A cartridge for flowable material has a flexible envelope having a first and a second opposed ends and defining an envelope volume for receiving the flowable material. A plunger is positioned at the first opposed end. A cover member is positioned at the second opposed end. The second opposed end has a dispensing opening. The dispensing opening has a dispensing diameter so dimensioned, according to a force exertable by the plunger in the envelope volume, a viscosity of the flowable material, and a flexibility of the envelope, as to ensure a minimum inner pressure in the envelope volume in order to prevent inward folding of the envelope into the interior of the envelope volume.

The invention relates to a cartridge for flowable media, comprising an envelope of a flexible material delimiting a volume, wherein the envelope can be provided at one end with a plunger-type pressing element and at the other end with an outlet element.
Cartridges for flowable media are known per se. They are containers for storing, transporting, and dispensing flowable media. Primarily, paste-like medias such as silicone rubber etc. are concerned, which are, for example, used in the construction industry. However, it is also known to fill adhesives, grease or other media into cartridges.
Different types of cartridges are known. In one type a sleeve or envelope delimiting a volume is provided in the form of a stable housing-like element which, in general, is provided at one end with a dispensing area and at the other end with an opening for a piston-like pressing element. The dispensing area comprises conventionally a dispensing opening, whereby it is known to close off the opening is by an element that is a unitary part of the envelope. When needed, this closing element is opened by cutting it open so that the dispensing opening results. In the area of the dispensing opening a socket provided with an inner or outer thread can be provided onto which a dispensing nozzle is placed. Such cartridges are primarily made of plastic so that with respect to their manufacture and disposal many expenditures are incurred.
The containers are primarily disposable containers because they cannot be completely emptied and they cannot be universally employed. Since the most favorable plastic is always selected for manufacturing the cartridges, they are not universally employable for all materials, but for different media different types of cartridges must be produced. A further problem is the incomplete and unsatisfactory emptying of the cartridges. Furthermore, it is easily possible that the operator becomes contaminated with the media. Finally, the produced empty cartridges are already of a size during transport to the filling station as they are after filling, i.e., they require a large transporting volume.
Stiff, tubular cartridges with a pressing area at one end and with a piston-shaped pressing element at the other end are emptied with a dispensing device into which the tubular element is clamped and with which the pressing element is moved by way of a pressure piston.
It is known to use, instead of the cylindrical containers, a hose container for the media to be dispensed. Such hose containers are comprised substantially of a foil hose which is closed off at both ends. It is known to close off the ends by so-called metal clips. The use of such hose containers is suggested primarily to avoid the disposal of a plurality of emptied cylindrical containers. The manufacture of hose containers is simpler and so is their disposal. Since the hose containers are not shape-stable, they are inserted into shape-stable cylindrical sleeves for dispensing the media contained therein whereby the sleeve has at one end a closure with a dispensing opening, for example, for arranging thereat a nozzle tip. At the other end of the cylindrical outer sleeve pressure can be applied onto the hose container. For dispensing the material contained in the hose container, the container must be opened, which in practice is achieved by destroying the hose container sleeve by slitting, puncturing etc. After emptying, the hose containers are removed from the cylindrical sleeves so that only a small, substantially empty hose container must be disposed of. Even though this is advantageous in comparison to cylindrical plastic cartridges, such hose containers have the disadvantage that they can only be used up to a certain filling volume, and it is especially disadvantageous that the dispensing device can be contaminated with the contained material. Also, the operator is usually also coming into contact with the medium. Often, a complete plugging of the dispensing means results so that, in practice, they must be disposed of also. Accordingly, the desired advantages are eliminated and the environmental impact caused by the disposal of the hose containers, on the one hand, and of the dispensing devices, on the other hand, is considerably increased. These disadvantages are even further complicated by the contamination of the operator, at the latest during removal of the hose container from the dispensing devices.
Hose containers are not shape-stable so that for dispensing of the media contained therein they must be inserted into a shape-stable cylindrical sleeve having at one end a closure with a dispensing opening, for example, for arranging thereat a nozzle tip. At the other end of the cylindrical outer sleeve pressure can be exerted on the hose container.
All of the cartridges of the aforementioned kind therefore have in common that their disposal is difficult and results in high disposal costs. Furthermore, the known cartridges cannot be universally employed, are inflexible with regard to their volume, and have disadvantages with respect to their uncontrollable handling.
Dispensing devices for cartridges of the aforementioned kind are known per se. A cylindrical receiving element, that is tubular or part-cylindrical, depending on the type of cartridge, has a dispensing area and a pressure generating device. The latter can be, for example, a pressure piston with which, by moving a lever, vacuum or an increased pressure within the cylindrical receiving element can be produced.
A prior art device has a pump piston which produces vacuum at the dispensing end of the cartridge, i.e., at the dispensing area of the cylindrical receiving member, and the flowable material thus is sucked out of the cartridge after opening.
However, it was found that such dispensing devices do not guarantee a complete emptying of the cartridges and, furthermore, do not ensure a defined behavior of the cartridge even within the tubular or cylindrical receiving member. A defined behavior is, for example, required for newer cartridges in order to ensure, on the one hand, a defined emptying of the remaining material and on the other hand a controlled folding of the cartridge material in order to make the empty cartridge to be disposed of as small as possible.
It is therefore an object of the present invention to provide a cartridge which is economical with regard to its manufacture and its filling, which is comprised of only a small amount of plastic and which only causes a minimal environmental impact upon disposal. Furthermore, an application as universally as possible should be provided, emptying as much as possible should be ensured, and a small transport volume should be provided.
Furthermore, the present invention provides a cartridge system which, in addition to a novel cartridge, also comprises a dispensing device and a pressure piston. With this complete cartridge system all economical and technical advantages of the new inventive cartridge can be optimally used and an optimal economic application is realized.


A bicyclolactam compound of the formula (1) is disclosed, which has an excellent anxiolytic effect, is high in safety, and is useful as an effective component of medicinals which are greatly diminished in side effects such as hypnotic, muscle relaxant and sedative effects

The present invertion relates to anxiolytic agents comprising a bicyclolactam derivative as their effective component and to the treatment of anxiety.
With rapid diversification of the social environment in recent years, an increasing number of people are suffering from anxiety, and it has been expected to develop psychosomatic therapies and excellent therapeutic agents.
Benzodiazepine compound such as diazepam have found wide use as anxiolyties. This group of agents, however, generally have side effects such as hypnotic effect, muscle relaxant effect and sedative effect. Setotonin anxiolytic agents such as buspirone are also recently developed as anxiolytics which are different from the benzodiazepine compounds in activity mechanism. Reportedly these serotonin agents are generally lesser than the benzodiazepines in side effects such as hypnotic, muscle relaxant and sedative effects, but they are lower in anxiolytic effect and have the problems of diminishing voluntary movements presumably owing to their activity as a dopamine antagonist, and causing serotonin syndrome which appears attributable to their properties as a full agonist for serotonin 1A receptor.
On the other hand, the bicyclolactam derivatives of the present invention are known compounds disclosed in International Public Disclosure No. WO 91/11434, and are known to have a cerebral function improving effect, cerebral metabolism activating or anoxic brain damage protecting effect and effect against sentile dementia. Nevertheless, nothing whatsoever is known about the anxiolytic effect of these compounds.
Anxiety is an essential symptom of neuroses and is a neurotic disorder involving no organic disorder of the brain.
In contrast, the term dementia refers to an organic mental disorder which is the sustained deterioration of acquired intelligence clue to an organic disorder of the brain. Many of dementias are caused by a wide variety of organic disorders of the brain and involve general deterioration of mental functions such as memory, calculation, orientation and discretion, leading to failure of correct recognition, judgement or behavior as to one""s own situation.
xe2x80x9cDiagnostic and Statistical Manual of Mental Disorders,xe2x80x9d Revised 3rd Ed. (DSM-III-R), widely used as a diagnostic manual and published by American Psychiatric Association in 1987, clearly classifies these diseases in the chapters xe2x80x9cAnxiety Disorders (or Anxiety and Phobic Neuroses)xe2x80x9d and xe2x80x9cOrganic Mental Syndromes and Organic Mental Disordersxe2x80x9d (see xe2x80x9cDSM-III-R Classification of Mental Disorders and Diagnostic Manual,xe2x80x9d(2nd Ed.), translated by Saburo Takahasi et al., published xe2x80x9cby Igaku Shoin (1988), pp. 71xcx9c94 and 121xcx9c129).
An object of the present invention is to provide a novel anxiolytic agent comprising a bicyclolactam derivative as its effective component, and a therapy of anxiety.
We have investigated the pharmacological activities of bicyclolactam derivatives from various viewpoints, consequently found that these compounds have a very high anxiolytic effect and are yet greatly diminished in side effects such as hypnotic, muscle relaxant and sedative effects and accomplished the present invention. More specifically, the invention provides an anxiolytic agent comprising as its effective component a bicyclolactam derivative represented by the following formula
(wherein R1 is a hydrogen atom or hydroxyl group, R2 is benzoyl group which may optionally have at least one substituent, l is 1 or 2, m is 0 or 1 and n is 0, 1 or 2, provided the case where both of m and n represent 0 simultaneously is excluded.
The present invention further includes a method of treating anxiety comprising administering an effective amount of the compound (1) to mammals including man, and also use of the compound (1) for the preparation of medicinals for treating anxiety.
Existing as bicyclolactam derivatives of the formula 1) are stereoisomers due to the presence of the bicyclo ring, and also geometric isomers and optical isomers due to the presence of the carbon atom at the bridgehead position of the bicyclo ring and the carbon atom having R1 attached thereto. The present invention includes all of these isomers.
In view of the numbers 1, m and n, the following ten kinds of bicyclo ring skeletons can be present in the compounds of the formula (1). The invention includes all of these cases.
Preferable among these is the case wherein the skeleton is (a), (b), (f), (g) or (h). More preferable is the case wherein m is 0, i.e., (a), (b), (f) or (g). The most preferable is (b), (f) or (g).
According to the invention, examples of substituents which may be present in the benzoyl group represented by R2 are a halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group, hydroxyl group or amino group. Examples of halogen atoms are fluorine, chlorine, bromine and iodine atom, among which chlorine atom is preferable. Examples of useful lower alkyl groups are straight-chain or branched alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, isopentyl and hexyl group. Preferable among these are methyl and ethyl groups. Methyl group is more preferable. Examples of useful lower alkoxyl groups are straight-chain or branched alkoxyl groups having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy and hexyloxy group, among which methoxy and ethoxy groups are preferable. Methoxy group is more preferable.
Preferable as R2 of the compound represented by the formula (1) is a benzoyl group having as a substituent a halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group or amino group, more preferably a benzoyl group having lower alkoxyl group. Especially preferable is a benzoyl group having methoxy group. The number of substituents is preferably 1 to 3. The substitient may be present at any of the ortho-, meta- and para-positions on the phenyl ring of the benzoyl group.
Among the compounds of the formula (1), preferable are those wherein m is 0, and more preferable are those wherein R2 is a benzoyl having lower alkoxyl group and wherein l is 1, m is 0 and n is 2, or 1 is 2, m is 0 and n is 1, or l is 2, m is 0 and n is 2 . More preferable are those wherein R2 is a benzoyl gronp having methoxy group and wherein l is 1, m is 0 and n is 2, or l is 2, m is 0 and n is 1, or l is 2, m is 0 and n is 2. In the case where R1 is hydroxyl group, especially preferred coinpounds are those wherein l is 1, m is 0 and n is 2.
Examples of the compound of the above formula (1) are
2-(4-methoxybenzoyl)-2-azabicyclol[3.3.0]octane-3-one,
2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(p-toluyl)-2-azabicyclo[4.3.0](nonane-3-one,
2- (3,4 -dichlorobenzoyl) -2 azabicyclo[4.3.0 ]nonane- 3-one,
2- (3,5dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3 - one ,
2- (4- cyanobenzoyl)- 2 -azabicyclo[4.3.0]nonane- 3-one ,
2- (4-nitrobenzoyl) -2-azabicyclo[4.3.0]nonane-3-one,
2-(4-aminobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-chlorobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
8- (4-methoxybenzoyl)-8-azabicyclo[4.3.0]nonane-7-one,
2-(4-hydroxybenzoyl)-2-azabicyclo[4.3.0nonane-3-one,
3-(4-methoxybenzoyl)-3-azabicyclo[3.3.0]octane-4-one,
3-(4-methoxybenzoyl)-3-azabicyclo[4.3.0]nonane-4-one,
3-(4-methoxybenzoyl) -3-azabicyclo[5.3.0]decane-4-one,
3-(4-methoxybenzoyl) -3-azabicyclo[4.4.0]decane-4-one,
3-(4 -methoxybenzoyl) -3-azabicyclo[5.4.0]undecane- 4-one,
7-(4-methoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(p-toluyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(3,4-dichlorobenzoyl)-7-azabicyclo[4.3.0]-nonane-8-one,
7-(3,5-dimethoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-cyanobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-nitrobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-aminobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-chlorobenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
7-(4-hydroxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
2-(4-methoxybenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
2- (p-toluyl) -2-azabicyclo-[4.4.0 ]decane-3-one,
2-(3,4-dichlorobenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
2- (3,5-dimethoxybenzoyl) -2-azabicyclo[4.4.0]decane-3-one,
2-(4-cyanobenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
2-(4-nitrobenzoyl)- 2-azabicyclo[4.4.0]decane-3-one,
2-(4-aminobenzoyl )-2-azabicyclo[4.4.0]decane-3-one,
2- (4-chlorobenzoyl-2)- 2-azabicyclo[4.4.0 ]decane-3-one,
2-(4-hydroxybenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-hydroxy-7-(4-methoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one and
7-hydroxy-2-(4-methoxybenzoyl)-7) -azabicyclo[4.4.0]decane-3-one.
Preferable examples are
2-(4-methoxybenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
2-(4-methoxybenzoyl)-2-azabicyclo[3.3.0]octane-3-one,
2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(p-toluyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(3,4-dichlorobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(3,5-dimethoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-cianobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-nitrobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-aminobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
2-(4-chlorobenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
7-(4-methoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one,
8-(4-methoxybenzoyl)-8-azabicyclo[4.3.0]nonane-7-one and
7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
More preferable examples are
2-(4-methoxybenzoyl)-2-azabicyclo[4.4.0]decane-3-one,
2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one,
7-(4-methoxybenzoyl)-7-azabicyclo[4.3.0]nonane-8-one and
7-hydroxy-2-(4-methoxybenzoyl)-2-azabicyclo[4.3.0]nonane-3-one.
The bicyclolactam derivative of the formula (1) is a known compound which is disclosed for example in International Public Disclosure No. WO 91/11434 (U.S. Pat. No.5,185,344, U.S. Pat. No. 5,214,039), etc.
The bicyclolactam derivative (1-a) of the present invention wherein Rxe2x80x2 is hydrogen atom can be prepared, for example, by the following reaction process
wherein R2, e, m and n are as defined above, X is halogen atom.
Bicyclolactam compound (2) is a known compound and is easily prepared by methods disclosed in Journal of American Chemical Society, 77, 409 (1955), Yakugaku Zasshi, 84, 674 (1964) and Journal of Chemical Society Perkin Transactions I 11, 2563 (1982). The compound of the formula (1 -a) can be prepared by reacting the bicyclolactam compound (2) with the halide compound (3), in the presence of a base in an appropriate solvent.
The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of solvents generally useful are hydrocarbon ha ides such as dichlorolmethane and chloroform, ethers such as ethyl ether and tetrahydrofuran, aromatic hydrocarbons such as benzene and toluene, aprotic polar solvents such as N,N-dimethylformamide and dimethylsulfoxide.
As to the proportion of the compound (2) and the halide compound (3), it is usual) to use 0.5 to 2 moles, preferably one mole of the compound (3) per mole of the compound (2). Examples of bases are organic amines such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as sodium hydride and sodium amide. The amount of the base is usually 0.5 to 2 moles, preferably one mole per mole of the compound (2). The reaction temperature is 0 to 150xc2x0 C. , preferably 50 to 100xc2x0 C. The reaction time is 1 to 48 hours, preferably 2 to 12 hours.
The bicyclolactam derivative (1-b) of the present invention wherein Rxe2x80x2 is hydroxyl group can be prepared, for example, by the following reaction process
wherein P3 is hydrogen atom, halogen atom, lower alkyl group, lower alkoxyl group, nitro group, cyano group, hydroxyl group or amino group.
(i) A known compound A disclosed in J. Org. Chem., 42, 3764xcx9c3767 (1977) is reacted with ethylene glycol in a suitable solvent in the presence of an acid catalyst to obtain a compound B. The solvent to be used is not particularly limited insofar as it does not participate in the reaction; it is, for example, an aromatic hydrocarbon such as benzene, toluene or xylene. Examples of useful acid catalysts are sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid the like. The reaction is conducted using ethylene glycol and the acid catalyst each in an amount of about 1 to about 2 moles per mole of the compound A. The reaction temperature is 80xc2x0 C. to a temperature around the boiling point of the solvent. For the completion of the reaction, the reaction time is 1 to 8 hours, preferable about 4 to about 7 hours. The compound B obtained by the reaction can be used for the subsequent reaction as isolated or without being isolated.
(ii) Next, the compound B is reacted with a reducing agent in a suitable solvent to obtain a compound C. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1, 2-dimethoxyethane, tetrahydrofuran and like ethers. Examples of useful reducing agents are lithium aluminum hydride, disobutyl aluminum hydride, diborane, sodium boron hydride and the like. The reaction is conducted using the reducing agent in about 1 to about 1.5 moles per mole of the compound C. The reaction temperature is xe2x88x925xc2x0 C. to room temperature, preferably about 0 to about 10xc2x0 C. The reaction time is preferably about 1 to about 3 hours. The compound C resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(iii ) The compound C is reacted with p-nitrobenzoic acid, triphenylphosphine and diethyl azodicarboxylate in a suitable solvent to obtain a compound D. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers, chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. The reaction is conducted using the latter three reactants each in about 1 to about 3 moles per mole of the compound C. The reaction temperature is xe2x88x925 to 50xc2x0 C., preferably about 0xc2x0 C. to around room temperature. The reaction times is 1 to 15 hours, preferably about 6 to about 12 hours. The compound D resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(iv ) The compound D is hydrolyzed in a suitable solvent with use of an anion exchange resin to obtain a compound E. The solvent to be used is not limited specifically insofar as it will not participate in the reaction. Examples of such solvents are methanol, ethanol, propanol, isopropanol and like alcohols. The reaction is conducted using the anion exchange resin in about 1 to about 10 moles per mole of the compound D. The reaction temperature is room temperature to 100xc2x0 C., and the reaction time is about 10 to about 24 hours. The compound F resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(v) The compound E is reacted with benzyl bromide in a suitable solvent in the presence of a base to obtain a compopund F. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile and like aprotic polar solvents, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Examples of useful bases are trimethylamine, triethylamine, pyridine and like tertiary amines, potassium carbonate, sodium carbonate and like alkali metal carbonate, and potassium hydride, sodium hydride and like alkali metal hydrides. For the reaction, the base and benzyl bromide are used each in about 1 to about 2 moles per mole of the compound E. The reaction temperature is room temperature to 100xc2x0 C., preferably room temperature to about 70xc2x0 C. The reaction time is 8 to 30 hours, preferably about 20 to about 28 hours. The compound F resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(vi) The compound F is subjected to a ketal removing reaction in a suitable solvent with use of an acid to obtain a compound G. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of solvents are alcohols such as methanol, ethanol, propanol and isopropanol, and ethers such as dioxane, 1,2-dimethoxyethane and tetrahydrofuran. Examples of useful acids are acetic acid, trifluoroacetic acid, oxalic acid and like organic acids, hydrochloric acid, bromic acid, sulfuric acid, nitric acid and like inorganic acids. The reaction temperature is 0 to 60xc2x0 C. preferably about 10 to about 70xc2x0 C. The reaction time is about 2 to about 8 hours. The compound G resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(vii-a) The compound G is reacted with hydroxylamine and sodium acetate in a suitable solvent to obtain an oxime of the compound G. The solvent is not limited specifically insofar as it does not participarte in the reaction. Examples of useful solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers. Hydroxylamine and sodium acetate are used each in about 1.5 to 2 moles per mole of the compound G. The reaction temperature is 0 to 50xc2x0 C., preferably room temperature. The reaction time is preferably 5 to 8 hours.
Subsequently, the resulting oxime of the compound G is reacted with p-toluenesulfonyl chloride in a suitable solvent in the presence of a base to obtain a p-tosylic acid ester of the compound G. Silica gel is added to the ester in the same solvent, followed by a Beckmann rearrangement reaction to obtain a mixture of compound Ha and compound Hb. The solvent to be used is not limited specifically insofar as it does not participate in the reaction. Examples of such solvents are benzene, toluene, xylene and like aromatic hydrocarbons, chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. Examples of useful bases are trimethylamine, triethylamine, pyridine and like tertiary amines. For the reaction, the base and p-tosyl chloride are used each in 2 to 3 moles per mole of the oxime of the compound G. The reaction temperature for tosylation is about 0 to 10xc2x0 C., and the reaction time is about 4 to about 8 hours. The Beckmann rearrangement reaction in silica gel is conducted at a temperature of about 10 to about 30xc2x0 C. for about 12 to about 24 hours.
(vii-b) The resulting mixture is reacted with a compound I in a suitable solvent in the presence of a base to obtain a compound Ja and compound Jb. The solvent is not limited specifically insofar as it does not participate in the reaction. Examples of useful solvents are chloroform, dichloromethane, dichloroethane and like hydrocarbon halides. Examples of useful bases are tertiary amines such as trimethylamine, triethylamine and pyridine. For the reaction, the base is used in about 1 to about 2 moles per mole of the mixture. The reaction temperature is about 5 to about 50xc2x0 C., preferably about 10xc2x0 C. to around room temperature. The reaction time is 12 to 36 hours, preferably about 24 to about 36 hours. The compound Ja or compound Jb resulting from the reaction can be used for the subsequent reaction, as isolated or without being isolated.
(viii) The compound Ja is hydrogenated in a suitable solvent in the presence of palladium-carbon to obtain a compound (1-b). The solvent is not limited specifically insofar as it does not participate In the reaction. Examples of useful solvents are methanol, ethanol, propanol, isopropanol and like alcohols, dioxane, 1,2-dimethoxyethane, tetrahydrofuran and like ethers, and methyl acetate, ethyl acetate and like acetic acid esters. For the reaction, palladium-carbon is used preferably in the ratio of 0.5 to 1 by weight based on the compound Ja. The reaction temperature is preferably around room temperature to about 50xc2x0 C. The reaction time is about 10 to about 20 hours.
The compound (1) thus obtained can be isolated and purified by a usual method such as recrystallization or column chromatography. The racemic compound obtained can be divided into the desired optical isomers, for example, by fractional recrystallization for the separation of salts from optically active acids or by passing a column packed with an optically active carrier. The stereoisomers can be individually separated off and purified by a usual method such as fractional crystallization or chromatography.
The anxiolytic agent embodying the present invention can be given orally or parenterally to mammals including man. The pharmaceutical preparations of the present invention are not limited specifically in the unit form of administration but can be in various forms in conformity with preventive or therapeutic purposes. These forms of preparations include, for example, oral preparations, infections, suppositories, external preparations (such as poultices and like plasters, ointments, creams and lotions), eye drops, nasal drops or sprays, etc.
The anxiolytic agent of the present invention is prepared and used in the form of a composition having a desired conventional pharmaceutical carrier or excipient incorporated therein by a usual method.
Stated more specifically, examples of carriers for use in formulating the agent as tablets, encapsulated preparations, granules, powders, etc. for oral administration are excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid binders such as water, ethanol, propanol, syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl starch, shellac, methyl cellulose, ethyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrators such as dried starch, sodium alginate, agar powder, laminaria powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, stearic acid monoglyceride, starch and lactose, disintegration suppressants such as sucrose, stearic acid, cacao butter and hydrogenated oils, absorption promoters such as quaternary ammonium bases and sodium laurylsulfate, humectants such as glycerin and starch, absorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid, glazing agents such as purified talc, stearic acid salts, boric acid powder and polyethylene glycol, corrigents such as sucrose, bitter orange peel, citric acid and tartaric acid, etc. When required, the tablets can be those having a usual coating, such as sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layer tablets and multi-layer tablets. The encapsulated preparation is made by mixing the present compound with carriers such as those exemplified above and filling the mixture into hard gelatin capsules or soft capsules.
Liquid preparations for oral administration include aqueous or oily suspensions, solutions, syrups and elixirs, and are prepared in the usual manner by adding a corrigent, buffer, stabilizer, flavoring agent, to the present compound. In this case, examples of useful corrigents are those exemplified above, useful buffers include sodium citrate, and useful stabilizers include tragacanth, gum arabic and gelatin, etc.
Injections are aqueous or oily suspensions and solutions, or powdery fillers and freeze-dried preparations which are dissolved when to be used. Injections are prepared in the usual manner by adding to the present compound a pH adjusting agent, buffer, stabilizer, isotonic agent, diluent, local anesthetic, etc. Examples of pH adjusting agents and buffers for use in this case are sodium citrate, sodium acetate, sodium phosphate and the like. Examples of useful stabilizers are sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples of useful diluents are water, aqueous solution of lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, etc. Examples of useful local anesthetics are procaine hydrochloride, lidocaine hydrochloride, etc.
In preparing suppositories, use can be made of carriers such as polyethylene glycol, lanolin, cacao fat, esters of higher alcohols, gelatin, semisynthetic glyceride, etc., and when required, surfactants such as Tween (trademark).
Ointments (pastes, creams, gels, etc.) are prepared by admixing with the present compound a base, stabilizer, lubricant, preservative, etc. which are usually used. Examples of bases are fluid paraffin, white petrolatam, bleached beeswax, octyldodecyl alcohol, paraffin and the like. Examples of useful preservatives are methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, hydroxybenzoate, propyl p-hydroxybenzoate and the like.
Plasters are prepared by applying the ointment, cream, gel, paste or the like to a usual support in the conventional manner. Examples of suitable supports are woven or nonwoven fabrics of cotton, staple fiber or chemical fiber, films of flexible polyvinyl chloride, polyethylene, polyurethane or the like, and foamed sheets of such material.
When required, the foregoing preparations may have further incorporated therein a coloring agent, preservative, perfume, flavoring, sweetener and the like, and other medicinals.
The method of administering the pharmaceutical preparation of the invention is not limited specifically but determined according to the form of preparation, age, sex and other conditions of the patient and degree of symptom of the patient. For example, tablets, pellets, powders, solutions, suspensions, emulsions, granules and catpsules are given orally. Suppositoties are introduced into the rectum. Injections are intravenously given singly or as mixed with a usual auxiliary Solution such as glucose or amino acid solution. Further when required, they are singly administered intra-arterially, intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Ointments are applied to the skin, mucous membrane of the oral cavity, etc. Plasters are applied to the skin.
The dosage of the effective component of the preparation of the invention can be suitably determined according to the mode of administration, age, sex and other conditions of the patient and degree of the symptom. Generally the effective component is administered at a daily dose usually of 0.001 to 10 mg/kg body weight, preferably 0.01 to 5 mg/kg body weight. The present preparation can be given once or in about 2 to about four divided doses per day.
The present invention will be described below with reference to reference examples, examples and test examples. However, the invention is not limited by these examples.

Bicyclolactam compounds, use thereof and intermediates for preparing thereof

Abstract: A bicyclolactam derivative represented by the following formula (1) is also disclosed, and is useful as an effective component of an anxiolytic agent


A fluid collection canister including a chamber to collect fluids and a canister top disposed over the chamber. The canister top includes a bottom side facing into the chamber, including first and second ribs disposed thereon, a filter membrane attached to the first and second ribs, a first port to communicate with the chamber and a pressure source external to the chamber, and a second port to communicate with the chamber and a sensor external to the chamber. The first port is in fluid communication with a first area, which is bounded by the filter membrane, the first and second ribs and the bottom side of the canister top. The second port is in fluid communication with a second area, which is bounded by the filter membrane, the second rib and the bottom side of the canister top.

1. Technical Field
The present disclosure relates to negative pressure wound therapy systems and, more particularly, to a fluid collection canister including a canister top with a filter membrane and negative pressure wound therapy systems including the same.
2. Discussion of Related Art
Negative pressure therapy, also known as suction or vacuum therapy, has been used in treating and healing wounds. Treating an open wound by applying negative pressure, e.g., reduced or sub-atmospheric pressure, to a localized reservoir over a wound has been found to assist in closing the wound by increasing blood circulation at the wound area, stimulating the formation of granulation tissue and promoting the migration of healthy tissue over the wound. Negative pressure therapy may also inhibit bacterial growth by drawing wound fluids from the wound such as exudate, which may tend to harbor bacteria. Negative pressure therapy can thus be applied as a healing modality for its antiseptic and tissue regeneration effects. This technique has proven effective for treating a variety of wound conditions, including chronic or healing-resistant wounds and ulcers, and is also used for other purposes such as post-operative wound care.
Generally, negative pressure therapy provides for a wound covering to be positioned over the wound to facilitate suction at the wound area. A conduit is introduced through the wound covering to provide fluid communication to an external vacuum source, such as a hospital vacuum system or a portable vacuum pump. Atmospheric gas, wound exudate or other fluids may thus be drawn from the reservoir through the fluid conduit to stimulate healing of the wound. Generally, a fluid collection canister for collecting fluids aspirated from the wound is positioned in the suction line between the wound covering and the vacuum source. Exudate drawn from the reservoir through the fluid conduit may thus be deposited into the collection canister.
During a treatment, vacuum levels within a negative pressure wound therapy system may be monitored and controlled. There are a variety of pressure detecting devices such as pressure gages, switches, transducers and transmitters that can be used for measuring vacuum levels. A negative pressure wound therapy system may not function properly when fluid contamination of various components degrades the capability to accurately measure vacuum levels in the negative pressure wound therapy system. When the collection canister is tilted from upright, fluid may occlude a filter in communication with a pressure detecting device, preventing accurate measurement of vacuum levels in the negative pressure wound therapy system. This may cause the negative pressure wound therapy system to react as if a pneumatic leak is present in the system and may cause vacuum level within the collection canister to go uncontrolled, which may result in improper therapy to the patient.
A mechanism for preventing overfilling of the collection canister may prevent fluid contamination of various components of the negative pressure wound therapy system and help to prevent spillage or leakage of exudate. During a treatment, the collection canister may be prevented from overfilling by a hydrophobic filter at the top of the collection canister that shuts off the air flow to the vacuum source when the collection canister is full. In portable negative pressure wound therapy systems, which may be worn or carried by a patient, there is a likelihood that the apparatus will shift into various orientations while the patient is ambulating, allowing exudate to occlude the filter when the collection canister is not full. Negative pressure therapy may be discontinued or interrupted inadvertently when the filter is occluded during patient ambulation or when the collection canister is tipped over. There is a need for a negative pressure wound therapy system that permits accurate measurement of vacuum levels in the negative pressure wound therapy system and is capable of providing negative pressure therapy for varied orientations of the collection canister.

Fluid collection canister including canister top with filter membrane and negative pressure wound therapy systems including same


An image forming apparatus and method for managing an image forming apparatus by using an external server are provided. In various examples, a system environment setting of an image forming apparatus is changed based on context information stored in the external server, without direct intervention of an administrator and without use of additional hardware.

The disclosure relates to an image forming apparatus and a method for managing an image forming apparatus by using an external server.
For efficient and effective use of an image forming apparatus such as a printer, system environment setting information of the image forming apparatus may need to be changed according to conditions of a user or a device. If a user without sufficient knowledge changes a system environment setting of the image forming apparatus for this purpose, the corresponding operation will be time-consuming and inconvenient. Also, when a large number of image forming apparatuses need to be managed, there might be a shortage of managing or technician staff for managing all of the image forming apparatuses.
Throughout the drawings, it should be noted that like reference numbers are used to depict the same or similar elements, features, parts, components, and structures.

Method of managing image forming apparatus by using external server and image forming apparatus using the method

Hewlett-Packard Development Company, L.P.


A bearing for a reciprocating floor conveyor. The reciprocating floor conveyor includes a plurality of sub-deck guide beams and a plurality of floor slats. The bearing includes a load carrying top having an upper surface to receive at least one floor slat thereon and an opposed lower surface mating with one of the guide beams. The upper surface of the top includes a plurality of clean-out grooves. A first leg and a second leg each extend from the top with the legs spaced from each other a distance slightly longer than the width of one of the guide beams. A hinge mechanism permits the legs to move between two positions, a use position with the distance between the legs slightly shorter than the width of one of the guide beams and an installation position where the legs are separated or wider than the guide beam while installing onto the guide beam.

1. Field of the Invention
The present invention is directed to a bearing for use with a reciprocating floor conveyor wherein bearings are mounted on sub-deck guide beams. In particular, the present invention is directed to a bearing for a reciprocating floor conveyor which includes a hinge mechanism to assist in installation of the bearing on and around a sub-deck guide beam and which provides an improved wear surface between the bearing and the floor sliding slat.
2. Prior Art
Reciprocating floor conveyors are well known for use in various applications. For example, vehicles, factory conveyors, large bunkers, truck boxes and semi-trailers or trailers will use reciprocating floor conveyors to transport and load or unload various types of cargo, such as bulk material, pallets, bales, sacks or commodities. One known application is in open top semi-trailers. The reciprocating floor conveyor systems might also be used in cargo containers or other storage devices. The reciprocating floor conveyor can also be driven on by forklifts making a reciprocating floor conveyor very versatile.
The reciprocating floor conveyor systems typically include a plurality of parallel floor slats or floor members which extend a portion or all of the floor length of the trailer and support the load. The floor slats are normally 3 to 12 inches wide so that many slats cover the inside width of the trailer. The floor slats are moved or reciprocated either manually or with a drive unit or units. The floor slats or floor members are slidably mounted to the floor.
In one well known arrangement, a plurality of plastic slide bearings support the floor slats so that the floor slats ride on the plastic bearings. The plastic bearings, in turn, are spaced along and mounted on a plurality of parallel guide beams. The bearings surround and are supported by the sub-deck guide beams. The guide beams are then supported by the trailer's structure. In one arrangement, the guide beams are composed of tubular metal and are, in turn, fastened to a plurality of transverse support beams with the guide beams extending across an upper surface of the support beams. The slide bearings usually are installed over and placed upon the guide beams where the guide beams and the trailer's cross members intersect each other.
There are often 1,000 to 1,500 plastic slide bearings on a single trailer and the plastic bearings wear over time. Dirt or dust from the road or the cargo load itself may get between the bearing and floor slat and accelerate wear. Various solutions to this problem have been proposed in the past including Assignee's prior U.S. Pat. No. 6,763,933 entitled "Reciprocating Floor Conveyor". Accordingly, the floor slats must be removed, the old slide bearings removed and disposed of, and a new set of slide bearings installed onto the guide beams and the floor slats replaced.
Each bearing may include a pair of inwardly facing flanges or clips at the end of the extending legs with the space between the clips less than the width of the tubular guide beam. Although the plastic bearings are somewhat resilient, they are not very flexible. Accordingly, it is necessary to pry open the bearing in order for it to fit over the tubular guide beams. Often a tool and considerable labor is required to install each bearing.
Several approaches to these issues have been taken in the past.
Foster (U.S. Pat. No. 4,679,686) in FIGS. 11 through 15 discloses a bearing with lock flanges 126 and 128 which extend downwardly and then upwardly. The lock flanges provide cam surfaces 134 and 136 which flare outwardly so that a downward force causes sides 96 and 98 to be sprung apart until the bearing snaps into place. In practice, considerable force, such as hammering, is required to force the side to be spread apart.
Foster (U.S. Pat. No. 4,492,303) discloses a slide bearing 26 with sidewall portions 50, 52, 54 and 56. Inwardly directed lock flanges 60, 62, 64 and 66 extends laterally inwardly from each sidewall portion. Longitudinal wings 68 and 70 project laterally outward on each side of the bearing.
Foster (U.S. Pat. No. 4,474,285) discloses floor members 94 mounted for sliding movement by means of slide bearings 96 which are required to be snap fit onto longitudinal guide beams 98.
Hallstrom (U.S. Pat. No. 4,144,963) discloses a bearing with a top wall 32, laterally resilient sidewalls 34, and downwardly and inwardly extending lugs 36. Sides must be spread apart in order to fit over a guide beam.
Foster (U.S. Pat. No. 4,749,075) discloses a bearing having sidewalls 40 and 42 that spread apart to receive a width of the guide beam 12 as seen in FIGS. 3 through 5.
Foster (U.S. Pat. No. 5,139,133) discloses bearings 18 which include opposite sidewalls 22 and 24, cams 30 and 32, and wings 34 and 36. A downward force applied to the bearing is required to cause the cams to move downwardly spreading the sidewalls apart.
Accordingly, it is a principal object and purpose of the present invention to provide a new type of slide bearing for a reciprocating floor conveyor which is easier to install and remove with less labor and in less time.
It is a further object and purpose of the present invention to provide a new type of slide bearing for a reciprocating floor conveyor which will have an improved wear surface between the bearing and the floor slat.

Bearings for reciprocating floor conveyor


The invention is directed to compositions and methods for the detection of a malignant condition, and relates to the discovery of soluble forms of mesothelin polypeptides, including mesothelin related antigen (MRA). In particular the invention provides a nucleic acid sequence encoding MRA and an MRA variant. The invention also provides a method of screening for the presence of a malignant condition in a subject by detecting reactivity of an antibody specific for a mesothelin polypeptide with a molecule naturally occurring in soluble form in a sample from such a subject, and by hybridization screening using an MRA nucleotide sequence, as well as other related advantages.

Cancer includes a broad range of diseases, affecting approximately one in four individuals worldwide. The severity of the adverse impact of cancer cannot be understated, influencing medical policy and procedure as well as society generally. Because a hallmark of many types of cancer is rapid and unregulated proliferation of malignant cells, an overarching problem in improving approaches to cancer is the need for early detection and diagnosis. Numerous attempts have been made to develop accurate and reliable criteria for diagnosing the presence of a malignant condition. In particular, efforts have been directed to the use of serologically defined antigenic markers known as tumor associated antigens, which are either uniquely expressed by cancer cells or are present at markedly higher levels in subjects having a malignant condition.
However, due to the high heterogeneity of tumor associated antigen expression, for example the extreme diversity of carcinoma antigens, there is a need for additional tumor markers that are useful in cancer diagnosis. Many monoclonal antibodies reactive with carcinoma associated antigens are known (see, e.g., Papsidero, 1985 Semin. Surg. Oncol. 1:171, Allum et al., 1986 Surg. Ann. 18:41). These and other described monoclonal antibodies bind to a variety of different carcinoma associated antigens including glycoproteins, glycolipids and mucins (see, e.g., Fink et al., 1984 Prog. Clin. Pathol. 9:121; U.S. Pat. No. 4,737,579; U.S. Pat. No. 4,753,894; U.S. Pat. No. 4,579,827; U.S. Pat. No. 4,713,352). Many such monoclonal antibodies recognize tumor associated antigens that exhibit restricted expression on some but not other tumors originating in a given cell lineage or tissue type.
There are only relatively few examples of tumor associated antigens that appear to be useful for identifying a particular type of malignancy. Monoclonal antibody B72.3, for example, specifically binds to a high molecular mass (>106 Da) tumor-associated mucin antigen that is selectively expressed on a number of different carcinomas, including most if not all ovarian carcinomas and an overwhelming majority of non-small cell lung carcinomas, colon carcinomas and breast carcinomas (see, e.g., Johnston, 1987 Acta Cytol. 1:537; U.S. Pat. No. 4,612,282). Nevertheless, detection of cell-associated tumor markers such as the mucin antigen recognized by B72.3 following surgical resection of a tumor may be of limited usefulness for diagnostic screening, in which early detection of a malignant condition prior to accumulation of substantial tumor mass is preferred.
An alternative to the diagnosis of a particular type of cancer by screening surgically resected specimens for tumor associated antigens, where invasive surgery is usually indicated only after detection of an accumulated tumor mass, would be to provide compositions and methods for detecting such antigens in samples obtained from subjects by non-invasive or minimally invasive procedures. In ovarian and other carcinomas, for example, there are currently a number of soluble tumor associated antigens that are detectable in samples of readily obtained biological fluids such as serum or mucosal secretions. One such marker is CA125, a carcinoma associated antigen that is also shed into the bloodstream, where it is detectable in serum (e.g., Bast et al., 1983 N. Eng. J. Med. 309:883; Lloyd et al., 1997 Int. J. Canc. 71:842). CA125 levels in serum and other biological fluids have been measured along with levels of other markers, for example, carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC), tissue polypeptide specific antigen (TPS), sialyl TN mucin (STN) and placental alkaline phosphatase (PLAP), in efforts to provide diagnostic and/or prognostic profiles of ovarian and other carcinomas (e.g., Sarandakou et al., 1997 Acta Oncol. 36:755; Sarandakou et al., 1998 Eur. J. Gynaecol. Oncol. 19:73; Meier et al., 1997 Anticanc. Res. 17(4B):2945; Kudoh et al., 1999 Gynecol. Obstet. Invest. 47:52; Ind et al., 1997 Br. J. Obstet. Gynaecol. 104:1024; Bell et al. 1998 Br. J. Obstet. Gynaecol. 105:1136; Cioffi et al., 1997 Tumori 83:594; Meier et al. 1997 Anticanc. Res. 17(4B):2949; Meier et al., 1997 Anticanc. Res. 17(4B):3019).
Elevated levels of serum CA125 alone or in combination with other known indicators, however, do not provide a definitive diagnosis of malignancy, or of a particular malignancy such as ovarian carcinoma. For example, elevated CA125, CEA and SCC in vaginal fluid and serum correlate most strongly with inflammation in benign gynecological diseases, relative to cervical cancer and genital tract cancers (e.g., Moore et al., 1998 Infect. Dis. Obstet. Gynecol. 6:182; Sarandakou et al., 1997 Acta Oncol. 36:755). As another example, elevated serum CA125 may also accompany neuroblastoma (e.g., Hirokawa et al., 1998 Surg. Today 28:349), while elevated CEA and SCC, among others, may accompany colorectal cancer (Gebauer et al., 1997 Anticanc. Res. 17(4B):2939). Thus the compelling need for additional markers to be used, including markers useful in multi-factor diagnostic screening, is apparent. (See, e.g., Sarandakou et al., 1998; Kudoh et al., 1999; Ind et al., 1997.)
The differentiation antigen mesothelin is expressed on the surfaces of normal mesothelial cells and also on certain cancer cells, including epithelial ovarian tumors and mesotheliomas. Also known as CAK1, mesothelin is identified by its reactivity with the monoclonal antibody K-1 (MAb K-1), which was generated following immunization with the OVCAR-3 ovarian carcinoma cell line (Chang et al., 1992 Canc. Res. 52:181; Chang et al., 1992 Int. J. Canc. 50:373; Chang et al., 1992 Int. J. Canc. 51:548; Chang et al., 1996 Proc. Nat. Acad. Sci. USA 93:136; Chowdhury et al., 1998 Proc. Nat. Acad. Sci. USA 95:669). Mesothelin is synthesized as an approximately 70 kDa glycoprotein precursor having a C-terminal glycosylphosphatidylinositol (GPI) linkage site for cell membrane attachment. This precursor is processed by, inter alia, proteolytic cleavage into at least two components: (i) a shed N-terminal ˜31 kDa polypeptide (Chowdhury et al., 1998 Proc. Nat. Acad. Sci. USA 95:669) having extraordinarily high homology to a soluble 31 kDa polypeptide known as megakaryocyte potentiating factor (MPF) that is similarly derived by proteolysis of an approximately 70 kDa GPI-linked glycoprotein precursor belonging to the mesothelin polypeptide family (Yamaguchi et al., 1994 J. Biol. Chem. 269:805; Kojima et al., 1995 J. Biol. Chem. 270:21984; and (ii) a mature 40 kDa GPI-linked, cell surface-bound C-terminal mesothelin glycosylated polypeptide, which bears the K-1 (MAb K-1) recognition epitope (Chang et al., 1996). As defined by reactivity with MAb K-1, mesothelin is present on a majority of squamous cell carcinomas including epithelial ovarian, cervical and esophageal tumors, and on mesotheliomas (Chang et al., 1992 Canc. Res. 52:181; Chang et al., 1992 Int. J. Canc. 50:373; Chang et al., 1992 Int. J. Canc. 51:548; Chang et al., 1996 Proc. Nat. Acad. Sci. USA 93:136; Chowdhury et al., 1998 Proc. Nat. Acad. Sci. USA 95:669). Using MAb K-1, mesothelin is detectable only as a cell-associated tumor marker and has not been found in serum from ovarian cancer patients, or in medium conditioned by OVCAR-3 cells (Chang et al., 1992 Int. J. Cancer 50:373). Thus mesothelin, despite an expression pattern that correlates with specific malignant conditions, does not appear to offer a useful marker for early diagnostic screening, because only cell-associated and not soluble forms of mesothelin may be detectable by known methods.
The compositions and methods of the present invention overcome these limitations of the prior art by providing a method of screening for the presence of a malignant condition using antibodies specific for mesothelin/MPF and/or mesothelin/MPF-related antigens to detect polypeptides that naturally occur in soluble form, and offer other related advantages.

This patent is subject to a terminal disclaimer.

Methods and compositions for diagnosing carcinomas


An arrangement and a method comprising maintaining knowledge of a number of current network connections that require performing a periodic network operation (204, 206, 208, 210), with one or more predetermined timing sequences, targeted to at least one remote entity for maintaining the connections, and adjusting the time of execution of at least two such network operations to regularly substantially coincide (212).

FIG. 1 depicts an example of a communication system, or an aggregate of multiple communication systems, that interconnects both mobile and computer networks. In the scenario of the figure, a mobile terminal 102 is communicating with a second terminal such as another mobile terminal or a desktop computer 112 reachable via radio access network 104, core (mobile) network 106, a public computer network 108 such as the Internet, and a local area network 110. Alternatively, either of the terminals 102, 112 may communicate with one or more network elements residing in one of the intermediate networks 104, 106, 108, and 110, for example. The figure is merely used to highlight the fact how far-situated two or more communicating parties having access to different networks may actually reside and how different information transfer technologies may be cleverly combined to provide nearly transparent communication experience. As transfer resources, being either wireless (frequencies, etc) or wired (time slots over a copper pair, etc), are in many cases designed for a certain average load only and the number of connections is generally increasing, the unnecessary or "idle" connections between two or more entities shall not be kept alive for unlimited period of time.
Terminal devices and various network elements may be required to execute a plurality of cyclic operations that are to be performed at least once per a predetermined time interval (e.g. once every N seconds or minutes). For example, let us refer to a scenario in which NAT (Network Address Translation) and/or firewall bindings refreshment is required. NAT functionality offers address mapping between two different networks (e.g. a private and a public one) whereas the firewalls monitor and limit traffic on the edge of a network. In practice, NAT and firewall functions may be implemented by the same apparatus, e.g. the GGSN (Gateway GPRS Support Node) of FIG. 1. One operation needed in this context utilizes a so-called keep-alive time, which refers to a time period X prior to or upon the expiration of which the terminal should send a keep-alive message to the NAT/firewall entity concerning each UDP (User Datagram Protocol) and TCP (Transmission Control Protocol) connection thereof, then the associated, connection-specific timer is reset and the same cycle repeats until the connection is finally terminated. For UDP this X may be something like 30 seconds, and for TCP somewhere around 1200 seconds, for example.
As the keep-alive operations are sent separately for each connection, there often are several keep-alive sequences simultaneously running. Particularly in the case of mobile apparatuses that most likely rely on somewhat limited power sources such as a rechargeable battery, constant wake up procedures from a sleep (or other power saving) state for executing each keep alive operation consume an unnecessary amount of power. For example, from idle operation mode (e.g. when there is no call or other payload data transfer ongoing) the wake up procedure causes a power consumption peak that may last for a relatively long time. In the worst case the connection-specific keep-alive transmissions may prevent the mobile apparatus from never really entering a true sleep state, and the apparatus constantly stays in some power inefficient mode instead.

Method and an apparatus for executing timed network operations


A compound represented by the following General Formula (I):

Kinesin is a motor protein which slides over microtubules using adenosine triphosphate and transports, for example, organelles and vesicles, playing an important role in a diverse variety of cell biological processes such as cell division and intracellular substance transportation (e.g., nerve axonal transportation).
At present, about 100 kinds of kinesin-like proteins have been identified. These proteins are presumed to play a very important role during mitosis of the cell cycle by directly interacting with microtubules or chromosomes of the mitotic spindle.
Cell division is a phenomenon that is indispensable for organisms to live and maintain homeostasis of internal environment. Meanwhile, it is also important that apoptosis occurs in organisms to maintain homeostasis. That is, cell division (proliferation) and apoptosis occurring in a balanced manner maintain homeostasis of internal environment of organisms.
However, when such a balance between cell division and apoptosis is lost to enhance cell division, cell proliferative diseases such as cancer develop.
In view of this, attempts have been made to inhibit the kinesin as a treating method for cell proliferative diseases such as cancer. Chemotherapeutic agents routinely used for treating cancer are, for example, taxanes and vinca alkaloids. Taxanes and vinca alkaloids act on microtubules existing in various kinds of cell structures. Presumably, these drugs break the mitotic spindle to inhibit division of cancer cells and induce death of the cancer cells.
Microtubules, however, have an important role not only in cancer cells but also normal cells such as nerve cells. Therefore, these routinely-used chemotherapeutic agents do not specifically target the mitotic spindle, causing problematic side effects of nerve disorders such as numbness in limbs.
A kinesin spindle protein (also called KSP, Eg5, KNSL1, TRIP5 or KIF11, for example), which is one of the identified kinesin-like proteins, is known to localize at the mitotic spindle and be responsible for formation and functions of the bipolar mitotic spindle (see Anne Blangy et al., "Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo" Cell, Vol. 83, pp. 1159-1169, 1995).
Eg5 is known to involve the development of neurons of mice but disappears from neurons immediately after birth, suggesting that the inhibition of Eg5 does not cause peripheral nerve disorders accompanied by routinely-used chemotherapeutic agents (see Lotfi Ferhat et al., "Expression of the mitotic motor protein Eg5 in postmitotic neurons: implications for neuronal development" Journal of Neuroscience 18(19), pp. 7822-7835, 1998).
Therefore, at present, demand has arisen for the provision of a low-molecular-weight new compound capable of inhibiting a kinesin spindle protein with high efficiency; a kinesin spindle protein inhibitor containing the low-molecular-weight compound; and a pharmaceutical composition containing the kinesin spindle protein inhibitor, capable of preventing or treating disorders mediated at least partially by a kinesin spindle protein, free of adverse side effects, and having high safety.

Compound, kinesin spindle protein inhibitor, and application thereof

Abstract: where, in General Formula (I),        R1 and R2 each represent an alkyl group which may have a substituent,        R3 represents the following General Formula (II) or (III), and        R1 and R2 may be identical or different,

Abstract: where, in General Formulas (II) and (III),        X represents a hydrogen atom or a halogen atom,        R4 represents a methyl group, a dimethyl group or an oxygen atom, and        * represents a binding position.


Control systems for industrial machinery (e.g., robots) or other devices such as medical devices utilize a safety processor (SP) designed for integration into safety applications and computational components that are not necessarily safety-rated. The SP monitors performance of the non-safety computational components, including latency checks and verification of identical outputs. One or more sensors send data to the non-safety computational components for sophisticated processing and analysis that the SP cannot not perform, but the results of this processing are sent to the SP, which then generates safety-rated signals to the machinery or device being controlled by the SP. As a result, the system may qualify for a safety rating despite the ability to perform complex operations beyond the scope of safety-rated components.

Industrial machinery is often dangerous to humans. Some machinery is dangerous unless it is completely shut down, while other machinery may have a variety of operating states, some of which are hazardous and some of which are not. In many cases, the degree of hazard depends on the location of the human with respect to the machinery. As a result, many "guarding" approaches have been developed to separate humans and machines and to prevent machinery from causing harm to humans.
One very simple and common type of guarding is a cage that surrounds the machinery, configured such that opening the door of the cage causes an electrical circuit to place the machinery in a safe state. The door may be located so that humans cannot reach the machine before it shuts down. Of course, this prevents all interaction between human and machine, or a human and the workplace the machine is processing, and severely constrains use of the workspace. Another simple guarding mechanism is a pressure-sensitive mat placed a distance from the dangerous machinery; stepping on the mat triggers a safe shutdown of the machinery.
More sophisticated types of guarding may involve, for example, optical sensors such as light curtains, which determine if any object has intruded into a monitored region; area scanners that detect intrusions optically; and 2D LIDAR sensors that use active optical sensing to detect the minimum distance to an obstacle along a series of rays emanating from the sensor. More recently, systems have begun to employ 3D depth information using, for example, 3D time-of-flight sensors, 3D LIDAR, 3D radar, and stereo vision cameras. These sensors offer the ability to detect and locate intrusions into the area surrounding industrial machinery in 3D and offer greater flexibility and power in identifying and tracking objects in workcells.
In industrial automation, the systems intended to ensure the safety of humans working in the surrounding environment of an industrial process are known as "safety systems." These safety systems incorporate a closed control loop together with the electronics and hardware associated with the light curtains, switches on cage doors, emergency stop buttons, and other machine control inputs used as safety interlocks. For example, when a light curtain is triggered, it issues a breach signal to a safety controller. The safety controller thereupon issues a signal to the equipment being guarded by the light curtain to shut down in a safe manner. The safety controller may include a "safety processor," i.e., a microprocessor, microcontroller, or other processor designed for integration into safety systems.
Safety systems usually include a set of redundant circuits separate and isolated from the industrial control system responsible for the associated industrial process. An alternative approach is to use a control device with an integrated safety system, in which case the controller carries out both standard and safety tasks—thereby rendering it unsuitable (for reasons discussed below) in particularly hazardous environments where a high safety rating is required. Additionally, it is expensive and difficult to develop software for integrated safety systems whose software controls both standard and safety tasks in a way that meets the stringent safety standards.
In their simplest implementation, safety systems are hardwired from switches and relays, including specialized safety relays that compare redundant signals and provide internal checking of machine and safety-system states. A "safety relay" has two mechanically-linked nodes, one which is normally open and one which is normally closed, and when the relay is toggled, the equipment is enabled. In safety-rated systems, two such safety relays are typically used for every safety output in a dual configuration but the feedback input is single-channel, providing redundant checking of the output safe state. More sophisticated systems employ "safety controllers," which receive signals from the safety interlocks (such as a light curtain), process the incoming signal, and issue a signal to the equipment to slow down or stop in a safe manner. Safety control can be implemented in various ways, depending on the required control and safety complexity, and can be passive or active.
Passive safety control is executed using a safety relay, and active safety control is executed using a safety controller. A safety controller can be a programmable logic controller ("safety PLC") module or modules that fulfill the criteria necessary to qualify for a safety rating or can be implemented as a more complex special-purpose industrial computer. Under the direction of a stored safety control program, a safety controller computer examines a series of inputs reflecting the status of the controlled processes and generates a series of safety outputs. A safety controller has as its core a safety processor that receives the inputs from the safety controller and determines a safe output to the machinery being controlled.
The inputs and outputs of the safety controller may be binary (on or off), or analog, in a continuous range. The inputs may be obtained from light curtains or other sensors attached to the industrial process equipment and the outputs may be signals to power control relays, actuators or motors on the equipment. The inputs and outputs can also originate with safety input-output (I/O) modules, which connect directly to the input sensors and the output actuators and are used as common interfaces to the safety controller. The safety I/O modules also provide monitoring functions and the ability to better troubleshoot the safety control system during installation and operation.
For the entire safety system to qualify for a safety rating, all of the elements of the safety system control loop (input sensors, output actuators, safety processor, and interconnects) must generally satisfy the rating criteria, and the interconnection of the different elements and their operation must also comply with industry safety standards. Because human safety is at stake, these standards are stringent, and may specify failure rates for hardware components and rigorous development practices for both hardware and software components.
Standards-compliant systems ensure that dangerous conditions can be detected with very high probability, that failures of the system itself are detected, and that the system will respond to detected failures by transitioning the controlled equipment to a safe state.
For example, the International Standards Organization (ISO) developed the ISO 13849 standard, Safety of Machinery: Safety-Related Parts of Control Systems. ISO 13849 provides safety requirements and guidance for the design of safety-related components. ISO 13849 provides guidelines on the probability of failure of components and circuitry as measured by a performance level (PL). The PL, defined as the average probability of a dangerous failure of the component per hour, ranges from a (lowest) to e (highest).
Similarly, the International Electrotechnical Commission (IEC) developed the general IEC 61508 (Functional Safety of Electrical/Electronic/Programmable Electronic Safety-Related Systems) and machinery-specific IEC 62061 (Safety of Machinery: Functional Safety of Electrical, Electronic and Programmable Electronic Control Systems) standards. IEC 61508 and IEC 62061 specify four safety integrity levels (SILs) of performance for a safety function. Safety systems with a SIL of 2 (SIL 2) and 3 (SIL 3) generally require hardware redundancy for sensors, computational elements, and power supplies, and a safety overlay that transitions the system to a failsafe state in the case of a safety fault. This increases cost, and in addition to being more expensive, safety-rated hardware tends to lag significantly in functionality and performance behind similar, non-safety systems.
A critical variable in a safety system is the "safety response time," which is the amount of elapsed time between a safety-related event (e.g., an intrusion breaching a light curtain) and when the equipment being monitored by the safety system has reached a safe state. This safety response time is a function of a number of variables and depends on the safety system architecture and configuration. For example, in the simple case of a light curtain intrusion triggering the stopping of a robot, it would be the sum of the time it takes the light curtain to issue a signal to the safety controller following a detected breach plus the time it takes for the signal to reach the safety processor (data transmission latency) plus the time it takes for the safety processor to issue a command (safety processor processing time) to the robot plus the time it takes for the signal to travel to the robot emergency stop circuitry plus the time it takes the robot to acknowledge the signal plus the time it takes the robot to stop from its moving state to a safe stopped state.
Each of these times depends on the interconnects and logic instructions within a specific safety program. The reaction time of a controller is the worst-case delay from any input change presented to the controller until the processed output is acknowledged and used to activate a safe state by the machinery being controlled. A properly designed safety system will have a timer to limit the safety task reaction time within an acceptable bound. Exceeding this time bound will cause the timer to transition the safety system output to a safe state.
It is desirable to have the safety response time to be as fast as possible, which allows the safety components such as light curtains to be placed close to the machinery. This is particularly helpful when space on the factory floor is at a premium and there is a need to put the guarding equipment as close to the machines as possible. Also, by minimizing this safety response time, it is more likely that the system will respond to situations where the intrusion itself is moving at high speed (e.g., a human tripping into a dangerous workcell); placing the machinery into a safe state as quickly as possible reduces the possibility of injury.
It is also important for this safety reaction time not to vary between operating cycles, or for it to drift as the system operates. The safety system needs to have a repeatable and reliable safety reaction time. This is critical because the locations where the guarding equipment may be installed depend on an experimentally determined or calculated safety reaction time.
Variations or drifts in this safety reaction time once the guarding equipment is installed and the system is in operation could lead to violations of the minimum distance between guarding and equipment required by safety-rating criteria. As sensing and computation equipment becomes more sophisticated and complex, it becomes progressively more difficult for such equipment to fulfill demanding safety-rating criteria. For example, 3D sensor systems offer the possibility of improved granularity in guarding systems. But 3D sensor systems are more complicated relative to 2D sensor systems, not to mention simple intrusion-detection mechanisms such as light curtains or pressure mats. First, specific safety zones must be identified, taking into account the hazards posed by the machinery, the motion and trajectory of the machinery, the possible actions of humans in the workspace, the workspace layout, and the location and field of view of each individual sensor. It can be difficult to calculate the optimal shapes of exclusion zones, especially when trying to preserve safety while optimizing floor space and system throughput, where one object may present an occlusion relative to a sensor, and where some objects may be out of range or undetectable by the sensor. Moreover, the computation times needed for 3D calculations are longer, and variations in computation time dependent on the possibly changing geometry or complexity of the workspace mean that the safety response time of a system using 3D sensors and computation elements is both longer and more variable than that of a simpler safety system using, for example, a light curtain.
At an extreme, the processing time involved in the detection and classification of elements within the scene is not only long but can also vary by measurement cycle as the environment changes. For example, in the case of a 3D sensing safety system, the more obstructions or occlusions there are in the cell, or the more cameras that are installed, the longer the computation time will be, and this may scale with the complexity of the observed scene. As obstructions are dynamic and can change over time (for example, as a varying number of humans or objects enter and exit the workcell under observation), computation time will vary over time. Consequently, it is not possible to meet safety criteria that require an upper bound on reaction time and/or a limit on reaction time variance.
In sum, in industrial safety, including applications involving robotics, good practice or formal safety regulations require all components of the safety system to be safety-rated. Unfortunately, traditional safety processors cannot perform all the necessary computing tasks involved in safety monitoring of the workcell. Frequently, safety processors lack the processing power to apply the necessary algorithms with sufficient throughput to avoid compromising safety requirements. Accordingly, there is a need for safety architectures that can comply with stringent safety-rating criteria while performing complex operations and accommodating heterogeneous, dynamic environments with unpredictable numbers of people and hazards.

System architecture for safety applications


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