Novel indole derivatives, pharmaceutical compositions containing these compounds and their use as inhibitors of the fatty acid synthase FabH are disclosed.

This invention relates to indole derivatives, pharmaceutical compositions containing these compounds and their use as inhibitors of the fatty acid synthase FabH and antibacterial agents.
The pathway for the biosynthesis of saturated fatty acids is very similar in prokaryotes and eukaryotes. However, although the chemical reactions may not vary, the organization of the biosynthetic apparatus is very different. Vertebrates and yeasts possess type I fatty acid synthases (FASs) in which all of the enzymatic activities are encoded on one or two polypeptide chains, respectively. The acyl carrier protein (ACP) is an integral part of the complex. In contrast, in most bacterial and plant FASs (type II) each of the reactions are catalyzed by distinct monofunctional enzymes and the ACP is a discrete protein. Mycobacteria are unique in that they possess both type I and II FASs; the former is involved in basic fatty acid biosynthesis whereas the latter is involved in synthesis of complex cell envelope lipids such as mycolic acids. There therefore appears to be considerable potential for selective inhibition of the bacterial systems by broad spectrum antibacterial agents (Jackowski, S. 1992. In Emerging Targets in Antibacterial and Antifungal Chemotherapy. Ed. J. Sutcliffe and N. Georgopapadakou. Chapman and Hall, New York: Jackowski, S. et al. (1989). J. Biol. Chem. 264, 7624-7629.)
The first step in the biosynthetic cycle is the condensation of malonyl-ACP with acetyl-CoA by FabH. In subsequent rounds malonyl-ACP is condensed with the growing-chain acyl-ACP (FabB and FabF, synthases I and II respectively). The second step in the elongation cycle is ketoester reduction by NADPH-dependent xcex2-ketoacyl-ACP reductase (FabG). Subsequent dehydration by xcex2-hydroxyacyl-ACP dehydrase (either FabA or FabZ) leads to trans-2-enoyl-ACP which is in turn converted to acyl-ACP by NADH-dependent enoyl-ACP reductase (FabI). Further rounds of this cycle, adding two carbon atoms per cycle, eventually lead to palmitoyl-ACP whereupon the cycle is stopped largely due to feedback inhibition of FabH and I by palmitoyl-ACP (Heath. et al. (1996). J.Biol.Chem. 271, 1833-1836). Fab H is therefore a major biosynthetic enzyme which is also a key regulatory point in the overall synthetic pathway (Heath, R. J. and Rock. C. O. 1996. J.Biol.Chem. 271. 1833-1836; Heath, R. J. and Rock, C. O. 1996. J.Biol.Chem. 271, 10996-11000).
The antibiotic thiolactomycin has broad-spectrum antibacterial activity both in vivo and in vitro and has been shown to specifically inhibit all three condensing enzymes. It is non-toxic and does not inhibit mammalian FASs (Hayashi, T. et al.,1984. J. Antibiotics 37, 1456-1461. Miyakawa. S. et al., 1982. J. Antibiotics 35, 411-419; Nawata, Y et al., 1989. Acta Cryst. C45, 978-979; Noto, T. et at., 1982. J. Antibiotics 35, 401-410; Oishi, H. et al., 1982. J. Antibiotics 35, 391-396. Similarly, cerulenin is a potent inhibitor of FabB and F and is bactericidal but is toxic to eukaryotes because it competes for the fatty-acyl binding site common to both FAS types (D""Agnolo. G. et al.,1973. Biochim. Biophys. Acta. 326, 155-166). Extensive work with these inhibitors has proved that these enzymes are essential for viability. Little work has been carried out in Gram-positive bacteria.
There is an unmet need for developing new classes of antibiotic compounds that are not subject to existing resistance mechanisms. No marketed antibiotics are targeted against fatty acid biosynthesis, therefore it is unlikely that novel antibiotics of this type would be rendered inactive by known antibiotic resistance mechanisms. Moreover, this is a potentially broad spectrum target. Therefore, FabH inhibitors would serve to meet this unmet need.
This invention comprises indole derivatives and pharmaceutical compositions containing these compounds, and their use as FabH inhibitors which are useful as antibiotics for the treatment of Gram positive and Gram negative bacterial infections. This invention further constitutes a method for treatment of a Gram negative or Gram positive bacterial infection in an animal, including humans, which comprises administering to an animal in need thereof, an effective amount of a compound of this invention.
The compounds of this invention are represented by Formula (I):
wherein:
R is xe2x80x94N(R1)xe2x80x94C(R2)Hxe2x80x94CO2H or
Q is O or CH2;
R1 is hydrogen or C1-5 alkyl;
R2 is hydrogen, C1-5alkyl, (CH2)nR3, CH(OH)CH3;
R3 is OH, CO2R1, CONH2, NH2, CH(OH)(CH2)nNH3, NHxe2x80x94C(NH)NH2,xe2x80x94SH, xe2x80x94SCH3 or phenyl which may be substituted or unsubstituted by OH:
R4 is hydrogen or OH;
n is an integer from 1to 5;
or a pharmaceutically acceptable salt thereof.
Also included in the invention are pharmaceutically acceptable salt complexes.
When used herein the terms xe2x80x98alkylxe2x80x99 includes straight and branched chain groups containing from 1 to 5 carbon atoms, such as methyl, ethyl, propyl and t-butyl.
The compounds of this invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. The compounds may be in the D or L form. All of these compounds and diastereomers are contemplated to be within the scope of the present invention.
Some of the compounds of this invention may be crystallised or recrystallised from solvents such as organic solvents. In such cases solvates may be formned. This invention includes within its scope stoichiometric solvates including hydrates as well as compounds containing variable amounts of water that may be produced by processes such as lyophilisation. All polymorhphs are also included.
Since the antibiotic compounds of the invention are intended for use in pharmaceutical compositions it will readily be understood that they are each provided in substantially pure form, for example at least 60% pure, more suitably at least 75% pure and preferably at least 85%, especially at least 95% pure, particularly at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds should contain at least 1%, more suitably at least 5% and preferably from 10 to 49% of a compound of the formula (I) or salt thereof.
Preferred compounds have Q as O and R is alanyl, prolyl, valyl, isoleucyl or leucyl. The L isomers are preferred. Especially preferred is prolyl. n-methyl alanyl, and leucyl.
Preferred compounds are:
N-methyl-1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-alanine amide:
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-proline amide;
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-alanine amide;
(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-leucine amide;
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-valine amide: and
1-(6-chloro-3,4-methylenedioxybenzyl)-5-(2,6-dichlorobenzyloxy)indole-2-carboxy-L-isoleucine amide.
Compounds of the formula I wherein Q is O are prepared by the method described in Schemes 1 and 2.
a) 6-chloropiperonyl chloride, NaH, DMF; b) 10% Pd/C, H2, EtOAc; c) 2,6 dichlorobenzyl bromide, NaH, DMF; d) KOH, EtOH/THF, reflux Indole ester 1-Scheme-1(Aldrich) and a base (such as sodium hydride) are treated with a solvent (such as DMF) and then 6-chloropiperonyl chloride is added and stirred (6 hours to 30 hours, preferably 20 hours) to yield 2-Scheme-1. 2-Scheme-1 is dissolved in a solvent (such as ethyl acetate) and treated with 10% Palladium on charcoal and the resulting mixture shaken (6 hours to 30 hours, preferably 20 hours) to yield 3-Scheme-1. Alkylation of 3-Scheme-1 with 2,6-dichlorobenzyl bromide using a base (such as sodium hydride) in a solvent (such as DMF) provides 4-Scheme-1. Saponification of 4-Scheme-1 with a base (such as potassium hydroxide) in a solvent (such as ethanol and tetrahydrofuran) provides 5-Scheme-1.
a) 1. amino acid ester hydrochloride, BOP, TEA, CH2Cl2; 2. LiOH, THF/MeOH 1-Scheme-2 is treated with an amino acid hydrochloride ester (such as L-alanine ethyl ester hydrochloride) and a coupling agent (such as BOP Reagent. Aldrich) and a base (such as triethyl amine) in a solvent (such as methylene chloride). Saponification of the resulting ester with a base (such as lithium hydroxide) in a solvent (such as methanol and THF) yields 2-Scheme-2.
FabH Inhibition
The assay is designed to measure IC50s against Streptococcus pneumoniae xcex2-ketoacyl-ACP synthase III (FabH). Substrates malonyl-ACP, [14 C]-acetyl-coA are combined with FabH to produce [14C]-acetoacetyl-ACP.
1) Compile all reagents minus enzyme and aliquot onto a 96 well plate already containing inhibitors.
2) Dilute FabH into assay buffer with 1 mM beta-mercaptoethanol and add to the plate to start the reaction. and incubate at 37C. for 40 minutes.
3) Stop reactions with 150ul 10%TCA.
4) Pre-wet GF/C filter mat with 10%TCA, filter stopped reactions, rinse wells with 150 ul of 10%TCA twice and filter.
5) Oven dry filter mat at 60C., seal filter mat in a clear plastic bag, add Betaplate scintillation cocktail and count with Wallac Microbeta liquid scintillation counter.
Antimicrobial Activity Assay
Whole-cell antimicrobial activity was determined by broth microdilution using the National Committee for Clinical Laboratory Standards (NCCLS) recommended procedure, Document M7-A4. xe2x80x9cMethods for Dilution Susceptibility Tests for Bacteria that Grow Aerobicallyxe2x80x9d (incorporated by reference herein). The compound was tested in serial two-fold dilutions ranging from 0.06 to 64 mcg/ml. A panel of 12 strains were evaluated in the assay. This panel consisted of the following laboratory strains: Staphylococcus aureus Oxford, Streptococcus pneumoniae R6. Streptococcus pyogenes CN10, Enterococcus faecalis I, Haemophilus influenzae Q 1. Escherichia coli DC0, E. coli ESS. E. coli 7623 (AcrAB+) E. coli 120 (AcrABxe2x88x92) Klebsiella pneumoniae E70, Pseudomonas aeruginosa K799wt and Candida albicans GRI 681. The minimum inhibitory concentration (MIC) was determined as the lowest concentration of compound that inhibited visible growth. A mirror reader was used to assist in determining the MIC endpoint.
The present invention also provides a pharmaceutical composition which comprises a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof and a pharmaceutically acceptable carrier. The compositions of the invention include those in a form adapted for oral, topical or parenteral use and may be used for the treatment of bacterial infection in mammals including humans.
The antibiotic compounds according to the invention may be formulated for administration in any convenient way for use in human or veterinary medicine, by analogy with other antibiotics.
The composition may be formulated for administration by any route, such as oral, topical or parenteral, especially oral. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form. and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatin, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories will contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilised before filling into a suitable vial or ampoule and sealing. The solution preferably contains a buffer (such as phosphate) to keep the pH in the range of about 3.5 to 7. DMSO or alcoholic solvents may also be present (at concentrations such as 0.01 to 10 mL/liter) to aid solubility and penetration of the compound of Formula (I).
Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilized powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilization cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. Where the compositions comprise dosage units, each unit will preferably contain from 50-500 mg of the active ingredient. The dosage as employed for adult human treatment will preferably range from 1 to 140 mg/kg of body weight, depending on the route and frequency of administration..
No unacceptable toxicological effects are expected when a compound of formula (I) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof is administered in the above-mentioned dosage range.
The compound of formula (I) may be the sole therapeutic agent in the compositions of the invention or a combination with other antibiotics or compounds which enhance the antibacterial activity of a compound of formula (I)may be employed.
The antibiotic compounds of the present invention are active against a wide range of organisms including both Gram-negative organisms such as Escherichia coli and Klebsiella pneumoniae and Gram-positive organisms such as Staphylococcus aureus, Streptococcus pneumoniae, Enterococcus faecalis and Enterococcus faecium, including isolates resistant to existing antibiotics.


An umbrella rib assembly includes a top rib pivotally connected with a stretcher rib both being made of aluminum alloy for light weight and easy processing; a middle rib pivotally secured to the stretcher rib and a tail rib pivotally connected with the middle rib, with the middle rib and the tail rib being made of light weight carbon-fiber-reinforced plastics.

This application is an improvement of U.S. Pat. No. 5,931,175 (hereinafter called xe2x80x9cthe prior patentxe2x80x9d) issued to the same inventors of this application.
The prior patent disclosed an umbrella rib assembly including a top rib made of light material including aluminum alloy and an outer rib made of composite or plastic materials having good resilience and mechanical strength to be connected with the top rib. However, such a rib assembly is not suitable for forming a multiple-fold umbrella having three or two folds.
The present inventor has found the limitation of the prior patent and invented the present rib assembly provided for multiple-fold umbrella.
The object of the present invention is to provide an umbrella rib assembly including a top rib pivotally connected with a stretcher rib both being made of aluminum alloy for light weight and easy processing; a middle rib pivotally secured to the stretcher rib and a tail rib pivotally connected with the middle rib, with the middle rib and the tail rib being made of light weight carbon-fiber-reinforced plastics.

Multiple-fold umbrella rib assembly having inner ribs of aluminum alloy and outer ribs of carbon-fiber-reinforced plastics


A detector device for detecting the locking state of a seat belt lock, such as for an automobile restraint system, is disclosed, which has a swivel lever that is designed like a strap and that is hinged to a switch housing via a swivel axis (A) that is arranged eccentrically and that has at least one operating arm projecting from the swivel axis (A), which arm extends above the switch housing and can move into a second end position by interaction with a component of a locking mechanism of the seat belt lock that can move in translation against a return force from a first end position, in which its at least one operating arm extends above the switch housing. The detector device has a sensor device for detecting the change in position of a section of the swivel lever that can swivel from the starting position into its laterally and vertically changed end position.

In restraint systems, for example in automobiles, it should be ensured for the proper operation of safety devices, such as front, knee, side and/or head airbags, that a restraint system provided in the motor vehicle is also used by a passenger and is also properly locked when the same is being used. Otherwise, the safety devices, such as airbag devices, could even lead to injuries of the affected passenger in the case of a collision. It has already been proposed to check the locking state of a latch of a seat belt inserted into a seat belt lock. From knowing the locking state of the seat belt, for example, signals can be generated to alert the passengers by way of a signal that they should put on and latch the seat belt. Ever since the introduction of airbag devices, the information on the locking state of the seat belt system has also become relevant to the activation or deactivation of mechanisms for inflating driver and passenger airbags or knee, side and head airbags.
Hall sensors are widely used as proximity switches or as sensors for non-contact determination of the state of components, which can occupy two positions. In principle, Hall sensors include (e.g., consist of) a semiconductor layer that is provided with constant current, such as in an integrated design. The constant current is influenced by a magnetic field component perpendicular to the semiconductor layer, and the sensor yields a Hall voltage that can be analyzed, that can be tapped off and that can be used to analyze a state or else can be employed directly as turn-on voltage. The integrated design of Hall sensors offers the possibility of integrating on the Hall sensor an analysis circuit that is suitable for analyzing the switch state.
From EP-A-0 861 763, a seat belt lock with an integrated prestressed Hall sensor is known, which detects, in a non-contact manner, the state of a locking body or an ejector for a lock latch introduced into the seat belt lock. In this case, a Hall sensor is arranged with a Hall field in the immediate vicinity of a permanent magnet. By a change in position of the locking body or the ejector, which to this end includes (e.g., consists of) a ferromagnetic material, the magnetic field of the permanent magnet is changed. As a result, the signal of the Hall signal is changed, and at the output of the Hall sensor, the change in state can be tapped off as a change in voltage. In an alternative variant embodiment, it is proposed to install the Hall sensor with a Hall field without a permanent magnet and for this purpose to design the locking body or the ejector as a permanent magnet. Also, in this arrangement, the change in position of the locking body or the ejector is to be detectable by a change in the Hall voltage.
In the seat belt lock according to EP-A-0 861 763, the Hall sensor is to be positioned very carefully relative to the locking element or the ejector. A subsequent incorporation of the Hall sensor can therefore be relatively labor-intensive and costly. In addition, the Hall sensor is relatively sensitive compared to outside scatter fields, which can even be caused by, for example, a magnetic key attachment. Optionally, even an additional shield should be attached, which can further complicate the design or incorporation. The susceptibility relative to outside scatter fields is also still magnified in that the signal changes—because of the comparatively short distances that are covered by the locking body or the ejector during the closing or opening of the seat belt locking—are relatively small. Also, the seat belt lock variants without prestressed Hall sensors, in which either the locking body or the ejector is designed as a permanent magnet, have proven to be not very practicable. The signal changes that can be achieved are also relatively small here. By the vibrations of the locking body and the ejector when the seat belt lock is opened and closed, a demagnetization can result over time. This can ultimately lead to the fact that the Hall sensor is ineffective, and the changes in state of the seat belt lock can no longer be detected.
To reduce fuel consumption, major efforts are being undertaken to reduce the weight of inserts and attachments of motor vehicles. To this end, inserts, such as, e.g., seat belt locks of restraint systems, are also made smaller. Because of the smaller space available, the devices for detecting the locking state of the seat belt locks should also be modified. With respect to the desired robustness of the devices, to ensure up to, for example, 100,000 cycles of operation, such modifications are not trivial.

Detector device for detecting the locking state of a seat belt lock, insert, and seat belt lock equipped with a detector device


There is provided Y-type hexagonal ferrite having a high density of sintered body and a low level of loss and an antenna.

In recent years, as miniaturized, high-speed, high-frequency electronic apparatuses have been introduced, circuit components used in such apparatuses need to have characteristics usable in a range from several hundreds of MHz to several GHz. For example, impedance elements for noise reduction need to maintain high impedance in the above high frequency band. As another example, communication apparatuses, such as mobile phones and wireless LANs, operate in a frequency band ranging from several hundreds of MHz to several GHz and need to be able to operate in a wide band and to have high efficiency in that band. Antennas used in such communication apparatuses also need to function with high gain in the above band in the first place, and need to be compact and low-profile from the viewpoint of their usage. Furthermore, in the digital terrestrial broadcasting, which has recently commenced, antennas to be used need to cover a wide frequency band ranging from 470 MHz to 770 MHz in order to receive all channels. In the present application, it is noted that the description of "a to b" means "equal to or greater than a and equal to or smaller than b."
As a compact, low-profile antenna suitable for the above-mentioned communication apparatuses, such as mobile phones, a so-called chip antenna based on dielectric material has been conventionally used (Patent Reference 1). At a fixed frequency, use of dielectric material with a higher dielectric constant allows reduction in the size of the chip antenna. There has also been proposed a chip antenna using magnetic material with high magnetic permeability as well as a high dielectric constant to reduce the size of the antenna (Patent Reference 2).
When magnetic material is used for a chip antenna, for example, spinel ferrite, such as Ni—Zn ferrite, has so-called Snoek's limit, which limits use of spinel ferrite in high frequency regions. In contrast, since hexagonal ferrite has an easy magnetization axis in a plane perpendicular to the c axis and hence maintains predetermined magnetic permeability even in a frequency b or higher than the frequency limit of spinel ferrite (Snoek's limit), so that hexagonal ferrite has been proposed as one of magnetic materials for chip antennas (Patent Reference 3). Patent Reference 3 discloses that Z-type ferrite in which most of particles have a single domain structure is particularly used in a high frequency region in an effective manner.
Although not particularly limited to the chip antenna application, Patent Reference 4 discloses, as a material for high frequency circuit components, magnetic oxide sintered body mainly made of Y-type hexagonal ferrite, occupying at least 80% of the composition, for the purpose of increasing the resistivity and lowering the dielectric constant. The magnetic oxide sintered body contains cobalt oxide, copper oxide and iron oxide as main components and AO (AO stands for at least one of BaO and SrO) for the remaining part, and also contains borosilicate glass and the like as sub-components.
Patent Reference 1: JP-A-2001-358516
Patent Reference 2: JP-A-49-40046
Patent Reference 3: WO 96/15078
Patent Reference 4: JP-A-2002-260912

Hexagonal ferrite, antenna using the same and communication apparatus

Abstract: The hexagonal ferrite having Y-type ferrite as the main phase is characterized in that main components of the hexagonal ferrite are M1O (M1 stands for at least one of Ba and Sr), M2O (M2 stands for at least one of Co, Ni, Cu, Zn and Mn) and Fe2O3, and the loss factor and the density of sintered body are 0.15 or lower and 4.6×103 kg/m3 or higher, respectively. The hexagonal ferrite is used to configure an antenna and a communication apparatus.


A portable fan assembly adapted for seatmant on a vehicular surface in a spaced apart relationship to a child car seat, comprising a front portion, a back portion, two side portions, a top portion, and a bottom portion. An interior void is positioned centrally within the assembly, extending from the front portion to the back portion. A fan unit having a housing that is positioned within the interior void. The housing includes a central hub and at least a pair of fan blades that are mounted to the hub. The hub is rotationally connected by an elongated shaft to a fan motor configured to be operative for rotating the fan blades for directing air through the interior void. The front portion, back portion, two side portions, the top portion, and the bottom portion are substantially padded for providing a cushioning effect that prevents injury to an child situated in close proximity to the assembly, and at least one attachment strap configured to securely position the assembly to a vehicular seat.

When a child under a certain age, as determined by law, travels in a motor vehicle, the child is required to be securely fastened within a child safety seat to prevent injury in the unfortunate, but occasional, vehicle accident. Child safety seats are designed, and in most instances required by law, to be positioned within the back seat of a motor vehicle. As a result, the child is substantially blocked from any direct air flow supplied by the vehicle's ventilation system by the seat backs of the front seats. In other instances the occupants of the front seat might not desire air flow, causing the air in the back of the car to become stagnated and undesirable for a child. Having a fan running near a sleeping infant was associated with a 72 percent decrease in the risk of sudden infant death syndrome, or SIDS, researchers reported in the Archives of Pediatrics and Adolescent Medicine. The study suggests that the fan use might reduce the risk for SIDS by decreasing rebreathing and increasing dispersion of carbon dioxide in the infant's airway. This may be advantageous for infants sleeping while traveling in a car as well. Furthermore, many children can become preoccupied by a rotating object, such as a fan, resulting in a more enjoyable ride for the older occupants of the vehicle.


A preform for a connecting rod of an engine is manufactured with a good productivity. The preform has a large-end mass portion which corresponds to a large-end portion of the connecting rod, a small-end mass portion which corresponds to a small-end portion thereof, and a shaft portion which corresponds to a rod portion thereof. There is manufactured a preform blank which has a shaft-shaped portion which is formed by extrusion. This shaft-shaped portion is made up of the shaft portion and an extended portion which extends axially forward from the shaft portion. The small-end mass portion is formed by squeezing the extended portion in the axial direction in a plurality of times starting with a portion near the shaft portion.

1. Field of the Invention
The present invention relates to a method of manufacturing a preform for a connecting rod of an engine. The connecting rod has a large-end portion, a small-end portion, and a rod portion which lies between the large-end portion and the small-end portion. The preform is used as a raw material (or a blank) in forming the connecting rod by means of forging.
2. Description of Related Art
As a method of manufacturing a connecting rod of an engine, there has hitherto been known the following in Published Unexamined Japanese Patent Application No. 137640/1986. Namely, in the method, a preform having a shaft portion corresponding to the rod portion of the connecting rod, that large-end mass portion on one end of the shaft portion which corresponds to the large-end portion thereof, and that small-end mass portion on the opposite end of the shaft portion which corresponds to the small-end portion thereof is set inside a die of a forging die apparatus. The connecting rod is thus formed by forging. The preform is normally manufactured by swaging.
Forming by the process of swaging is sequentially performed while either a die or a blank is rotated. The preform for a connecting rod has a large difference in diameters between the large-end mass portion and the shaft portion. Therefore, there is a disadvantage in that the forming takes time and that the equipment becomes large in size.
In view of the above points, the present invention has an object of providing a method of manufacturing a preform for a connecting rod of an engine, in which the productivity can be improved.
In order to attain the above and other objects, the present invention is a method of manufacturing a preform for a connecting rod of an engine, the connecting rod having a large-end portion, a small-end portion, and a rod portion between the large-end portion and the small-end portion, the preform being used for forging the connecting rod and having a shaft portion corresponding to the rod portion, that large-end mass portion on one end of the shaft portion which corresponds to the large-end portion, and that small-end mass portion on the other end of the shaft portion which corresponds to the small-end portion, the method comprising the steps of: forming a preform blank comprising the large-end mass portion and a shaft-shaped portion, the shaft-shaped portion being formed by extrusion and including the shaft portion and an extended portion which extends axially forward from the shaft portion; and forming the small-end mass portion by squeezing the extended portion in the axial direction.
According to the present invention, the shaft portion which has a large difference in diameter relative to the large-end mass portion is formed by extrusion together with the extended potion which is converted into the small-end mass portion. Therefore, the forming of the shaft portion does not take much time and, therefore, the productivity of the preform is improved.
The upsetting ratio of the small-end mass portion (axial length of the extended portion required for forming the small-end mass portion/diameter of the extended portion) becomes relatively large. Therefore, at the time of squeezing, the extended portion is likely to give rise to buckling. Since buckling becomes the cause for poor forming such as the presence of biased material thicknesses, folds, or the like, it is preferable to prevent the occurrence of buckling. In this case, if the step of forming the small-end mass portion comprises squeezing the extended portion in a plurality of times starting with a portion near the shaft portion, the upsetting ratio per one time (length of squeezing of the extended portion/diameter of the extended portion) becomes small. As a result, the occurrence of buckling can be prevented, and the small-end mass portion can be formed at a higher accuracy.
The conventional large-end mass portion and the small-end mass portion are formed into a sphere or a circular column. This kind of preform is, however, poor in sitting stability. Therefore, the preform is likely to roll (or move) inside the die of the forging die apparatus out of an ordinary set position. Biased material thicknesses will thus occur due to this positional deviation, resulting in a poor forming accuracy of the connecting rod. As a solution, it is preferable in the step of forming the preform blank, the large-end mass portion is formed into a noncircular cross section having flat surfaces which are parallel with an axial line of the shaft portion, the flat surfaces being formed in a part along an outer periphery of the large-end mass portion. According to this arrangement, when the preform is set inside the die of the forging die apparatus, the flat surface of the large-end mass portion is caused to sit on the die surface. The preform is thus prevented from rolling inside the die. As a result, the biased material thicknesses due to the positional deviation of the preform can be prevented.

Method of manufacturing preform for connecting rod


A radar apparatus is disclosed which includes: a distance detecting part configured to detect, among plural bins, an existence distance bin in which the target object exists, a direction detecting process executing part configured to execute a process of detecting a direction in which the target object exists, with respect to a distance bin other than the existence distance bin detected by the distance detecting part, among plural bins from which relative distances to the target object can be calculated, if a predetermined criterion is met; an existence area detecting part configured to detect, based on an execution result of the direction detecting process executing part, an area in which the target object exists.

A radar apparatus is known which detects the target object by transmitting the radio wave in the forward direction of the vehicle and receiving the reflected wave of the transmitted radio wave generated by the reflection on the target object, and the detection result is used for preventing a collision with the target object such as a preceding vehicle, a oncoming vehicle, a wall, etc., or controlling the distance between the host vehicle and the preceding vehicle (see Patent Document 1, for example). According to the disclosed radar apparatus, reflection points are detected in plural directions. The reflection points, which are estimated to belong to the same target object, are classified into the same group. The lines defining the area of the target object are extracted based on an arrangement of the reflection points of the group. Therefore, according to the radar apparatus, the area of the target object can be detected.
[Patent Document 1] Japanese Laid-open Patent Publication No. 2000-206241


An apparatus for detecting flaws generated in the cut edges of cut glass plates is disclosed. The light emitted from a linear light source (11 and 21) and transmitted and reflected by a glass plate (1) is received by a one-dimensional imaging device (12 and 22), and the flaws in the cut edges of the glass plate are detected by a discriminator (13 and 24) based on the output voltage of the one-dimensional imaging device. The linear light source and the one-dimensional imaging device are disposed in such a manner that the longitudinal direction of the linear light source and the arranging direction of the imaging elements of the one-dimensional imaging device are parallel with each other, and that the longitudinal direction of the linear light source and the arranging direction of the imaging elements of the one-dimensional imaging device are oblique to the travelling direction of the glass plate on a plane parallel with the glass plate.

The manufacture of glass plates generally involves the cutting and sorting of glass plates out of a glass strip pulled up from molten glass bath in the furnace as the glass strip travels on a line conveyor at a constant speed. In cutting the glass strip, trimming lines are marked in the direction parallel with the strip travelling direction by means of a trimming-line marker, cutting lines are marked in the direction perpendicular to the strip travelling direction by means of a diagonal cutter, and then the strip is cut along the cutting lines by means of a breaker and along the trimming lines by means of a slitter. In cutting the glass strip into a glass plate, various flaws are often caused on the cut edges of the glass plate, including chips produced by gouging the glass plate in a fish-scale shape in the through-thickness direction of the glass plate, serrations produced by gouging the glass plate in the through-thickness direction, burrs outwardly protruding from the cut line of the glass plate, and notches inwardly notched from the cut line of the glass plate.
Glass plates having such so-called cut-edge flaws have to be discarded as rejects. Conventional methods for detecting cut-edge flaws include the following.
First comes detection by visual inspection. This involves throwing a light beam from under a glass plate travelling on a line conveyor and monitoring by visual inspection the shadow of the glass plate projected on a screen located above the glass plate. With this method, such flaws as chips and serrations can be easily detected as shadows because light transmission remarkably deteriorated at chips and serrations, resulting in remarkably lowered transmitted light volume, while burrs and notches, which cause less changes in the volume of transmitted light, do not appear as clearly discernible shadows, making it difficult to detect them. In addition, visual inspection by human eyes has its limitation in terms of detecting accuracy.
The prior art as shown in FIG. 1 is a cut-edge flaw detecting device which does not rely on visual inspection has such a construction that a fluorescent lamp 2 is disposed below a line conveyor carrying a glass plate 1. The fluorescent lamp 2 is positioned parallel with the plane of the glass plate 1 and perpendicular to the travelling direction of the glass plate 1, a plurality of 1024-bit one-dimensional CCD (charge-coupled device) cameras 3 are disposed above the line conveyor to receive the light emitted from the fluorescent lamp 2 and transmitted through the glass plate 1. The outputs of the cameras 3 being sent to a discriminator 4 incorporating a microcomputer for processing to discriminate flaws present in the cut edges of the glass plate 1.
In the following description, the travelling direction of a glass plate on a plane parallel with the glass plate is termed as the Y-axis direction, and the direction orthogonal to the travelling direction of the glass plate as the X-axis direction.
Since the one-dimensional CCD cameras 3 of the conventional cut-edge flaw detecting apparatus are disposed in such a manner that the direction in which CCD-elements are arranged coincides with the X-axis direction, the apparatus can detect only cut-edge flaws present on the trimmer sides 5, i.e., two sides parallel with the Y-axis direction, but cannot detect those on the breaker sides 6, i.e., the two other sides parallel with the X-axis direction. Furthermore, this method, which also uses the CCD camera 3 to receive transmitted light has low accuracy in detecting burrs and notches for the same reasons as described above.
The conventional cut-edge flaw detecting device, which judges the size of a cut-edge flaw based on the magnitude of the differentiation signal obtained by differentiating the output of the CCD camera 3, has low accuracy in judging the size of flaw because the size of the cut-edge flaw is not necessarily proportional to the size of the differentiation signal.

Apparatus for detecting cut-edge flaws in glass plates


Methods, systems, and media for generating and presenting supplemental content based on contextual information are provided. In some implementations, a method for presenting content to a user is provided, the method comprising: identifying a program based on first media data; identifying one or more keywords associated with the program; determining a popularity score associated with each of the one or more keywords; obtaining one or more properties associated with a particular keyword of the one or more keywords based on the popularity score associated with each keyword; generating supplemental content for the program based on the one or more properties; receiving a request for supplemental content and second media data from a computing device; and upon determining that the second media data corresponds to the program, causing the generated supplemental content to be presented by the computing device.

Many viewers are interested in interacting with the media content that they are viewing. In response, some content providers or other third parties have created applications for mobile devices that provide a viewer with a poll, a quiz, or other content relating to the programming provided by a particular content provider. For example, upon downloading an application corresponding to particular piece of media content (e.g., a particular television program), a viewer can use a mobile device to launch the content specific application which provides a quiz or other related content. This related content is often generated by a person that develops content for the content specific application relating to the particular content provided by the content provider.
However, generating content using these approaches can be costly and time consuming. In addition, some content does not have any associated supplemental content. This may disappoint some viewers and, in some cases, may cause certain viewers to cease watching the content that lacks associated supplemental content. Moreover, new content is constantly being distributed to viewers and, as such, it can be difficult to constantly generate new supplemental content.


A puncture assisting tool for assisting in a puncturing operation by a puncture tool that is used to insert and place a spacer between bones and includes an arc-shaped needle includes a base section configured to be in contact with a skin of a patient; and a guide unit configured to be fixed with respect to the base section. The guide unit has a curvature that is approximately the same as a curvature of an arc shape of the puncture tool. The guide unit is configured such that an outer arc-shaped surface of the puncture tool can be placed in contact with the guide unit to guide the puncture tool in an arc trajectory while the puncture tool is being inserted into the patient.

Technical Field
The present disclosure relates to a puncture tool assembly and a puncture assisting tool that assists in a puncturing of a puncture tool which is used to insert a spacer to be placed between bones.
Background Art
Lumbar spinal canal stenosis is a stenosis of a vertebral canal caused by a regressive degeneration of an intervertebral disk, a ligament, and the like, and causes symptoms such as lumbago, melosalgia, and intermittent claudication. In order to treat the lumbar spinal canal stenosis, a surgical operation through which a spinal column of a part that narrows the vertebral canal is partially incised (laminectomy) and a surgical operation through which the spinal column is fixed (spinal fusion) are in prevalent use. In recent years, a method of placing a metallic spacer between spinous processes and releasing compression of a spinal nerve and a nerve root was developed as a relatively more minimally invasive procedure than laminectomy and a spinal fusion. However, according to the method, a back muscle and ligament have to be incised in order to place the spacer, and thus the degree of an invasion to a patient is still high, and long-term hospitalization is caused.
In order to deal with the problem, a method for inserting and placing the spacer between the spinous processes in a further minimally invasive manner has been proposed. According to this method, an expandable balloon is used as the spacer. The balloon, in a folded state, is percutaneously inserted and placed between the spinous processes. Then, the balloon is filled with a filling material such as a bone cement so that the balloon is expanded,. The filling material is cured after the balloon is filled therewith, and thus the expansion state of the balloon can be maintained semi-permanently.
US Patent Application Publication 2011/0093013A1 discloses a device for inserting and placing a hard spacer between the spinous processes. The device includes an arc-shaped needle, and the arc-shaped needle is inserted into the skin and muscle of the patient so that the spacer, which is attached to a distal end of the needle, is inserted between the spinous processes. However, because the needle is arc-shaped, a force added on a proximal end side of the needle is not transmitted to the distal end of the needle, and it is difficult to insert the needle due to a deformation of the skin and a repulsive force from the skin.

Puncture assisting tool and puncture tool assembly


A method includes sending, by a user device, a request for video content based on a selected video content chapter of the video content. The method also includes receiving video content information that includes a list of video content chapters of the video content. The method includes determining, for each listed video content chapter, whether the video content chapter has been previously stored on the user device. The method further includes downloading particular chapters of the video content in a priority order based on the selected chapter in response to a determination that the particular chapters have not been previously stored on the user device, and playing the video content based on the selected chapter.

Video service providers currently provide multiple services and programs, including cable television, network television, and video-on-demand content, to their customers. Individual customers may receive combinations of these services from one or more video service providers. Video service providers manage relationships with their customers using customer accounts that correspond to the multiple services.


The present disclosure is directed to techniques for estimating network performance of a mobile device. The techniques include a performance logging module and a performance analysis module. The performance logging module logs realized network performance of previously performed network operations and the operational conditions of a mobile device at the time of the performed network operations. The performance analysis module receives requests to estimate network performance, the requests including the current condition of the mobile device at the time of the request. The performance analysis module determines a network performance estimate based on the current condition of the mobile device and the operational conditions of the previously performed network operations, and the realized network performances of the previously performed network operations. It is appreciated that the proposed techniques allow applications to execute faster, as the applications can tune network operations based on the network performance estimates.

This section provides background information related to the present disclosure which is not necessarily prior art.
Mobile devices are configured to execute a host of applications designed by a wide array of developers. Many of these applications are configured to send and receive data. For instance, such applications can include video streaming, audio streaming, video chat, file transfer, and messaging applications. The perceived quality of applications streaming large amounts of data can be adversely affected when the network performance, e.g., throughput or network delay, is suboptimal.
For example, a video streaming application may request a lower quality video stream or a photo sharing application may send a lower resolution photo when the network performance is suboptimal. These applications however try to determine the current network performance based solely on the current session or by performing diagnostics. Thus, if the application has just started executing or if the application has not been executing for a sufficient duration, the application cannot efficiently adjust network operations to compensate for the network condition of the mobile device. Thus, there is a need for an efficient means to estimate network performance.

System and method for estimating network performance


A mass memory system for digital computers is disclosed. The system has a plurality of disk drives coupled to a plurality of small buffers. An Error Correction Controller is coupled to a plurality of X-bar switches, the X-bar switches being connected between each disk drive and its buffers. Data is read from and written to the disk drives in parallel and error correction is also performed in parallel. The X-bar switches are used to couple and decouple functional and nonfunctional disk drives to the system as necessary. Likewise, the buffers can be disconnected from the system should they fail. The parallel architecture, combined with a Reed-Solomon error detection and correction scheme and X-bar switches allows the system to tolerate and correct any two failed drives, allowing for high fault-tolerance operation.

Field of the Invention
This invention is in the field of mass data storage systems for digital computers. Specifically, it is a control system for use with a plurality of disk drive memories, the memories being controlled in parallel and the control system being capable of detecting and correcting data transmission errors and disk drive failures without interrupting the operation of the system.


Disclosed herein is a method of using metaxalone. In one embodiment, the method comprises obtaining metaxalone from a container providing information that metaxalone affects the activity of a cytochrome p450 isozyme. In another embodiment, the method comprises informing a user that metaxalone affects the activity of a cytochrome p450 isozyme. Also included are articles of manufacture comprising a container containing a dosage form of metaxalone, wherein the container is associated with published material informing that metaxalone affects activity of a cytochrome p450 isozyme. Also disclosed are a method of treatment and a method of manufacturing a metaxalone product.

This application relates to metaxalone products for therapeutic purposes, and in particular to improved methods of use of metaxalone.
Metaxalone, 5-[(3,5-dimethylphenoxy)methyl]-2-oxazolidinone, is used as a skeletal muscle relaxant. The mechanism of action of metaxalone in humans has not been established but may be due to general central nervous system depression.
Metaxalone was approved by the U.S. Food and Drug Administration (FDA) in 1962 as an adjunct to rest, physical therapy, and other measures for the relief of discomforts associated with acute, painful musculoskeletal conditions, such as muscles in spasm. Metaxalone is marketed in the United States under the brand name SKELAXIN®. The dosage forms currently approved for marketing are tablets containing 400 milligrams (mg) or 800 mg of metaxalone. The currently recommended dose for adults and children over 12 years of age is 800 mg, three to four times a day.
Food can affect gastric emptying, and may also alter the release of an active agent from a dosage form, the solubilization of the active agent, and the transport of the active agent across the intestinal wall. For lipophilic, water-insoluble active agents, fatty meals can increase gastric residence time thereby increasing the time available for solubilization and also may enhance the solubilization of the active agent by the lipids contained in the meal. According to U.S. Pat. No. 6,407,128, evaluation of the effect of food on the pharmacokinetics of metaxalone showed that food increased the rate and extent of absorption of a 400 mg oral dosage form in humans.
Studies directed to possible interactions of metaxalone with other active agents have been limited. There have been no detailed studies of the specific enzymes involved in metabolism of metaxalone or of the inhibitory or inducing effects of metaxalone on any Phase I or Phase II metabolic enzymes. In particular, there appear to be no published studies of the inhibitory and inducing effects of metaxalone on particular human cytochrome p450 isozymes or the possible metabolism of metaxalone by particular human cytochrome p450 isozymes.
Several major enzymes and pathways are involved in drug metabolism. Pathways of drug biotransformation are usually divided into two major groups of reactions: Phase I and Phase II metabolism.
Some typical examples of Phase I metabolism include oxidation, hydrolysis and reduction. Examples of Phase I enzymes involved in oxidation reactions are the cytochrome p450 monooxygenase system, the flavin-containing monooxygenase system, alcohol dehydrogenase and aldehyde dehydrogenase, monoamine oxidase, and peroxidases for co-oxidation. Examples of Phase I enzymes involved in reduction are NADPH-cytochrome p450 reductase and reduced (ferrous) cytochrome p450. Examples of Phase I hydrolysis enzymes are epoxide hydrolase, esterases and amidases.
Phase II metabolism involves conjugation reactions. Typical conjugation reactions are glucuronidation, sulfation, amino acid conjugation, acetylation, methylation, and mercapturic acid conjugation. Examples of Phase II metabolic enzymes are glutathione S-transferases (GSTs), mercapturic acid biosynthetic enzymes (transpeptidases, peptidases, and N-acetylases), UDP-glucoron(os)yltransferases, N-acetyltransferases, amino acid N-acyl transferases, and sulfotransferases.
One of the most important groups of Phase I enzymes are the cytochrome p450 monooxygenase system enzymes. The cytochrome p450 enzymes are a highly diverse superfamily of enzymes. NADPH is required as a coenzyme and oxygen is used as a substrate. Each enzyme is termed an isoform or isozyme since each derives from a different gene.
Many members of the cytochrome p450 family are known to metabolize active agents in humans. Active agent interactions associated with metabolism by cytochrome p450 isoforms generally result from enzyme inhibition or enzyme induction. Enzyme inhibition often involves competition between two active agents for the substrate binding site of the enzyme, although other mechanisms for inhibition exist. Enzyme induction occurs when an active agent activates an enzyme or stimulates the synthesis of more enzyme protein, enhancing the enzyme's metabolizing capacity.
Cytochrome p450 isozymes identified as important in active agent metabolism are CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4. Examples of cytochrome p450 enzymes known to be involved in active agent interactions are the CYP3A subfamily, which is involved in many clinically significant active agent interactions, including those involving non-sedating antihistamines and cisapride, and CYP2D6, which is responsible for the metabolism of many psychotherapeutic agents, such as thioridazine. CYP3A4 and CYP1A2 enzymes are involved in active agent interactions involving theophylline. CYP2C9, CYP1A2, and CYP2C19 are involved in active agent interactions involving warfarin. Phenytoin and fosphenytoin are metabolized by CYP1A2, CYP2C9, CYP2C19, and CYP3A4; mexiletine is metabolized by CYP2D6 and CYP1A2; and propafenone is metabolized by CYP2D6, CYP3A4, and CYP1A2.
Additionally, several cytochrome p450 isozymes are known to be genetically polymorphic, leading to altered substrate metabolizing ability in some individuals. Allelic variants of CYP2D6 are the best characterized, with many resulting in an enzyme with reduced, or no, catalytic activity. Gene duplication also occurs. As a result, four phenotypic subpopulations of metabolizers of CYP2D6 substrates exist: poor (PM), intermediate (IM), extensive (EM), and ultrarapid (UM). The genetic polymorphisms vary depending on the population in question. For example, Caucasian populations contain a large percentage of individuals who are poor metabolizers, due to a deficiency in CYP2D6—perhaps 5–10% of the population, while only 1–2% of Asians are PMs. CYP2C9, which catalyzes the metabolism of a number of commonly used active agents, including that of warfarin and phenytoin, is also polymorphic. The two most common CYP2C9 allelic variants have reduced activity (5–12%) compared to the wild-type enzyme. Genetic polymorphism also occurs in CYP2C19, for which at least 8 allelic variants have been identified that result in catalytically inactive protein. About 3% of Caucasians are poor metabolizers of active agents metabolized by CYP2C19, while 13–23% of Asians are poor metabolizers of active agents metabolized by CYP2C19.
By understanding the unique functions and characteristics of Phase I and Phase II metabolic enzymes, physicians may better anticipate and manage active agent interactions and may predict or explain an individual's response to a particular therapeutic regimen.
There accordingly remains a need in the art for improved methods for the administration and use of metaxalone, in particular methods that take into account the effects of metaxalone on activity of Phase I and Phase II metabolic enzymes, including the cytochrome P450 isozymes.

Metaxalone products, method of manufacture, and method of use


This disclosure is directed to product merchandising systems that are designed to prevent brute force attempts to steal a product on display. The merchandising systems include security features that enhances the strength of the connection between a puck assembly and a base assembly and between the base assembly and a display surface. The merchandising systems are suited for withstanding brute force pulling attacks on the puck assembly and the base assembly.

Products are often merchandised to customers using merchandising systems that are designed and constructed to prevent theft of the products on display. FIGS. 1A and 1B show examples of a product display assembly 100 that includes a puck assembly 102 and a base assembly 104. The base assembly 104 can be secured to a display table or a shelf. A tether 110 connects the puck assembly 102 to the base assembly 104. A product such as an electronic device 106 is mounted on a top or upper surface of the puck assembly 102 so that the electronic device 106 can be securely displayed to customers in a store. The electronic device 106 may be a smart phone, a tablet computer, a camera, or a wearable device (e.g., smart watches). The puck assembly 102 is moveable between a rest position shown in FIG. 1A and a lift position shown in FIG. 1B. FIG. 1B also shows how the tether 110 connects the puck assembly 102 to the base assembly 104 when the puck assembly 102 is in the lift position. The tether 110 allows a customer to pick up, hold, and inspect the electronic device. To provide ease of handling, the tether 110 may be a retractable tether that is included as part of a retractable tether assembly.
However, typical display assemblies are unable to resist brute force attempts to steal a product on display. Such attempts include breaking a connection between the puck assembly 102 and the tether 110, breaking a connection between the tether 110 and base assembly 104, and/or breaking a connection between the base assembly 104 and display surface. In one example, a thief grabs the puck assembly 102 and pulls on the puck assembly 102 in an attempt to tear the puck assembly 102 away from the base assembly 104. While pulling on the puck assembly 102, the thief may also apply twisting and shearing forces to the puck assembly 102 and the tether 110. In another example, a thief grabs the base assembly 104 and applies strong pulling, twisting, and/or shearing forces to the base assembly 104 in an attempt to sever a connection between the base assembly 104 and the display surface. Through such brute force attacks, the connection between the puck assembly 102 and the tether 110, the connection between the tether 110 and the base assembly 104, and/or the connection between the base assembly 104 and the display surface may be broken, enabling the thief to make off with the product.

Product merchandising systems with enhanced security features


Efficient recursive audio processing of one or more input data streams using a multistage processor for performing one or more predetermined functions and programmable audio effects. A first stage performs a first predetermined function, such as frequency shifting function. Intermediate results are preferably mixed. The second stage applies programmable audio effects to the mixed data, such as a reverberation effect, and stores the second stage output in a destination mix bin. The second stage output is preferably transferred to a main memory accessible to a primary processor. The second stage output is directed back to the first stage of the multistage processor to perform a second predetermined function, such as three dimensional spatialization. The primary processor modifies parameters of the first predetermined function to efficiently perform dynamic operations, such as Doppler shifts and volume transitions between multiple sound sources and a mixture of those sounds as a single point source.

Many electronic devices include both a primary and a secondary processor. The primary processor is typically used to perform core functions of the electronic device. The secondary processor performs other functions, such as media processing, math co-processing, and other specialized functions, freeing the primary processor from such tasks. Typically, the hardware structure of the secondary processor is optimized to perform the desired specialized functions. For example, an audio processor may have a pipeline stage architecture that performs one or more predetermined functions on a stream of input audio data prior to applying programmable audio effects to the audio data.
A pipelined stage architecture is efficient for processing a stream of data, but may be inefficient for multiple streams of data. For instance, in performing a predetermined three-dimensional (3D) audio spatialization function on a single input data stream, an audio processor produces multiple outputs corresponding to multiple speakers (e.g., five speakers). Each of the multiple outputs is stored in local memory of the secondary processor at a separate location (sometimes referred to as a mix bin). The audio processor can then apply a programmable audio effect, such as reverberation, to the data passing through each mix bin. However, there is typically more than a single input data stream that must be processed for 3D audio spatialization. Thus, the total number of mix bins required to process 3D output data would be equal to the product of the number of input streams multiplied by the number of speakers. Unfortunately, the number of mix bins is usually limited on a secondary processor. Also, the same programmable audio effects are typically applied to each of the multiple outputs of the predetermined functions. Thus, a conventional use of a pipelined stage architecture results in inefficient processing of multiple input data streams.
It would be desirable to use the pipelined stage architecture for such audio processing, because of the low cost of the secondary processors. However, a technique is needed to improve the processing efficiency of secondary processors having one or more input data streams. It would also be desirable to modify parameters of one or more of the predetermined functions in relation to the output of the programmable audio effects. Another desirable objective would be to enable reprocessing of an output from the programmable audio effects through one or more of the predetermined functions.


A cylinder injection type fuel injection valve 1 has a valve body 10 of a hollow cylindrical shape, a valve seat 12 having a fuel injection nozzle 11 at its center, which is disposed at an end of the valve body 10, a hollow housing 2 having an end connected to the valve body, which is capable of coming to contact with and separating from the valve seat 12 so as to open and close the injection nozzle 11, a core 3 disposed in the housing 2 and a coil assembly 4 disposed around the core 3 and inside the housing to cause opening and closing operations of the valve body 10, wherein an O-ring 14 is fitted to a space defined by the housing 2 and the core 3, in which the coil assembly 4 is disposed, at a side to which a fuel pressure is applied, so that the pressure is not applied to the coil assembly, or wherein a sealing ring having a hollow cylindrical shape 17 is fitted to a space defined by the housing 2 and the core 3, in which the coil assembly 4 is disposed, at a side to which a fuel pressure is applied, and an O-ring 18 is disposed at each side of the inside and the outside of the sealing ring 17.

1. Field of the Invention
The present invention relates to a cylinder injection type fuel injection valve to be attached to a cylinder head in order to directly inject fuel into a combustion chamber in an internal combustion engine.
2. Discussion of Background
A conventional cylinder injection type fuel injection valve has a general structure in a combination of an injection valve body with a needle valve and a solenoid for operating the needle valve. The solenoid comprises a housing, a core, a coil assembly and O-rings for sealing fuel which are provided between the coil assembly and the housing and between the coil and coil assembly so as to prevent fuel from leaking.
FIG. 24 is a cross-sectional view partly omitted showing an example of a conventional cylinder injection type fuel injection valve wherein numeral 31 designates a coil, numeral 32 designates a mold portion in a coil assembly, numeral 33 designates a core, numeral 34 designates a housing, numeral 35 designates an armature, numeral 36 designates a valve unit, and numerals 37, 38 designate O-rings.
In such cylinder injection type fuel injection valve attached to the cylinder head of a fuel engine so that fuel is directly injected into a fuel chamber, a quicker response is required. Accordingly, in order to obtain a high response characteristic, the coil is so made as to have a low resistance of 5.OMEGA. or less, or to increase a voltage to be applied, or to employ both the techniques.
In employment of the above-mentioned techniques, however, when an intense current of, for example, 3A or higher is passed, there causes a fault in a driving circuit or insulation breakdown. Further, in a case that an intense current is continuously passed for a certain time or more, the coil 31 (FIG. 24) generates heat, and the mold portion 32 of the coil assembly is softened or molten, whereby a gap is produced at a portion other than the sealing portion in the coil assembly thereby resulting leakage of fuel, or a surface of elements at a portion A or a portion B is deformed thereby causing leakage of fuel.

Cylinder injection type fuel injection valve


Use of a compound of formula I

The present invention relates to a new use for a compound group comprising 2-amino-1,3-propanediol derivatives.
Compounds for use according to the invention are compounds of formula I
wherein
R1 is an optionally substituted straight- or branched carbon chain having 12 to 22 carbon atoms which may be optionally interrupted by an optionally substituted phenylene, and
each of R2, R3, R4 and R5, independently, is H or lower alkyl, in free form or in pharmaceutically acceptable salt form.
When the carbon chain as R1 is substituted, it is preferably substituted by halogen, nitro, amino, hydroxy or carboxy. When the carbon chain is interrupted by an optionally substituted phenylene, the carbon chain is preferably unsubstituted. When the phenylene moiety is substituted, it is preferably substituted by halogen, nitro, amino, methoxy, hydroxy or carboxy.
Such compounds are disclosed in EP-A1-627,406 the relevant disclosure of which, in particular with respect to the compounds, is incorporated herein by reference.
Preferred compounds of formula I are those wherein R1 is a straight or branched, preferably straight, chain alkyl having 13 to 20 carbon atoms, optionally substituted by nitro, halogen, amino, hydroxy or carboxy, and, more preferably those wherein R1 is phenylalkyl substituted by a straight or branched C6-14 alkyl chain optionally substituted by halogen and the alkyl moiety is a C6-14 alkyl optionally substituted by hydroxy. More preferably, R1 is phenyl-C1-6 alkyl substituted on the phenyl by a straight or branched, preferably straight, C6-14 alkyl chain. The C6-14 alkyl chain may be in ortho, meta or para, preferably in para.
Preferably each of R2 to R5 is H.
Examples of the pharmaceutically acceptable salts of the compounds of the formula (I) include salts with inorganic acids, such as hydrochloride, hydrobromide and sulfate, salts with organic acids, such as acetate, fumarate, maleate, benzoate, citrate, malate, methanesulfonate and benzenesulfonate salts, and when a carboxy group is present, salts with metals such as sodium, potassium, calcium and aluminium, salts with amines, such as triethylamine and salts with dibasic amino acids, such as lysine. The compounds and salts of the present invention encompass hydrate and solvate forms.
When the compounds of formula I have one or more asymmetric centers in the molecule, the present invention is to be understood as embracing the various optical isomers, as well as racemates, diastereoisomers and mixtures thereof are embraced.
Particularly preferred compounds of formula I are 2-amino-2-tetradecyl-1,3-propanediol and especially 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol, (hereinafter Compound A) e.g. in hydrochloride form.
Compounds of formula I have, on the basis of observed activity, e.g. as described in EP-A1-627,406 been found to be useful e.g. as immunosuppressant, e.g. in the treatment of acute allograft rejection.
Organ transplants of liver, kidney, lung and heart are now regularly performed as treatment for endstage organ disease. Allograft as well as xenograft transplants have been performed. However, because of problems with long-term chronic rejection, organ transplantation is not yet a permanent solution to irreversible organ disease. Chronic rejection, which manifests as progressive and irreversible graft dysfunction, is the leading cause of organ transplant loss, in some cases already after the first postoperative year. The clinical problem of chronic rejection is clear from transplantation survival times; about half of kidney allografts are lost within 5 years after transplantation, and a similar value is observed in patients with a heart allograft.
Chronic rejection is considered as a multifactorial process in which not only the immune reaction towards the graft but also the response of the blood vessel wall in the grafted organ to injury (xe2x80x9cresponse-to-injuryxe2x80x9d reaction) plays a role. The variant of chronic rejection with the worst prognosis is an arteriosclerosis-like alteration, also called transplant vasculopathy graft vessel disease, graft atherosclerosis, transplant coronary disease, etc. This vascular lesion is characterized by migration and proliferation of smooth muscle cells under influence of growth factors, that are amongst others synthesized by endothelium. It appears to progress also through repetitive endothelial injury induced amongst others by host antibody or antigen-antibody complexes, through intimal proliferation and thickening, smooth muscle cell hypertrophy repair, and finally to gradual luminal obliteration. Also so-called non-immunological factors like hypertension, hyperlipidemia, hypercholesterolemia etc. play a role.
Chronic rejection appears to be inexorable and uncontrollable because there is no known effective treatment or prevention modality. Thus, there continues to exist a need for a treatment effective in preventing, controlling or reversing manifestations of chronic graft vessel diseases.
In accordance with the present invention, it has now surprisingly been found that compounds of formula I in free form or in pharmaceutically acceptable salt form inhibit graft vessel disease and are particularly indicated to prevent or treat chronic rejection in a transplanted organ.
Furthermore, it has also been found that compounds of formula I in free form or in pharmaceutically acceptable salt form suppress xenograft rejection. In accordance with the particular findings of the present invention, there is provided:
1.1. A method of preventing or treating manifestations of chronic rejection, e.g. to avoid, reduce or restrict chronic rejection, in a recipient of organ or tissue allo- or xeno-transplant, e.g. heart, lung, combined heart-lung, liver, kidney or pancreatic transplant, comprising the step of administering to said recipient a therapeutically effective amount of a compound of formula I in free form or in pharmaceutically acceptable salt form;
1.2. A method of preventing or treating graft vessel diseases, e.g. transplant vasculopathy, arteriosclerosis or atherosclerosis, in a recipient of organ or tissue allo- or xeno-transplant, e.g. heart, lung, combined heart-lung, liver, kidney or pancreatic transplants, comprising the step of administering to said recipient a therapeutically effective amount of a compound of formula I in free form or in pharmaceutically acceptable salt form;
In a series of further specific or alternative embodiments, the present invention also provides:
2. A method of preventing or controlling acute rejection in a xenograft transplant recipient, e.g. a patient receiving a heart, lung, combined heart-lung, kidney, liver, bone marrow, pancreatic bowel, skin or corneal xenotransplant, comprising administering to said recipient a therapeutically effective amount of a compound of formula I in free form or in pharmaceutically acceptable salt form.
As alternative to the above the present invention also provides:
3. A compound of formula I in free form or in pharmaceutically acceptable salt form for use in any method as defined under 1 or 2 above; or
4. A compound of formula I in free form or in pharmaceutically acceptable salt form for use in the preparation of a pharmaceutical composition for use in any method as defined under 1 or 2 above; or
5. A pharmaceutical composition for use in any method as defined under 1 or 2 above comprising a compound of formula I in free form or in pharmaceutically acceptable salt form together with one or more pharmaceutically acceptable diluents or carriers therefor.
Utility of the compounds of formula I in free form or in pharmaceutically acceptable salt form in chronic rejection, as well as utility in treating diseases and conditions as hereinabove specified, may be demonstrated in animal tests for example in accordance with the methods hereinafter described, as well as in clinic where e.g. the transplanted organ or tissue may be submitted to regular biopsy controls and in the case of heart transplant additionally to ultrasound scanning.
A. Prevention of Graft Vessel Disease
Experimental animals:
Inbred rat strains DA (RT1a, donors) and Lewis (RT11, recipients of allografts), weighing between 200 and 350 grams are used. The animals are allowed unrestricted access to food and water before and after the operation.
Carotid artery transplantation:
The rats are anaesthetised with isofluorane (Abbott), (4-5% for induction, 1.5-2% for maintenance) and 300 xcexcg atropin sulphate is injected subcutaneously following the induction. The left carotid artery is dissected free. The artery is clamped proximally and distally and a segment of about 7-10 mm is removed. The gap is bridged by an allograft which had also been subjected to 45 min cold ischemia. Ethilon 10/o sutures are used. Finally the skin is closed with 4/0 sutures. If needed, an Alzet osmotic minipump (Alza Corp. Palo Alto, Calif.) is then implanted subcutaneously over the back (alternatively the animals are treated orally).
The rats are subject to one of the following treatments: A compound of formula I alone at the doses of 0.1 to 10 mg/kg, or in combination with Cyclosporin A at the dose of 0.03, 0.3, or 1 mg.kgxe2x88x921xc2x7dayxe2x88x921 is administered for 8 weeks either by using Alzet osmotic minipumps implanted subcutaneously or alternatively by oral administration. At 8 weeks the rats are sacrificed, the carotid arteries are perfused for 1 min with 0.1 M phosphate buffered saline solution (PBS, pH 7.4) and then for 15 min with 2.5% glutaraldehyde in phosphate buffer (pH 7.4). The carotid arteries are then excised and stained in Giemsa solution for histological evaluation. Morphometric analysis includes the measurement of the thickness of the media and intima. A qualitative analysis of the morphological changes includes a scoring on an 0-3 scale for adventitial infiltration of mononuclear cells and necrosis (vacuolar degeneration, hypertrophy of cells), the number of smooth muscle cells (SMC) nuclei in the media (0-10,  less than 100,  greater than 100 and  greater than  greater than 100 nuclei for scores, 0, 1, 2 and 3 respectively, SMC necrosis (vacuolar degeneration and hypertrophy of SMC) and the intimal infiltration of mononuclear cells (13).
In both experiments, the compounds of formula I, particularly Compound A in hydrochloride form, significantly inhibit graft infiltration and neointima formation.
B. In vivo heart xenotransplantation (hamster-to-rat)
The hamster-into-rat xenograft combination is a so-called difficult concordant combination. Rats do not have natural anti-hamster antibody in sufficient amounts to yield immediate hyperacute rejection as observed in concordant combinations; however, rejection in untreated recipients occurs within 3-4 days, by antibodies in combination with complement. This is visualized in histology by destruction of blood vessels, exsudation and extravasation of erythrocytes, and influx by polymorphonuclear granulocytes; often there are signs of hemorrhage and thrombosis. Once this rejection has been overcome by effective inhibition of antibody synthesis or complement inactivation, a cellular rejection can emerge later on. This is visualized in histology by influx of mononuclear cells, including lymphocytes, lymphoblastoid cells, and macrophages, and destruction of the myocyte parenchyma. The inhibition of cellular rejection requires more immuno-suppression than that of allografts. Congenitally athymic (rnu/rnu) rats lack a competent (thymus-dependent) cellular immune system and generally are unable to reject allografts. Such animals do reject a hamster xenograft within 3-4 days in a similar fashion as euthymic rats, indicative that (at least part of) anti-hamster antibody synthesis in rats occurs following a thymus-independent B-cell response. Such recipients are useful in hamster xenografting to evaluate rejection by thymus-independent antibody-mediated rejection.
The heart of a Syrian hamster is heterotopically transplanted in the abdomen of a male Lewis (RT1xe2x80x2) rat with anastomoses between the donor and recipient""s aorta and the donor right pulmonary artery to the recipient""s inferior vena cava. The graft is monitored daily by palpation of the abdomen. Rejection is concluded in case of cessation of heart beat. Animals are weighed weekly. In the present series of experiments, the endpoint is set to 28 days. Animals are subjected to autopsy; apart from the graft, weight and histology is assessed for thymus, spleen, liver, seminal vesicles and testes. Blood is taken and processed to serum for the determination of cytolytic anti-hamster erythrocyte antibody and hemolytic complement activity.
Compounds are dissolved in water and administered daily orally in a volume of 2 ml/kg body weight. Administration of 5-30 mg/kg/day, of a compound of Formula I, e.g. Compound A in hydrochloride form, results in prolonged graft survival, in both athymic and euthymic recipients.
Daily dosages required in practicing the method of the present invention will vary depending upon, for example, the compound of formula I employed, the host, the mode of administration, the severity of the condition to be treated, and the optionally concomitantly used immunosuppressive drug e.g. CysA. A preferred daily dosage range is about from 0.03 to 2.5 mg/kg per day, particularly 0.1 to 2.5 mg/kg per day, e.g. 0.5 to 2.5 mg/kg per day as a single dose or in divided doses. Suitable daily dosages for patients are on the order of from e.g. 1 to 100 mg p.o. Suitable unit dosage forms for oral administration comprise from ca. 1 to 50 mg, usually 5 to 30 mg active ingredient, e.g. Compound A, e.g. in hydrochloride form, together with one or more pharmaceutically acceptable diluents or carriers therefor. As an alternative, the compound of formula I in free form or in pharmaceutically acceptable salt form may also be administered twice or three times a week, e.g. at a dosage as indicated above.
The compounds of formula I may be administered by any conventional route, in particular enterally, e.g. orally, for example in the form of solutions for drinking, tablets or capsules or parenterally, for example in the form of injectable solutions or suspensions. Pharmaceutical compositions comprising the compounds of formula I may be manufactured in conventional manner, e.g. as described in EP-A1-627,406.
The compounds of formula I may be administered as the sole active ingredient or together with other drugs in immunomodulating regimens or other anti-inflammatory agents. For example, the compounds of formula I may be used in combination with cyclosporins, rapamycins or ascomycins, or their immunosuppressive analogs, e.g. cyclosporin A, cyclosporin G, FK-506, rapamycin, 40-O-(2-hydroxy)ethyl-rapamycin, etc.; corticosteroids; cyclophosphamide; azathioprene; methotrexate; brequinar; leflunomide; mizoribine; mycophenolic acid; mycophenolate mofetil; 15-deoxyspergualine; immuno-suppressive monoclonal antibodies, e.g., monoclonal antibodies to leukocyte receptors, e.g., to MHC, CD2, CD3, CD4, CD7, CD25, CD28, B7, CD40, CD45, or CD58 or to their ligands; or other immunomodulatory compounds, e.g. CTLA4-Ig.
Where the compounds of formula I are administered in conjunction with other immunosuppressive/immunomodulatory therapy, e.g. for preventing or treating chronic rejection as hereinabove specified, dosages of the co-administered immunosuppressant or immuno-modulatory compound will of course vary depending on the type of co-drug employed, e.g. whether it is a steroid or a cyclosporin, on the specific drug employed, on the condition being treated, and so forth. In accordance with the foregoing the present invention provides in a yet further aspect:
6. A method as defined above comprising co-administration, e.g. concomitantly or in sequence, of a therapeutically effective amount of a compound of formula I and a second drug substance, said second drug substance being an immunosuppressant or immunomodulatory drug, e.g. as set forth above.
7. A kit or package for use in any method as defined under 1 or 2 above, comprising a compound of formula I, in free form or in pharmaceutically acceptable salt form, with at least one pharmaceutical composition comprising an immunosuppressant or immunomodulatory drug. The kit or package may comprise instructions for its administration.

Abstract: Use of a compound of formula I

Abstract: wherein

Abstract: each of R2, R3, R4 and R5, independently, is H or lower alkyl, in free form or in pharmaceutically acceptable salt form,

Abstract: in the prevention or treatment of chronic rejection in a recipient of organ or tissue allo- or xenotransplant, or of acute rejection in a xenograft transplant recipient.


A socket for securing an integrated circuit (IC) during burn-in or test procedures. The socket includes a base which carries a plurality of electrically conductive contacts. Opposed hold down rollers are shiftably journaled in the base. The socket also includes a movable top connected to the base and a contact with the rollers. Movement of the top shifts the rollers between secured and open positions. A rotatable lever housed in the base is connected to an actuating arm which is also shiftable by movement of the top. The lever is operably associated with the contacts and shifts the contacts between an operative position in contact with the IC chip leads and a standby position spaced from the IC chip leads.

An integrated circuit package contain an integrated circuit (IC) in the form of a wafer or chip, and electrically conductive leads or pads extend from the chip. IC chips are generally mounted in carriers for test purposes and for protection of the leads.
As is well known in the art, IC carriers are often subjected to rigorous testing to ensure their stability and usefulness. Various IC carrier sockets have been developed for IC testing and burn-in procedures. Most of the development in IC carrier sockets has centered on providing zero insertion force (ZIF) characteristic in socket design as shown in U.S. Pat. Nos. 4,491,377; 4,623,208; and 4,715,823, and in my U.S. Pat. Nos. 5,114,358 granted May 19, 1992 and 5,205,756 granted Apr. 27, 1993.
In all the prior art devices identified above, flexible cantilevered contacts are spaced apart by some engagement of the contacts directly with some portion of a movable socket housing to allow introduction of the IC carrier into the socket with zero force exerted on the IC chip leads from the socket contacts. The IC carrier merely rests inside the socket until movement of the socket housing releases the contacts to engage the IC chip leads.
Inherent play in the movement of the base housing members creates functional and operational problems. Unbalanced tensioning of the contacts against the IC chip leads can result in a weak or failed electrical connection. The carrier itself may shift or even dislodge from the socket.


A data storage device is disclosed comprising a non-volatile storage medium (NVSM), and control circuitry configured to receive a plurality of access commands, process the plurality of access commands using a customer prediction model to predict a customer of the data storage device, wherein the customer prediction model is trained off-line based on access patterns of a plurality of different customers. The control circuitry then configures access to the NVSM based on the predicted customer.

Data storage devices, such as disk drives, tape drives, and solid state drives, include one or more types of non-volatile storage mediums, such as a magnetic disk, a magnetic tape, or a non-volatile semiconductor memory. The non-volatile storage mediums are typically accessed through indirect mapping wherein logical block addresses (LBA) are mapped to physical block addresses (PBA) representing contiguous segments of the storage medium. In some cases, a data storage device may implement log-structured writes wherein data received from a customer is written to the head of a write buffer defined within a zone of the storage medium. That is, the LBA of a current data block is mapped to a new PBA at the head of the write buffer which means the data stored at the old PBA is effectively "overwritten" and becomes invalid data. The PBAs storing invalid data typically remain allocated (unusable) until a garbage collection operation recovers these invalid data blocks. During a typical garbage collection operation, the valid data blocks within a write buffer may be rewritten to the head of the write buffer (or rewritten to a new write buffer), thereby enabling the resulting contiguous data blocks to be reconfigured as "free" data blocks. Since the garbage collection operations consume bandwidth that may otherwise be used to service customer access commands, it is desirable to configure a data storage device so as to reduce garbage collection operations as well as other background operations.

Data storage device self-configuring based on customer prediction model


This invention provides water-based compositions, particularly coating, ink, and agricultural compositions, manifesting reduced equilibrium and dynamic surface tension by the incorporation of an effective amount of certain N,N-dialkyl urea compounds of the structure ##STR1## where R and R' are independently C1 to C6 alkyl or cycloalkyl with the sum of the carbon atoms in both R.sub.1 and R.sub.2 being 6 to 12.

The ability to reduce the surface tension of water is of great importance in waterborne coatings, inks, adhesives, and agricultural formulations because decreased surface tension translates to enhanced substrate wetting in actual formulations. Surface tension reduction in water-based systems is generally achieved through the addition of surfactants. Performance attributes resulting from the addition of surfactants include enhanced surface coverage, fewer defects, and more uniform distribution. Equilibrium surface tension performance is important when the system is at rest. However, the ability to reduce surface tension under dynamic conditions is of great importance in applications where high surface creation rates are utilized. Such applications include spraying of coatings or agricultural formulations, or high speed gravure or ink-jet printing. Dynamic surface tension is a fundamental quantity which provides a measure of the ability of a surfactant to reduce surface tension and provide wetting under such high speed application conditions.
Traditional nonionic surfactants such as alkylphenol or alcohol ethoxylates, and ethylene oxide (EO) propylene oxide (PO) copolymers have excellent equilibrium surface tension performance but are generally characterized as having poor dynamic surface tension reduction. In contrast, certain anionic surfactants such as sodium dialkyl sulfosuccinates can provide good dynamic results, but these are very foamy and impart water sensitivity to the finished coating.
The objective of this invention is to provide a family of surfactants which provide good equilibrium and dynamic surface tension properties and are low-foaming.
The importance of reducing equilibrium and dynamic surface tension in applications such as coatings, inks, and agricultural formulations is well-appreciated in the art.
Low dynamic surface tension is of great importance in the application of waterborne coatings. In an article, [Schwartz, J. "The Importance of Low Dynamic Surface Tension in Waterborne Coatings", Journal of Coatings Technology, September 1992] there is a discussion of surface tension properties in waterborne coatings and a discussion of dynamic surface tension in such coatings. Equilibrium and dynamic surface tension were evaluated for several surface active agents including the ethylene oxide adducts of acetylenic glycols. It is pointed out that low dynamic surface tension is an important factor in achieving superior film formation in waterborne coatings. Dynamic coating application methods require surfactants with low dynamic surface tensions in order to prevent defects such as retraction, craters, and foam.
Efficient application of agricultural products is also highly dependent on the dynamic surface tension properties of the formulation. In an article, [Wirth, W.; Storp, S.; Jacobsen, W. "Mechanisms Controlling Leaf Retention of Agricultural Spray Solutions"; Pestic. Sci. 1991, 33, 411-420], the relationship between the dynamic surface tension of agricultural formulations and the ability of these formulations to be retained on a leaf was studied. These workers observed a good correlation between retention values and dynamic surface tension, with more effective retention of formulations exhibiting low dynamic surface tension.
Low dynamic surface tension is also important in high-speed printing as discussed in the article "Using Surfactants to Formulate VOC Compliant Waterbased Inks" [Medina, S. W.; Sutovich, M. N. Am. Ink Maker 1994, 72 (2), 32-38]. In this article, it is stated that equilibrium surface tensions (EST's) are pertinent only to ink systems at rest. EST values, however, are not good indicators of performance in the dynamic, high speed printing environment under which the ink is used. Dynamic surface tension is a more appropriate property. This dynamic measurement is an indicator of the ability of the surfactant to migrate to a newly created ink/substrate interface to provide wetting during high speed printing.
U.S. Pat. No. 5,098,478 discloses water-based ink compositions comprising water, a pigment, a nonionic suifactant and a solubilizing agent for the nonionic surfactant. Dynamic surface tension in ink compositions for publication gravure printing must be reduced to a level of about 25 to 40 dynes/cm to assure that printability problems will not be encountered.
U.S. Pat. No. 5,562,762 discloses an aqueous jet ink of water, dissolved dyes and a tertiary amine having two polyethoxylate substituents and that low dynamic surface tension is important in ink jet printing.
U.S. Pat. No. 3,814,705 discloses the use of long chain 1,1-dialkyl ureas of the type R2NC(O)NH2 (R=alkyl group of C8 to C18) as foam suppressants in detergent compositions containing organic detergents, such as sulfate and sulfonate detergents, and alkaline builder salts.
Similarly, U.S. Pat. No. 3,691,082 discloses low-foaming rinsing, washing and cleaning compositions comprising (a) at least one compound having a cleaning or complexing action, (b) a foam-inhibiting isocyanurate and (c) an alkylated urea having at least eight substituents carbons on each of the urea nitrogens.
U.S. Pat. No. 2,708,183 discloses synthetic detergent compositions comprising a sulfated or sulfonated detergent and a minor amount of a higher alkyl substituted urea characterized by limited water-solubility.
U.S. Pat. No. 2,374,187 discloses non-allergenic toilet bars comprising sulfonated detergents and water-soluble, solid organic compounds which contain within the molecule the carboacylamido radical, e.g., ureas. The ureas are a significant amount of the final composition (50-95%).
U.S. Pat. No. 3,965,015 discloses bleach-stable fabric detergent and/or softening compositions comprising effective amounts of a urea represented by the formula: RNHCXNH(CH2)nNH2 where R is a C2-C18 alkyl group, X is oxygen or sulfur and n is 2-12.
U.S. Pat. No. 4,272,413 discloses softening and antistatic laundering compositions compatible with detergents comprising as the softening and antistatic agents short chain carbamoyl derivatives of long chain aliphatic amines, where the amino nitrogen is attached to a non-terminal or internal methylene group.
U.S. Pat. No. 2,335,862 discloses N,N-dibutylurea as a good solvent for rotenone in a non-aqueous herbicidal application.

Surface tension reduction with N,N-dialkyl ureas