A hermetic reciprocating piston compressor capable of reducing vibration, noise, starting voltage, and power consumption, comprising a cylinder block; a cylinder head that is attached at the cylinder block and having a discharging chamber; a valve plate inserted between the cylinder block and the cylinder head: a first discharging muffler connected with the discharging chamber by a discharging passage disposed between the valve plate and the cylinder block; and a second discharging muffler connected to the first muffler at one end thereof by the connection pipe, and the discharging pipe being connected with another end the second discharging muffler, wherein the connection pipe has plural passages in a middle part thereof, and the passages merge to become one passage at both ends thereof.

1. Field of the Invention
The present invention relates generally to a hermetic reciprocating piston compressor, and more particularly to a hermetic reciprocating piston compressor having a reduced discharge pulse structure.
2. Description of the Related Art
A compressor having a conventional discharge pulse reduced structure is disclosed in Korean patent application No. 2001-11835, which is an unpublished prior application of the applicant.
The compressor having the above conventional discharge pulse reduced structure has the remarkable improvement of reducing vibration and noise. However, a problem exists in that the starting voltage and the power consumption are increased due to the passage resistance of the discharging part.
Moreover, if a different end of the discharge passage of the cylinder block is reduced and the diameter of the connection pipe and the discharge passage is broadened to improve the above-mentioned problem, then the starting voltage and the power consumption is reduced, however, this increases the problem of noise.
An object of the present invention is to solve the above-mentioned problem of conventional compressors, and to provide a hermetic reciprocating piston compressor having a discharge pulse reduced structure capable of reducing vibration, noise, starting voltage, and power consumption.
The above object is accomplished by providing a hermetic reciprocating piston compressor according to the present invention, comprising: a cylinder block; a cylinder head that is attached at the cylinder block and has a discharging chamber; a valve plate inserted between the cylinder block and the cylinder head: a first discharging muffler connected with the discharging chamber by a discharging passage disposed at the valve plate and the cylinder block; and a second discharging muffler, in fluid communication with the first muffler, and having a discharging pipe connected at one end thereof to the second discharging muffler, wherein the connection pipe comprises plural in a middle part thereof, with the plural passages becoming one passage at both ends thereof at the connections of the connecting pipe to the discharging mufflers.
It is preferable that the connection pipe is disposed so that the middle part thereof is immersed in cooling oil, that there be two passages in the middle of the connection pipe, and the ratio of the cross-sectional areas of the two passages of the connection pipe is 1:1.
Moreover, it is preferable that the inner diameters of both ends of the connection pipe are between approximately 1.5 and 4.0 mm, the inner diameters of the two passages in the middle part are between approximately 1.5 and 4.0 mm, the length of the connection pipe is between approximately 70 and 170 mm, and the volume of the first discharging muffler and the second discharging muffler is between approximately 25 and 50 cc.

Hermetic reciprocating piston compressor


A puffed food dough and method for producing a puffed food product from the dough. The dough contains soybean protein, starch and dietary fiber in a ratio by weight of from 1:0.2 to 0.8:0.01 to 0.4, respectively, and from 0.5 to 5 parts by weight of a vegetable foaming agent and from 150 to 300 parts by weight of water per 100 parts by weight in total of the soybean protein, starch, and dietary fiber. The dough does not contain a chemical leavening agent or yeast.

Recently, to avoid various problems caused by eating too much animal food, low-calorie foodstuffs have been drawing public attention as healthy food. In addition, the relation between food and prevention of diseases has been clarified, and it is known, for example, that those containing fibers and less fat help to reduce risks of cancer, and those containing fibers and less cholesterol reduce risks of coronary heart diseases. Thus, healthy food that helps to maintain and promote human health attracts public attention, and such food that is rich in protein and low in calories and contains dietary fibers and the like is studied, and sold in the market.
Although various healthy foods have been studied and commercialized as described above, because the term, "healthy food", has not been clearly defined, and has for different meanings, it has caused a problem that misunderstanding or confusion on the part of consumers In order to solve the problem, the U.S. Food and Drug Administration (FDA) has established a guideline stating, if total fat, saturated fat, cholesterol and sodium contained in a serving size of a particular foodstuff are higher than specified levels, the foodstuff cannot be claimed as being a healthy food. More specifically, a foodstuff of a meal type, for example, cannot be claimed as being healthy food, if total fat of 26.0 g or more, saturated fat of 8.0 g or more, cholesterol of 120 mg or more and sodium of 960 mg or more are contained in a serving size of the particular foodstuff. In the case of packaged foodstuffs, a nutritional specification showing contents of ingredients must be provided as well.
Of the above-mentioned healthy foods, those using a soybean protein instead of animal meat protein are very important to prevent intake of excessive fat and calories. Since a soybean protein is particularly excellent in the balance of essential amino acids, and very nutritious, a variety of foodstuffs rich in protein and low in calories with a soybean protein contained-as a protein source are studied. As a part of such study, addition of a soybean protein to such puffed food as bread has been also studied. In a puffed food like bread which is made from such milled grains as wheat flour, starches and such expanding agent as yeast and baking powder, if a soybean protein is used entirely or partly in place of such material as wheat flour, the puffed food obtained is low in loaf capacity and gives a tough touch, when it is eaten, so a foodstuff that sufficiently satisfies the human taste has never been obtained. In order to solve the problem, the inventors proposed a method of obtaining a bread-like puffed food that comprises a soybean protein, wheat flour and eggs, and that has a high content of soybean protein by puffing a dough using an expanding agent (see Japan Laid-open Pat. No. 144936/1989).
The puffed food produced by such method as disclosed in the laid-open patent is high in loaf capacity, excellent in touch, flavor and nutritional balance, and is favorably accepted in Japan, United States and many other countries. However, has the problem that the puffed food obtained in such manner contains much cholesterol, and fails to meet the above-mentioned FDA specification, because eggs that are high in cholesterol content are used as a foaming agent for improving the touch and the puffing effect. It is another problem that the food cannot be served to those who are religiously prohibited from eating eggs. Additionally, use of chemical expanding agents has been a problem as well.
In the light of such problems, it is an object of the invention to provide a method for producing a food superior in flavor, touch and nutritional balance, low in cholesterol content, and containing a soybean protein and dietary fibers and a dough for such puffed food.

Production method of puffed food and puffed food dough


A liquid-jet head, including: a plurality of head bodies each furnished with a nozzle plate having a plurality of nozzles formed therein; a joining member, adhered to the nozzle plate via an adhesive agent, for binding and fixing the plurality of head bodies; an opening formed in a region of the joining member corresponding to the nozzles; and a protrusion formed in an edge portion of the opening facing the nozzle plate, and protruding toward the nozzle plate, wherein when the joining member is joined to the nozzle plate via the adhesive agent, the protrusion is allowed to bite into the nozzle plate.

1. Technical Field
The present invention relates to a liquid-jet head and a liquid-jet apparatus in which liquid droplets are ejected through a nozzle bored in a nozzle plate. More particularly, the invention relates to an ink-jet recording head and an ink-jet recording apparatus in which a part of a pressure generating chamber communicating with the nozzle is constructed from a vibration plate, and a piezoelectric element provided on the vibration plate is displaced to eject ink droplets through the nozzle.
The invention also relates to a method for producing a liquid-jet head in which liquid droplets are ejected through a nozzle bored in a nozzle plate. More particularly, the invention relates to a method for producing an ink-jet recording head in which a part of a pressure generating chamber communicating with the nozzle is constructed from a vibration plate, and a piezoelectric element provided on the vibration plate is displaced to eject ink droplets through the nozzle.
2. Related Art
A liquid-jet head for ejecting liquid droplets through a nozzle by imparting pressure to a liquid by a piezoelectric element or a heating element has been known, and its representative example is an ink-jet recording head for ejecting ink droplets. The ink-jet recording head, for example, has a structure in which a nozzle plate having nozzles for ejection of ink droplets is joined onto an ink chamber body having pressure converting elements for imparting pressure to ink, and a protective plate or a nozzle cover, which is a joining member, is joined onto the nozzle plate via an adhesive agent (see, for example, JP-A-5-201000 (FIG. 1, pages 3 to 4, etc.)).
With such an ink-jet recording head, metal components constituting the ink-jet recording head are charged by a recording medium such as recording paper, or static electricity from the outside, with the result that the pressure converting elements for imparting pressure to ink, or a driver IC or the like for driving the pressure imparting elements may be destroyed. Such a problem is apt to occur, particularly when the nozzle plate is formed from a metallic material. In the ink-jet recording head described in JP-A-5-201000, for example, the protective plate or the nozzle cover joined onto the nozzle plate via the adhesive agent is brought into contact with the nozzle plate at a contact portion different from the site of adhesion to establish conduction between the protective plate or the nozzle cover and a ground line, thereby suppressing charging of the nozzle plate.
With the ink-jet recording head of the earlier technology, moreover, the protective plate or the nozzle cover, which is the joining member, is joined onto the nozzle plate via the adhesive agent. If the adhesive agent oozes out or squeezes out, therefore, the adhesive agent may extend into the site of contact between the protective plate or the nozzle cover and the nozzle plate, causing insulation and making it impossible to suppress charging. The use of a film adhesive agent is conceivable to prevent oozing-out or squeezing-out, but control over the position of film adhesion is so difficult that the cost will increase. Oozing-out or squeezing-out may be prevented with the use of an adhesive agent having a spacer, such as beads, kneaded therein. However, quality control of the adhesive agent has to be exercised carefully to avoid dispersion or settlement of the spacer, rendering control difficult and resulting in cost increase.
If the nozzle plate is subjected to insulating, water repellent treatment, the applied ink repellent film needs to be partly removed for formation of a conductive portion, thereby increasing processing man-hours. Furthermore, the protective plate or the nozzle cover is conductive to the nozzle plate by contact. Thus, a clearance can be produced at the site of contact because of an environmental change, such as a temperature change. As a result, elimination of static electricity is not reliably carried out, thus rendering reliability dubious. Besides, an adhesion surface and a contact surface are required between the protective plate or the nozzle cover and the nozzle plate, posing the problem of upsizing the entire head.
Such problems are true of other liquid-jet heads for ejecting other liquids than ink, as well as the ink-jet recording head for ejecting ink.

Liquid-jet head apparatus having a fixing plate formed with a protrusion


Disclosed herein is a biodegradable latex web material which is suitable as a replacement for plastic in a wide variety of uses due to its good overall strength and its ratio of wet strength to dry strength. The material includes a web of cellulose fibers which, prior to treatment with a saturant, has a breaking length in the dry state ranging from about 0.80 to about 6.20 km. Optionally, the web can contain synthetic fibers to improve the tear strength of the material. In order to obtain tensile strengths which are comparable to plastics, the fibrous web is saturated with a latex composition which may be natural, synthetic or a combination of natural and synthetic polymers. In addition to latex, other additives may be incorporated into the saturant for special end use properties. The latexes used will have glass transition temperatures (Tg) of between about -50.degree. C. and about 20.degree. C. If mixing natural and synthetic polymers together, the ratio of synthetic to natural polymers should be about 2:1 to about 4:1 by weight. The saturant compositions are applied to the base web at an add on from about 16 to about 80 dry parts saturant per 100 parts fiber by weight to form a latex web composite. The composite once formed should have an average strength of at least about 50 kg/cm.sup.2 and a ratio of wet strength to dry strength ranging from about 0.2 to about 0.6.

The present invention relates to a biodegradable and mulchable web material. More specifically the web material is a fibrous web of cellulose treated with a latex to yield a product with a ratio of wet strength to dry strength ranging from about 0.2 to about 0.6. The material is suitable for use in a wide variety of applications including, but not limited to, agricultural mulch and row covers, bags and outer covers for personal care absorbent products such as diapers, feminine pads, training pants, incontinence products and wound dressings. Other possible applications include surgical drapes and gowns as well as other disposable items.
Biodegradability has become one of the most important, discussed and researched topics as the beginning of a new century approaches. The topic of biodegradability is being researched for a wide variety of products and materials. Plastics, however, are the materials which are getting the most attention when it comes to biodegradability. Plastics are widely regarded as not being biodegradable because of the large amount of time it takes to break these materials down. Examples of such materials include: polyethylene, polypropylene, poly vinyl chloride, and most polyesters. A problem though in discussing the term biodegradability is the term itself. There are an abundance of definitions as to what is biodegradable and what biodegradability means from the standpoint of time and end degradation components.
One factor in determining biodegradability is the amount of oxygen and moisture available for the degradation process. Recent articles such as "Rubbish!" by William L. Rathje, The Atlantic Monthly, December 1989, ppg. 99-109, indicate that many landfills have insufficient oxygen and moisture to permit aerobic decomposition. One example given in the above article involved the excavation of a landfill which revealed newspapers from 1959 which were completely legible and in near perfect condition. Thus it can be seen that even materials such as newsprint, which is considered very biodegradable, will not degrade unless given the proper conditions.
One type of disposal which is fairly aerobic is mulching and composting. When certain materials are chopped and then mixed in with the top soil, an environment is created which is fairly conducive to degradation. Here again, however, some materials are more predisposed to degrading than others. For example, polyolefin films take lengths of time which are magnitudes greater than paper to break down. Today, many plastics are being mixed and extruded with other constituents, such as starch, to help them break down faster. But even in these cases the time to degrade is much longer than common paper. It is therefore an object of the present invention to provide a material which will degrade significantly when mulched and composted into the soil and yet will have the useful properties of many plastic films.
Thin plastic films are widely used today as replacements for paper. Perhaps one of the most common reasons plastics and especially plastic films are used instead of paper is the strength of plastics in both the wet and dry state. In addition, plastic films have gained their own niche due to the inherent properties of plastic. Examples of the widespread use of plastic include plastic bags, plastic wrap and outer covers for disposable products such as diapers, training pants, incontinence products and sanitary napkins. In all such cases the plastic is usually low cost, lightweight and high in strength in both the wet and dry states. As a result, at least from a convenience standpoint, products including these plastics are readily utilized by the consumer.
The agricultural field is another area where plastics are gaining wider use, particularly with respect to row covers and plastic mulches. Row covers or mulches are large strips of material which are laid down between rows of plants to control weeds, soil temperature and erosion. Under such conditions, the plastic has sufficient strength and integrity to withstand the rigors of usage including wind and rain. Despite these advantages, however, disposal becomes a problem. At some point in the agricultural cycle, the row covers must either be removed or mulched into the ground. Removal is very time consuming and mulching can result in the creation of a top soil layer which is laden with undecomposed or slowly decomposing plastic.
It is therefore an object of the present invention to provide a cellulose-based material which will have sufficient strength and barrier properties to act as a replacement for the above products while also having a sufficient degree of biodegradability.
These and other objects of the present invention will become more apparent upon a further review of the following specification and claims.


A method is described for fabricating an encapsulated metal structure in a feature formed in a substrate. The sidewalls and bottom of the feature are covered by a barrier layer and the feature is filled with metal, preferably by electroplating. A recess is formed in the metal, and an additional barrier layer is deposited, covering the top surface of the metal and contacting the first barrier layer. The additional barrier layer is planarized, preferably by chemical-mechanical polishing. The method may be used in fabricating a MIM capacitor, with the encapsulated metal structure serving as the lower plate of the capacitor. A second substrate layer is deposited on the top surface of the substrate, with an opening overlying the encapsulated metal structure. A dielectric layer is deposited in the opening, covering the encapsulated metal structure at the bottom thereof. An additional layer, serving as the upper plate of the capacitor, is deposited to cover the dielectric layer and to fill the opening. The dielectric layer and the additional layer are planarized, preferably by CMP.

This invention relates to semiconductor processing, and more particularly to a process for encapsulating an electroplated metal structure in a semiconductor device. This invention also relates to a metal-insulator-metal (MIM) capacitor in the device which incorporates such a metal structure.
In the fabrication of semiconductor devices, metal lines are often embedded in dielectric layers in a multilevel structure, particularly in the latter stage (xe2x80x9cback end of the linexe2x80x9d or xe2x80x9cBEOLxe2x80x9d) of the fabrication process. In general, it is necessary to isolate the metal lines on one level from the other levels. This is typically done by providing a high-dielectric-constant barrier (for example, silicon nitride) between the levels.
A conventional BEOL process, providing an electroplated metal line in an interlevel dielectric and an interlevel barrier, is shown in FIGS. 1A-1E. An interlevel dielectric layer (such as SiO2) 10 has a feature 11 formed therein. A liner/adhesion promoter 12 for the plated line is deposited on the surface, including the sidewalls and bottom of feature 11 (FIG. 1A). In the case of copper electroplating, layer 12 is typically a combination of tantalum nitride (in contact with the substrate 10) and tantalum; layer 12 serves as a copper diffusion barrier while promoting adhesion to the substrate. As shown in FIG. 1B, a seed layer 13 for the metal to be plated is deposited over the entire surface. Plating is then performed on the entire surface, until feature 11 is filled in with plated metal 14 (see FIG. 1C). To ensure that the entire feature is filled in, plating continues until an excess of plated metal appears in areas 15 outside feature 11. This excess metal, along with the liner material in areas 15, is then removed with a planarization process such as chemical-mechanical polishing (CMP), to yield a metal line as shown in FIG. 1D. The plated metal 14 is surrounded by the liner 12, except on the top surface 14a.
In order to encapsulate the metal line (to prevent electrical shorts and degradation of the metal line due to electromigration and diffusion of the metal), the top surface of the interlayer dielectric 10 is blanketed with a dielectric layer 16 (see FIG. 1E). This layer is typically silicon nitride. The high dielectric constant of layer 16 increases the overall dielectric constant of the level structure (which includes interlevel dielectric 10, metal 14 and layer 16). This has the effect of degrading the performance of the completed semiconductor device.
There is a need for an improved BEOL fabrication process in which the plated metal is encapsulated but the blanket dielectric layer is eliminated, so that the performance of the semiconductor device is enhanced.
The present invention addresses the above-described need by providing a method of fabricating an encapsulated metal structure in a feature of a substrate, where the top surface of the substrate is exposed. This is done by covering the sidewalls and bottom of the feature with a first barrier layer; filling the feature with metal; forming a recess in the metal; and then depositing an additional barrier layer covering the top surface of the metal and contacting the first barrier layer. The additional barrier layer is then planarized, so that the top surface of the substrate is exposed. The planarization is preferably performed by CMP, and the feature is preferably filled by depositing a seed layer of metal in the feature and electroplating the metal.
According to one aspect of the invention, the recess in the metal is formed (preferably by CMP) so that a top surface of the metal is lower than the top surface of the substrate. A second barrier layer is then deposited on the top surface of the metal, and the first barrier layer and the second barrier layer are planarized. After planarization, the top surface of the substrate is exposed, the metal is encapsulated by the first barrier layer and the second barrier layer, and the second barrier layer is planar with the top surface of the substrate.
According to another aspect of the invention, planarizing the first barrier layer and the second barrier layer causes the top surface of the substrate to be exposed, and also causes a portion of the top surface of the metal to be exposed, with a remaining portion of the second barrier layer on the top surface of the metal. A second recess is then formed in the metal at the exposed portion thereof, and a third barrier layer is deposited on the top surface of the metal and on the remaining portion of the second barrier layer, thereby filling the second recess in the metal. The third barrier layer is then planarized so that the top surface of the substrate is exposed and the metal is encapsulated by the first barrier layer, the second barrier layer and the third barrier layer.
The present invention also provides a method of fabricating a metal-insulator-metal (MIM) capacitor which includes the above-described encapsulated metal structure. A first substrate layer has a feature formed therein, and an encapsulated metal structure is formed in the feature; the sidewalls and bottom of the feature are covered by a first barrier layer and the feature is filled with metal, covered by an additional barrier layer in contact with the first barrier layer. A second substrate layer is then deposited on the top surface of the first substrate layer and overlying the encapsulated metal structure; an opening is formed in the second substrate layer to expose the encapsulated metal structure. A dielectric layer is deposited on the second substrate layer, covering the sidewalls of the opening and the exposed encapsulated metal structure at the bottom of the opening. An additional layer is deposited, to cover the dielectric layer on the sidewalls and on the bottom of the opening and to fill the opening. The dielectric layer and the additional layer are then planarized.
According to an additional aspect of the invention, an encapsulated metal structure formed in a feature of a substrate is described. This structure includes a first barrier layer covering the sidewalls and bottom of the feature; metal filling the feature and having a recess formed therein, so that a top surface of the metal is lower than the top surface of the substrate; and an additional barrier layer covering the top surface of the metal and contacting the first barrier layer, so to encapsulate the metal. The additional barrier layer is planarized so that the top surface of the substrate is exposed.
According to another aspect of the invention, a metal-insulator-metal (MIM) capacitor structure is described. This structure includes an encapsulated metal structure in a feature formed in a first substrate layer; the sidewalls and bottom of the feature are covered by a first barrier layer and the feature is filled with metal covered by an additional barrier layer in contact with the first barrier layer, to form a lower plate of the capacitor structure. The structure also includes a second substrate layer on the top surface of the first substrate layer; the second substrate layer has an opening formed therein overlying the encapsulated metal structure. A dielectric layer covers the sidewalls of the opening and a portion of the encapsulated metal structure at the bottom of the opening. An additional layer covers the dielectric layer on the sidewalls and bottom of the opening and fills the opening, to form an upper plate of the capacitor structure. The dielectric layer and the additional layer are planarized so that the top surface of the second substrate layer is exposed.

Encapsulated metal structures for semiconductor devices and MIM capacitors including the same

International Business Machines Corporation


A U-shaped surgical clip having two arms is provided. The arms are connected to one another via a deformable web. In order firstly to increase the application safety and secondly to simplify application, it is proposed that, via the junction point of the arms with the web, the arms comprise rearwardly projecting extensions. Interacting catches are disposed at these extensions and/or at the deformable web. The catches fix the extensions to one another and/or fix the web to these extensions when the web is deformed upon the compression of the arms and is forced against the extensions.

The present invention relates to a U-shaped surgical clip having two arms that are connected to one another via a deformable web.
Such surgical clips are used to clamp vessels. In the case of known surgical clips, the arms, which on the inside are constructed as clamping jaws, are laid against both sides of a vessel and are compressed, deforming the clip. Thus the webs firstly have to be easily deformable for the application of the clips. Secondly, in the case of conventional clips, they have to absorb the clamping forces. In order to remain in this clamping position, the web connecting the arms has to have a very strong construction, since it has to retain the already assumed position after deformation. As a result, different demands on the webs are produced, which are to some extent difficult to meet. In many cases the strength of a clip whose arms are held together just by the web is not sufficient.


The present invention provides compounds of the formula:

Briefly, according to the present invention, there are provided selective modulators of nicotinic acetylcholine receptors. More particularly, the present invention provides pyridyl ethers and thioethers as selective nicotinic acetylcholine receptor agonists, partial agonists, antagonists or allosteric binding molecules useful in the treatment of pain, Alzheimer""s disease, memory loss or dementia or loss of motor function.
Holladay, et. al., in xe2x80x9cIdentification and Initial Structure-Activity Relationship of (R)-5-(2-Azetidinylmethoxy)-2-chloropyridine (ABT594), a Potent, Orally Active, Non-Opiate Analgesic Agent Acting via Neuronal Nicotinic Acetylcholine Receptorsxe2x80x9d, 1998, J. Med. Chem., 41, 407, describe the preparation of ABT594 and its therapeutic utility. A similar disclosure is made by Donnelly-Roberts, et. al., 1998, J. Pharmacol. Exp. Ther., 285, 777 and 787; Decker, et. al., 1998, Eur. J. Pharmacol., 346, 23 and in WO 98/25920; wherein ABT594 is contained within the general structure:
Abreo, et. al., in xe2x80x9cHeterocyclic Ether Compounds that enhance Cognitive Functionxe2x80x9d, 1994, W.O. Patent 94/08992, describes the preparation of heterocyclic ether compounds and itstherapeutic utility. A similar disclosure is made in Abreo, et. al., 1996, J. Med. Chem. 39, 817. Generally, the heterocyclic ether compounds have the structure:
where A is saturated heterocycle, B is unsaturated heterocycle and R is H or C1-6alkyl.
Lin, et. al., in xe2x80x9c3-Pyridyloxymethyl Heterocyclic ether Compounds useful in Controlling Chemical Synaptic Transmissionxe2x80x9d, 1997, U.S. Pat. No. 5,629,325, describe the preparation of pyridyl ether compound and its therapeutic utility. A similar disclosure is made by Lin, et. al., 1997, J. Med. Chem. 40, 385. Generally, the 3-Pyridyloxymethyl heterocyclic ether compounds have the structure:
wherein R1 is H or C1-6alkyl; R2 is H, F, Cl, vinyl or phenyl; L is a C1-6 linking group and R3 is H or C1-6alkyl.
Shanklin, et. al., in xe2x80x9cAryloxy and Aryloxyalklazetidines as Antiarrhythmic and Anticonvulsant Agentsxe2x80x9d, 1992, U.S. Pat. No. 5,130,309, describe the preparation of Aryloxy and aryloxyalkyllazetidines and their therapeutic utilities. Generally, the described azetidines have the formula:
wherein n is 0 to 3, R is H, C1-4alkyl or arylalkyl and Ar is phenyl or substituted phenyl.
Cosford, et. al., in xe2x80x9cSubstituted Pyridine Derivatives, Their Preparation and Their Use as Modulators of Acetylcholine Receptorsxe2x80x9d, 1996, W.O. Patent 96/31475, describe the preparation of substituted pyridine derivatives and its therapeutic utility. Generally, the pyridine derivative have the formula:
wherein A is 1-6 atoms bridging species linking pyridine and N, B is 1-4 atoms bridging species linking N and Z, Z is H, C1-6alkyl, alkynyl or aryl; R3 is H or lower alkyl; and R2, R4, R5, and R6 are H, C1-6alkyl, alkynyl, aryl or S-containing groups.
McDonald, et. al., in xe2x80x9cModulators of Acetylcholine Receptorsxe2x80x9d. 1998, U.S. Pat. No. 5,723,477, describe the preparation of C-3 substituted pyridyl compounds and its therapeutic utility. A similar disclosure is made in McDonald, et. al., 1997, U.S. Pat. No. 5,703,100; McDonald, et. al., 1997, U.S. Pat. No. 5,677,459; Menzaghi, et. al., 1997, J. Pharmacol Exp. Ther. 280, 373, 384, and 393; and Lloyd, et. al., 1998, Life Sci., 62, 1601. Generally, the C-3 substituted pyridyl compounds have the formula:
wherein A is 1-3 atom bridging moiety, forming a 5-7 membered ring; B is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NR10xe2x80x94, xe2x80x94CHR10xe2x80x94, xe2x95x90CR10xe2x80x94 or xe2x95x90Nxe2x80x94; R2, R4, R5 and R6 are H, C1-6alkyl, aryl, alkynyl, or O-, S-, or N(R)-containing group; and R7 and R9 are H, C1-6alkyl, aryl, or alkynyl.
Caldwell, et. al., in xe2x80x9cMethod for Treatment of Neurodegenerative Diseasesxe2x80x9d 1993, U.S. Pat. No. 5,212,188, describe the preparation of alkenyl pyridyl compounds and its therapeutic utility. A similar disclosure is made in Bencherif, et. al., 1996 J. Pharmacol. Exp. Ther., 279, 1413 and 1422. Generally, the alkenyl pyridyl compounds have the general formula:
wherein n is 1-5, R is H or C1-5alkyl and X is halogen.
Crooks, et. al., in xe2x80x9cNicotinic Receptor Antagonists in the Treatment of Neuropharmacological Disordersxe2x80x9d 1997, U.S. Pat. No. 5,691,365, describe the preparation of nicotine analogs and its therapeutic utility. Generally, the nicotinic analogues have the structure:
wherein R is alkyl or branched alkyl with 2-19 carbon atoms, cycloalkyl, aralkyl or alkenyl.
Shen, et. al., in xe2x80x9c7-Azabicyclo[2.2.2]-Heptane and -Heptene Derivatives as Cholinergic Receptor Ligandsxe2x80x9d 1996, W.O. Patent 96/06093, describe the preparation of 7-azabicyclo[2.2.2]-heptane and -heptene derivatives and their therapeutic utilities. A similar disclosure is made by Shen, et. al., 1994, W.O. Patent 94/22868. Generally, the heptane and heptene derivatives have the formula:
wherein R1, R2, R3, R4, R5, R6, and R7 are H, alkyl or an alkyl-heteroatom containing group.
Dybes, et. al., in xe2x80x9cAnticoccidal Cyclicaminoethanols and Esters Thereofxe2x80x9d 1978, U.S. Pat. No. 4,094,976, describe the preparation of cyclicaminoethanols and esters and their therapeutic utilities. Generally, the cyclicaminoethanols have the formula:
wherein n is 3-5 and R is H or acyl radical.
Caldwell, et. al., in xe2x80x9cMethod for Treatment of Neurodegenerative Diseasexe2x80x9d 1993, U.S. Pat. No. 5,214,060 describes the preparation of 3-aminoalkylpyridines and its therapeutic utilities. Generally, the 3-aminoalkylpyrimidines have the formula:
wherein R is C1-7alkyl, X is substituent other than H, p is 1-5, m is 0-4 and n is 0-8.
There are two recent reviews on the topic of the nicotinic acetylcholine receptor: Holladay, et. al., in xe2x80x9cNeuronal Nicotinic Acetylcholine Receptors as Targets for Drug Discoveryxe2x80x9d 1997, J. Med. Chem., 40, 4169; and Holladay, et. al., in xe2x80x9cStructure-Activity Relationships of Nicotinic Acetylcholine Receptor Agonists as Potential Treatments for Dementiaxe2x80x9d 1995, Drug Dev. Res., 35, 191.
There are provided by the present invention selective modulators of the nicotinic acetylcholine receptor of the general formula:
wherein
m is selected from 0, 1 or 2;
p is selected from 0 or 1;
Y is selected from the group consisting of O, S, S(O) and S(O)2;
R1 is independently selected from the group consisting of Hxe2x80x94, HOxe2x80x94, Oxe2x80x94, C1-6alkyl-, C2-6alkenyl-, C2-6alkynyl-, C3-6cycloalkylC1-3alkyl-, phenylC1-3alkyl-, xe2x80x94C(O)C1-6alkyl, xe2x80x94C(O)phenyl, xe2x80x94C(O)C1-6alkylphenyl, xe2x80x94C(O)OC1-6alkyl, xe2x80x94C(O)Ophenyl, xe2x80x94C(O)NHC1-6alkyl, xe2x80x94C(O)N(C1-6alkyl)2 and xe2x80x94C(O)NHphenyl; wherein R1 is optionally substituted on a carbon atom with one to three Ra substituents; wherein Ra is independently selected from the group consisting of C1-4alkyl, C1-4alkoxy, hydroxyC1-4alkyl, carbomethoxy, acetoxy, nitro, Cl, Br and F;
R2 is independently selected from the group consisting of H, C1-6alkyl, phenyl and heteroaryl; wherein heteroaryl is as defined below;
R3 is selected from the group consisting of H, C1-6alkyl, Cl, Br and F; with the proviso that if m is 0, then R3 is not Cl, Br or F; and
R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen and selected radicals; wherein the radicals are selected from the group consisting of:
a) a trifluoromethyl group: xe2x80x94CF3;
b) a halogen atom: xe2x80x94Br, xe2x80x94Cl, xe2x80x94F or xe2x80x94I;
c) a C1-4alkoxy radical: xe2x80x94OC1-4alkyl; wherein the alkyl is optionally mono- or di-substituted by Rq; wherein
Rq is selected from the group consisting of xe2x80x94OH, xe2x80x94OCH3, xe2x80x94CN, xe2x80x94C(O)NH2, xe2x80x94OCxe2x80x94(O)NH2, CHO, xe2x80x94OC(O)N(CH3)2, xe2x80x94SO2NH2, SO2N(CH3)2, xe2x80x94SOCH3, SO2CH3, xe2x80x94F, xe2x80x94CF3, xe2x80x94COOMa (wherein Ma is selected from the group consisting of hydrogen, alkali metal, methyl and phenyl), tetrazolyl (wherein the point of attachment is the carbon atom of the tetrazole ring and one of the nitrogen atoms is mono-substituted by Ma, as defined previously) and xe2x80x94SO3Mb (wherein Mb is selected from the group consisting of hydrogen and an alkali metal);
d) a hydroxy group: xe2x80x94OH;
e) a carbonyloxy radical: xe2x80x94O(Cxe2x95x90O)Rs; wherein
Rs is a group selected from the group consisting of C1-4alkyl, phenyl and heteroaryl (each of which is optionally mono- or di-substituted with Rq, as defined previously); wherein
heteroaryl is a monocyclic aromatic hydrocarbon group having five or six ring atoms, having at least one carbon atom which is the point of attachment, having from one to three carbon atoms replaced by N in the case of six ring atoms, having one carbon atom replaced by O, S or N in the case of five ring atoms and, optionally, having up to three additional carbon atoms replaced by N;
f) a carbamoyloxy radical: xe2x80x94O(Cxe2x95x90O)N(Ry)Rz; wherein
Ry and Rz are independently selected from the group consisting of H, C1-4alkyl (optionally mono- or di-substituted by Rq, as defined previously), a three to five membered diradical to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously) and a two to five membered diradical interrupted by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94 or xe2x80x94S(O)2xe2x80x94 to form a ring wherein Ry and Rz are fused (optionally mono- or di-substituted with Rq, as defined previously);
g) a sulfur radical: xe2x80x94(Sxe2x95x90(O)n)xe2x80x94Rs; wherein n is selected from 0, 1 or 2 and Rs is as defined previously;
h) a sulfamoyl group: xe2x80x94SO2N(Ry)Rz; wherein Ry and Rz are as defined previously;
i) an azido radical: N3;
j) a formylamino group: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)H; wherein
Rt is selected from the group consisting of H and C1-4alkyl; wherein the alkyl chain is optionally mono- or di-substituted by Rq, as defined previously;
k) a (C1-4alkyl)carbonylamino radical: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)xe2x80x94C1-4alkyl; wherein
Rt is as defined previously; wherein the alkyl chain is optionally mono-or di-substituted by Rq, as defined previously;
l) a (C1-4alkoxy)carbonylamino radical: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)xe2x80x94Oxe2x80x94C1-4alkyl; wherein
Rt is as defined previously; wherein the alkyl chain is optionally mono-substituted by Rq, as defined previously;
m) a ureido group: xe2x80x94(Nxe2x80x94Rt)xe2x80x94(Cxe2x95x90O)N(Ry)Rz; wherein Rt, Ry and Rz are as defined previously;
n) a sulfonamido group: xe2x80x94(Nxe2x80x94Rt)SO2Rs; wherein Rs and Rt are as defined previously;
o) a cyano group: xe2x80x94CN;
p) a (C1-4alkyl)carbonyl radical; wherein the carbonyl is acetalized: xe2x80x94C(OMe)2C1-4alkyl; wherein the alkyl is optionally mono-substituted by Rq, as defined previously;
q) a carbonyl radical: xe2x80x94(Cxe2x95x90O)Rs; wherein Rs is as defined previously;
r) a hydroximinomethyl radical; wherein the oxygen or carbon atom is optionally substituted with a C1-4alkyl group: xe2x80x94CRyxe2x95x90NORz; wherein Ry and Rz are as defined previously;
with the proviso that Ry and Rz may not be joined together to form a ring;
s) a (C1-4alkoxy)carbonyl radical: xe2x80x94(Cxe2x95x90O)OC1-4alkyl; wherein the alkyl is optionally mono- or di-substituted by Rq, as defined previously;
t) a carbamoyl radical: xe2x80x94(Cxe2x95x90O)N(Ry)Rz; wherein Ry and Rz are as defined previously;
u) a N-hydroxycarbamoyl or N(C1-4alkoxy)carbamoyl radical in which the nitrogen atom may additionally be substituted by a C1-4alkyl group: xe2x80x94(Cxe2x95x90O)xe2x80x94N(ORy)Rz; wherein Ry and Rz are as defined previously;
with the proviso that Ry and Rz may not be joined together to form a ring;
v) a thiocarbamoyl group: xe2x80x94(Cxe2x95x90S)N(Ry)Rz; wherein Ry and Rz are as defined previously;
w) a carboxyl radical: xe2x80x94COOMb; wherein Mb is as defined previously;
x) a thiocyanate radical: xe2x80x94SCN;
y) a trifluoromethylthio radical: xe2x80x94SCF3;
z) a tetrazolyl radical; wherein the point of attachment is the carbon atom of the tetrazole ring and any one nitrogen atom is mono-substituted by a substituent selected from the group consisting of hydrogen, an alkali metal and a C1-4alkyl radical; wherein the C1-4alkyl radical is optionally mono- or di-substituted by Rq, as defined previously;
aa) an anionic function selected from the group consisting of phosphono [Pxe2x95x90O(OMb)2], alkylphosphono [Pxe2x95x90O(OMb)xe2x80x94[O(C1-4alkyl)]], alkylphosphinyl [Pxe2x95x90O(OMb)xe2x80x94(C1-4alkyl)], phosphoramido [Pxe2x95x90O(OMb)N(Ry)Rz and Pxe2x95x90Oxe2x80x94(OMb)NHRx], sulfino (SO2Mb), sulfo (SO3Mb) and acylsulfonamides selected from the group consisting of CONMbSO2Rx, CONMbSO2N(Ry)Rz, SO2NMbCON(Ry)Rz and SO2NMbCN; wherein
Rx is selected from the group consisting of phenyl and heteroaryl; wherein heteroaryl is as defined previously and the phenyl and heteroaryl substituents are optionally mono- or di-substituted with Rq, as defined previously; Mb, Ry and Rz are as defined previously;
ab) a C5-C7 cycloalkyl group; wherein any one carbon atom in the ring is replaced by a heteroatom selected from the group consisting of O, S, NH and N(C1-4alkyl); and, in which any one additional carbon atom may be replaced with NH or N(C1-4alkyl) and in which at least one carbon atom adjacent to each nitrogen heteroatom has both of its attached hydrogen atoms replaced by one oxygen whereby a carbonyl moiety is formed;
with the proviso that there are at most two carbonyl moieties present in the ring;
ac) a C2-C4 alkenyl radical; wherein the radical is optionally mono-substituted by a substituent selected from the group consisting of any one of a) to ab) or is optionally mono-substituted by substituents selected from the group consisting of phenyl, pyridyl, quinoline and isoquinoline; wherein each phenyl, pyridyl, quinoline or isoquinoline substituent is optionally mono- or di-substituted by Rq, as defined previously;
ad) a C1-C4 alkyl radical;
ae) a C1-C4 alkyl mono-substituted by a substituent selected from the group consisting of any one of a) to ad);
af) a 2-oxazolidinonyl moiety; wherein the point of attachment is the nitrogen atom of the oxazolidinone ring; wherein the ring oxygen atom is optionally replaced by a heteroatom selected from the group consisting of S and NRt (wherein Rt is as defined previously) and one of the saturated carbon atoms of the oxazolidinone ring is optionally mono-substituted by a substituent selected from the group consisting of any one of a) to ae);
ag) a C2-C4 alkynyl radical; wherein the radical is independently selected from the group consisting of any one of a) to af) and trialkylsilyl;
ah) phenyl radicals
ai) bicyclic radicals; wherein the radical is independently selected from the group consisting of naphthyl, biphenyl, quinoline, indolizine, indole, isoindole, indoline, benzofuran, indazole, benzimidazole, purine, quinolizine, cinnoline, quinoxaline, phthalazine and quinazoline;
aj) heterocyclic radicals; wherein the radical is independently selected from the group consisting of furyl, thienyl, pyrazinyl, pyridazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, quinolinyl and isoquinolinyl; and
ak) aryl and heteroaryl radicals; wherein the radical is independently selected from the group consisting of any one of ah) through aj); wherein the radical is substituted with one to two substituents independently selected from the group consisting of C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6alkoxyC1-C6alkyl, C1-C6alkoxyC1-C6alkoxy, C1-C6 thioalkyl, halogen, cyano, hydroxy, amino, nitro and C1-C6alkylamino, in which any terminal carbon atom may be replaced by a group selected from the group consisting of carboxyl and C2-C6alkoxycarbonyl;
and pharmaceutically acceptable salts and esters thereof.
Relative to the above generic description, certain compounds of the general formula (I) are preferred. Particularly preferred embodiments are those compounds wherein:
R1 is selected from the group consisting of hydrogen, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl, n-pentyl, cyclohexylmethyl, 3-methyl-1-butyn-3-yl, 4-dimethylaminobenzoyl, 2-hydroxymethylbenzoyl, acetyl, t-butyloxycarbonyl, ethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, 4-methoxyphenoxycarbonyl, 4-carbomethoxyphenoxycarbonyl, 4-methylphenoxycarbonyl, 2,6-dimethylphenoxycarbonyl, 1-acetoxy-1-methyl-ethoxycarbonyl and benzyloxycarbonyl;
R2 is selected from the group consisting of hydrogen, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl, n-pentyl, phenyl, thienyl and pyridyl;
R3 is selected from the group consisting of hydrogen, Cl, Br, F, methyl, ethyl, i-propyl, n-propyl, i-butyl, t-butyl, n-butyl, t-pentyl and n-pentyl; preferably, R3 is hydrogen;
R4, R5, R6 and R7 are independently selected from the group consisting of hydrogen, xe2x80x94CH3, xe2x80x94CH2CH3, xe2x80x94(CH2)3CH3, xe2x80x94OCH3, xe2x80x94SCH3, -tetrazolyl, xe2x80x94COOH, xe2x80x94CH2CONH2, xe2x80x94CH2CH2SO3H, xe2x80x94CONH2, xe2x80x94SO2NH2, xe2x80x94SO3H, xe2x80x94CON(CH3)2, xe2x80x94CN, xe2x80x94CH2CN, xe2x80x94CH2SCH3, xe2x80x94CH2SO3H, xe2x80x94CH2SOCH3, xe2x80x94CH2SO2CH3, xe2x80x94SO2CH3, xe2x80x94SOCH3, xe2x80x94CH2OCH3, xe2x80x94N3, xe2x80x94OCOCNH2, xe2x80x94OH, xe2x80x94CHO, xe2x80x94CH2P(O)(OCH3)OH, xe2x80x94CF3, CH2OC(O)NH2, xe2x80x94CH2SO2NH2, xe2x80x94SCH2CH2CN, Br, Cl, F, xe2x80x94SCF3, xe2x80x94CH2SCF3, xe2x80x94SCH2CF3, xe2x80x94COCH3, xe2x80x94CHxe2x95x90NOH, xe2x80x94CONHOH, xe2x80x94C(S)NH2, xe2x80x94OCOCH3, xe2x80x94NHCOCH3, xe2x80x94NHCO2CH3, xe2x80x94NHCONH2, xe2x80x94NHSO2CH3, xe2x80x94SCN, xe2x80x94CHxe2x95x90CHCHO, xe2x80x94SCH2CH2OH, xe2x80x94CH2OH, xe2x80x94CHxe2x95x90NOCH2CO2H, xe2x80x94CO2CH2CH2OH and xe2x80x94SO2NHCH2CONH2; and
heteroaryl is selected from the group consisting of pyrrole, pyridine (1N); oxazole, thiazole, oxazine (1N+1O or 1S); thiadiazole (2N+1S); furan (1O); thiophene (1S); pyrazole, imidazole, pyrimidine, pyrazine (2N); triazole, triazine (3N); and tetrazole (4N);
and pharmaceutically acceptable salts and esters thereof.
Representative compounds of the present invention can be synthesized in accordance with the general synthetic method schemes described below and are illustrated more particularly in the specific synthetic method schemes that follow. Since the schemes are illustrations, the invention should not be construed as being limited by the chemical reactions and conditions expressed. The preparation of the various starting materials used in the schemes is well within the skill of persons versed in the art.
Compounds of the present invention may be made in a preferred one-step reaction scheme that may be preceded or followed by various processes to obtain the desired substituents R1 to R7 and is followed by deprotection of Nxe2x80x94RPR to Nxe2x80x94R1. The preferred one-step reaction is carried out by the conventional procedure known as the Mitsunobu reaction [O. Mitsunobu, Synthesis, 1(1981)].
Referring to Scheme A, the pyridinyl alcohol Compound A1 is reacted under Mitsunobu conditions with the cyclic alkanol Compound A2 to produce the desired base ring structure of the pyridinyl ethers herein. The reaction takes place in the presence of 1 or 2 equivalents each of triphenylphosine and either diethyl- or diisopropylazodicarboxylate in a suitable solvent such as benzene, toluene or THF at room temperature to reflux overnight. Subsequently, the protecting group RPR is removed and replaced as desired. Suitable protecting groups include C1-8 substituted or unsubstituted alkyl; such as, methyl, ethyl or propyl; or C1-8 substituted acyl; such as, benzyl carboxylate, allyl carboxylate, acetyl, benzoyl or propanoyl. Many specific protecting groups RPR are included within the definition of R1. Thus, the end product may conveniently have a substitution with R1 which was utilized in the synthesis as a nitrogen protecting group. In such case, deprotection is unnecessary.
A person skilled in the art can imagine other processes for producing compounds of Formula (I). For example, leaving groups might be employed on analogous starting material Compound A2xe2x80x2 wherein the hydroxy on Compound A2xe2x80x2 is replaced with with xe2x80x94OMs or xe2x80x94OTs and reacted with Compound A1 to form an ether linkage. The conditions for this reaction are well documented. The thioether linkage; wherein Y is S in Formula (I), can be produced in the manner employing Compound A2xe2x80x2 just described using analogous starting material Compound A1xe2x80x2, wherein hydroxy is replaced with sulfhydryl. The thioether linkage can be oxidized to S(O) or S(O)2 by the use of oxidizing agents such as the peroxides.
The terms used in describing the invention are commonly used and known to those skilled in the art.
With reference to the above definitions, the term xe2x80x9calkylxe2x80x9d refers to a straight or branched chain aliphatic hydrocarbon radical.
The term xe2x80x9cpharmaceutically acceptable salts and esters thereofxe2x80x9d refers to those salt and ester forms of the compounds of the present invention which would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which would favorably affect the pharmacokinetic properties of said compounds of the present invention. Those compounds having favorable pharmacokinetic properties would be apparent to the pharmaceutical chemist, i.e., those which are non-toxic and which possess such pharmacokinetic properties to provide sufficient palatability, absorption, distribution, metabolism and excretion. Other factors, more practical in nature, which are also important in the selection, are cost of raw materials, ease of crystallization, yield, stability, hygroscopicity, and flowability of the resulting bulk drug.
Examples of suitable salts include hydrobromic, hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and saccharic.
Examples of suitable esters include such esters wherein xe2x80x94COOMa, xe2x80x94COOMb and xe2x80x94COOH are replaced with p-methoxybenzyloxycarbonyl, 2,4,6-trimethylbenzyloxycarbonyl, 9-anthryloxycarbonyl, CH3SCH2COOxe2x80x94, tetrahydrofur-2-yloxycarbonyl, tetrahydropyran-2-yloxycarbonyl, fur-2-uloxycarbonyl, benzoylmethoxycarbonyl, p-nitrobenzyloxycarbonyl, 4-pyridylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-tribromoethoxycarbonyl, t-butyloxycarbonyl, t-amyloxycarbonyl, diphenylmethoxycarbonyl, triphenylmethoxycarbonyl, adamantyloxycarbonyl, 2-benzyloxyphenyloxycarbonyl, 4-methylthiophenyloxycarbonyl or tetrahydropyran-2-yloxycarbonyl.
The preferred compounds of the present invention are listed in Table 1 and include compounds of the formula:
wherein R1 to R7 and m are selected concurrently from the group consisting of:
Compounds of Formula (I) may be used in pharmaceutical compositions to treat patients (humans and other primates) with disorders related to the modulation of the nicotinic acetylcholine receptor. Thus, the compounds are effective in the treatment of pain, Alzheimer""s disease, memory loss/dementia or loss of motor function. The compounds are particularly effective in the treatment of pain.
The preferred route is oral administration, however compounds may be administered by intravenous infusion or topical administration. Oral doses range from about 0.05 mg to about 100 mg, daily. Some compounds of the invention may be orally dosed in the range from about 0.05 mg to about 50 mg daily, while others may be dosed in the range from about 0.05 mg to about 20 mg daily. Infusion doses can range from about 1.0 to about 1.0xc3x97104 mg/min of inhibitor, admixed with a pharmaceutical carrier over a period ranging from several minutes to several days. For topical administration, compounds of Formula (I) may be mixed with a pharmaceutical carrier at a concentration from about 0.1% of drug to about 10% of drug to vehicle.
The pharmaceutical compositions can be prepared using conventional pharmaceutical excipients and compounding techniques. Oral dosage forms may be elixirs, syrups, capsules tablets and the like. Where the typical solid carrier is an inert substance such as lactose, starch, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, mannitol and the like; and typical liquid oral excipients include ethanol, glycerol, water and the like. All excipients may be mixed as needed with disintegrants, diluents, granulating agents, lubricants, binders and the like using conventional techniques known to those skilled in the art of preparing dosage forms. Parenteral dosage forms may be prepared using water or another sterile carrier.
In order to illustrate the invention the following examples are included. These examples do not limit the invention. They are only meant to suggest a method of practicing the invention. Those skilled in the art may find other methods of practicing the invention, which are obvious to them. However those methods are deemed to be within the scope of this invention.
Reagents were purchased from Aldrich, Lancaster, Pfaltz and Bauer, TCI America, and used without further purification. 1H NMR spectra were collected on a Bruker AC-300 spectrometer. Chemical shifts are reported with respect to tetramethylsilane (TMS) xcex4H,C=0.0 ppm. Spectra were acquired at ambient temperature using DMSO-d6, CD3OD or CDCl3. Mass spectral analyses were performed on a Fisons instrument (Hewlett-Packard HPLC driven electrospray MS instrument). Analytical HPLC analyses were performed on a Hewlett-Packard liquid chromatography system (YMC column, 4 mmxc3x9750 mm, 4 mm C18, 1.0 mL/min, 8 min gradient from 95% aqueous media (0.1% TFA) to 95% CH3CN (0.1% TFA), 220 and 260 nm).

Pyridyl ethers and thioethers as ligands for nicotinic acetylcholine receptor and its therapeutic application

Abstract: wherein m is 0, 1 or 2; p is 0 or 1; Y is O, S, S(O) or S(O)2 and R1 to R7 are various substituents as selective modulators of the nicotinic acetylcholine receptor useful in the treatment of pain, Alzheimer""s disease, memory loss or dementia or loss of motor function.


In a multiplexing/demultiplexing apparatus, readiness of stand-by circuits is monitored through a variety of switching arrangements, by routing a monitoring signal through the circuits. In one alternative embodiment, level correcting means are provided so that the monitoring signal is kept at the proper level, thus ensuring accurate monitoring of the stand-by circuits.

The present invention relates to a method of monitoring a circuit or an apparatus and, more particularly, to a method of monitoring stand-by circuits (apparatuses) which are installed in equipment having a redundant configuration.
Communication equipment or similar equipment which has to be extremely reliable is provided with a stand-by circuit which replaces an active circuit when the active circuit fails. Such equipment is also provided with a monitor for constantly monitoring the stand-by circuit, so that the stand-by circuit may function normally in the event that the active circuit is replaced. Typically, a dummy signal or a similar monitoring signal is fed to the stand-by circuit so as to determine whether the circuit is normally operable on the basis of the resultant output signal of the circuit. It has been customary to provide a monitor of the type using such a monitoring method with monitoring signal generating circuits and monitoring signal receiving circuits, each being associated with a particular stand-by circuit.
The conventional monitor as stated above has a problem left unsolved. Specifically, in the case of an apparatus for multiplexing communication channels, for example, the number of monitoring signal generating circuits and the number of receiving circuits needed are the same as the number of channels. This increases the overall dimensions, cost, and power consumption of the monitor.

Monitoring method for stand-by circuits suitable for a multiplexing/demultiplexing apparatus


A secret cipher (Ki) that is the same for all user terminals is formed of two sub-components (KTi, KT'i) whereof the one sub-component (KTi) is deposited in an erasable, programmable read-only memory (EEPROM). For the second sub-component (KT'i), an encoded data block (E(KT'i)) is transmitted from the outside to a decoder means (DEC) provided in the security module, the decoded output signal thereof being deposited as second sub-component (KT'i) in a first sub-area of a write-read memory (RAM) present in the security module of the user terminal. An overall cipher (Ki) is calculated from the two sub-components (KTi, KT'i) and the result is deposited in a second sub-area of the write-read memory (RAM).

The invention is directed to a data exchange system, including a plurality of user terminals using a secret cipher.
The protection of data is playing an increasingly important part in modern data processing and communications systems. The quality of a system with respect to an adequate data protection is critically dependent upon the degree to which one succeeds in making access to the system possible only for authorized persons and, conversely, keeping unauthorized persons locked out with absolute certainty. A simple although not absolutely certain possibility for checking the access authorization to a system is, for example, to use passwords that are only known to the authorized user and that the user can change as often as he desires. Since there is the risk given passwords that unauthorized persons will find them out or hear them, additional protection measures are indispensible. One of these measures, for example, is the encoding and decoding of the transmitted information, a measure that is realizable in data processing systems, among other things, with the assistance of a chip card. With the increasing involvement of the chip card in data processing systems, however, an additional security risk again arises because chip cards can be relatively easily lost. Care must therefore be absolutely exercised to see that the chip card is protected against potential misuse in all instances when lost. The chip card is therefore designed such that the data stored in a protected chip card can only be accessed when the user previously inputs an identifier that is only stored in the chip card, for example, a personal identification number, referred to as a PIN.
A further security barrier can be erected with the assistance of the authentication of the chip card to the system. This authentication prevents an arbitrary subscriber from being authorized to access secret information in the system. A critical precondition for the authentication is a personal feature of the subscriber that cannot be copied. This non-copyable feature of the subscriber is achieved with the assistance of a secret cipher for the encoding and decoding that is known to the two partners, i.e., to the chip card on the one hand and to the system on the other hand, being known, namely, only to these two partners.
In a POS banking system on a chip card basis, it is assumed, for example, that secret data in the cashier terminal are stored in a separate security module, for example, in what is referred to as a security chip card. Given the employment of a symmetrical encoding algorithm, the same, secret terminal cipher must exist in all terminals. This cipher is required in order to calculate a common communication cipher from the card identification number of a customer card. The existence of a universal, secret cipher in the security module or, respectively, in the security chip card of every POS terminal of an overall system, however, is an extremely critical point and, so to speak, the vulnerable location of the system. A number of protective measures have therefore already been considered that make it more difficult to obtain knowledge of a secret, global cipher. According to a first protective measure, a single secret, global cipher K is replaced by a series of n different global ciphers Kl, Kn and, correspondingly, there are different terminal types. Should this cipher potentially become known, thus, the entire system is not jeopardized. However, a customer card must also contain n different ciphers KKl, ..., KKn of which respectively only one is valid at a specific terminal. A second protective measure likewise provides a plurality of ciphers Kl, ..., Kn that are cyclically changed at certain time intervals. For example, a plurality of terminal ciphers Klp, ..., Knp are valid in a certain time phase p. The appertaining customer ciphers KKlp, ..., KKnp, of course, must then be present in a customer chip card.

Data exchange system comprising a plurality of user terminals each containing a chip card reading device


A fully passive-type solar lumber drying house classified into two models, one is an east-west model configured as a half Quonset hut that lumber's axis loaded is parallel to the east-west direction, and another is a north-south model configured as a Quonset hut that lumber's axis loaded is parallel to the north-south direction and the house is fully surrounded by a triple transparent film and a carbon fiber sheet and is available to be used through all year in which stacked lumber can be dried due to solar energy being assisted by auxiliary heat for one or two weeks under leaving the dry process controlled automatically, and besides moist air inside the house is exhausted through an insulated cylinder.

This invention is related to the fully passive-type solar lumber drying house H which is a hot house made up by improving an agricultural vinyl-house in which the stacked lumber is dried due to solar energy collected passively, then moist air yielded when drying the lumber is exhausted passively through an insulated cylinder 10.
Up to this time, an artificial lumber drying has been carried out applying rapid drying technique, under the high temperature over 100° C. and due to rapid drying method which is able to dry out for three or four days and because of deformation of the lumber and appearance of cracks and flaws on the lumber surface, a quality of the lumber production dried is not so good.
Up to this time, the solar lumber drying method utilized is related into two types that a fully active-type solar lumber drying house which collects actively solar energy and an active passive-type solar lumber drying house which collects solar energy actively in a partial part and passively in a most part have been developed.
(a) The former case is related to a typical active-type solar lumber drying house, that a large solar collector of 120 m2 area in which a porous sheet is inserted as collecting material is put on a roof of the drying house made of wood to collect solar energy actively using a large fan, and then hot air warmed by which is introduced into and circulated within the drying house forcefully by the other large fans to dry out the lumber (Japanese Published Unexamined Patent Application No. 63-70048).
Applying this apparatus which was cost comparable in that time, net volume 11 m3 of needle-leave tree could be dried out from 45% to below 20% for nine days, however the electric power consumption was too much to spread widely the technique over the area in this country and over seas.
(b) The latter case is related to an active passive-type solar lumber drying house that a handmade solar lumber dryer constructed with wooden frame and transparent plate had been made and spread in some area of Hokkaido twenty years ago because of cheap and simple structure (T. Norota, et al., Report of the Hokkaido Forest Products Research Institute, No. 72, March 1983, P96-124).
(c) Another case defined to the latter is a lumber drying house supplying latent regional energy as a heat source, for example solar energy and hot water from a spring, to make the house-build lumber of larch with high quality under low temperature drying. In the large log-house made of larch and covered by transparent film, from the roof of which a large boxy sack made of transparent film is hanged from the roof like a mosquito net, in which several groups of the lumber mounted on a trolley placed on the floor can be dried using solar energy and auxiliary heat from a floor heater, through fan-cons with heat exchanger and small fans. (Japanese Patent No. 3577483)

Fully passive-type solar lumber drying house


A method for determining an exposure condition for use in projecting an image of a pattern of an original on a substrate includes a setting step of setting an exposure condition, an image calculating step of calculating a dimension of an image to be projected on the substrate under the set exposure condition, an electrical characteristic calculating step of calculating an electrical characteristic of at least one of a portion for use as an interconnection and a portion for use as a transistor in a pattern to be formed on the substrate in accordance with a result calculated in the image calculating step, a determining step of determining whether the electrical characteristic calculated in the electrical characteristic calculating step satisfies a requirement, and an adjusting step of adjusting the set exposure condition when the electrical characteristic is determined not to satisfy the requirement in the determining step.

1. Field of the Invention
The present invention relates to a method for determining an exposure condition and a computer-readable storage medium that stores a program for determining an exposure condition.
2. Description of the Related Art
Exposure is the process most important in determining a line width in a circuit pattern of a semiconductor device in the manufacture of a semiconductor device. In exposure, an original is illuminated by an illumination optical system with light from a light source, an image of a pattern of the original is projected on a photosensitive material applied onto a substrate and exposure is made through a projection optical system. This processing is performed by an exposure apparatus.
Exposure apparatuses that use a technique for achieving higher resolution are being developed because circuits are required to have smaller line width compared with a wavelength of light of a light source used in exposure. Examples of parameters that determine resolution include a wavelength of light of a light source, a numerical aperture (NA) of a projection optical system, and a process-dependent numerical value, so-called a process factor k1. Examples of techniques for achieving higher resolution, as described above, include increasing NA and reducing k1. Examples of techniques for reducing k1 include modified illumination, polarized illumination, and adjustment of an aberration in a projection optical system.
The number of techniques for achieving high resolution is increasing and such techniques are becoming increasingly complicated. Therefore, in order to project a pattern onto a substrate and expose the substrate with high accuracy, it is desirable to appropriately set a condition for exposure (i.e., an exposure condition) by setting various parameters (e.g., the shape of illumination light (hereinafter referred to as an illumination shape), NA, aberration, the state of polarization of illumination light) by making full use of the above techniques.
One approach is a method for determining an illumination shape for optimally resolving a pattern by simulation. For example, Japanese Patent Laid-Open No. 6-120119 discloses a method that sets initial values of an optical condition (e.g., NA, wavelength, σ) and an illumination shape, calculates a pattern image on the surface of a substrate when a pattern of an original is projected on the substrate, and alters the illumination shape repeatedly until the pattern image is as close to a target pattern image as possible.
Japanese Patent Laid-Open No. 2005-26701 discloses a method for optimizing optical proximity correction and parameters for use in an exposure apparatus. Examples of the parameters for use in an exposure apparatus include NA and σ. Examples of the optical proximity correction include change of a line width in a designed pattern and addition of a supplement pattern that is not to be resolved.
Also in the method disclosed in this patent document, a pattern image to be projected on a substrate is calculated by simulation, as in Japanese Patent Laid-Open No. 6-120119, and exposure conditions including parameters for use in an exposure apparatus and optical proximity correction for a layout pattern are repeatedly modified until the pattern image to be projected on the substrate is as close to a target pattern image as possible.
The methods disclosed in both patent documents determine an exposure condition that enables a target pattern to be optimally reproduced on a substrate. This reduces the number of defects in resolving a pattern formed on the substrate.
Whether a produced device is defective or non-defective is determined by inspection of electrical characteristics of the device. Therefore, a device that has irregular line widths in an evaluation pattern formed on the substrate may be determined to be a non-defective product, and, on the contrary, a device that has a uniform line width in an evaluation pattern formed on the substrate may be determined to be a defective product. In other words, optimal reproduction of a target pattern on the substrate and manufacturing yield of devices do not completely match each other.
As a result, in order to enhance manufacturing yield of devices, it is necessary to consider electrical characteristics of devices to be produced in setting exposure conditions.

Method for determining exposure condition and computer-readable storage media storing program for determining exposure condition


Apparatus for reading a mold-identifying code in the form of a plurality of surface irregularities extending in an arcuate array around the container heal concentrically with the container axis. A starwheel conveyor sequentially moves a series of containers in an arcuate path about a conveyor axis to and through a reading station. A belt positioned adjacent to the conveyor periphery engages containers at the reading station and is driven so as to rotate the containers about their central axes. A light source is imaged at the conveyor axis through container heel. A scanning mirror is positioned to receive an image of the light source transmitted through the container heel and to reflect such image onto a camera. The scanning mirror is driven as a function of conveyor rotation so as to follow a container traveling through the reading station and reflect onto the camera an image of that circumferential portion of the illuminated container heel closest to the conveyor axis.

Commercial variations or checks in molded containers such as glass bottles and jars are often related to anomalies in the associated molds of origin For this reason, it is desirable in an automated operation having a plurality of molds to possess the ability of identifying a specific molded container with its mold of origin A mold associated with anomalous containers may then be shut down for repair while the remaining molds continue operation Alternatively, containers from the anomalous mold may be automatically sorted as they proceed along the production line.
Mold identification is generally accomplished by molding a mold-identifying code into each container during the forming process. This code may be read by a suitable scanner for identifying the container with its mold of origin U.S. Pat. No. 4,644,151 discloses a system in which each container has molded therein a plurality of indicia in the form of surface irregularities (bumps or protrusions) extending in a arcuate array around the container heel perpendicularly of the container axis. A source of semi-diffused light energy is directed onto the container heel as the container is rotated about its central axis, with the light energy source having an intensity gradient at predetermined orientation with respect to the container axis. A camera, which includes a linear array of light elements optically coplanar with the container axis, is positioned to receive an image of the light source reflected by the container heel, such that individual irregularities in the code array alter the intensity of light reflected by the heel onto the camera. An information processor receives electrical signals from the camera associated with intensity of light at the various camera elements, and the code is read as a function of alterations in light intensity caused by reflections from the bump side edges.
Although the apparatus disclosed in the noted U.S. Patent represents a significant advance in the art theretofore developed, further improvements remain desirable. For example, use of reflected light energy in the preferred embodiment of the disclosed apparatus makes alignment and setup of apparatus components somewhat critical, and necessitates resetup for containers of differing sizes and/or having bumps or protrusions of differing geometries. Further, in the preferred embodiment of the disclosed apparatus, the containers are held stationary and rotated about their central axes to sweep the heel codes across the light source, thereby necessitating interruption of continuous motion of the containers through the production facility. It is a general object of the present invention to provide an apparatus and method for reading a mold-identifying code on a container of the described character that are adapted to operate as the container is fed in a continuous uninterrupted motion through the apparatus code-reading station, and/or that employ an image of the light source that is transmitted through rather then reflected by the container, thereby rendering apparatus setup less sensitive to size and shape of the containers and/or the code-identifying irregularities.

Indentification of a molded container with its mold of origin


In an electric motor for a vehicle, a fan integrally rotatable with a rotor is located on one end in a direction of the axis of the rotor, a bracket for accommodating the fan is joined on one end in the direction of the axis of a stator frame for accommodating a stator, and the bracket is provided with an outside air inlet and a dust emission outlet. The bracket is provided with an expanded section which has an inner peripheral surface bulging on an outer peripheral side in a radial direction beyond a peripheral surface of the stator frame, and at least a part of the dust emission outlet opens to the inner peripheral surface of the expanded section.

An electric motor which cools the inside by using the air taken in as cooling air is known. As this electric motor, an open type electric motor which cools a stator and a rotor by taking the cooling air into the electric motor (for example, refer to JP-A-2001-095204) and a hermetic type electric motor which cools a hermetically-sealed stator and rotor by supplying the cooling air to the outside (for example, refer to JP-A-Hei09-046971) are known.

Fan cooled motor with dust cleaning vent


Apparatus for installing fasteners in a workpiece is mounted for computer controlled movement over the workpiece surface. The apparatus includes all of the tools, fasteners, drives and controls on-board that are needed to operate autonomously, without external connections. The apparatus may also include an on-board power supply for powering the tools, drives and controls. A supply of fasteners is held in an on-board replaceable cassette. An on-board fastener transferring device transfers individual fasteners from the cassette to the tools.

In the production assembly of aircraft, the outer skin may be joined to fuselage frames, wing spars and ribs using a variety of fasteners. The fasteners may be of differing types, with variations in diameters and grip lengths. These fasteners may be installed using semi-automated equipment that may include one or more tools mounted on a base. The base may be mounted for movement over the outer skin to different positions where fasteners are to be installed. The equipment described above may install fasteners in either longitudinal or radial joints, under computer control. Some of the subsystems of this equipment are positioned on the factory floor, away from the base and are connected to tools and drives on the base by hoses and/or wire bundles. For example, computer controls, electromechanical valves, pneumatic logic, power supplies and a supply of fasteners are typically located on the factory floor and are connected to the machine base using the hoses and wire bundles mentioned above.
The use of hoses and wire bundles to connect the fastener installation equipment to off-board subsystems results in a relatively complex system, may require frequent equipment maintenance and displaces factory floor space. Moreover, feeding fasteners from an off-board supply of fasteners through hoses can result in misfeeds, in which fasteners become clogged in the hoses, prompting the need for intervention by factory personnel and resulting accompanying production downtime.
Accordingly, there is a need for a fastener installation apparatus which obviates the problems mentioned above and integrates all of the systems and sub-systems onboard that are needed to allow the apparatus to function autonomously, without connections to sub-systems on the factory floor. The illustrated embodiments of the disclosure are directed towards satisfying this need.

Method and apparatus for installing fasteners


The disclosure relates to the use of a MEMS magnetometer or an array of MEMS magnetometers as energy harvesting sensor(s) in a hearing assistance device. The MEMS magnetometer(s) can be located within the existing geometry of a typical balanced-armature receiver currently used in hearing assistance devices.

Hearing aids are electronic instruments worn in or around the ear that compensate for hearing losses by specially amplifying sound. Hearing aids use transducer and electro-mechanical components which are connected via wires to the hearing aid circuitry. In addition to transducers, modern hearing assistance devices incorporate A/D converters, DAC's, signal processors, memory for processing the audio signals, and wireless communication systems. The components frequently include multiple housings or shells that are connected to assemble the hearing aid.
In a hearing assistance device, electrical current consumption and battery life are important aspects to the device's performance and acceptance in the marketplace. Longer battery life may allow additional hardware functionality or algorithm capability. There is a desire, therefore, to develop and integrate technologies that could increase battery life or increase the available electrical current. Energy harvesting is one technology that can meet this desire. It would be advantageous to integrate this technology in a small form factor within the hearing assistance device.

Method and apparatus for harvesting energy in a hearing assistance device


An audio mixer console and a power amplifier are mounted in a self contained carrying case that provides both protection for the console and amplifier during transportation and storage and a support during use. A power amplifier is fixedly connected between lower portions of first and second spaced sides at the upper end of which is pivoted a front section of the mixer console. In stored position the mixer console extends downwardly between the sides to a position adjacent the amplifier, and a detachable cover is secured to the sides to extend over both the mixer console and amplifier. Parts of the mixer console and amplifier form at least portions of a forward cover of the completed carrying case. For use of the mixer console and amplifier the detachable cover is detached, the mixer console is pivoted upwardly and rearwardly, and the detached cover is inserted between the case sides at an acute angle to the sides, to provide an "X" shaped support configuration, so that an upper part of the cover supports the outwardly and rearwardly extending rear section of the mixer console and a bottom part of the cover contacts the ground to cooperate with the lower portions of the sides to form an extended support base for the assembly.

1. Field of the Invention
The present invention relates to portable instruments and more particularly concerns a portable control console that is self contained for transportation and storage and is self supporting for operation.
2. Description of Related Art
Traveling musical groups of instrumental and vocal artists generally employ electronic instrumentation in the form of loudspeakers, power amplifiers and pre-amplifiers, and microphones. Sound received by several microphones, and, at times, sound produced by auxiliary sound sources, are electronically combined and mixed in an electronic mixing console, fed through a pre-amplifier and power amplifier, and thence to loudspeakers for presentation of the music to an audience.
In addition to loudspeakers, the instrumental and vocal group will carry with it a power amplifier and pre-amplifier and an electronic mixing console. Loudspeakers are plugged into the amplifier and microphones or other auxiliary sound sources are plugged into the mixing console, to allow the operator of the console to selectively control amplification of each of the input sound sources and to mix these in desired proportions. Frequently the amplifier and mixing console are mounted in suitable carrying cases, and at the site of the performance are removed from the cases and set up for use. The console is conveniently placed on some suitable surface, such as a table top, and the amplifier, after removal from its case, is frequently placed on the floor. The equipment is large, heavy and bulky and at least the mixer console must be set up on a table at the performance location. Thus, the performing group not only must carry its instrumentation and electronic equipment, but also must either carry or provide at the performing site suitable supporting structures for the mixing console and amplifier. The requirement for several different pieces, separate supports and separate carrying cases greatly complicates the problem of transporting and handling the equipment.
Accordingly, it is an object of the present invention to provide transportable equipment that avoids or eliminates above mentioned problems.


Provided is an acellular mammalian tooth-shaped scaffold including a compound that is chemotactic, osteogenic, dentinogenic, amelogenic, or cementogenic. Also provided is a method of replacing a tooth in the mouth of a mammal, where the tooth is absent and a tooth socket is present in the mouth at the position of the absent tooth. The method includes implanting an acellular scaffold having the shape of the missing tooth into the tooth socket. Additionally, a method of making a tooth scaffold is provided. The method includes synthesizing an acellular scaffold in the shape of a mammalian tooth and adding at least one compound that is chemotactic, osteogenic, dentinogenic, amelogenic, or cementogenic.

The present invention relates to tissue engineering scaffolds.
Biomedical Engineering and Tooth Regeneration.
Tooth loss often results from a variety of oral diseases and physiological causes, including dental caries, periodontal disease, trauma, genetic disorders and aging (Amar 2003, Philstrom 2005, Kim 2006). Tooth loss can lead to physical and mental suffering that can lower an individual's self-esteem and quality of life (Amar 2003, Philstrom 2005, Kim 2006). Many forms of dental disease and some medical conditions like uncontrolled diabetes increase the risk of tooth loss. For the treatment of edentulism, the current options have been limited to the use of dental implants and/or conventional fixed or removable prostheses.
Recently, the emergence and development of biomedical engineering tools have led to a new scope of patient care in the field of medicine. For example, preliminary human clinical trials have reported of improved levels of bone formation in children with osteogenesis imperfecta, following systemic infusions of bone marrow stromal stem cells (BMSSC) or bone marrow cells (Horwitz 2001, Horwitz 2002). Recent advances in the fields of dental tissue engineering, materials science and stem cell biology suggest that tooth regeneration will be possible (Duailibi 2006). Additionally, the recent identification of different mesenchymal stem cells (MSCs) residing in dental or craniofacial tissues expands the scope of potential clinical benefits in helping to regenerate the dental tissues such as dentin, cementum and periodontal ligament (PDL) (Shi 2005). Dental tissue progenitor cells present in the pulp tissue of deciduous and adult teeth can be used to regenerate dentin and alveolar bone (Shi 2005; Zhang 2005). Additionally, cells isolated from both rat and pig tooth buds can be used to bioengineer anatomically correct tooth crowns but with limited predictability (Duailibi 2004, Honda 2005, Young 2002, Young 2005).
The tooth/periodontal complexes are often referred to as an individual organ. Although this organ is considered relatively small, its structural and developmental complexity is well recognized. The tooth structure consists of three calcified tissue types—enamel, dentin and cementum, and dental pulp. Dentin occupies the bulk of the tooth, while enamel and cementum cover the coronal and apical portions, respectively. The periodontium has a supportive role to the teeth and consists of cementum, periodontal ligaments, alveolar bone and gingiva. Periodontal ligaments are connective tissues that attach the cementum to the alveolar bone via the Sharpey's fibers. Periodontal ligaments enable sensory perception and cushion mechanical forces during mastication.
Despite the tooth's structural complexity, the advancement of biomedical engineering techniques has given rise to two currently employed approaches for tooth regeneration. The first is based on tissue engineering, aiming to regenerate teeth by seeding stem cells in scaffolding biomaterials (Young 2002, Duailibi 2004, Honda 2005). This technique has shown promising results in regeneration of the periodontium (Nakahara 2006). The second approach attempts to reproduce or mimic the developmental processes of embryonic tooth formation (Nakahara 2006). This approach uses embryonic tissues (dental epithelium and dental mesenchyme) harvested from a mouse fetus and requires an understanding of the principles that regulate early tooth development in the embryo (Ohazama 2004, Hu 2006, Nakao 2007). Following these approaches, in many studies, biologically engineered tooth germs are transplanted into the bodies of animal hosts, usually rodents, where there is sufficient blood flow to provide the necessary nutrients and oxygen to optimize tissue formation (Nakahara 2006).
Use of Stem Cells in Tissue Regeneration and Challenges Encountered.
Stem cells are quiescent cell populations present in normal tissue, which exhibit the distinct characteristic of asymmetric cell division, the formation two daughter cells—a new progenitor/stem cell, and another daughter cell capable of forming differentiated tissue (Hawkins 1998, Lin 1998). Dental mesenchymal progenitor cells have been identified and characterized in the dental pulp of both deciduous and adult human teeth (Gronthos 2000, Mooney 1996, Shi 2005). As previously mentioned, these postnatal epithelial and mesenchymal dental stem/progenitor cells present in immature tooth buds have demonstrated the ability to generate bioengineered and anatomically correct, but miniature-sized tooth crowns containing enamel, dentin, pulp, and alveolar bone (Shi 2005; Zhang 2005).
Periodontal ligament cells are known for their regenerative potential to give rise to the formation of lamina propria, cementum, bone, and periodontal ligament (Melcher 1985, McCulloh 1985). The capacity of periodontal ligament stem cells to form mineralized deposits in vitro has been demonstrated for a subpopulation of cells derived from primary explants of periodontal ligament (Arceo 1991, Cho 1992). It is believed that periodontal ligament stem cells require a suitable scaffold to induce the formation of bone, dentin and cementum in vivo (Gronthos 2000, Krebsbach 1998). When periodontal ligament stem cells were incorporated into a hydroxyapatite/tricalcium phosphate scaffolds and ectopically implanted in the subcutaneous regions of the mouse dorsum, a typical cementum/periodontal ligament-like structure formed (Seo 2004). Moreover, a type I collagen-positive periodontal ligament-like tissue within the transplants connecting with the newly formed cementum that is morphologically similar to Sharpey's fibers has been demonstrated (Seo 2004).
Recent advances in dental stem cell biotechnology and cell-mediated murine tooth regeneration have encouraged researchers to explore the potential for regenerating living teeth with appropriate functional properties (Duailibi 2004, Ohazama 2004, Shi 2005). Murine teeth can be regenerated using many different stem cells to collaboratively form dental structures in vivo (Duailibi 2004, Ohazama 2004, Young 2005). In addition, dentin/pulp tissue and cementum/periodontal complex have been regenerated by human dental pulp stem cells (DPSCs) and periodontal ligament stem cells (PDLSCs) respectively, when transplanted into immune-compromised mice (Gronthos 2000, Seo 2004). However, owing to the complexity of human tooth growth and development, the regeneration of a whole tooth structure including enamel, dentin/pulp complex, and periodontal tissues as a functional entity in humans is a challenge with the currently available regenerative biotechnologies (Sonomaya 2006).
The challenges with the use of stem cells in regeneration of dental tissues have been reported in previous studies (Duailibi 2004, Young 2002, Young 2005). It is acknowledged that, while formation of multiple miniature tooth crowns in the bioengineered tooth constructs is possible, real-size whole-tooth regeneration encounters a number of challenges. These challenges are attributed, again, to the complex nature of tooth development (Duailibi 2006, Tummers 2003).
Concepts of Cell Homing.
As put forward, conventional approaches of stem cell-seeding within a scaffold aim to mimic cellular structure and recreate a functional tissue equivalent in vitro or in vivo. The cells are derived from end organs or from more undifferentiated sources such as the bone marrow (Schantz 2007). These approaches are limited by issues such as donor site morbidity from harvesting of cells and tissue formation of heterogeneous quality at the site of implantation of the cell-scaffold construct (Schantz 2007). Hence, the concept of cell homing is recently attracting more attention. Cell homing aims to induce the homing of desired cells to cytokine-impregnated scaffolds at specific anatomical sites (Schantz 2007). This approach attempts in vivo tissue regeneration without cell-seeding. Therefore, cell homing could provide enhancements in cellular methodology for tissue engineering and a novel, minimally invasive option for tissue regeneration (Schantz 2007).
Based on the above discussion, further development of tooth scaffolds is needed. The present invention address that need.

The Trustees of Columbia University in the City of New York


A test apparatus and a method for controlling the same are provided. The test apparatus may receive information about a reaction device, information about a storage environment, and external environment information from a storage storing a sample and a sensor sensing the external environment of the test apparatus. The test apparatus may perform a variety of control actions for testing the sample based on a temperature of and around the reaction device, resulting in increased reliability of the test result.

1. Field
Apparatuses and methods consistent with exemplary embodiments relate to a test apparatus and a method for controlling the same, which can perform in-vitro diagnosis using small samples.
2. Description of the Related Art
To perform in-vitro diagnosis, various tests, for example, an immune test, a clinical chemical test, gene analysis, and the like, are performed on samples of patients. These tests are very important as they may be used to diagnose and cure a disease of which a patient is afflicted as well as observe prognosis thereof.
In-vitro diagnosis may be performed by a reaction device in which a sample reacts with a reagent and a test apparatus that obtains a result of the in-vitro diagnosis result by measuring a reaction that occurs in the reaction device.
When the test apparatus obtains the result of the diagnosis, a storage temperature of a sample and a reaction temperature of the sample are important to the in-vitro diagnosis result, and. Accordingly, a precise temperature control is important for acquiring an accurate result and ultimately in making an accurate diagnosis.

Method for controlling a test apparatus in response to external room conditions and reaction device storage conditions