, xe2x80x9cINDOLE DERIVATIVES AS 5-HT1-LIKE AGONISTS FOR USE IN MIGRAINExe2x80x9d to Wythes and U.S. Pat. No. 5,998,438, xe2x80x9c5-CYCLO INDOLE COMPOUNDSxe2x80x9d to Slassi et. al., the respective disclosures of which are hereby incorporated herein by reference.
Exemplary substituted indole compounds include: 3-[2-N,N-dimethylamino)ethyl]-5(tetrahydropyran-2-yl)-1H-indole, 3-[2-(N,N-dimethylamino)ethyl]-5-(1-thiacyclohex-4-yl)-1H-indole, 5-(1-aza-1-tert-butoxycarbonylcyclohex-3-en-4-yl)-3-[(N-methylpyrrolidin-2-yl)methyl]-1H-indole, 5-(1-aza-1-benzylcyclohex-3-4yl)-3-(2-pyrrolidinylethyl)-1H-indole, 5-(1-aza-1-methyl-4-hydroxycyclohex-4-yl)-3(2-pyrrolidinylethyl)-1H-indole, 5-(1-aza-1-tert-butoxycarbonyl-4-hydroxycyclohex-4-yl)-3-(2-pyrrolidinylehtyl)-1H-indole, 5-[2-hydroxycyclopentyl)ethyl]-3-[N-[2-(N,N-dimethylcarbamoyl)ethyl]-2(R)-pyrrolidinylmethyl]-1H-indole, and 5[2-(1-hydroxycyclopentyl)ethyl]-3-(2(R)-pyrrolidinylmethyl)-1H-indole.

Method for making aryl hydrazines and substituted indoles


A recording medium accommodation cassette, wherein a part of a cassette shell is formed of a metallic plate, which is formed with a punched hole formed by press, and the metallic plate is disposed such that a shear face of the punched hole therein is located inwardly of the cassette thereby being in contact with a structural part within the cassette thereby inhibiting a burr produced in a punched hole in the metallic plate from being in contact with a structural component within the cassette (e.g., a reel) to produce shaving powders or particles.

The present invention relates to a recording medium accommodation cassette and more particularly to a cassette in which a part of a cassette shell thereof is formed of a metallic plate.
Referring to FIGS. 1 to 3, the structure of a so-called 8-mm video cassette will be described as an example of a recording medium accommodation cassette.
Referring to the Figures, reference numeral 1 denotes an entire 8-mm video cassette and reference numeral 2 denotes a cassette shell (case) thereof. This cassette shell 2 is formed by combining an upper shell 3 and a lower shell 4 and fixing them to each other with screws and so on.
The cassette shell 2 accommodates therein a pair of reels, that is, a take-up reel 6 and a supply reel 7 such that they are rotatable.
The reels 6, 7 comprise hubs 6a, 7a, upper flanges 6b, 7b, and lower flanges 6c, 7c respectively and a magnetic tape 8 is wound around the hubs 6a, 7a of the reels 6, 7 respectively such that both ends of the tape 8 are fixed to the hubs 6a, 7a, respectively.
Tape guide portions 9a, 9b are provided on the left and right sides of the front portion of the lower shell 4. Then, a tape traveling path is formed such that the magnetic tape 8 derived from the supply reel 7 passes through the tape guide portion 9b, runs over the front part of the cassette shell, then passes through the tape guide portion 9a and finally is wound up by the take-up reel 6.
Reference numeral 10 denotes a lid for protecting the magnetic tape 8 which travels over the front part of the cassette shell. When the cassette is not in use, the lid 10 covers an exposed portion of the magnetic tape 8 over the front part of the cassette shell, while when the cassette is in use (when the cassette is inserted into a cassette deck), the lid 10 is rotated upward so that it opens so as to expose the magnetic tape 8.
Further, a pair of reel springs 11a, 11b (left, right springs) each being made of a leaf spring are attached to an internal surface of the upper shell 3 so that the reels 6, 7 are always pressed down to the lower shell 4 by the reel springs 11a, 11b thereby preventing the reels 6, 7 from being loose.
Further, within the cassette shell 2, a reel lock member 12 is assembled to a backward portion between both the reels 6 and 7. The reel lock member 12 is always urged toward the reels 6, 7 by the force of a reel lock spring 13. When the cassette is not in use, the reel lock member 12 engages engaging teeth 6d, 7d formed on outer peripheral edges of the lower flanges 6c, 7c of the reels 6, 7 so that the reels 6, 7 are locked from rotation thereby preventing the magnetic tape 8 from being loose.
In the tape cassette 1 having the above described structure, the cassette shell 2 is generally formed of resin (plastics) such as an ABS or the like. However, recently, formation of a part of the cassette shell with a metallic plate has been considered so as to further improve the stiffness of the cassette shell and also produce a luxurious feeling in its appearance.
As evident in FIGS. 2 and 3, a metallic plate 15 made of metal such as aluminum or the like is inserted into the central portion of a bottom portion 4a of the lower shell 4 supporting the reels 6, 7.
The metallic plate 15 is inserted upon molding of the lower shell 4. That is, upon molding of the lower shell 4, the metallic plate 15 is inserted within a molding die from the beginning and then with that condition, resin is injected into the molding die, so that the lower shell 4 having the metallic plate 15 integrally as shown in FIG. 3 is molded.
The metallic plate 15 to be inserted into lower shell 4 is provided with a plurality of punched holes 16 as shown in FIG. 3.
Here, 16a and 16b are reel driving shaft insertion holes, respectively, and 16c is a reel lock releasing member insertion hole.
The reel driving shaft insertion holes 16a, 16b are punched holes provided corresponding to the reels 6, 7, respectively. The reel driving shafts provided on the side of a cassette desk are inserted into these holes and engaged with the reels 6, 7, respectively.
The reel lock releasing member insertion hole 16c is a punched hole corresponding to the reel lock member 12. A reel lock releasing member provided on the cassette deck is inserted into this hole and then the reel lock member 12 is operated thereby unlocking the reels 6, 7.
These punched holes 16 are formed by punching the metallic plate 15 by means of press. This punching operation is outlined in FIGS. 5A-5C.
In FIGS. 5A-5C, reference numeral 20 denotes a punch and numeral 21 denotes a die having a concave portion 21a corresponding to the punch 20. Meantime, there is a slight clearance between the punch 20 and the die 21 such that an inner diameter of the concave portion 21a of the die 21 is slightly larger than an outer diameter of the punch 20.
With the metallic plate 15 set over the die 21 with the concave portion 21a as shown in FIG. 5A, when the punch 20 is descended from a higher position than the metallic plate 15 at a large pressing force, then as shown in FIG. 5B, until the punch reaches a middle portion in the thickness of the metallic plate 15, the metallic plate 15 is shorn between the punch 20 and the concave die 21, and finally the metallic plate 15 is punched out as shown in FIG. 5C in such a state that the metallic plate 15 is ruptured between the punch 20 and the concave die 21.
FIG. 4 shows an enlarged view of a condition of the punched hole 16 formed in the metallic plate 15 by punching work.
As evident from FIG. 4, the punched face (internal circumferential face) of the punched hole 16 is formed of a shear face 17 and a fracture face 18. Up to the middle in the punching direction, there is provided the shear face 17 which shows a straight surface produced by shearing, and which is followed by the fracture face 18 which shows sawtooth shape produced by fracture.
An end edge portion 17a of the shear face 17 of the punched hole 16 is formed in a mild round corner shape deformed by the pressing force upon punching, while an end edge portion of the fracture face 18 has a so-called punch-out burr 19 produced upon fracture, which protrudes sharply. A protrusion amount h.sub.1 of the punched-out burr 19 differs depending on a thickness of the metallic plate 15. If the thickness of the metallic plate 15 is 1.2-1.5 mm, h.sub.1 is about 20-30 .mu.m.
Thus, if as shown in FIGS. 6, 7, the punched-out burr 19 is in contact with a structural component in the cassette or the lower flanges 6c, 7c of the reels 6, 7, in this example and hence friction is generated between the burr 19 and the lower flanges 6c, 7c of the reels 6, 7 so that the resin of the lower flanges 6c, 7c of the reels 6, 7 is shaved thereby producing shaving powders. Further, if the shaving powders adhere to the magnetic tape, it may cause a dropout in recording and reproduction signals thereby deteriorating largely the reliability.
Although there is a method of removing the burr 19 on the metallic plate 15 so as to solve the above problem, it takes a long time and labor to remove the burr completely, so that production cost of the metallic plate 15 is increased. Thus, this is not a practical solution.
Further, although narrowing the clearance between the punch 20 of the press and the concave die 21 is effective as a method of suppressing an occurrence of the burr, in this case, the service life of the die remarkably shortens, so that this method is not suitable for mass production thereof. Still further this method is not capable of removing the burr completely.


Spectral Purity Filters, or SPFs, are disclosed. Such SPFs are designed to block out the 1030 nm drive laser and other undesired out of band light in a EUV mask inspection system. Different phase grating configurations for near normal incidence and grazing incidence are provided in the present disclosure and are configured specifically for EUV mask inspection.

Mask inspection, or photo mask inspection, is an operation of checking the correctness of the fabricated photo masks (e.g., used for semiconductor device fabrications). Modern technologies for locating defects in photo masks are automated systems that involve scanning electron microscopy and other advanced tools. Existing optical systems in the market for mask inspection employ ultra-violet light at or above 193 nm that are not sufficient to resolve the features and defects below the 22 nm node. In order to resolve features and defects below 22 nm node, light of shorter wavelength in the EUV (e.g., 13.5 nm) region needs to be used.
Laser produced plasma (LPP) is a good candidate light source for extreme ultraviolet (EUV) mask inspection. LPP light source may use Xenon as fuel and Nd:YAG laser at wavelength near 1030 nm as driver laser. It has been observed that a few percent of the driver laser may enter the inspection system and cause enough detrimental thermal damage and image flare, and thus its intensity needs to be significantly reduced. Out of band radiation with wavelength from a few nm to 1000 nm also exists in the light source and needs to be suppressed.
While there are some Spectral Purity Filter (SPF) methods available, they are developed for EUV lithography which use CO2 laser of wavelength 10.6 um on Sn target. That is, these SPF methods are not developed specifically for mask inspection using Xenon LPP source with 1030 nm light, and due to the significant difference in laser wavelength (e.g., ten times the difference) and different use cases between inspection and lithography, the existing SPF methods are not applicable for EUV mask inspection.
Therein lies a need for providing phase grating for mask inspection without the aforementioned shortcomings.

Phase grating for mask inspection system


Systems and methods provide control of operating states of an electronic device. A first exemplary electronic device detects a consumer electronic control (CEC) communication sent from a second electronic device to a third electronic device, the CEC communication communicated over high-definition multimedia (HDMI) connectors communicatively coupling the first electronic device, the second electronic device and the third electronic device; determines, based on information in the CEC communication, whether the CEC communication is one of a first kind of CEC communication or a second kind of CEC communication; in response to determining that the CEC communication is one of the first kind of CEC communication, transitions the first electronic device to a predefined operating state; and in response to determining that the CEC communication is one of the second kind of CEC communication, maintains the first electronic device in a current operating state.

Electronic devices, such as a set top box, a stereo, a television, a computer system, a game system, or the like, are often configured to enter into various operating states based on use. For example, an electronic device may enter into a deep sleep state to conserve power at times when it is not being used, or is not likely to be used. On the other hand, the electronic device may remain in an active state, or in standby state, if the electronic device has recently been used, or is likely to be used.
When the electronic device is in a deep sleep state, a period of time may be required for the electronic device to leave its deep sleep state and to "wake up" so as to be ready for operation. Typically, the electronic device leaves its deep sleep state upon receiving an initial command from a user and/or upon receiving information from another electronic device. However, the time required for the electronic device to transition out of its deep sleep state may require an unacceptably long duration, especially if the user or another electronic device needs to operate the electronic device in a relatively short period of time.
Accordingly, there is a need in the arts to provide alternative ways for a electronic device to transition out of its deep sleep state so as to be able to more quickly respond to an initial command from a user and/or to information received from another electronic device.

Apparatus, systems and methods for modifying operating states based on monitored HDMI CEC communications


The invention relates to a process for melt-spinning, drawing and winding multiple synthetic threads and to an apparatus for performing the process. The synthetic threads are spun concurrently side by side through extrusion of fine filamentous strands, cooled down and hauled off to be then collectively drawn as a sheet of threads and wound up on bobbins. To obtain ideally identical physical properties in the collective treatment of the threads, the threads are hauled off independently of each other by separate individual godets after extrusion and before collective drawing. This makes it possible to realize for each thread the same conditions during extrusion, cooling and hauling off. The apparatus includes multiple individual godets arranged side by side, which are arranged upstream of the drawing facility and are each associated with one of the threads. To pull off the threads, the individual godets are configured to be individually driveable.

In the production of synthetic threads in a melt-spinning process, it is usual that in a spinning position side by side, a plurality of threads are extruded, cooled, drawn and wound in parallel to bobbins. After extrusion, the threads are led as a sheet of strands and collectively drawn by godets and collectively wound in multiple winding stations on bobbins. In order to be able to simultaneously pull off the plurality of threads by a godet from the spinnerets, it is also usual to guide the threads in a first transition section to a smaller distance from each other. During the extrusion and the cooling stages, the spinnerets are kept spaced with respect to each other so that the threads are guided within a vertical spinning section at a spinning distance near each other. The collective guidance of the threads on the godets requires a smaller distance godets so that the transition section between the spinning apparatus and the drawing apparatus is used for merging the threads. For this purpose, it is necessary to deflect in particular the threads in the outer regions of the sheet of strands. In addition, there thus result different pull-off ratios of the threads during the extrusion of the thread strands at the spinnerets.
Such a method and such an apparatus are known, for example, from EP 0 845 550 A1. In this method and apparatus, after drawing and before winding up, the threads are guided through individually driven delivery apparatuses in order to be able to compensate for the differences in tension arising from the different deflection of individual threads before winding up the threads. It is true that a homogenization of differences in tension caused by multiple deflections in the threads of the sheet of strands can be achieved. However, the different thread guiding paths occurring already before and during the drawing remain here ignored and directly affect the individual threads during the drawing of the threads.
Such disadvantages in the production of multiple synthetic threads parallel side by side can be entirely avoided only if every single thread is separately and independently pulled off, drawn and wound to bobbins. Such a method and such an apparatus are known, for example, from DE 102 36 826 A1. In this method and apparatus, a separate drawing apparatus is provided for each thread, which interacts with a winding apparatus. This permits substantially straight thread runs between the spinning apparatus and the drawing apparatus. However, such methods and apparatuses require much more space, because all devices for pulling-off, drawing, treatment and winding of threads must be present in multiple numbers. To this extent, these methods and apparatuses are preferably used for the production of composite fibers, in which each of the generated partial threads must have the same properties.
New developments, such as for example those known from DE 10 2009 021 131 A1, are based on an arrangement in which the drawing device is arranged laterally adjacent to the spinning device, wherein between the spinneret and the drawing device deflecting rollers are arranged for each thread. This allows larger deflections in the transition region between the drawing device and the spinning device to be avoided. However, the free thread route between the drawing device and the spinnerets is formed differently in length for each thread. In that regard, differences can also be expected in this method.

Apparatus for melt-spinning, drawing and winding multiple synthetic threads


A method for depositing real items into real containers, wherein the real items are transported along a picking line and are deposited into spaces in the real containers using robots. Placement of the items is predetermined by a controller. The controller provides for the real items and the real containers to be previously associated with one another by virtue of graphical symbols for items being placed into at least one graphical symbol for a container on a screen that is connected to the controller. The method according to the invention thus makes it possible to easily and quickly fill a container with an assortment of items in the desired manner using real robot movements.

1. Field of the Invention
The invention relates to a method for depositing individually packaged items in containers and to a controller for performing the method.
2. Description of the Prior Art
It is known to use robot lines for depositing individually packaged items in containers. The individually packaged items and the containers are conveyed into work zones of individual robots, and the individually packaged items are deposited by robots in predefined empty spaces of the container in accordance with a controller. Picking lines are described for instance in International Patent Disclosure WO 2004/113030, U.S. Pat. Nos. 6,122,895 and 5,040,046, German Patent Disclosure DE 37 04 423, and Swiss Patent Disclosure CH 693 710. International Patent Disclosure WO 2004/018332 describes how products can be automatically recognized and selected. International Patent Disclosure WO 03/103903 and U.S. Pat. No. 4,503,507 disclose a common controller for a plurality of robots.
Enabling the robot to know which individually packaged items it is supposed to deposit and in which empty space requires complex learning processes. These learning processes must typically be performed by personnel who are especially trained for the system. If the type of packaging is to be changed, then the system has to be stopped and reprogrammed.

Method for depositing individually packaged items in containers


A valve comprises a housing, a conduit, and a shut-off member, and a plurality of ribs. The conduit is fixed in position relative to the housing. The ribs are spaced from the conduit. The shut-off member is fixed in position within a cavity of the housing via the ribs. The gate has a fluid passageway extending therethrough and is movable relative to the shut-off member between opened and closed positions. The gate is able to linearly reciprocate between opened and closed positions along the center axis of the conduit. The gate is engaged with the shut-off member when the gate is in the closed position in a manner preventing fluid from flowing through the fluid passageway of the gate. The opened position of the gate allows fluid to flow through the fluid passageway of the gate.

1. Field of the Invention
This invention pertains generally to low head loss flow control valves. More particularly, the invention pertains to fixed cone sleeve valves having ribs downstream of the gate for supporting the cone, velocity diffusers, and velocity shredders.
2. General Background
Sleeve valves have been employed to control the flow rate and head pressure of fluids in industrial piping systems, hydro power facilities, agricultural facilities, water and sewage distribution systems, and industrial piping systems. Sleeve valves are often utilized for their ability to operate without the moving components of the valve having to work against the head pressure of the fluid being supplied to the valve. An example of a fixed cone sleeve valve is described in U.S. Pat. No. 6,296,009, entitled Arm-Driven Sleeve Valve With Centralized Drive Mechanism, which issued Oct. 2, 2001 and is hereby incorporated in its entirety by reference. Conventional arm-driven sleeve valves often comprise a tubular inlet conduit, a tubular gate, and a cone shaped shut-off member. It is common for the shut-off member to be rigidly attached to the inlet conduit via a plurality of ribs that extend into the fluid passageway of the inlet conduit. Other sleeve valves, such as is disclosed in U.S. Pat. No. 1,477,722, entitled Valve, which issued Dec. 18, 1923, and is hereby incorporated in its entirety by reference, comprise ribs downstream of the inlet conduit for supporting the shut-off member. The gate typically is linearly movable over the inlet conduit in a telescoping manner and in a manner such that it is able to engage against the shut-off member to prevent fluid from passing through the valve.
Although such fixed cone sleeve valves have proven to be highly useful, there are also problems related to such valves. One such problem with valves in which the shut-off member is rigidly attached to the inlet conduit via a plurality of ribs that extend into the fluid passageway of the inlet conduit is that the ribs that secure the shut-off member to the inlet conduit obstruct the fluid passageway within the inlet conduit, and thereby slightly restrict the flow through the valve. As can be appreciated, this lowers the overall efficiency of the valve. Even in sleeve valves in which the ribs downstream of the inlet conduit support the shut-off member, the flow downstream of the inlet conduit is non-linear and can cause non-uniform pressure differentials that can cold work or work harden the housing and ribs of such valves. Cold working the housing and ribs can cause the housing and ribs to become brittle and fracture due to fatigue. Moreover, velocity differentials of the fluid flow downstream of the inlet conduit can cause significant drag on the fluid as it passes through a sleeve valve.

This patent is subject to a terminal disclaimer.

Fixed cone sleeve valve having ribs downstream of the gate for supporting the cone and other components of the valve


A bearing which includes a series of spaced bearing surfaces so as to distribute load amongst a series of spaced bearing surfaces thereby increasing the load carrying capacity of the assembly. The bearing surfaces are formed of a high PV material. The bearing assembly can be either a radial bearing for supporting radial loads or a thrust bearing for supporting thrust loads.

Unlubricated plastic sleeve bearings are sometimes used as an alternative to expensive ball bearings. Perhaps the biggest advantage of plastic sleeve bearings is their remarkably low cost compared to roller bearings. There are, however, also performance advantages. Sleeve bearings require less radial space than roller bearings. They are better able to withstand shock conditions and have less difficulty with fatigue. Sleeve bearings are also much more quiet in operation than roller bearings.
The principal limitation in a sleeve bearing's performance is the so-called PV limit. PV is the product of load or pressure (P) and sliding velocity (V). A sleeve bearing subjected to increasing PV loading will eventually reach a point of failure known as the PV limit. For instance, high edge loading causes a sleeve bearing to reach its PV limit. The failure point is usually manifested by an abrupt increase in the wear rate of the bearing material.
As long as the mechanical strength of the bearing material is not exceeded, the temperature of the bearing surface is generally the most important factor in determining PV limit. Therefore, anything that affects surface temperature--coefficient of friction, thermal conductivity, lubrication, ambient temperature, running clearance, hardness and surface finish of mating materials--will also affect the PV limit of the bearing.
Thus, the first step in selecting and evaluating a sleeve bearing is determining the PV limit required by the intended application. It is usually prudent to allow a generous safety margin in determining PV limits, because real operating conditions often are more rigorous than experimental conditions
Determining the PV requirements of any application is a three step process First, the static loading per unit area (P) that the bearing must withstand in operation must be determined. For journal bearing configurations, the calculation is as follows: EQU P=W/(d.times.b)
P=pressure, psi(kg/cm.sup.2) PA1 W=static load, lb(kg) PA1 d=bearing surface ID, in.(cm) PA1 b=bearing length, in.(cm) PA1 V=surface velocity, in/min(cm/min) PA1 N=speed of rotation, rpm or cycles/min PA1 d=bearing surface ID, in.(cm)
Pressure (P) should not exceed certain maximum values at room temperature. These can be derived from a table of allowable static bearing pressure for most known materials. Next, the velocity (V) of the bearing relative to the mating surface must be calculated. For a journal bearing experiencing continuous rotation, as opposed to oscillatory motion, velocity is calculated as follows: EQU V=(dN)(.pi.)
where:
Finally, calculate PV as follows: EQU PV(psi-ft/min)=P(psi).times.V(in/min)12 or, in metric units: EQU PV(kg/cm.sup.2 -m/sec)=P(kg/cm.sup.2).times.V(cm/min)/6000
The PV limits of unlubricated bearing materials are generally available from the manufacturer of the material or from technical literature. Since PV limits for any material vary with different combinations of pressure and velocity as well as with other test conditions, it is prudent to consult the manufacturer for detailed information.
One material which is particularly well suited to bearing applications is the polyimide thermoset material sold by Hoechst Celanese under the trademark CELAZOLE.TM.. Properly lubricated CELAZOLE.TM. parts can withstand approximately 1 million psi-ft/min.
Despite the availability of new high performance materials such as CELAZOLE.TM. and the advantages sleeve bearings offer, sleeve bearings are still not used in many applications. This is believed to be due in part to the load limits of such bearings. Accordingly, there remains a need for improved sleeve bearings.

Plain bearing with multiple load bearing surfaces


A battery includes at least one battery module that has several battery cells arranged next to each other on a support plate. The battery module is arranged with the support plate on a base plate of the battery or on a base plate of a lower unit of the battery. The support plate and the base plate are fixed together by at least one fixing system that includes at least two fixing elements engaging in each other. The first fixing element is arranged on the battery module and the second fixing element is arranged on the base plate. A motor vehicle includes the battery.

The present disclosure relates to a battery and to a motor vehicle comprising said battery, wherein the battery has at least one battery module which comprises a plurality of battery cells which are arranged on a support plate and at the same time the battery module is arranged by way of its support plate on a base plate of the battery or a base plate of a subunit of the battery, and the support plate and the base plate are connected to one another in a stationary manner by way of at least one fastening system.
It is known to design the basic structure of a battery such that in each case a plurality of battery cells are combined to form one battery module in the battery, and a plurality of battery modules are in turn arranged in a subunit. The battery is then formed from a plurality of said subunits.
In this case, said components are joined to form the assemblies usually by screw or rivet connections, as a result of which tools have to be used and an increased level of expenditure on installation is required for assembly.

Battery and motor vehicle comprising said battery


An apparatus and method for a solution that permits a carpenter to make exact, on-the-spot time-efficient cross-cuts of their boards while holding the board in one-hand and the circular saw in the other hand. A cross-out apparatus includes a guide system including a housing and a range of motion control for defining a processing path for a guide element as it moves from a first position to a second position relative to the housing; a workpiece coupler, coupled to the guide element, for defining a desired processing orientation with respect to a workpiece for maintaining the desired processing orientation as the guide element moves from the first position to the second position; and an attachment system, coupled to the housing, for cooperating with a hand-held power processing tool to position a processing implement at a reference location relative to the workpiece and at the desired processing orientation, the attachment system coupled to the housing so the guide element maintains the desired processing orientation along the processing path from the reference location during use of the hand-held power processing tool to process the workpiece.

The invention relates generally to processing guides used in cooperation with hand-held power tools, and more specifically to a cross-cut guide for a hand-held circular saw.
Home construction in the United States produces an enormous range of house styles that include an enormous range of finishing styles. Even so, it is true that a huge majority of these homes are built using completely standardized building practices. Partially this is because building codes across the United States are mostly uniform, and also because the use of standard building practices permit reliable housing to be quickly constructed at a lower cost than would be the case without the standardization. The construction sequence, especially of a brand new home, typically includes most the following steps: grading/site preparation, foundation construction, framing, window/door installation, roofing, siding, rough electrical, rough plumbing, rough HVAC, insulation, drywall, underlayment, trim, painting, finish electrical, bathroom/kitchen counters/cabinets, finish plumbing, carpet and flooring, finish HVAC, water main/well drilling, sewer hookup/septic installation, and a punch list.
Construction framing, particularly for human-occupied buildings, commonly uses wooden framing materials also called boards, such as 2×4s (1.5″ by 3.5″) and 2×10s (1.5″ by 9.5″) that come in many lengths but each are usually at least about 8 feet long. The boards are purchased too long for most uses and they must be individually cut to size. The framing of the floor, the walls, the ceiling, and the roof require that a carpenter individually cut many boards to exact size. The preferred method is to have the boards cut on location to the precise length. For speed and efficiency, each board is individually measured using a tape measure to mark the cut location. The carpenter then holds the board in one hand and makes a cross-cut using a hand-held circular saw (e.g., a Skillsaw circular saw). The carpenter must try to maintain a right-angle during the cut while holding the board and operating the saw. Results can vary considerably in maintaining a right-angle cut at the desired location for a single board, much less hundreds of boards.
One solution employed by many construction framing crews is the use of a square that is used to mark a right-angle across the board at the correct location, with the line providing a visual guide to the carpenter during the cut. This improves the right angle cuts but it requires use of another tool and is therefore slower. Also the line for the cut is not constrained to the visual cue, thus the conformance of the final cut to the desired angle is not always as close as the carpenter would like.
It is therefore desirable to provide a solution that permits a carpenter to make exact, on-the-spot time-efficient cross-cuts of their boards while holding the board in one-hand and the circular saw in the other hand.