In one embodiment, a particle-retrieval device in accordance with the present teachings includes a receiver tube, vacuum-flow providing means and particle-disengaging means. The receiver tube is in fluid communication with the vacuum-flow providing means such that when flow is introduced into the vacuum-flow providing means, a suction or vacuum flow is developed at an end of the receiver tube. The suction causes a particle to adhere to the end of the receiver. A particle is disengaged by discontinuing the suction and, advantageously, by wetting the engaged particle.

The present invention relates generally to an apparatus and method for retrieving a single small particle from a plurality of particles.
Through combinatorial chemistry scientists can create combinatorial libraries of compounds, en masse, and rapidly test such libraries for physiological or other activity. The combinatorial libraries are generated by successively partitioning a group of solid supports, which are typically embodied as beads having a diameter in the range of about 50 to 1000 microns. With each successive partitioning, the solid supports are uniquely treated, such as by adding a chemical moiety thereto. The partitionings are repeated until a desired combinatorial library is produced. The combinatorial library comprises a large number of library compounds, each of which compounds is attached to a solid support.
For screening purposes, a combinatorial library is typically segregated into a plurality of small groups containing about 1-30 solid supports (i.e., library compounds) per group. The small groups of solid supports are usually retained in collection plates, referred to as microtiter or microwell plates, that have a multiplicity of small wells (e.g., 96-, 384-, 1536-well plates). To segregate a combinatorial library into such small groups, a device for handling a few or even an individual solid support is required. Such a device must be able to reliably withdraw a solid support from a large number of such solid supports contained in a fluid, and then deliver and deposit the withdrawn support to a desired site.
Aside from the difficulties inherent in handling an individual small particle, in the realm of combinatorial chemistry, a further complication arises. In particular, treatments steps (e.g., reaction steps, washing steps, etc.) often increase the tendency of the solid supports to adhere to one another or the transport/delivery means. Such increased adhesion complicates and frustrates individual particle retrieval.
Various devices are available for sorting, counting and retrieving particles from large groups of such particles. Such devices have been used for sorting or counting biological cells (U.S. Pat. Nos. 3,710,933; 4,173, 415; 4,606,631), transferring yeast containing beads (U.S. Pat. No. 4,655,265), dispensing reagent spheres (U.S. Pat. No. 5,616,299), arraying small objects into containers (U.S. Pat. No. 5,649,576), transferring articles contained in a fluid medium (U.S. Pat. No. 5,722,470) and placing a biological reagent on a substrate (U.S. Pat. No. 5,731,152). None of the above-referenced devices reliably retrieves a single particle from a group of such particles, transfers the retrieved particle to a desired destination, and deposits the particle at the desired destination.
More recently, a robot equipped with capillary tubes that pick up beads (i. e., solid supports) using a suction force has been disclosed. While such a device may reliably engage a particle, it will not reliably disengage the particle. More particularly, once a bead is engaged to a capillary tube, various physical phenomena cause an attraction between the bead and the capillary tube that tend to keep the bead engage d to the tube. Simply discontinuing suction will not reliably disengage the bead.
As such, an article and method for reliably retrieving, transferring and depositing a single particle is needed.
Satisfying the aforementioned need, a particle-retrieval device in accordance with the present teachings comprises, in some embodiments, a receiver tube, vacuum-flow providing means and particle-disengaging means. The receiver tube contains a bore or lumen running its full length. The bore is in fluid communication with the vacuum-flow providing means. When flow is introduced into the vacuum-flow providing means, a suction or vacuum flow is developed at the second end of the receiver. For the purposes of this Specification, when a first and a second region are described to be in xe2x80x9cfluid communication,xe2x80x9d it means that fluid flow and/or pressure conditions prevailing in the first region affect fluid flow and/or pressure conditions in the second region.
The suction developed at the second end of the receiver causes a particle to adhere thereto. A particle-engagement site at the second end of the receiver is advantageously physically adapted to receive a single particle.
Once a particle is engaged to the receiver, various physical phenomena work in concert with the continuing suction force to keep the particle engaged. Such physical phenomena cause an increased adhesion between a particle and the receiver. As such, action in addition to discontinuing the suction force is required to reliably disengage a particle from the receiver tube. To that end, a particle-retrieval device in accordance with the present teachings advantageously incorporates particle-disengaging means.
In the illustrated embodiments, the particle-disengaging means advantageously delivers a droplet of liquid that is conducted to and wets an engaged particle. Discontinuing suction and wetting the particle reliably disengages the particle from the receiver.
To retrieve a particle from a source vessel requires that positioning means place the device and vessel in alignment and in sufficiently close proximity such that the suction developed at the particle-engagement site can xe2x80x9cgrabxe2x80x9d a particle. In various embodiments, positioning means are configured to move either the particle-retrieval device, a source vessel or both. In one embodiment, the positioning means is an x-y-z stage.
In addition to the one particle that is engaged at the particle-engagement site, other particles and particle fragments may disadvantageously adhere to the receiver and/or the particle near the particle-engagement site. As such, in some embodiments, the present invention includes an excess particle/fragment remover for removing excess particles and particle fragments. The excess particle/fragment remover can be embodied in a variety of ways that are described later in this specification.
Since the present invention is capable of retrieving very small particles that may be difficult to directly observe, the present invention advantageously includes a particle detector. In one embodiment, the particle detector is realized as a bellows that is in fluid communication with the bore running through the receiver tube. As a particle engages the particle-engagement site at the second end of the receiver tube, pressure within the bore changes. Such a pressure change is observed as a collapse of the bellows (i.e., the bellows xe2x80x9ccompressesxe2x80x9d or decreases in length). The change in bellows length can be detected and indicates that a particle is engaged.
Further features of the present invention will become apparent from the Detailed Description of specific embodiments thereof when read in conjunction with the accompanying drawings, which are described briefly below.

Article comprising a particle retrieval device


An illuminated sign includes a housing and/or a frame, a plate of a light-transmitting material and at least one three-dimensional body, likewise of a light-transmitting material such as a convex strip, in the form of figure, a sign, a decoration or the like, and a light source, which is mounted on the housing and/or the frame. The illuminated sign further includes one or more light guides for coupling light from the light source into the three-dimensional body or bodies. The light guide(s) make(s) it possible to capture light from, for example, one centrally disposed TL tube and couple said light into at least one three-dimensional body, so that an effective lighting of said body is obtained.

Illuminated signs are known and include a housing, for example in the form of a logo. The housing is provided with a light-transmitting plate, which comprises an opaque coating on the front side, in which openings are present, for example in the form of letters and/or a border. A strip having a convex upper side, which consists of a light-transmitting paste, is applied in said openings. Fluorescent or thin light (hereinafter "TL") tubes are mounted across the width of the plate, at least under the openings. The TL tubes cause the convex strips to light up when they are turned on, making said strips resemble neon tubes.
Existing illuminated signs are relatively complex and heavy, because a large number of TL tubes are required in order to provide sufficient lighting of the strips. In addition, the tubes must frequently be arranged in such a manner that that they conform to the shape of, for example, a border as well as possible.
As a result, there is a need for an improved illuminated sign as an alternative to those discussed above.


A new and distinct cultivar of Petunia plant named xe2x80x98Dancasoftxe2x80x99, as described and illustrated, and particularly characterized by the combined features of pastel pink flower color, single flower type, medium flower size, early year round flowering time, spreading, well-branched vigorous growth habit, good weather tolerance, suitable for hanging baskets and bedding.

Petunia hybrida.
Dancasoft.
The present invention comprises a new and distinct cultivar of petunia, known by the cultivar name xe2x80x98Dancasoftxe2x80x99.
xe2x80x98Dancasoftxe2x80x99 originated from a hybridization made by the inventor in a controlled breeding program in Mishmar Hashiva Israel in 1998. The female was Chipper(copyright) by Danziger (unpatented). The male parent of xe2x80x98Dancasoftxe2x80x99 was xe2x80x98CV. 322xe2x80x99 (unpatented).
xe2x80x98Dancasoftxe2x80x99 was discovered and selected as one flowering plant within the progeny of the stated cross by or under the supervision of the inventor Gabriel Danziger in May 1998 in a controlled environment in Mishmar Hashiva, Israel.
The first act of asexual reproduction of xe2x80x98Dancasoftxe2x80x99, was accomplished when vegetative cuttings were taken from the initial selection in June 1995 in a controlled environment in Mishmar Hashiva, Israel by a technician working under formulations established and supervised by the inventor. Horticultural examination of selected units initiated in September 1998 has demonstrated that the combination of characteristics of xe2x80x98Dancasoftxe2x80x99, as herein disclosed, are firmly fixed and are retained through successive generations of asexual reproduction.
xe2x80x98Dancasoftxe2x80x99 has not been observed under all possible environmental conditions. The phenotype may vary somewhat with variations in environment such as temperature, light intensity and day length, however, without any variations in genotype. The following observations, measurements and comparisons describe the plants grown in Mishmar Hashiva, Israel under greenhouse conditions which approximate those generally used in commercial practice.
The following traits have been repeatedly observed and are determined to be basic characteristics of xe2x80x98Dancasoftxe2x80x99 which in combination distinguish this petunia as a new and distinct cultivar:
1. Pastel pink flower color;
2. Single flower type;
3. Medium flower size;
4. Early, year round flowering time;
5. Spreading, well branched, vigorous growth habit;
6. Good weather tolerance; and
7. Suitable for hanging baskets and bedding.
Of the many commercial cultivars known to the present Inventor, the most similar in comparison to xe2x80x98Dancasoftxe2x80x99 is Chipper(copyright) by Daniziger xe2x80x9cDanxe2x80x9d Flower Farm.
In comparisons to Chipper(copyright), xe2x80x98DANCASOFTxe2x80x99 has brighter flower color, more upright growth habit, earlier flowering time, more flowers, and a longer flowering season.

Danziger xe2x80x9cDANxe2x80x9d Flower Farm


A housing is provided which is positionable adjacent a surface of a material to be treated. The housing and the surface of the material cooperate to form a reaction chamber. An exposure environment is provided having a plurality of components within the reaction chamber. A first component comprises charged particles. A second component comprises chemically active neutral particles. A third component comprises electromagnetic radiation. When the housing is so positioned adjacent a surface and the desired exposure environment is provided, the surface is altered as desired for cleaning, material removal or as preparation for adhesive bonding or etching.

1. Field of the Invention
The present invention relates to enhancing the surface of a material for cleaning, material removal for the preparation of adhesive bonding or etching, and more particularly, to the generation and use of neutral, chemically active particles to chemically react with a material surface, so as to alter the surface as desired for the cleaning, material removal or preparation for adhesive bonding or etching.
2. Description of the Related Art
Large scale low-temperature plasma related methods and devices are needed for surface cleaning and pre-conditioning materials, for both laboratory, manufacturing, and field applications. One of the problems encountered in developing such procedures and devices is scaling up specific processing environments, which produces desired material effects on a small scale, such that large scale exposure can be effectively performed. The coupling of system parameters is strong for low-temperature plasma systems. This coupling makes scaleup difficult since both substrate temperatures and reactive species need to be controlled or altered, and since the coupling of operating parameters which influence reactivity and temperatures severely restrict the degree of such controllability. There are no process models or experimental database, or other knowledge database which permit scaleup system design.
Systems are needed for plasma processing a broad scope of materials for field and manufacturing applications. Critical to cost effectiveness is flexibility in design for the purpose of varying plasma generated environments over materials to be processed.
U.S. Pat. No. 4,588,641, issued to Haque et al., discloses a 3-step plasma treatment for improving a laminate adhesion of metallic and non-metallic substrates. The treatment comprises sequentially exposing the substrate to a first plasma of oxygen gas, a second plasma of a hydrocarbon monomer gas and a third plasma of oxygen gas. The process has particular utility in forming polymeric films on one or more surfaces of copper or copper alloy foils to be used in printed circuit applications.
U.S. Pat. No. 3,462,335, issued to R. H. Hansen et al., discloses subjecting hydrocarbon, fluorocarbon and polyamide polymers to a stream of excited inert gas.
U.S. Pat. No. 4,765,860, issued to S. Ueno et al., discloses a method for the preparation of a flexible base for printed circuit board of the type formed of lamination of a flexible sheet-like polymeric base and a metal, e.g. copper, foil adhesively bonded thereof by use of an adhesive, in which the surface of the polymeric base prior to bonding of the metal foil is subjected to exposure to low temperature plasma so that the adhesive bonding strength between the polymeric base and the metal foil can be improved.
None of the above described references discusses plasma processing systems for cost effective and flexible design field and manufacturing applications which vary plasma generated environments over a variety of materials to be processed.

Plasma system for enhancing the surface of a material


The present invention relates to an apparatus and a method of acquiring an image for dental diagnosis. More particularly, the present invention relates to an apparatus and a method of acquiring a near-infrared image for dental diagnosis, wherein an image for dental diagnosis is acquired using near-infrared radiation and a general image camera rather than using X-rays.

Generally, in dentistry, before a dental treatment, a mouth portion of a patient is subjected to radiography such that an X-ray image showing patient's teeth structure and condition is acquired.
The dental X-ray image may show information on cavities and voids of the dental tissue, and information on a desalinized portion in which the mineral components of the dental tissue have been removed and the tissue is porous.
In X-ray imaging, emptied or desalinized portions transmit X-rays more than nearby tissue and transmit X-rays with higher intensity radiated from the source more than the nearby tissue. More exposure occurs to the photographic films or the electronic imaging devices due to the emptied or desalinized portions than exposure formed by the radiation coming along the path that the emptied or desalinized portions do not block.
Typically, such an X-ray method has several disadvantages. X-rays are dangerous because X-rays ionize molecules of living tissue. When the cavity area is empty, this is completely transparent. However, the cavities with a small volume having higher permeability or lower attenuation make only a small partial change in the intensity of the transmitted radiation, so that for the portion of the small cavities, contrast in the X-ray image is poor. Therefore, it is difficult to detect cavities with a small volume from general X-ray images. Nevertheless, the cavities occurring in the edge portion of the tooth may often be detected. On the other hand, in general, there is a problem in that it is difficult to find occlusal cavities on the wide and flat chewing surfaces.
In addition to when searching for cavities, dentists need a means for detecting cracks in teeth when replacing old fillings, when deciding whether to use another inlay, and when deciding whether to use a crown. However, the X-ray method has a problem that the reliability for detecting cracks is poor.

Apparatus and method for acquiring near infrared-based diagnostic images of teeth


A clamping device is attached to a front part of a body of a boring machine for clamping the boring machine and a workpiece together. The clamping device comprises a fixed piston fixed on the front part of the body, a movable piston equipped over the front part of the body movably in the axial direction of a spindle of the boring machine, a first pressure chamber, a second pressure chamber, a pressurized fluid-supply device to supply pressurized air to the first pressure chamber and the second pressure chamber so that the movable cylinder is moved in the axial direction, a connecting mechanism an end portion of which is connected to the movable cylinder, and a clamping unit which is connected to the other end portion of the connecting mechanism, and is fixed to a certain position of the workpiece.

1. Technical Field
The present invention relates to a clamping device for a portable boring machine which is for boring a workpiece, and a portable air-drive-drilling machine with the clamping device. The clamping device is for clamping the portable boring machine and the workpiece together.
2. Description of Background Art
In a portable boring machine for boring a workpiece, the technique for boring a workpiece while clamping the portable boring machine and the workpiece together in the fixed state so that a position to be bored and posture between the machine and the workpiece are stable when the workpiece is bored, is known (for example, patent literatures 1 and 2). A portable boring machine is disclosed in the patent literature 1, and a cam is driven by a return spring and an air cylinder to enlarge or reduce a head and a collet in diameter, so that the whole of the machine is fixed to the workpiece.
Another portable boring machine is disclosed in the patent literature 2. A collet of a clamping mechanism is enlarged or reduced in diameter by pressing force in a vertical direction along a shaft of a clamping means (the clamping mechanism) connected to the drilling unit, and the pressing force is due to driving force of a motor. In this way, the whole of the machine is fixed to the workpiece.
Patent literature 1: U.S. Pat. No. 3,663,115 (FIG. 3)
Patent literature 2: U.S. Pat. No. 5,062,746 (FIG. 1)

Clamping device for portable boring machine and portable air-drive-drilling machine with clamping device


An intervertebral support assembly, comprising a pair of bone allografts positioned between two adjacent vertebrae, the bone allografts being positioned towards the anterior portion of the adjacent vertebrae; and a pair of facet screws, each facet screw securing together a facet joint between the two adjacent vertebrae.

The present invention relates to intervertebral support systems, and to systems for promoting intervertebral bone fusion.
A variety of support assemblies currently exist which may be surgically implanted into a patient""s intervertebral space so as to provide support between two (or more) adjacent vertebrae. Surgical implantation of such systems is typically used to provide support along the spinal column in cases where a portion of the patient""s intervertebral anatomy has become diseased or destroyed. In addition, such support systems are also commonly used following a diskectomy, wherein the patient""s intervertebral disk is surgically removed.
A drawback of these existing support systems is that they tend to be somewhat large and bulky, especially when these systems operate to provide support across a large portion of the patient""s vertebral region. Being large and bulky, surgical implantation of these systems into a patient""s vertebral region often creates a substantial amount of trauma to the patient.
Moreover, the installment of such large, bulky support systems into a patient""s intervertebral space typically also requires a large amount of tissue to first be removed from the patient""s intervertebral space so as to make way for the device.
Most commonly, existing support systems typically operate by inhibiting (normal) movement between the adjacent vertebrae, thereby holding these vertebrae at fixed positions relative to one another, with the mechanical body of the supporting structure providing the needed support along the patient""s spinal column. Such supporting systems are typically made of stainless steel or titanium, and are designed to permanently remain within the patient""s body.
The present invention provides a novel system of intervertebral support using a pair of bone allografts and a pair of facet screws.
An advantage of the present system is that, by inhibiting motion between two adjacent vertebrae, it facilitates natural bone fusion between these vertebrae. An advantage of the present invention""s use of bone allografts (positioned between the vertebrae) is that these allografts will eventually be resorbed into the patient""s body as bone growth between the immobilized vertebrae progresses. In contrast, existing mechanical (e.g.: metallic) intervertebral support structures simply remain as large permanent foreign structures within the patient""s body. In preferred aspects, motion between the two adjacent vertebrae is specifically inhibited by the facet screws, as will be explained.
The present system advantageously provides intervertebral support at three locations in particular, with these three locations together forming a triangle. Specifically, each of the facet screws provides support at the facet joints (which are disposed at two symmetrically spaced apart locations at the posterior or rear of the vertebral column). The bone allografts are preferably positioned to provide support at an anterior (i.e. front), central location in the vertebral column. An advantage of the present three point (i.e.: triangular) support system is that support is provided in three perpendicular directions, (thereby providing support with respect to forward-backward bending, side-to-side bending and torsion of the spine). Furthermore, the present three point (i.e.: triangular) support system provides support at three separate locations which are spaced apart over a relatively large section of the patient""s spinal column, providing enhanced stability. Specifically, the three sides of the present support triangle correspond to the locations of the two facet joints and the inter vertebral disc.
An important advantage of the present system is that it can be assembled in a minimally invasive percutaneous (preferably cannulated) surgical approach. In contrast, existing systems which provide support across a wide area of the patient""s vertebrae typically comprise a single large integrated structure which substantially fills the patient""s intervertebral space, and which is typically installed during a major invasive open surgical procedure. A further advantage of the present assembly is that since it comprises four separate components, (two bone allografts and two facet screws), these four components can be installed sequentially, with each of the components being installed through a cannula. In contrast, existing intervertebral support systems typically comprise a single large assembly which cannot be installed through a cannula.
In preferred aspects, the two bone allografts are positioned at an angle to one another. An advantage of having the bone allografts disposed angled to one another is that they provide support in perpendicular directions (i.e.: along two axes which are angled to one another). Specifically, in a preferred case using long, narrow shaped bone allografts, the bone allografts are preferably positioned with their long central longitudinal axes disposed at an angle to one another.
Since the present pair of bone allografts are positioned at an angle to one another, tall, narrow bone allografts can be used. Advantages of using a tall, narrow bone allograft include its fabrication requiring less bone material than would be used in conventionally manufactured allografts (which tend to be both flatter and wider, or large in diameter and length, e.g.: cylindrical). In addition, the present narrow bone allografts are more easily inserted into the patient through a (narrower) cannulated passageway.
In preferred aspects, two cannulae are used for positioning the pair of bone allografts, with the cannulae positioned at opposite posterolateral angles to one another. One cannula is used to position the first bone allograft and one cannula is used to position the second bone allograft. In this aspect, the angle between the bone allografts preferably corresponds to the angle between the cannulae. Accordingly, each of the bone allografts can be inserted directly into the patient""s intervertebral space in a relatively straight path through the cannula(e) and into the patient""s intervertebral space. As such, the present pair of bone allografts are easily positioned at a preferred angle to one another when initially deployed in a percutaneous posterolateral approach procedure. Moreover, in preferred aspects, the bone allografts can be inserted into the intervertebral space and then rotated by approximately 90xc2x0 to achieve vertebral distraction, tensioning the annulus and opening the foramen, thereby decompressing the nerve root.
As stated above, in a preferred aspect of the present invention, both the bone allografts and the facet screws are positioned in the patient""s spinal region through a posterolateral minimally invasive approach, which may optionally include a cannulated approach.
Prior to installing the present bone allografts and facet screws, a portion (or all) of the patient""s intervertebral disk may be removed (i.e.: a xe2x80x9cdiskectomyxe2x80x9d may be performed). Thereafter, the opposite vertebral endplates of the adjacent vertebrae may optionally be decorticated, which may produce a natural healing (bone fusion) response, if desired.
Thereafter, and in accordance with the present invention, the pair of bone allografts are positioned in the patient""s intervertebral space. Preferably the bone allografts are inserted through posterolaterally introduced cannulae. In preferred aspects, two cannulae are used, with one positioning each bone allograft; however, the use of a single cannula to place the two bone allografts one after another (in opposite posterolateral approaches) is also contemplated. Additionally, the two bone allografts could be placed through one cannula positioned from only one posterolateral direction. Advantageously, each of the pair of bone allografts can be positioned (i.e.: inserted into the intervertebral space) through a separate cannula with the posterolateral angle at which the cannulae are disposed corresponding to the angle between the bone allografts.
Preferably, after the bone allografts have been positioned between the adjacent vertebrae, the bone allografts will support the vertebrae, causing the vertebrae to move into a natural lordotic angle limiting facet joint movement such that it becomes easier to insert the facet screws.
The present facet screws are used to secure a patient""s facet joints together, thus preventing relative movement therebetween. An advantage of using facet screws is that they provide stabilization to the spine, but are not as surgically time consuming to install as, for example, pedicle screws. Another advantage of the present system is that, by immobilizing adjacent facet joints, it provides stability for vertebral arthrodesis between the adjacent vertebrae.
In accordance with the present invention, therefore, a system is provided to position a facet screw to secure a patient""s opposite adjacent first and second facet joints together, and to promote fusion therebetween. Each of the facet screws may preferably be positioned such that it passes through, and locks together, the superior articular process of one vertebrae with the inferior articular process of an adjacent vertebrae. Preferably, the threads of the facet screw extend all the way into the pedicle, thus providing increased anchoring strength. This embodiment is called the transfacet approach. Other approaches for facet screw placement are also contemplated (i.e. the translaminar approach) within the scope of the present invention.
Accordingly, each of the facet screws provides support at an opposite posterior (rear) side of the patient""s vertebral column. Together with the bone allografts, which provide support at the anterior (front center) of the vertebral column, the present system of two bone allografts and two facet screws, provides a xe2x80x9ctriangularxe2x80x9d support structure.
In an optional preferred aspect of the invention, autologous bone graft material is harvested from the patient and is delivered percutaneously into the patient at a location adjacent to the bone allografts. Specifically, the autologous bone graft material may be positioned both behind the allografts (i.e.: within the V-shape formed by the two allografts) and to the rear of the bone allografts (i.e.: behind the allografts in their posterolateral direction of approach). In preferred aspects, the autologous bone graft material may be harvested from the patient""s iliac crest. Such harvesting of bone graft material directly from the patient""s iliac crest is especially advantageous when the minimally invasive approach used passes through the patient""s iliac crest, with bone material being removed from the iliac crest to provide cannulated access to the patient""s intervertebral space.
In preferred aspects, the present bone allografts are dimensioned with a height of 0.20 to 0.75 inches, a width of 0.20 to 0.75 inches, and a length of 0.60 to 1.20 inches. In one particular preferred aspect, the present bone allografts are dimensioned with a height of about 0.40 inches, a width of about 0.25 inches, and a length of about 0.80 inches.
In preferred aspects, the height to width ratio of the allografts is about 1.2 to 2.0. In more preferred aspects, the height to width ratio of the allografts is about 1.4 to 1.8. In more preferred aspects, the height to width ratio of the allografts is about 1.6.
In preferred aspects, the bone allografts are positioned between adjacent vertebrae by an inserter. Optionally, a two pronged inserter may be used with each of the bone allografts held between the prongs of the inserter. In preferred aspects, the bone allografts may be formed with lateral gooves in which the prongs of the inserter are received.
In optional preferred aspects, the bone allografts may be formed with a curved front edge such that they can be positioned near the outer (front) perimeter of the intervertebral space, thereby advantageously resting on the hard cortical bone at the perimeter of the vertebrae. Most preferably, each of the bone allografts are formed such that their curved front end is the hardest portion of the bone allograft, thereby providing greatest support around the curved front end of the allograft.
In optional aspects, the positioning of the bone allografts may also involve distraction of the vertebrae, which may be performed by the inserter itself, by the shape of the bone allograft itself, or by additional tools (which may also be received through the cannula(e).
In accordance with the present invention, the two facet screws are also positioned in a percutaneous posterolateral approach (which may optionally be cannulated).
In preferred aspects, the cannulae (through which both the bone allografts and the facet screws are advanced) are positioned with the assistance of a surgical guideframe.

Facet screw and bone allograft intervertebral support and fusion system

Abstract: A method of providing support between two adjacent vertebrae, comprising positioning a pair of bone allografts between the two adjacent vertebrae at a location towards the front of the adjacent vertebrae; and securing together facet joints between the two adjacent vertebrae with a pair of facet screws.


The invention relates to isolated nucleic acid molecules and to host cells comprising such nucleic acid molecules. Moreover, the invention relates to a polypeptide having PIM-3 activity and having a definite amino acid sequence, as well as to the use of PIM-3 as a screening agent for identifying anti-type 2 diabetes mellitus drugs and for preparing a medicament for the treatment of insulin resistance or type 2 diabetes mellitus.

The rat PIM-3 (originally termed KID-1, KID "kinase induced by depolarisation"), frog PIM-1, and human and murine PIM-1 are all known to have serine/threonine protein kinase activity in in vitro phosphorylation assays. The high polypeptide sequence similarity between human, murine and rat PIM-3, frog PIM-1, and human and murine PIM-1, demonstrates that human and murine PIM-3 are a serine/threonine protein kinase.
Rat PIM-3 is described by Feldman, J. D. et al. (J. Biol. Chem. (1998) 273, 16535–16543). Rat PIM-3 is induced in specific regions of the hippocampus and cortex in response to kainic acid and electroconvulsive shock suggesting that PIM-3 is involved in neuronal function, synaptic plasticity, learning, and memory as well as kainic acid seizures and some nervous system-related diseases such as seizures and epilepsy.
U.S. Pat. No. 6,143,540, Konietzko, U. et al. (EMBO (1999) 18, 3359–3369) and Eichmann, A. (Oncogene (2000) 19, 1215–1224) also refer to PIM-3 kinase.

PIM-3 kinase as a target for type 2 diabetes mellitus


Updates to a plurality of data sets may be recorded in a shared update log. Whenever a server responsible for the plurality of data sets fails, other servers may reconstruct the data sets using the shared update log and redundant copies of the data sets. As part of the reconstruction process, the other servers reorganize (e.g., by sorting) the update records of sub-logs of the update log to group update records corresponding to the same data set together. The updates are applied to the redundant copies of the data set snapshots to reconstruct the data set.

Organization of information is an important part of any enterprise. Proper organization of information or data makes the data easier to find and use, which helps to increase data access efficiency, and also facilitates data recovery in case of a system failure.
Data may be stored in a distributed system. The distribution spreads the data over many computers and can improve efficiency in accessing the data. However, a problem arises when a computer in the system fails. The failed computer may be responsible for many sets of data and any appreciable delay in recovering the data sets handled by the failed computer can greatly reduce the effectiveness of the distributed system.
Accordingly, it is highly desirable to provide an efficient manner of data recovery in a distributed system.

Data reconstruction from shared update log


A pivotable rollover bar for motor vehicles, in particular for four-seater convertibles, which, bent in the shape of a U, surrounds the rear seating area of a passenger compartment in a lowered rest position. The rollover bar can be pivoted by a drive about lateral bearings on a vehicle body, about a transverse axis of the vehicle, into a raised operative position in which its crossbar spans the interior of the passenger compartment. The rollover bar is provided on its lateral limbs with a flattened portion on the side facing the interior of the passenger compartment, this flattened portion enlarging the interior or the passenger compartment at the sides of the seat. At least one supporting tube projects from the rollover bar towards the vehicle body, the supporting tube being displaceable together with the rollover bar and being guided in a guide in the vehicle body and positioned to take up forces in the transverse direction of the vehicle.

The invention relates to a pivotable rollover bar assembly for motor vehicles, in particular for four-seater convertibles, comprising a rollover bar curved in the shape of a U to surround a rear seating area of a passenger compartment in a lowered rest position and drive apparatus for raising the rollover bar to its raised operative position in which its crossbar spans the interior of the passenger compartment.
It is known from the field of motor vehicle construction, particularly in the case of vehicles without a rigid top, to arrange a U-shaped rollover bar on the vehicle body. In its operative position, the rollover bar spans the passenger compartment starting from a side edge of the vehicle and thus protects persons sitting in the vehicle from direct contact with the ground if the vehicle rolls over. A rollover bar of this kind is illustrated, for example in German Patent 3,410,676.
This rollover bar must be able to provide high supporting forces with its lateral limbs and with its crossbar. For this reason, the cross-section of the rollover bar is large. However, this has the effect that the interior of the vehicle, and, especially, the shoulder space for the person sitting between the limbs of the lowered rollover bar, is restricted.
An object on which the invention is based is to create more interior space for the seated persons in a motor vehicle with a rollover bar of the generic type.
This object is achieved according to preferred embodiments of the invention by providing an arrangement wherein the rollover bar is provided on its lateral limbs with a flattened portion on the side facing the interior of the passenger compartment, this flattened portion enlarging the interior of the passenger compartment at the sides of the seat, and wherein at least one supporting tube projects from the rollover bar towards the vehicle body, said at least one supporting tube being displaceable together with the rollover bar and being guided in a guide in the vehicle body and serving to absorb forces acting on the rollover bar in the transverse direction of the vehicle.
The pivotable rollover bar is bent or curved in the shape of a U and surrounds the rear seating area of the passenger compartment in a lowered rest position. The rollover bar can be pivoted by a drive unit up about lateral bearings on the vehicle body about a transverse axis of the vehicle, into a raised operative position in which it spans the passenger compartment with a crossbar. The rollover bar has lateral limbs with flattened portions of narrow design to the side of the rear seat backs and these enlarge the interior of the passenger compartment at the sides of the seat. To ensure that these flattened portions on the lateral limbs do not lead to any loss in rigidity in the rollover bar in the event of a rollover, at least one supporting tube displaceable together with the rollover bar and taking up forces at least in the transverse direction of the vehicle projects from the rollover bar towards the vehicle body.
In an easily constructed embodiment of the invention, this supporting tube is in the form of a circular arc in its longitudinal direction, in conformance with the movement of the point of connection to the rollover bar, and can slide in a guide which closely surrounds the supporting tube.
The supporting tube can also serve to support the rollover bar in its operative position if the supporting tube can be locked in this position by customary latching means, according to preferred embodiments of the invention.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Pivotable rollover bar for motor vehicles


A card reader having an antiabrasion member for preventing a bottom surface of a card checking passage of the card reader from card contact abrasion. This antiabrasion member is easily inserted in a mold before an injection molding of a main body of the card reader and prevented from displacement in the mold, and allows a magnet head to be easily changed with new one to provide a good compatibility of the magnet head. The plurality of notches prevents the antiabrasion member from being horizontally displaced in a mold and are provided at both sides of the member, and engage with individual ribs of the mold when the member is located in the mold. The slit is provided as a result of lateral cutting of the member between the notches. The resilient part integrally extends from a side of the member near the slit and allows the slit to be inserted in a rib of the mold, and prevents the member from being vertically displaced in the mold.

1. Field of the Invention
The present invention relates in general to a card reader for checking cards, such as credit cards, and more particularly to a card reader having an anitabrasion member preventing a card checking passage of the card reader from being abraded due to direct contact with the card and integrally formed with a main body of the card reader.
2. Description of the Prior Art
Recently, credit cards are regarded as the third currency and wide used instead of cash. Such a wide use of the credit cards is necessarily attended with checking whether the credit card is valid and this causes wide use of the card readers.
Conventionally in order to check whether the credit card has been stolen, lost or expired or it is a card which is unusable as a result of exceeding its credit limit, a card reader reads, by using a magnet head, information recorded on the card and stores the card data, such as the number of remaining months of installment and a totaled amount of used money, in its memory. The card reader in turn transmits the card data to a host computer through a modem employing a public data network. Upon reception of the card data, the host computer analyzes the card data in order to give the inquirer the response. In inquiry of the credit card by employing such a card reader, the information recorded on the credit card should be read by the magnet head so that the card is required to be inserted into a narrower card checking passage, generally formed at the right side of the card reader and provided with the magnet head, and to be rectilinearly reciprocated therein.
With reference to FIGS. 1A and 1B, there is partially shown an embodiment of a conventional card reader. The conventional card reader has a narrower card checking passage 2 which is provided with the magnet head 1 for reading the information recorded on a card (not shown) to be checked. In application, the repeated rectilinear reciprocation of the cards causes the abrasion of a bottom surface of the checking passage 2 due to a contact pressure generated between the bottom surface of the checking passage 2 and the card. In this regard, it has been required to provide the card checking passage 2 with an antiabrasion member for prevention of the contact abrasion of the bottom surface of the passage 2.
In order to achieve such an object, an antiabrasion member 3 of a metal plate has merged with the bottom part of the checking passage 2. Such a merging of the antiabrasion member 3 with the passage 2 is accomplished by inserting this member 3 in an injection mold before an injection molding of a main body 4 of the card reader and, thereafter, molding the main body 4 integrated with the member 3. Here, the antiabrasion member 3 has bent parts 5 at its both ends for facilitating the insertion of the card. In application, the narrower side surface of the card comes into contact with the antiabrasion member 3 instead of the bottom surface of the checking passage 2 when the card is rectilinearly reciprocated in the checking passage 2 with respect to the magnet head 1. Therefore, the bottom surface of the checking passage 2 comes into direct contact with the card and prevented from contact abrasion.
However, such a conventional card reader has a problem in the insertion of the antiabrasion member 3 into the injection mold before the injection molding of the main body 4. Otherwise stated, the insertion of the antiabrasion member 3 into the mold, the insertion having been generally achieved by employing, for example, tweezers since a part of the mold corresponding to the checking passage 2 is narrower and deeper, is very difficult because the member 3 has no grip means. Furthermore, the antiabrasion member 3 is apt to be displaced from its place in the mold even by a slight vibration generated when a movable part and a stationary part of the injection mold engage other, thereby causing the mold to be broken away. In addition, the antiabrasion member 3 having the magnet head 1 at its center portion is integrally formed with the main body 4 of the card reader such that the magnet head 1 can not be changed with new one. Thus, the known card reader has a problem in that the magnet head can not be changed with a low-priced one, the magnet head having been cheaper according to the remarkable technical development in the art, thereby providing no reduction in the manufacturing and maintaining cost.


This disclosure provides a package structure and its fabrication method. The package structure includes: a protective insulation layer; a wiring layer including at least one metal wire and disposed on the protective insulation layer; and a first package unit disposed on the wiring layer and including a plurality of metal pillars, a first integrated-circuit chip and a first molding compound layer; wherein the plural metal pillars are located in a pillar region and electrically connected to the at least one metal wire, the first integrated-circuit chip is located in a device region and electrically connected to the at least one metal wire, and the first molding compound layer filling up the remaining part of the first package unit.

As recent rapid trend in modern electronic devices is not only toward thinner, lighter and smaller devices, but also toward multifunctional and high-performance devices, the fabrication and technology of integrated circuits (ICs) has to evolve correspondingly toward a more high-density and miniature design so as to allow more electronic components to be received inside limited chip space. Consequently, the relating IC package substrate and the package technology are evolved accordingly to meet the trend. One example is the development of the flip-chip packaging technology, especially the flip-chip chip size package (FCCSP) and the flip-chip package-on-package (FCPOP), which are advanced IC fabrication methods capable of assembling and packaging various IC components of different characteristics and are being applied primarily in network communication devices, whichever require high performance in high-frequency high-speed operations and high-density distribution in IC packages that are thinner, lighter and smaller, such as smart phones, tablet computers, and notebook computers. In response to the aforesaid trend of thinner, lighter and smaller, it is in need of a new and advanced flip-chip packaging solution.

Package structure and its fabrication method


This invention pertains to a novel perfluoroalkyl-crosslinked fluoropolymer with perfluoroether pendant groups. The perfluoroalkyl-crosslinked fluoropolymer hereof is particularly well-suited for use in chemically and thermally aggressive environments, in part by virtue of the highly stable perfluoroalkyl crosslink. The perfluroalkyl-crosslinked fluoropolymer hereof can be prepared by crosslinking in situ a crosslinkable precursor in the form of a shaped article. A crosslinkable precursor is a fluoropolymer having a dichloroamino-functionalized functionalized perfluoroether pendant group.

Hynes et al., inorganic Chemistry, 5 (3) 488-489 (March 1966), disclose compositions of the formula RfCF2NCl2 wherein Rf is CF3 or C2F5. They also disclose CClF2CF2NCl2, and NCl2CF2CF2CF2NCl2. Further disclosed is a process for synthesizing those species by reacting at −78° C. the condensed vapors of, respectively, C2F5CN, C3F7CN, CCl—F2CN, and CF2(CN)2, with Cl—F, followed by warming to 0° C. Further disclosed is the pyrolytic transformation at ca. 200° C. of the fluorinated chloroamines to azo compounds represented, inter alia, by the structure RfCF2N═NCF2Rf where Rf is CF3, C2F5, or CCl—F2, as well as a cyclic structure when the starting material was NCl2CF2CF2CF2NCl2. The subsequent thermolysis of azo RfCF2N═NCF2Rf has been reported to follow multiple reaction paths (Scherer, Jr. et al., International Journal of Kinetics, 26, 73(1994)).
Logothetis, U.S. Pat. No. 5,447,993 discloses nitrile containing fluoroelastomers that are copolymers of tetrafluoroethylene, a perfluoro(alkyl vinyl ether) and a nitrile containing cure site monomer. Particularly preferred is the cure site monomer represented by the structureCF2═CFOCF2CF(CF3)OCF2CF2CNAlso disclosed in Logothetis is a process for crosslinking the nitrile-containing fluoroelastomer comprising using a tin catalyst capable of catalyzing the crosslinking, a peroxide, and a diene or triene coagent, the process comprising heating first to 150 to 220° C. followed by further heating to 250 to 310° C. The second heating is said to produce a cured sample that is thermally stable.

Perfluoroalkyl-crosslinked fluoropolymer with perfluoroether pendant groups


This invention relates to novel lactams having the Formula (I):

This invention relates to novel lactams having drug and bio-affecting properties, their pharmaceutical compositions and methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.
Alzheimer""s disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, temporal and local orientation, cognition, reasoning, judgment and emotionally stability. AD is a common cause of progressive dementia in humans and is one of the major causes of death in the United States. AD has been observed in all races and ethnic groups worldwide, and is a major present and future health problem. No treatment that effectively prevents AD or reverses the clinical symptoms and underlying pathophysiology is currently available (for review, Dennis J. Selkoe; Cell Biology of the amyloid (beta)-protein precursor and the mechanism of Alzheimer""s disease, Annu Rev Cell Biol, 1994, 10: 373-403).
Histopathological examination of brain tissue derived upon autopsy or from neurosurgical specimens in effected individuals revealed the occurrence of amyloid plaques and neurofibrillar tangles in the cerebral cortex of such patients. Similar alterations were observed in patients with Trisomy 21 (Down""s syndrome), and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type. Neurofibrillar tangles are nonmembrane-bound bundles of abnormal proteinaceous filaments and biochemical and immunochemical studies led to the conclusion that their principle protein subunit is an altered phosphorylated form of the tau protein (reviewed in Selkoe, 1994).
Biochemical and immunological studies revealed that the dominant proteinaceous component of the amyloid plaque is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids. This protein was designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4; referred to herein as Axcex2. In addition to its deposition in amyloid plaques, Axcex2 is also found in the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. Axcex2 was first purified and a partial amino acid reported in 1984 (Glenner and Wong, Biochem. Biophys. Res. Commun. 120: 885-890). The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829.
Compelling evidence accumulated during the last decade revealed that Axcex2 is an internal polypeptide derived from a type 1 integral membrane protein, termed xcex2 amyloid precursor protein (APP). xcex2 APP is normally produced by many cells both in vivo and in cultured cells, derived from various animals and humans. Axcex2 is derived from cleavage of xcex2 APP by as yet unknown enzyme (protease) system(s), collectively termed secretases.
The existence of at least four proteolytic activities has been postulated. They include xcex2 secretase(s), generating the N-terminus of Axcex2, xcex1 secretase(s) cleaving around the 16/17 peptide bond in Axcex2, and xcex3 secretases, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides.
Several lines of evidence suggest that abnormal accumulation of Axcex2 plays a key role in the pathogenesis of AD. Firstly, Axcex2 is the major protein found in amyloid plaques. Secondly, Axcex2 is neurotoxic and may be causally related to neuronal death observed in AD patients. Thirdly, missense DNA mutations at position 717 in the 770 isoform of xcex2 APP can be found in effected members but not unaffected members of several families with a genetically determined (familiar) form of AD. In addition, several other xcex2 APP mutations have been described in familiar forms of AD. Fourthly, similar neuropathological changes have been observed in transgenic animals overexpressing mutant forms of human xcex2 APP. Fifthly, individuals with Down""s syndrome have an increased gene dosage of xcex2 APP and develop early-onset AD. Taken together, these observations strongly suggest that Axcex2 depositions may be causally related to the AD.
It is hypothesized that inhibiting the production of Axcex2 will prevent and reduce neurological degeneration, by controlling the formation of amyloid plaques, reducing neurotoxicity and, generally, mediating the pathology associated with Axcex2 production. One method of treatment methods would therefore be based on drugs that inhibit the formation of Axcex2 in vivo.
Methods of treatment could target the formation of Axcex2 through the enzymes involved in the proteolytic processing of xcex2 amyloid precursor protein. Compounds that inhibit xcex2 or xcex3 secretase activity, either directly or indirectly, could control the production of Axcex2. Advantageously, compounds that specifically target xcex3 secretases, could control the production of Axcex2. Such inhibition of xcex2 or xcex3 secretases could thereby reduce production of Axcex2, which, thereby, could reduce or prevent the neurological disorders associated with Axcex2 protein.
As evidenced by the interest in the treatment of neurological disorders related to xcex2-amyloid production, such as Alzheimer""s disease and Down""s Syndrome, a wide variety of compounds which inhibit Axcex2 protein production have been studied. For example, PCT publication number WO 98/28268 describes compounds of the general formula:
as inhibitors of xcex2-amyloid peptide release and having utility in treating Alzheimer""s disease. Though some of the present compounds of this invention appear to fall within the generic description of the above publication, they are not specifically disclosed, suggested, or claimed therein.
Thus, it is desirable to develop additional inhibitors of Axcex2 protein production to treat Alzheimer""s disease or Down""s syndrome. The present invention discloses compounds of enhanced activity in inhibiting Axcex2 protein production.
One object of the present invention is to provide novel compounds which are useful as inhibitors of the production of Axcex2 protein or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating degenerative neurological disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of Formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein R1, R2, R3, n, Y and Z are defined below, are effective inhibitors of the Axcex2 protein-production.
[1] In a first embodiment, the present invention provides a novel compound of Formula (I):
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is C1-C6 alkyl substituted with 0-3 R1a; C6-C10 aryl substituted with 0-3 R1b; C3-C6 cycloalkyl substituted with 0-3 R1b; or 5 to 10 membered heterocycle substituted with 0-3 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I, xe2x95x90O, CN, NO2, NR15R16; C3-C10 carbocycle substituted with 0-3 R1b; C6-C10 aryl substituted with 0-3 R1b; and 5 to 10 membered heterocycle substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, N3, NO2, NR15R16, phenoxy, C1-C4 thioalkoxy and CF3;
R5 is C1-C4 alkyl, cyclopropyl, cyclopropylmethyl, cyclopropylethyl, cyclobutyl, cyclobutylmethyl, or cyclobutylethyl;
R3, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
n is 0, 1, 2, or 3;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(R19)xe2x80x94, xe2x80x94C(xe2x95x90O)NR19bxe2x80x94, xe2x80x94NR19bC(xe2x95x90O)xe2x80x94, xe2x80x94NR19bS(xe2x95x90O)2xe2x80x94, xe2x80x94S(xe2x95x90O)2NR19bxe2x80x94, xe2x80x94NR19bS(xe2x95x90O)xe2x80x94, xe2x80x94S(xe2x95x90O)NR19bxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; C6-C10 aryl substituted with 0-4 R12b; C3-C10 carbocycle substituted with 0-2 R12; or C5-C10 membered heterocycle substituted with 0-4 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b; or C3-C10 carbocycle substituted with 0-2 R12;
R12b, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, C1-C6 thioalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 haloalkyl, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, phenyl, benzyl, C1-C6 alkyl, or C2-C6 alkoxyalkyl;
R15, at each occurrence, is independently selected from H, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R16, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl) and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl);
R19, at each occurrence, is independently selected from H, OH, C1-C6 alkyl, phenyl, benzyl, phenethyl, xe2x80x94C(xe2x95x90O)xe2x80x94(C1-C6 alkyl), and xe2x80x94S(xe2x95x90O)2xe2x80x94(C1-C6 alkyl); and
R19b is H, C1-C6 alkyl, C3-C8 cycloalkyl, phenyl, benzyl or phenethyl.
[2] In a more preferred embodiment, the present invention provides for a compound of Formula I,
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is C1-C6 alkyl substituted with 0-1 R1a; C3-C6 cycloalkyl substituted with 0-1 R1b; phenyl substituted with 0-2 R1b; naphthyl substituted with 0-2 R1b; or pyridyl substituted with 0-2 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I; C3-C10 carbocycle substituted with 0-3 R1b; and C6-C10 aryl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, C1, F, Br, I, CN, NO2, N3, SCH3, NR15R16, phenoxy, and CF3;
R5 is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopropylmethyl, or cyclobutylmethyl;
R3, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, and CF3;
n is 0, 1, or 2;
Y is a bond, xe2x80x94C(xe2x95x90O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94C(xe2x95x90O)Oxe2x80x94, or xe2x80x94OC(xe2x95x90O)xe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; or C6-C10 aryl substituted with 0-4 R12b;
R12 is C6-C10 aryl substituted with 0-4 R12b; or C3-C6 carbocycle substituted with 0-4 R12b;
R12b, at each occurrence, is independently selected from H, OH, C1-C4 alkyl, C1-C4 alkoxy, Cl, F, Br, I, CN, NO2, SCH3, NR15R16, and CF3;
R14 is H, phenyl, benzyl, or C1-C6 alkyl;
R15, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, and phenethyl; and
R16, at each occurrence, is independently selected from H, C1-C4 alkyl, benzyl, and phenethyl.
[3] In an even more preferred embodiment, the present invention provides for a compound of Formula I,
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl, pyridyl; methyl substituted with 1 R1a; ethyl substituted with 1 R1a; or phenyl substituted with 1-3 R1b;
R1a, at each occurrence, is independently selected from: H, CF3, OR14, Cl, F, Br, I; C3-C6 cycloalkyl substituted with 0-3 R1b; and phenyl substituted with 0-3 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, N3, SCH3, NR15R16, phenoxy, and CF3;
R5 is methyl;
R3, at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, NO2, and CF3;
n is 0 or 1;
Y is a bond or xe2x80x94Oxe2x80x94;
Z is C1-C3 alkyl substituted with 0-2 R12; or phenyl substituted with 0-3 R12b;
R12 is C3-C6 cycloalkyl substituted with 0-3 R12b; phenyl substituted with 0-3 R12b;
R12b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, SCH3, C1-C2 haloalkyl, C1-C2 haloalkoxy, Cl, F, Br, I, CN, NO2, NR15R16, and CF3;
R14 is H, methyl, ethyl, phenyl, or benzyl;
R15, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl; and
R16, at each occurrence, is independently selected from H, methyl, ethyl, propyl, butyl, benzyl, and phenethyl.
[4] In another embodiment, the present invention provides for a compound of Formula (Ia),
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl substituted with 1 R1a; ethyl substituted with 1 R1a; phenyl substituted with 1-3 R1b; methyl, ethyl, propyl, butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, naphthyl, or pyridyl;
R1a is phenyl substituted with 0-3 R1b; cyclopropyl substituted with 0-1 R1b; cyclobutyl substituted with 0-1 R1b; cyclopentyl substituted with 0-1 R1b; or cyclohexyl substituted with 0-1 R1b;
R1b, at each occurrence, is independently selected from H, OH, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, Cl, F, Br, I, CN, NO2, N3, SCH3, phenoxy, and CF3;
Z is methyl substituted with R12; or phenyl substituted with 0-2 R12b;
R12 is phenyl substituted with 0-2 R12b;
R12b, at each occurrence, is independently selected from H, OH, methyl, ethyl, methoxy, ethoxy, Cl, F, Br, I, CN, NO2, SCH3, NR15R16, OCF3, and CF3;
R15, at each occurrence, is independently selected from H, methyl, and ethyl; and
R16, at each occurrence, is independently selected from H, methyl, and ethyl.
[5] In an even more preferred embodiment, the present invention provides for a compound Formula (Ib);
or a pharmaceutically acceptable salt or prodrug thereof, wherein:
R1 is methyl, ethyl, n-propyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-valeryl, n-hexyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, xe2x80x94CH2-cyclopropyl, xe2x80x94CH2-cyclobutyl, xe2x80x94CH2-cyclohexyl, xe2x80x94CH2-cyclopentyl, xe2x80x94CH2CH2-cyclopropyl, xe2x80x94CH2CH2-cyclobutyl, xe2x80x94CH2CH2cyclohexyl, xe2x80x94CH2CH2cyclopentyl, phenylmethyl, 2-chlorophenylmethyl, 2-fluorophenylmethyl, 2-bromophenylmethyl, 2-hydroxyphenylmethyl, 2-nitrophenylmethyl, 2-methylphenylmethyl, 2-methoxyphenylmethyl, 2-phenoxyphenylmethyl, 2-trifluoromethylphenylmethyl, 3-hydroxyphenylmethyl, 3-nitrophenylmethyl, 3-fluorophenylmethyl, 3-chlorophenylmethyl, 3-bromophenylmethyl, 3-thiomethoxyphenylmethyl, 3-methylphenylmethyl, 3-trifluoromethylphenylmethyl, 3-methoxyphenylmethyl, 4-chlorophenylmethyl, 4-bromophenylmethyl, 4-nitrophenylmethyl 4-methylphenylmethyl, 4-hydroxyphenylmethyl, 4-methoxyphenylmethyl, 4-ethoxyphenylmethyl, 4-butoxyphenylmethyl, 4-iso-propylphenylmethyl, 4-trifluoromethylphenylmethyl, 4-azidophenylmethyl, 4-cyanophenylmethyl,4-ethylphenylmethyl, 4-fluorophenylmethyl, 4-iodophenylmethyl, 2,3-dichlorophenylmethyl, 2,5-difluorophenyl, 2,3-difluorophenylmethyl, 2,4-dichlorophenylmethyl, 2,5-dimethoxyphenylmethyl, 3,4-dichlorophenylmethyl, 3,4-difluorophenylmethyl, 3,4-dimethoxyphenylmethyl, 3,5-difluorophenylmethyl, 3,5-dichlorophenylmethyl, 3,5-di-(trifluoromethyl)phenylmethyl, 3,5-dimethoxyphenylmethyl, 2,4-difluorophenylmethyl, 2,6-difluorophenylmethyl, 2,5-difluorophenylmethyl, 2-fluoro-3-trifluoromethylphenylmethyl, 4-fluoro-2-trifluoromethylphenylmethyl, 2-fluoro-4-trifluoromethyl-phenylmethyl, 2-choro-6-fluorophenylmethyl, 2-fluoro-6-chlorophenylmethyl, 2,5-dimethylphenylmethyl, 2-fluoro-3-trifluoromethylphenylmethyl, 3-(trifluoromethyl)-(4-chloro-phenylmethyl, 3-chloro-4-cyano-phenylmethyl, 3-chloro-4-iodo-phenylmethyl, 3,4,5-trichlorophenylmethyl, 3,4,5-trifluorophenylmethyl, 3,4,5-trimethoxyphenylmethyl, 3,4,5-tri(trifluoromethyl)phenylmethyl, 2,4,6-trifluorophenylmethyl, 2,4,6-trimethylphenylmethyl, 2,4,6-tri-(trifluoromethyl)phenylmethyl, 2,3,5-trifluorophenylmethyl, 2,4,5-trifluorophenylmethyl, 2-phenylethyl, 2-(4-nitrophenyl)ethyl, 2-(4-methoxyphenyl)ethyl, (1-phenyl)ethyl, 1-(p-chorophenyl)ethyl, (1-trifluoromethyl)phenylethyl, (4-methoxyphenyl)ethyl, 1-naphthyl, 2-naphthyl, pyrid-2-yl, pyrid-3-yl, or pyrid-4-yl; and
Z is is phenyl, 2-F-phenyl, 3-F-phenyl, 4-F-phenyl, 2-Cl-phenyl, 3-Cl-phenyl, 4-Cl-phenyl, 2,3-diF-phenyl, 2,4-diF-phenyl, 2,5-diF-phenyl, 2,6-diF-phenyl, 3,4-diF-phenyl, 3,5-diF-phenyl, 2,3-diCl-phenyl, 2,4-diCl-phenyl, 2,5-diCl-phenyl, 2,6-diCl-phenyl, 3,4-diCl-phenyl, 3,5-diCl-phenyl, 3-F-4-Cl-phenyl, 3-F-5-Cl-phenyl, 3-Cl-4-F-phenyl, 2-MeO-phenyl, 3-MeO-phenyl, 4-MeO-phenyl, 2-Me-phenyl, 3-Me-phenyl, 4-Me-phenyl, 2-MeS-phenyl, 3-MeS-phenyl, 4-MeS-phenyl, 2-CF3O-phenyl, 3-CF3O-phenyl, or 4-CF3O-phenyl.
[6] In another more preferred embodiment the present invention provides for a compound of Formula (I) which is
or a pharmaceutically acceptable salt or prodrug thereof.
[7] In a second embodiment the present invention provides for pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable carrier.
[8] In a third embodiment the present invention provides for a method for the treatment of neurological disorders associated with xcex2-amyloid production comprising administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I).
[9] In a fifth embodiment the present invention provides for a method for inhibiting xcex3-secretase activity comprising administering to a host in need of such inhibition a therapeutically effective amount of a compound of Formula (I) that inhibits xcex3-secretase activity.
As used herein, the term xe2x80x9cAxcex2xe2x80x9d denotes the protein designated Axcex2, xcex2-amyloid peptide, and sometimes xcex2/A4, in the art. Axcex2 is an approximately 4.2 kilodalton (kD) protein of about 39 to 43 amino acids found in amyloid plaques, the walls of meningeal and parenchymal arterioles, small arteries, capillaries, and sometimes, venules. The isolation and sequence data for the first 28 amino acids are described in U.S. Pat. No 4,666,829. The 43 amino acid sequence is:
The term xe2x80x9cAPPxe2x80x9d, as used herein, refers to the protein known in the art as xcex2 amyloid precursor protein. This protein is the precursor for Axcex2 and through the activity of xe2x80x9csecretasexe2x80x9d enzymes, as used herein, it is processed into Axcex2. Differing secretase enzymes, known in the art, have been designated xcex2 secretase, generating the N-terminus of Axcex2, xcex1 secretase cleaving around the 16/17 peptide bond in Axcex2, and xe2x80x9cxcex3 secretasesxe2x80x9d, as used herein, generating C-terminal Axcex2 fragments ending at position 38, 39, 40, 42, and 43 or generating C-terminal extended precursors which are subsequently truncated to the above polypeptides
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is an keto (i.e. xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g. R12) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R12, then said group may optionally be substituted with up to two R12 groups and R12 at each occurrence is selected independently from the definition of R12. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d or xe2x80x9calkylenexe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms; for example, xe2x80x9cC1-C6 alkylxe2x80x9d, denotes alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. Preferred xe2x80x9calkylxe2x80x9d group, unless otherwise specified, is xe2x80x9cC1-C4 alkylxe2x80x9d. Additionally, unless otherwise specified, xe2x80x9cpropylxe2x80x9d denotes n-propyl or i-propyl; xe2x80x9cbutylxe2x80x9d denotes n-butyl, i-butyl, sec-butyl, or t-butyl.
As used herein, xe2x80x9calkenylxe2x80x9d or xe2x80x9calkenylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain. Examples of xe2x80x9cC2-C6 alkenylxe2x80x9d include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 2-pentenyl, 3-pentenyl, hexenyl, and the like.
As used herein, xe2x80x9calkynylxe2x80x9d or xe2x80x9calkynylenexe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more carbon-carbon triple bonds which may occur in any stable point along the chain, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d or xe2x80x9calkyloxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy. Similarly, xe2x80x9calkylthioxe2x80x9d or xe2x80x9cthioalkoxyxe2x80x9d is represents an alkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo. Unless otherwise specified, preferred halo is fluoro and chloro. xe2x80x9cCounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl, 2,2,2-trifluoroethyl, 2,2-difluoroethyl, heptafluoropropyl, and heptachloropropyl. xe2x80x9cHaloalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge; for example trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy, and the like. xe2x80x9cHalothioalkoxyxe2x80x9d is intended to mean a haloalkyl group as defined above with the indicated number of carbon atoms attached through a sulphur bridge.
xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, having the specified number of carbon atoms. For example, xe2x80x9cC3-C6 cycloalkylxe2x80x9d denotes such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
As used herein, xe2x80x9ccarbocyclexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin). Preferred xe2x80x9ccarbocyclexe2x80x9d are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic heterocyclic ring which is saturated partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3 or 4 heteroatoms independently selected from the group consisting of N, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred 5 to 10 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl, benzofuranyl, benzothiofuranyl, indolyl, benzimidazolyl, 1H-indazolyl, oxazolidinyl, isoxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, quinolinyl, and isoquinolinyl. Preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, pyrrolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, tetrazolyl; more preferred 5 to 6 membered heterocycles include, but are not limited to, pyridinyl, pyrimidinyl, triazinyl, furanyl, thienyl, thiazolyl, piperazinyl, piperidinyl, pyrazolyl, imidazolyl, and tetrazolyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
As used herein, the term xe2x80x9carylxe2x80x9d, xe2x80x9cC6-C10 arylxe2x80x9d or aromatic residue, is intended to mean an aromatic moiety containing the specified number of carbon atoms; for example phenyl, pyridinyl or naphthyl. Preferred xe2x80x9carylxe2x80x9d is phenyl. Unless otherwise specified, xe2x80x9carylxe2x80x9d may be unsubstituted or substituted with 0 to 3 groups selected from H, methyl, ethyl, propyl, butyl, methoxy, ethoxy, propoxy, butoxy, amino, hydroxy, Cl, F, Br, I, CF3, SCH3, S(O)CH3, SO2CH3, xe2x80x94N(CH3)2, N(CH3)H, CN, NO2, OCF3, C(xe2x95x90O)CH3, CO2H, CO2CH3, or C1-C4 haloalkyl.
The compounds herein described may have asymmetric centers. One enantiomer of a compound of Formula (I) may display superior biological activity over the opposite enantiomer. For example carbon 3 of lactam ring of Formula (Ixe2x80x2) may exist in either an S or R configuration. Thus, for example, both R or S configurations at carbon 3 in Formula (Ixe2x80x2-3R) and (Ixe2x80x2-3S) are considered part of the invention. Examples of such configuration include, but are not limited to,
The (S)xe2x80x94configuration at carbon 3 of the lactam ring is preferred.
When required, separation of the racemic material can be achieved by methods known in the art. Additionally, the carbon atom to which R5 is attached may display superior biological activity over the opposite enantiomer. For example, when R5 is C1-C4 alkyl, the configuration of the carbon may be described as R or S. All configurations are considered part of the invention; however, the S configuration of the carbon bearing R5 is more preferred.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release the active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug or compound of Formula (I) is administered to a mammalian subject, cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and acetamide, formamide and benzamide derivatives of amine functional groups in the compounds of Formula (I), and the like.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated in their entirety herein by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of Formula (I) can be prepared by methods described in Scheme 1. The protected xcex1-amine 2 of the xcex1-amino-xcex5-caprolactam 1 can be prepared by methods well known in the literature for amino protecting groups as discussed in Theodora W. Greene""s book xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, like N-Boc using di-t-butyldicarbonate in an appropriate solvent like DMSO. The lactam nitrogen of compound 2 can be alkylated to give compound 3 by generating the anion with bases such as LDA, lithium bis(trimethylsilyl)amide or sodium hydride in solvents like THF, with or without co-solvents such as DMPU or HMPA and reacting this with a variety of groups, each of which containing a leaving groups (LG) such as a bromide, iodide, mesylate or tosylate. Alkylating agents such as xcex1-bromo amides, ketones and acids can be prepared by a number of literature methods including halogenation of amino acids by diazotization or are commercially available. Other suitable alkylating agents such as alkyl, allylic and benzylic halides can be formed form a variety of precursors such as free-radical addition of halides or activation of alcohols, and other chemistries known to those skilled in the art. For discussion of these types of reactions, see Carey, F. A. and Sundberg, R. J., Advanced Organic Chemistry, Part A, New York: Plenum Press, 1990, pages 304-305, 342-347, 695-698.
The N-Boc protecting group of compound 3 can be removed by any number of methods well known in the literature like TFA in methylene chloride to give an amine 4. The amine 4 can be coupled to an appropriately substituted carboxylic acid 5 or acid chloride by methods well described in the literature for making amide bonds, like TBTU in DMF with a base like NMM to give an elaborated compound of Formula (I).
Appropriate carboxylic acid 5 is available through the chemistry shown in Scheme 2. Thus, coupling of an amino acid ester 5b under standard conditions including Schotten-Bowman conditions produces an amide 5a. The carboxylic acid 5 is available through saponification of the ester 5a under standard basic conditions. Alternatively, the amide 5a can be formed using the amino acid ester 5b and a carboxylic acid using any of the standard coupling agents mentioned above or known to one skilled in the art.
Methods for the synthesis of lactams and alkylation of lactams are known in the art and are disclosed in a number of references including PCT publication number WO 98/28268 (published Jul. 2, 1998) and PCT publication number WO 00/07995 (published Feb. 17, 2000), which are hereby incorporated in their entirety by reference.
Chemical abbreviations used in the Examples are defined as follows: xe2x80x9cDMPUxe2x80x9d for 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone, xe2x80x9cTBTUxe2x80x9d for O-(1H-benzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium tetrafluoroborate, xe2x80x9cHATUxe2x80x9d for O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetrmethyluronium hexafluorophosphate, xe2x80x9cTFAxe2x80x9d for trifluoroacetic acid, xe2x80x9cNMMxe2x80x9d for n-methylmorpholine, and xe2x80x9cBOPxe2x80x9d for benzotriazol-1-yloxytris-(dimethylamino-phosphonium hexafluorophosphate. xe2x80x9cHPLCxe2x80x9d is an abbreviation used herein for high pressure liquid chromatography.
Using conditions generally known to one skilled in the art, compounds of the present invention are generally purified by HPLC. Reverse-phase HPLC can be carried out using a Vydac C-18 column with gradient elution from 10% to 100% buffer B in buffer A (buffer A: water containing 0.1% trifluoroacetic acid, buffer B: 10% water, 90% acetonitrile containing 0.1% trifluoroacetic acid). If necessary, organic layers can be dried over sodium sulfate unless otherwise indicated. However, unless otherwise indicated, the following conditions are generally applicable.

Lactams as inhibitors of A-xcex2 protein production

Abstract: to their pharmaceutical compositions and to their methods of use. These novel compounds inhibit the processing of amyloid precursor protein and, more specifically, inhibit the production of Axcex2-peptide, thereby acting to prevent the formation of neurological deposits of amyloid protein. More particularly, the present invention relates to the treatment of neurological disorders related to xcex2-amyloid production such as Alzheimer""s disease and Down""s Syndrome.


A storage control apparatus for controlling memory elements having a data hold mode is provided with a switching circuit for switching a first voltage for a normal operation mode and a second voltage for the data hold mode as a power supply voltage applied to the memory elements, and a control circuit for controlling the switching operation of the switching circuit in accordance with accessing conditions of the memory elements. The control circuit is adapted to monitor accessing conditions of the respective memory elements and control the switching circuit to set all or a part of the memory elements except for accessed memory elements in the data hold mode.

1. Field of the Invention
The present invention relates to a control apparatus for a data storage apparatus, and more particularly to a control apparatus suitable for use in, for example, a main storage apparatus provided with a data hold mode which is capable of utilizing the data hold mode in which a power consumption is low even when the main storage apparatus is being accessed.
2. Related Art
In memory elements constituting a main storage apparatus in a computer or the like, an interruption of voltage supply causes data in the elements to be destroyed. However, known memory elements include one which is provided with a data hold mode such as a static RAM (hereinafter simply referred to as "SRAM"). The data hold mode is defined as a mode in which a supplied voltage is decreased below an allowable operation voltage in a non-select state of the memory elements, wherein data can be held if the supplied voltage presents a voltage value larger than a data hold voltage. In the data hold mode, merely several .mu.A of a power supply current flows, and accordingly the power consumption is extremely low.
The related art has utilized this mode to perform a battery backup in case of system power supply interruption.
The following is a procedure of switching from the system power supply to a battery power supply:
(1) A voltage drop is detected in the system power supply;
(2) The memory elements are set to a non-select state; and
(3) The power supply is switched from the system power supply to the battery power supply (the supply voltage of which is lower than that of the system power supply) to set the storage elements to a data hold mode.
For recovery, after confirming that the system power supply has been turned on, the storage elements are released from the non-select state after a time period required to recover the operation of the storage elements.
As explained above, the data hold mode in which the power consumption is low has been conventionally utilized only when the memory elements are backed up by a battery.
The above-mentioned related art has not considered reduction in the electric power consumed by the main storage apparatus except for the case where it is backed up by a battery. Specifically, when the system power supply is turned on, all memory elements are in either the operating state or the non-select state (hereinafter, the two states are collectively referred to as "the normal mode"), whereby the storage elements are never set in the data hold mode in which the power consumption is low.

Control apparatus for data storage apparatus


The invention is directed to a glycosylated or nonglycosylated protein which is composed of the amino acid sequence of a first .alpha. subunit common to the glycoprotein hormones linked covalently, optionally through a linker moiety, to the amino acid sequence of a second .alpha. subunit of said hormones, wherein said first and second .alpha. subunits consist of the native amino acid sequences or variants of said amino acid sequences. These proteins are useful as agonists or antagonists of glycoprotein hormone activity.

In humans, four important glycoprotein hormone heterodimers (LH, FSH, TSH and CG) have identical .alpha. subunits and differing .beta. subunits. Three of these hormones are present in virtually all other vertebrate species as well; CG has so far been found only in primates and in horses.
PCT application WO90/09800, published 7 Sep., 1990, and incorporated herein by reference, describes a number of modified forms of these hormones. One important modification is C-terminal extension of the .beta. subunit of FSH, LH, and TSH by the carboxy terminal peptide (CTP) of human chorionic gonadotropin .beta.-subunit or a variant thereof. Other muteins of these hormones are also described. The CTP-extended .beta. subunit of FSH is also described in two papers by applicants herein: LaPolt, P. S. et al.; Endocrinology (1992) 131:2514-2520 and Fares, F. A. et al.; Proc Natl Acad Sci USA (1992) 89:4304-4308.
The crystal structure of the heterodimeric form of human chorionic gonadotropin has now been published in more or less contemporaneous articles; one by Lapthorn, A. J. et al. Nature (1994) 369:455-461 and the other by Wu, H. et al. Structure (1994) 2:545-558. The results of these articles are summarized by Patel, D. J. Nature (1994) 369:438-439.
PCT application WO91/16922 published 14 Nov., 1991 describes a multiplicity of chimeric and otherwise modified forms of the heterodimeric glycoprotein hormones. In general, the disclosure is focused on chimeras of .alpha. subunits or .beta. subunits involving portions of various .alpha. or .beta. chains respectively. One construct simply listed in this application, and not otherwise described, fuses substantially all of the .beta. chain of human chorionic gonadotropin to the .alpha. subunit preprotein, i.e., including the secretory signal sequence for this subunit.
PCT application WO96/05224 describes single-chain forms of the glycoprotein hormone wherein the .alpha. and .beta. subunits are covalently linked through their N- or C-termini so as to form agonists or antagonists. The linkage can be either .beta.-.alpha. or .alpha.-.beta.. Also described are single-chain forms wherein two .beta. subunits are covalently linked through their termini. Preferred embodiments of such single-chain forms are fusion proteins wherein the linkage is effected through peptide bonds, optionally through additional amino acid sequence forming a "linker."
It has now been found by applicants that single-chain proteins which consist essentially of two .alpha. subunits covalently linked through their N- or C-termini, optionally through a linker moiety can behave as agonists or antagonists of the glycoprotein hormones by interacting with the relevant receptors.