An electronic device may have housing structures, electrical components, and other electronic device structures. Adhesive may be used to join electronic device structures. Adhesive may be dispensed as liquid adhesive and cured to form adhesive joints. Adhesive joints may be debonded. Chain reactions may be initiated by applying a localized initiator such as a chemical or localized energy to the adhesive. Once initiated, the chain reaction may spread throughout the adhesive to cure the adhesive, to globally change adhesive viscosity, or to weaken the adhesive to facilitate debonding. Local changes to adhesive may also be made such as local increases and decreases to adhesive viscosity. Chain reaction curing may be used to cure adhesive or debond adhesive that is hidden from view within gaps in the electronic device structures. Viscosity changes may be used to control where adhesive flows.

This relates generally to electronic devices, and, more particularly, to assembling structures in electronic devices using adhesive.
Electronic devices include components such housing structures, electrical devices, printed circuits, and other device structures. Some structures may be assembled using screws and other fasteners. In other situations, adhesive is used to attach structures together.
It can be challenging to assemble structures in electronic devices using adhesive. Light-cured adhesive can be difficult to cure within recesses that are hidden from view. Liquid adhesive can be too viscous to dispense into narrow gaps or can be insufficiently viscous so that the adhesive wicks into locations where no adhesive is desired. After curing adhesive, it can be difficult to disassemble joined parts without damaging the parts.
It would therefore be desirable to be able to provide improved arrangements for using adhesive to join structures in electronic devices.

Methods for assembling electronic devices with adhesive


A thin film transistor includes a gate electrode, a gate insulating layer on the gate electrode, a semiconductor on the gate insulating layer, and a drain electrode and a source electrode on the semiconductor and spaced apart from each other. Each of the drain electrode and the source electrode includes a first metal diffusion preventing layer which prevents diffusion of metal atoms, and a second metal diffusion preventing layer on the first metal diffusion preventing layer. At least one of the first and second metal diffusion preventing layers includes grains in a columnar structure, which are in a direction substantially perpendicular to a lower layer. First grain boundaries of the first metal diffusion preventing layer and second grain boundaries of the second metal diffusion preventing layer are substantially discontinuous in a direction perpendicular to the semiconductor.

1. Field of the Invention
The invention relates to a wiring, a thin film transistor, a thin film transistor panel, and methods for manufacturing the same.
2. Description of the Related Art
In general, wirings or electrodes including chrome (Cr), aluminum (Al), molybdenum (Mo), or an alloy thereof are mainly used in semiconductor devices or liquid crystal display devices. For microfabrication of the semiconductor devices, due to high integration and a fast operating speed, copper (Cu) which has a lower electric resistance and has a higher resistance to electromigration and stress migration compared to aluminum, has been used for wirings or electrodes in semiconductor devices.
Even in the field of display devices represented by liquid crystal display devices and the like, low-resistance wirings are required due to the increase in resolution and display area, and the integration of devices including sensors and driver circuits, which may be integrated in the display devices. Therefore, gate or data wirings made of copper, or gate, drain and source electrodes of a thin film transistor ("TFT"), which are also made of copper, are applied to display devices.
However, when copper is used for wirings or electrodes, the diffusion of copper into adjacent circuit elements or a semiconductor layer of a TFT may degrade characteristics of pixel elements or TFTs. Therefore, it is required to prevent metal atoms, for example, copper atoms, contained in wirings or electrodes from being spread around and diffused into adjacent elements or layers.

Wiring, thin film transistor, thin film transistor panel and methods for manufacturing the same


The invention relates to an automatic central buffer coupling having a coupling head, a coupling rod and a shock absorber including a destructively-configured force-absorbing member in the form of a deformable tube. The invention provides additional functionality of extendability and retractability to the coupling rod, the and for the central buffer coupling to include a controllable linear drive for the axial displacement of the coupling rod relative the fixing plate and for the bearing block to include a first bearing block component against which adjoins the coupling head-side end of the deformable tube, and a second bearing block component to which the vehicle-side end of the coupling rod is articulated, whereby the second bearing block component is axially displaceable relative the first bearing block component by means of the linear drive.

1. Field of the Invention
The present invention relates to an automatic central buffer coupling for a vehicle, a rail-mounted vehicle in particular, including a coupling head, a coupling rod connected to the coupling head, a bearing block to which the vehicle-side end of the coupling rod is articulated so as to be horizontally pivotable, a fixing plate preferably attachable to the underframe of the vehicle to secure the central buffer coupling to the vehicle, and a shock absorber having a destructively-configured force-absorbing member in the form of a deformable tube with its coupling head-side end against the bearing block and its vehicle-side end against the fixing plate, whereby the shock absorber includes a bolted connection which axially braces the bearing block, the deformable tube and the fixing plate, and upon excessive impact, i.e., upon a predefinable operating load for the central buffer coupling being exceeded, permits an axial displacement of the bearing block relative the fixing plate.
2. Description of the Related Art
Existing central buffer couplings, in particular in the field of railway technology, serve to transfer tensile and compressive forces impacting a car body of a first vehicle from the car body to a neighboring second vehicle when the central buffer coupling is coupled to a central buffer coupling of the second vehicle.
In order to ensure cushioning of the tensile and compressive forces occurring during normal vehicle operation, and transferred, for example, in the case of a multi-member vehicle, between the individual car bodies during the normal vehicle operation by the central buffer coupling, a normally regeneratively-configured drawgear is customarily provided in the coupling rod and/or in the bearing provided to articulate the coupling rod to the bearing block. The drawgear is usually designed to accommodate tensile and compressive forces up to a defined magnitude and relay any forces exceeding that to the vehicle underframe.
Thus, while tensile and compressive forces which occur during normal vehicle operation are cushioned by the drawgear, once the operating load of the drawgear is exceeded, however, for instance, upon the vehicle colliding with an obstacle or upon the vehicle abruptly decelerating, there is the risk that the normally regeneratively-configured drawgear and conceivably also the coupling link between the individual car bodies, the interface between the individual car bodies respectively, will be destroyed or damaged. In any case, the drawgear is inadequate to absorb the whole of the resultant force. Hence, the drawgear is then not integrated into the force-absorbing concept of the vehicle as a whole such that the resulting impact force is transferred directly to the vehicle underframe. Doing so subjects the same to extreme loads and may possibly damage or even destroy the same. With multi-member rail vehicles in such cases, there is the risk of car body derailment.
Frequently used with the objective of protecting the vehicle underframe against damage from strong rear-end impacts, is a shock absorber including a destructively-configured force-absorbing member, for example, in the form of a deformable tube, whereby the force-absorbing member of this shock absorber is designed so as to be activated when the operational absorption of the drawgear is exhausted, and will absorb and thus, dissipate at least a portion of the force transferred through the force-absorbing member in the force flow. In the case of a shock absorber including a destructively-configured force-absorbing member in the form of a deformable tube, the deformable tube is plastically deformed in a defined and destructive manner such that the resulting impact force is at least partly converted into deformation work and heat.
Thus, the problem relates to an automatic central buffer coupling of the type cited above, i.e., including a shock absorber having a destructively-configured force-absorbing member, which frequently needs to have the additional functionality of the central buffer coupling being displaceable in the axial direction, i.e., in the longitudinal direction of the vehicle, between a first extended position, in which the coupling head of the central buffer coupling is in the coupling plane of the vehicle and thus, ready to be coupled, and a second retracted position in which the coupling head is in a position rearward of the coupling plane close to the vehicle.
This additional functionality can, for example, be necessary when the central buffer coupling is utilized in a high-speed train. This type of train is characterized by its end car frequently being built according to optimized aerodynamic observations in terms of the vehicle dynamics. Specifically, the nose cone of such a vehicle, the end car respectively, is frequently manufactured in accordance with aerodynamic specifications, with the objective of reducing cross-wind sensitivity, bow wave and so-called sonic booms.
A preferably glass-fiber reinforced nose cone is usually utilized in order to accommodate the aerodynamic requirements, the nose cone including, for example, a pneumatically-openable front hatch, whereby the automatic central buffer coupling with the shock absorber as well as the actuating mechanism for the front hatch and further components such as for instance signal lights and air ducts for climate control are disposed in the nose cone. The shell of the nose cone itself, made from reinforced glass fiber, for example, is often supported on a supporting structure which itself is in turn bolted to the car body structure. This supporting structure can also serve as the fixing base for the e.g., pneumatically-operating actuating mechanism of the front hatch or a front lifeguard pilot (if provided).
So that two such end cars configured according to the aerodynamic concept can be coupled/uncoupled as quickly as possible, the profiling to the nose cone calls for a coupling concept which ensures a specific axial distance for the extendable automatic central buffer coupling in conjunction with the e.g. pneumatically-actuated front hatch. The distance to be provided is—contingent upon the design of the nose cone—usually in a range of from approximately 100 mm to 400 mm.
Necessary to give an automatic central buffer coupling of the type specified at the outset the additional functionality of axial extendability is, for example, a linear drive, with which the central buffer coupling, the coupling arm of the central buffer coupling respectively, can be axially displaced along with the coupling head relative the vehicle underframe or relative the fixing plate serving to secure the central buffer coupling to the vehicle respectively. Since the mounting space in the vehicle nose cone for the automatic central buffer coupling is often limited, however, the linear drive provided to axially displace the central buffer coupling so as to realize the additional desired functionality of axial extendability and retractability for the central buffer coupling needs to be realized in as compact and space-saving a manner as possible.
Based on this problem, it is necessary to find an automatic central buffer coupling of the type cited at the outset which exhibits the additional functionality of axial extendability and retractability without the need to increase the space in the vehicle nose cone needed to mount the central buffer coupling.


A self-locking support system includes a female profile having a first profile leg extending approximately orthogonally from a base, a first locking leg extending from the first profile leg, and a first tip extending from the first profile leg, wherein a gap is formed between the base and the first profile leg, and a first male profile having a fulcrum formed at an intersection of a second profile leg and a second locking leg, the second profile leg having a second tip extending therefrom. When the second locking leg is inserted into the gap, and a locking bead is positioned between the first and second tips, the first male profile is caused to rotate about the fulcrum and the first and second locking legs are caused to engage against each other.

1. Field
The current disclosure relates to a unique and compact self-lock glazing system composed of two aluminum extrusion profiles—a male profile and a female profile—designed in such a way to self-lock glass panels using beadings. The mechanism functions when a glass panel is positioned on setting blocks over the flat surface of the upper leg of the said female profile—with spacers between the vertical leg of the said female profile and the said glass panel (as illustrated in FIGS. 3, 4, 5, 6, 7, 8) and the said male profile with the locking tip facing upward on its horizontal leg inserted into the gap between the upper leg and the lower leg of the said female profile against the female locking tip above. The locking tips of both male and female profiles are then engaged by tilting the vertical leg 30 of the said male profile outward about its built-in fulcrum, and inserting wedges into the space so created between the said glass panel and the vertical leg of the male profile, for keeping the said glass panel locked in position. The mechanism further tightens grip on the edges of the said glass panel when the said spacers and wedges are replaced by rubber beadings of appropriate resilience (which, for a glazing, avoids touching metal, to allow expansion and to absorb impacts).
In one example, the system may include locking beads or a locking bead profile that cause the male and female profiles, typically made of metal, to engage and self-lock. The introduction of the locking bead profile lends a unique dynamism to the mechanism. The tensile nature of the vertical legs causes a mating action in the locking chamber and the resulting equal and opposite reactions keeps the locking bead profile in equilibrium between the horizontal tips of both the male and female profiles by means of the built-in fulcrum. This balancing act of forces remains in the locking system throughout the life of the system.
2. General Background
U.S. Pat. No. 5,007,221 entitled "snap-in glazing pocket filler" disclosed a snap-in pocket filler for use with a structural frame member having an unused glazing pocket, or for use as gap filler on aluminum profiles to cover the unused area for aesthetic reason.
It was noticed that a proper glazing system was lacking in the market to meet the increasing demand for thicker glazing (e.g. shop fronts and partitions) and it has become a necessity for those skilled in the art to develop a system which must be simple, technically safe and aesthetically impressive.
The following U.S. patents are incorporated herein by reference:
TABLEPATENT NO.TITLEISSUE DATE3,774,363Glazing Window or Windscreen Open-Nov. 27, 1973ings, Particularly in Vehicle Bodies3,881,290Glazed Impervious Sheet AssemblyMay 6, 1975and Method of Glazing4,689,933Thermally Insulated Window SashSept. 1, 1987Construction for a Casement WindowDE2614803GLASFALZLEISTEOct. 27, 1977JP10184208Filling to Which Glass and the LikeJul. 14, 1998can be Easily Attached/DetachedJP11256942Glazing GasketSept. 21, 1999UK2237600Preventing Removal of Glazing BeadMay 8, 1991
In addition, in the construction industry and in other industries it is generally desirable to have a high strength-weight ratio load-bearing material for supporting loads over extended lengths. For instance, I-beams are commonly used as support structures in construction and civil engineering. Typically, I-beams are oriented such that flanges are maintained horizontally, while a web between the flanges is in a vertical orientation. In such fashion, gravitational loads along the length of the I-beam are oriented about the maximum moment of inertia, providing an efficient design for both bending and shear loads in the plane of the web. In a transverse orientation, for instance in an orientation where the flanges themselves are oriented in a vertical direction, loads are transverse to the flanges and an I-beam in this orientation is not an efficient support structure.
In general the moment of inertia is based on a distance that material is located from its neutral axis. As commonly known, the neutral axis is an axis in the cross section of a beam (a member resisting bending) or shaft along which there are no longitudinal stresses or strains. Thus, when oriented such that the flanges bear the load, because the flanges of an I-beam are located distant from the neutral axis the flanges provide an efficient structural design.
However, I-beams are not only costly to build but they are also costly to transport to construction sites, and bulky to work with at construction sites. For instance, in construction of a skyscraper, I-beams may be transported to very high sections of a building and may be difficult to move about and position during such construction. One reason for such inconvenience is because the I-beams are constructed to span great lengths, and they therefore are bulky to transport and install in their final end-use location. Thus, although I-beams have long provided a capability to support tremendous loads in an efficient fashion in construction and other engineering activities, their use includes the setbacks that include costly construction and costly transportation and assembly challenges. As such, there is a need for an improved construction support design that is less expensive and more convenient to fabricate, transport, and install.

This patent is subject to a terminal disclaimer.


A method, apparatus and system for transparently unifying virtual machines (“VMs”) is disclosed. An embodiment of the present invention enables a user to interact with various applications on a VM host while unaware of the VM structure on the VM host. The user may be presented with a unified desktop interface representing a composite and/or unified view of the VM host. Via this unified desktop interface, the user may perform all necessary commands and/or receive output. Invisible to the user, the unified desktop interface represents a unification console. The unification console may be an independent component (e.g., an enhanced VM) and/or a subset of a virtual machine manager (“VMM”) component on the VM host. In either situation, the unification console may, alone and/or in conjunction with the VMM, route and/or redirect and/or transform and/or filter the user's commands to the appropriate applications and redirect and/or copy and/or transform and/or filter the output from the applications to be displayed in the unified desktop interface.

Virtualization technology enables a single host computer running a virtual machine monitor ("VMM") to present multiple abstractions and/or views of the host, such that the underlying hardware of the host appears as one or more independently operating virtual machines ("VMs"). Each VM may function as a self-contained platform, running its own operating system ("OS") and/or a software application(s). The VMM manages allocation and virtualization of host resources, and performs context switching as necessary to cycle between various virtual machines according to a round-robin or other scheduling algorithms.
Given the complexity and processing requirements of virtualization, this technology has typically been available only on workstations, servers and/or mainframes for use by sophisticated users. As processor technology advances, however, virtualization is being made available in the desktop environment for use by average users.

Method, apparatus and system for transparent unification of virtual machines


A disk changer apparatus includes a rotation base on which a turntable and a head are mounted. The rotation base can rotate about the rear end thereof as a fulcrum. The disk changer apparatus further includes a base supporter opposed to the top end of the rotation base when the rotation base moves to a driving position where the rotation base can drive a disk selected from a plurality of disks, a lock member movably mounted on the rotation base, and a lock control mechanism for causing the lock member to be connected to the base supporter when the rotation base moves to the driving position. The disk changer apparatus having such a structure stably supports both ends of the rotation base when the rotation base rotates to the driving position.

1. Field of the Invention
The present invention relates to a disk changer apparatus capable of storing a plurality of disks, such as compact disks (CDs) and digital versatile disks (DVDs), in a case and selecting one of the disks to drive it.
2. Description of the Related Art
Disk changer apparatuses are used as, for example, in-car disk apparatuses, in which a plurality of disks are stacked in the thickness direction and are stored in a case. When a user selects one of the disks, the selected disk is rotated to read and/or record information.
Such a disk changer apparatus includes a plurality of disk supporters for holding the disks, a disk selection mechanism for moving one of the disk supporters to a selected position, a rotation base which has a turntable and a head and which is rotatable, in a case, about a rear end thereof as a fulcrum, a driving mechanism for rotating the rotation base between a driving position and a standby position, and a disk transport mechanism for transporting a disk inserted into a disk insertion port on the case to the disk supporter and ejecting the disk from the disk supporter to the disk insertion port. Here, the driving position is a position where the center of a disk held by a disk supporter located at the selected position or a disk pulled out from the disk supporter is aligned with the center of the turntable, and the standby position is a position where the rotation base does not overlap the disk supported by the disk supporter.
To properly clamp a selected disk on the turntable of the rotation base and reliably carry out playback and recording of information in the disk by the head, the rotation base needs to be precisely positioned at the driving position. Also, a vibration-proof structure is required to prevent vibration caused by, for example, a moving vehicle from being transmitted to the rotation base via the case.
To precisely position the rotation base, a disk apparatus such as is disclosed, for example, in Japanese Unexamined Patent Application Publication No. 10-003729 has been known. The disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 10-003729 includes a rotation arm (rotation base) which has a turntable and a head and which rotates about a rear end thereof as a fulcrum (a first fulcrum). The disk apparatus further includes a link which rotates about a rear end thereof as a fulcrum (a second fulcrum). The top end of the link is connected to the rotation base by a pin (a third fulcrum). When the rotation arm moves from the standby position to the driving position, the link rotates while following the rotation arm. When the rotation arm reaches the driving position, the rotation arm is properly positioned by the first, second, and third fulcrums. Furthermore, two positioning tabs are provided to a disk holder in a disk holding unit. The two positioning tabs pinch the top end of the rotation arm when a disk held by the disk holder is mounted on the turntable so as to determine the position of the rotation arm.
On the other hand, Japanese Unexamined Patent Application Publication No. 11-162079, for example, discloses a disk apparatus having a vibration-proof structure for the rotation base. In the disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 11-162079, a swing arm which rotates between a driving position and a standby position and a drive arm which also rotates between the driving position and the standby position are coaxially aligned and are rotatably mounted on a support part resiliently supported by two vibration dampers provided in a case. A turntable and a head are mounted on this drive arm. Another vibration damper is attached to an end of the swing arm. The drive arm is supported by the swing arm via the vibration damper. When a disk is clamped on the turntable, the drive arm is resiliently supported by the three vibration dampers, namely, the two dampers for resiliently supporting the support part and the vibration damper attached to the swing arm.
In the disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 10-003729, the position of the rotation base rotated to the driving position is determined by three points using the link. At the same time, two positioning tabs provided to a disk supporter limit the movement of the rotation base in the vertical direction (in the thickness direction of a disk).
However, in the disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 10-003729, the link is always connected to the rotation base and rotates with the rotation base. Accordingly, the structure is complicated. Also, to precisely position the rotation base at the driving position, the positions of three fulcrums need to be precisely determined. This requires high precision machining and assembly, thus increasing the manufacturing cost.
Additionally, two positioning tabs formed on the disk supporter limit the position of the rotation base in the vertical direction. These positioning tabs are required to be provided to all of the disk supporters in the case. This further increases the cost.
In the disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 11-162079, three vibration dampers are disposed between a case and a rotation base to prevent vibrations from being transmitted via the case.
However, when the rotation base rotates to the driving position, positioning of the top end of the rotation base, on which a turntable is mounted, is not precisely determined. Therefore, when a disk clamped on the turntable is driven to rotate, vibration tends to occur at the end of the rotation base.
Furthermore, in the disk apparatus disclosed in Japanese Unexamined Patent Application Publication No. 11-162079, the damper arranged in the vicinity of the turntable is not secured to the case, but is mounted to the end of the swing arm, which rotates about the base end thereof as a fulcrum on the case. Accordingly, if vibration is transmitted to the case, the swing arm also receives the vibration. This vibration tends to be transmitted to the rotation base having the turntable and the head.

Apparatus for changing multiple media disks


A doubles detection system for detecting doubled documents. The system comprises one or more light sources disposed on a first side of a test document and one or more reflected light sensors disposed along the first side of the test document. The reflected light sensors are adapted to generate reflected light signals. The system also comprises one or more transmitted light sensors disposed along a second side of the test document which are adapted to generate transmitted light signals. The system also comprises a memory having a master reflected light value and a master transmitted light value stored therein. The system comprises a processor adapted to receive the reflected light signal, generate a reflected light value for the test document, and calculate a reflectance ratio between the reflected light value of the test document and a master reflected light value. The processor is also adapted to receive the transmitted light signal, generate a transmitted light value for the test document, and adjust the transmitted light value for the test document based on the reflectance ratio. The processor is adapted to compare the adjusted transmitted light value for the test document to the master transmitted light value and generate a doubles signal if the comparison of the adjusted transmitted light value for the test document with the master transmitted light value indicates that more than one document is present.

Some systems for counting, denominating, and for sorting documents such as paper currency require documents to be separated so that documents can be fed one by one along a transport path. If, however, documents get stuck to neighboring documents in a stack, it can become difficult or impossible to accurately count and/or sort individual documents.
A known method for determining whether a device is transporting a single document or doubled documents is to pass light through the document(s). Because doubled documents will generally not allow as much light through as single documents, a light sensor on the opposite side of the document from a light source will give a lower reading when doubled documents are encountered. This does not completely solve the problem, however. Because of the variations of cleanliness or dirtiness in individual bills, the transmitted light reading may be inaccurate. This is especially true in countries where the quality of circulated currency varies greatly. For example, an especially dirty bill may pass relatively little light through, thus appearing as two bills to the light sensor. Conversely, doubled bills that are especially clean or worn may let more light through than an average bill, giving the sensor the impression that a single bill is being transported. Thus, there exists a need for an system for detecting doubled bills that accounts for differences in the qualities of individual bills.

Method and apparatus for detecting doubled bills in a currency handling device


A cleaning swab is for wet or dry use. The swab includes an elongated handle defining a longitudinal axis. The handle has a cleaning head end and a grasping end. The swab includes a multi layer cleaning head having a core, a mid-layer and an outer layer. The core and the mid-layer are absorbent. The outer layer is formed from a cleaning textile. The outer layer is sealed to itself and to the handle to isolate the core and mid-layer.

The present invention is directed to a swab for cleaning. More particularly, the present invention pertains to a multi-layer swab having a sealed outer layer or cover.
Swabs are used in all manners of cleaning. For example, everyone will recognize common cotton tipped swabs that are used for person hygiene and care. Because of the compact and effective nature of these swabs, they have been adopted for use in numerous areas of technology and manufacture. One such area is the manufacture of advanced optical components for use in aerospace and navigation systems.
During manufacture and use of optical components it is not unusual for pieces of manufacturing debris, such as dust and fibers or other particulate debris to be left on surface of the components. It is also not unusual for light oils, such as fingerprint and other natural skin oils to be found on many of these parts. The debris and oils can significantly degrade, distort or prevent the proper and precise transmission of images.
Numerous types of cleaning implements have been used, with some degrees of success, to clean these particularly sensitive areas. It has, however, been observed that cleaning implements formed from non-particulate removing materials may not be acceptable for this use. Specifically, it has been found that particulates that are not removed can become lodged in and around these components, thus adversely effecting the quality of the images.
Often, liquids are used to assist in the cleaning process. For example, water or other light solvents maybe applied to the swab to assist in removing contaminants such as oils, particulates and the like.
Other cleaning swabs have also been used with varying degrees of success. For example, one known swab includes a polyurethane foam over a cotton core. However, it has been found that polyurethane is not sufficiently soft (for contact with sensitive components and surfaces), and is not sufficiently hydrophilic (to absorb water or other solvents) to facilitate the cleaning process.
Accordingly, there exists a need for a swab-type cleaning device that can be used for cleaning sensitive components and surfaces. Desirably, such a device leaves little to no residue from the device within the component or on the surface. More desirably, such a device can be used wet or dry; that is, it can be used with or without a solvent (such as water) to facilitate cleaning. Most desirably, such a cleaning device is structurally stable when wet, serves well to distribute any liquid throughout the device and is resistant to cutting.


This invention relates to compounds of formula (I), wherein A, B, D, E, K, G, Z, R3 and R5 are defined as in the specification, and to the pharmaceutically acceptable salts of such compounds. Compounds (I) are corticotropin releasing factor (hormone) CRF (CRH) antagonists.

This invention relates to certain pharmaceutically active substituted pyrido- or pyrimido-containing 6,6- or 6,7-bicyclic derivatives, pharmaceutical compositions containing them and methods of administering them to subjects in need of their corticotropin releasing factor antagonist activity.
The substituted heterocyclic derivatives claimed in this case exhibit activity as corticotropin releasing factor (hormone) CRF (CRH) antagonists.
CRF antagonists are mentioned in U.S. Pat. Nos. 4,605,642 and 5,063,245 referring to peptides and pyrazolinones, respectively. They are also referred to in the following: PCT Patent Application PCT/IB95/00439, which designates the United States and was filed on Jun. 6, 1995 and published on Dec. 14, 1995; PCT patent application PCT/IB95/00373, which designates the United States and was filed on May 18, 1995 and published on Dec. 21, 1995; U.S. patent application Ser. No. 08/448,539, which was filed in the PCT on Nov. 12, 1993 and entered the U.S. national phase on Jun. 14, 1995; PCT patent application WO 95/10506, which was filed on Oct. 12, 1993 and published on Apr. 20, 1995, and U.S. patent application 08/481,413, which was filed in the PCT on Nov. 26, 1993 and entered the U.S. national phase on Jul. 24, 1995; U.S. patent application Ser. No. 08/254,820, which was filed on Apr. 19, 1995; Provisional U.S. patent application Ser. No. 60/008,396, which was filed on Dec. 8, 1995; and Provisional U.S. patent application Ser. No. 60/006,333, which was filed on Nov. 8, 1995. All the foregoing patent applications are incorporated herein by reference in their entireties.
The importance of CRF antagonists is set out in the literature, e.g., P. Black, Scientific American SCIENCE and MEDICINE, 1995, p. 16-25; T. Lovenberg, et al., Current Pharmaceutical Design, 1995, 1, 305-316; and U.S. Pat. No. 5,063,245, which is referred to above. A recent outline of the different activities possessed by CRF antagonists is found in M. J. Owens et al., Pharm. Rev., Vol. 43, pages 425 to 473 (1991), also incorporated herein by reference. Based on the research described in these two and other references, CRF antagonists are effective in the treatment of a wide range of stress-related Illnesses, mood disorders such as depression, major depressive disorder, single episode depression, recurrent depression, child abuse induced depression, postpartum depression, dysthemia, bipolar disorders and cyclothymia; chronic fatigue syndrome; eating disorders such as anorexia and bulimia nervosa; generalized anxiety disorder; panic disorder; phobias; obsessive-compulsive disorder, post-traumatic stress disorder, pain perception such as fibromyalgia; headache; gastrointestinal diseases; hemorrhagic stress; ulcers; stress-induced psychotic episodes; fever; diarrhea; post-operative ileus, colonic hypersensitivity; irritable bowel syndrome; Crohn""s disease; spastic colon; inflammatory disorders such as rheumatoid arthritis and osteoarthritis; pain; asthma; psoriasis; allergies; osteoporosis; premature birth; hypertension, congestive heart failure; sleep disorders; neurodegenerative diseases such as Alzheimers disease, senile dementia of the Alzheimer""s type, multiinfarct dementia, Parkinson""s disease, and Huntington""s disease; head trauma; ischemic neuronal damage; excitotoxic neuronal damage; epilepsy; stroke; spinal cord trauma; psychosocial dwarfism; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone; obesity; chemical dependencies and addictions; drug and alcohol withdrawal symptoms; infertility, cancer; infertility; muscular spasms; urinary incontinence; hypoglycemia and immune dysfunctions including stress induced immune dysfunctions, immune suppression and human immunodeficiency virus infections; and stress-induced infections in humans and animals.
The compounds of this invention are also believed to be inhibitors of CRH binding protein and therefore useful in the treatment of disorders the treatment of which can be effected or facilitated by inhibiting such protein. Example of such disorders are Alheimer""s disease and obesity.
The present invention relates to compounds of the formula
the dashed lines represent optional double bonds;
A is nitrogen or CR7:
B is xe2x80x94NR1R2, xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, xe2x80x94NHCR1R2R10, xe2x80x94OCR1R2R10, xe2x80x94SCR1R2R10, xe2x80x94CR2R10NHR1, xe2x80x94CR2R10OR1, xe2x80x94CR2R10SR1 or xe2x80x94COR2, and is single bonded to D; or B is xe2x80x94CR1R2, and is double bonded to D and D is carbon;
D is nitrogen or CR4 and is single bonded to all atoms to which it is attached, or D is carbon and is double bonded to E or double bonded to B;
E is oxygen, nitrogen, sulfur, Cxe2x95x90O, Cxe2x95x90S, CR6R12, NR6 or CR6; or E is a two atom spacer, wherein one of the atoms is oxygen, nitrogen, sulfur, Cxe2x95x90O, Cxe2x95x90S, CR6R12, NR6 or CR6, and the other is CR6R12 or CR9;
K and G are each, independently, Cxe2x95x90O, Cxe2x95x90S, sulfur, oxygen, CHR8 or NR8 when single bonded to both adjacent ring atoms, or nitrogen or CR8 when it is double bonded to an adjacent ring atom;
the 6- or 7-membered ring that contains D, E, K and G may contain from one to three double bonds, from zero to two heteroatoms selected from oxygen, nitrogen and sulfur, and from zero to two Cxe2x95x90O or Cxe2x95x90S groups, wherein the carbon atoms of such groups are part of the ring and the oxygen and sulfur atoms are substituents on the ring;
R1 is C1-C6 alkyl optionally substituted with from one or two substituents independently selected from hydroxy, fluoro, chloro, bromo, iodo, C1-C4 alkoxy, CF3, xe2x80x94C(xe2x95x90O)(C1-C4alkyl), xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94(C1-C4)alkyl, xe2x80x94OC(xe2x95x90O)(C1-C4 alkyl), xe2x80x94OC(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C4 alkyl), xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO(C1-C4 alkyl), xe2x80x94SO2(C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl) and xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl), wherein each of the C1-C4 alkyl groups in the foregoing R1 groups may optionally contain one or two double or triple bonds;
R2 is C1-C12 alkyl which may optionally contain from one to three double or triple bonds, aryl or (C1-C4 alkylene)aryl, wherein said aryl and the aryl moiety of said (C1-C4 alkylene)aryl is selected from phenyl, naphthyl, thienyl, benzothienyl, pyridyl, quinolyl, pyrazinyl, pyrimidinyl, imidazolyl, furanyl, benzofuranyl, benzothiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, indolyl, pyrrolopyridyl, oxazolyl and benzoxazolyl; C3-C8 cycloalkyl or (C1-C6 alkylene)(C3-C8 cycloalkyl), wherein one or two of the carbon atoms of said cycloalkyl and the 5 to 8 membered cycloalkyl moieties of said (C1-C6 alkylene)(C3-C8 cycloalkyl may optionally and independently be replaced by an oxygen or sulfur and wherein each of the foregoing R2 groups may optionally be substituted with from one to three substituents independently selected from chloro, fluoro, hydroxy and C1-C4 alkyl, or with one substituent selected from C1-C6 alkoxy, xe2x80x94OC(xe2x95x90O)(C1-C6 alkyl), xe2x80x94OC(xe2x95x90O)N(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C6 alkyl), amino, xe2x80x94NH(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94N(C1-C4 alkyl)xe2x80x94COxe2x80x94(C1-C4 alkyl), xe2x80x94NHCO(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94COO(C1-C4 alkyl), xe2x80x94CONH(C1-C4 alkyl), xe2x80x94CON(C1-C4 alkyl)(C1-C2 alkyl), xe2x80x94SH, xe2x80x94CN, xe2x80x94NO2, xe2x80x94SO(C1-C4 alkyl), xe2x80x94SO2(C1-C4 alkyl), xe2x80x94SO2NH(C1-C4 alkyl) and xe2x80x94SO2N(C1-C4 alkyl)(C1-C2 alkyl);
xe2x80x94NR1R2 or CR1R2R10 may form a ring selected from saturated 3 to 8 membered rings, the 5 to 8 membered rings of which may optionally contain one or two double bonds, and wherein one or two of the ring carbon atoms of such 5 to 8 membered rings may optionally and independently be replaced by an oxygen or sulfur atom or by NZ3 wherein Z3 is hydrogen or C1-C4 alkyl;
R3 is hydrogen, C1-C4 alkyl, xe2x80x94O(C1-C4 alkyl), chloro, fluoro, bromo, iodo, xe2x80x94S(C1-C4 alkyl) or xe2x80x94SO2(C1-C4 alkyl)
R4 is hydrogen, C1-C2 alkyl, hydroxy or fluoro;
each R6, R8 and R9 that is attached to a carbon atom is selected, independently, from hydrogen, C1-C2 alkyl, fluoro, chloro, bromo, iodo, hydroxy, hydroxymethyl, formyl, trifluoromethyl, cyano, amino, nitro, xe2x80x94O(C1-C2 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C2 alkyl), xe2x80x94S(C1-C2 alkyl), xe2x80x94CO(C1-C2 alkyl), xe2x80x94C(xe2x95x90O)H or xe2x80x94C(xe2x95x90O)O(C1-C2 alkyl), wherein each of the C1-C2 alkyl moieties in the foregoing R6, R8, and R9 groups may optionally contain one double or triple bond; and each R6, R8, and R9 that is attached to a nitrogen atom is selected, independently, from hydrogen and C1-C4 alkyl;
R5 is substituted phenyl, naphthyl, pyridyl or pyrimidyl, wherein each of the foregoing R5 groups is substituted with from two to four substituents R15, wherein from one to three of said substituents may be selected, independently, from chloro, C1-C6 alkyl, xe2x80x94O(C1-C6 alkyl) and xe2x80x94(C1-C6 alkylene)O(C1-C6 alkyl), and wherein one of said substituents may be selected, independently, from bromo, iodo, formyl, cyano, trifluoromethyl, nitro, amino, xe2x80x94NH(C1-C4 alkyl), xe2x80x94N(C1-C2 alkyl)(C1-C5 alkyl), xe2x80x94C(xe2x95x90O)O(C1-C4 alkyl), xe2x80x94C(xe2x95x90O)(C1-C4 alkyl), xe2x80x94COOH, xe2x80x94SO2NH(C1-C4 alkyl), xe2x80x94SO2N(C1-C2 alkyl)(C1-C4 alkyl), xe2x80x94SO2NH2, xe2x80x94NHSO2(C1-C4 alkyl), xe2x80x94S(C1-C6 alkyl) and xe2x80x94SO2(C1-C6 alkyl), and wherein each of the C1-C4 alkyl and C1-C6 alkyl moieties in the foregoing R5 groups may optionally be substituted with one or two substituents independently selected from fluoro, hydroxy, amino, methylamino, dimethylamino and acetyl;
R7 is hydrogen, methyl, halo (e.g., chloro, fluoro, lodo or bromo), hydroxy, methoxy, xe2x80x94C(xe2x95x90O)(C1-C2 alkyl), xe2x80x94C(xe2x95x90O)O(C1-C2 alkyl), trifluoromethoxy, hydroxymethyl, trifluoromethyl, or formyl;
R10 is hydrogen, hydroxy, methoxy or fluoro;
R11 is hydrogen or C1-C4 alkyl;
R12 is hydrogen or methyl; and
Z is NH, oxygen, sulfur, xe2x80x94N(C1-C4 alkyl), or CR13R14 wherein R13 and R14 are independently selected from hydrogen, and methyl with the exception that one of R13 and R14 may optionally be cyano;
with the proviso that: (a) in the six or seven membered rings of structures in formula I, there can not be two double bonds adjacent to each other; and (b) when D is carbon and is double bonded to B, then B is CR1R2;
and the pharmaceutically acceptable salts of such compounds.
Examples of more specific embodiments of formula I are the following, wherein (R)n represents from zero to two substituents, wherein such substitutents are as defined above in the definition of formula 1.
More specific embodiments of this invention include compounds of the formula I wherein B is xe2x80x94CHR1R2 or xe2x80x94NR1R2, and R1 is C1-C6 alkyl which may optionally be substituted with one hydroxy, fluoro, trifluoromethyl or C1-C4 alkoxy group and may optionally contain one double or triple bond; and R2 is benzyl or C1-C6 alkyl which may optionally contain one double or triple bond, and wherein said C1-C6 alkyl and the phenyl moiety of said benzyl may optionally be substituted with one fluoro, C1-C2 alkyl, C1-C2 alkoxy or chloro group.
Other more specific embodiments of the invention include compounds of formula I wherein R3 is methyl, ethyl, chloro or methoxy; R6, R8 and R9 are selected, independently, from hydrogen and methyl; R5 is di- or tri-substituted phenyl, pyridyl, or pyrimidyl, in which up to three of the substitutents can be independently selected from C-C4 alkyl, xe2x80x94Oxe2x80x94(C1-C4 alkyl) and (C1-C2 alkylene)xe2x80x94Oxe2x80x94(C1-C4 alkyl), and wherein one of the substituents can be independently selected from trifluoromethyl, trifluoromethoxy, xe2x80x94CHO, (C1-C4 alkyl)xe2x80x94OH, cyano, chloro, fluoro, bromo, iodo and nitro, and wherein each of the foregoing (C1-C4) alkyl groups may optionally contain one double or triple bond; and Z is oxygen or NH.
Other more specific embodiments of the invention include compounds of the formula I wherein A is nitrogen or CH.
Examples of preferred compounds of the invention are:
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one; and
1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine.
Other compounds of the formula I include the following:
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido [3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
1-(1-ethyl-propyl)-7-methyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-bromo-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6]-naphthyridin-2-one;
1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-bromo-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido [3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid methyl ester;
1-(1-ethyl-propyl)-7-methyl-2-oxo-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine-3-carboxylic acid isopropyl ester;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-[1,6]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,2,3,4-.tetrahydro[1,6]naphthyridine;
1-(1-ethyl-propyl)-7-methyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(4-chloro-2,6-dimethyl-phenoxy)-3,4-dihydro-1H-3-oxa-[1,6-naphthyridin-2-one;
1-(1-ethyl-propyl)-3,3,6-trimethyl-4-(4-chloro-2,6-dimethyl-phenoxy)-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine;
[1-(1-ethyl-propyl)-7-methyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-y-(2,4,6-trimethyl-phenyl)-amine;
3-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-pentan-1-ol; 2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-4H-3-oxa-1,6-diaza-naphthalen-1-yl]-butan-1-ol;
1-(1-ethyl-butyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
8-(1-ethyl-propyl)-2-methyl4-(2,4,6-trimethyl-phenylamino)-7,8-dihydro-5H-pyridin-6-one;
8-(1-ethyl-propyl)-2-methyl-4-(2,4,6trimethyl-phenoxy)-7,8-dihydro-5H-pyridin-6-one;
8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine; 8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyridine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyridin-4-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin in-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
8-(1-ethyl-propyl)-2-methyl-4-(2,4,6-trimethyl-phenoxy)-5,6,7,8-tetrahydro-pyrido(2,3d]pyrimidine;
[8-(1-ethyl-propyl)-2-methyl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazine;
[1-(1-ethyl-propyl)-4,7-dimethyl-1,4-dihydro-2H-pyrimido[4,5-d][1,3]oxazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-4,7-dimethyl-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-hydroxymethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-(1-hydroxymethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
2-[4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-1-yl]-butan-1-ol;
2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-pyrido[3,4-b]pyrazin-1-yl]-butan-1-ol;
2-[7-methyl-5-(2,4,6-trimethyl-phenoxy)-3,4-dihydro-2H-[1,6]naphthyridin-1-yl]-butan-1-ol;
2-[4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)4H-3-oxa-1,6-diaza-naphthalen-1-yl]-butan-1-ol;
5-(1-ethyl-propyl)-3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinoline;
diethyl-[3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinolin-5-yl]-amine;
[5-(1-ethyl-propyl)-3-methyl-isoquinolin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;
N-5-butyl-N-5-ethyl-3-methyl-N1-(2,4,6-trimethyl- phenyl)-isoquinoline-1,5-diamine;
5-(1-ethyl-propyl)-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,6]naphthyridine;
5(1-ethyl-propyl)-3-methyl-1-(2,4,6-tnimethyl-phenoxy)-[2,7]naphthyridine;
4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;
[5-(1-ethyl-propyl)-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenylamino-1H-[1,6]naphthyridin-2-one;
4-(1-ethyl-propyl)-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalene;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-2,3-dihydro-1H4-thia-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-(1-ethyl-propyl)-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine tetrahydro-pyrido[4,3-d]pyrimidine;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-(1-ethyl-propyl)-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[4,3-d]pyrimidine;
4-(1-ethyl-propyl)-6-methyl-8-(2,4-trimethyl-phenoxy)-pyrano[2,3-c]pyridin-2-one;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-pyrido[3,4-b]pyrazin-3-one;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]3naphthyridine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-oxa-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4dihydro-2H-3-ixa-1,6-diaza-napthalene;
1-sec-butyl4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-]pyrazine;
7-methyl-1-(1-propyl-butyl)-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]naphthyridine;
5-sec-butyl-3-methyl-1-(2,4,6trimethyi-phenoxy)-isoquinoline;
diethyl-[3-methyl-1-(2,4,6-trimethyl-phenoxy)-isoquinolin-5-yl]-amine;
[5-sec-butyl-3-methyl-isoquinolin-1-yl]-(2,4,6-trimethyl-phenyl)-amine;
N-5-butyl-N-ethyl-3methyl-N1-(2,4,6-trimethyl-phenyl)-isoquinoline-1,5diamine;
5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,61naphthyeidine;
5-sec-butyl-3-methyl-1-(2,4,6-trimethyl-phenoxy)-[2,7]naphthyridine;
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-[1,7]naphthyridine;
[5-sec-butyl-3-methyl-[2,6]naphthyridin-1-yl]-(2,4,6trimethyl-phenyl)-amine;
1-sec-butyl-7-methyl-5-(2,4,6tnimethyl-phenylamino)-1H-[1,6]naphthyridin-2-one;
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
4-diethylamino-6-methyl-8-(2,4,6-trimethyl-phenoxy)-1H-[1,7]naphthyridin-2-one;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalene;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-[1,6]naphthyridin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-oxa-1,6-diaza-naphthalen-5-yl]-(2,4,6trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-2,3-dihydro-1H-4-thia-1,6-diaza-naphthalen-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido [3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
[1-sec-butyl-7-methyl-1,2,3,4-tetrahydro-pyrido[3,4-b]pyrazin-5-yl]-(2,4,6-trimethyl-phenyl)-amine;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-sec-butyl-7-methyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,3-d]pyrimidine;
1-sec-butyl-3,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-pyrido-[4,-d]pyrimidine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4-tetrahydro-[1,6]-naphthyridine tetrahydro-pyrido[4,3-d]pyrimidine;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,4-dihydro-2H-3-thia-1,6-diaza-naphthalene;
1-sec-butyl-4,7-dimethyl-5-(2,4,6-trimethyl-phenoxy)-1,2,3,4tetrahydro-pyrido-[4,3-d]pyrimidine; and
4-sec-butyl-6-methyl-8-(2,4,6-trimethyl-phenoxy)-pyrano[2,3-c]pyridin-2-one.
Unless otherwise indicated, the alkyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) or be linear or branched and contain cyclic moieties.
The invention also relates to a pharmaceutical composition for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia;
mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome, Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimers disease, Parkinson""s disease and
Huntington""s disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; chemical dependencies and addictions (e.g., dependencies on alcohol, nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer""s type; multiinfarct dementia; amyotrophic lateral sclerosis; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof, that is effective in the treatment of such disorder, and a pharmaceutically acceptable carrier.
The invention also relates to a method for the treatment, prevention or inhibition of (a) a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitator by CRF, or (b) a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic; phobias; obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, mood disorders associated with premenstrual syndrome, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; chronic fatigue syndrome; stress-induced headache; cancer; irritable bowel syndrome; Crohn""s disease; spastic colon; post operative ileus; ulcer; diarrhea; stress-induced fever; human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer""s disease, Parkinson""s disease and Huntington""s disease; gastrointestinal diseases; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimers type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, nicotine, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; hypertension; tachycardia; congestive heart failure; osteoporosis; premature birth; and hypoglycemia in a mammal, including a human, comprising administering to a subject in need of said treatment an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating such disorder.
This invention also relates to a method of treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, including a human, comprising administering to said mammal a CRH binding protein inhibiting amount of a compound of the formula I or a pharmaceutically acceptable salt thereof.
This invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition, the treatment or prevention of which can be effected or facilitated by inhibiting CRH binding protein in a mammal, including a human, comprising a CRH binding protein inhibiting amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The invention further includes intermediate compounds of formulas
a wherein T is chloro, bromo, iodo, or xe2x80x94OSO2CF3; U is CN, xe2x80x94COO(C1-C4 alkyl), chloro, bromo, iodo, xe2x80x94OSO2CF3, hydroxy or amino when D is carbon, and U is hydrogen when D is nitrogen.
This invention includes all optical isomers and other stereoisomers of compounds of the formula I. When such compounds contain one or more chiral centers, it is understood that the invention includes the racemic mixtures as well as all individual enantiomers and diastereomers of such compounds, and mixtures thereof.
The compounds of this invention include compounds identical to those described above but for the fact that one or more hydrogen, nitrogen or carbon atoms are replaced by isotopes thereof (e.g., tritium or carbon-14 isotopes). Such compounds are useful as research and diagnostic tools in metabolism pharmokinetic studies and in binding assays.
The following compounds having the formulas II, III, and IV are useful as intermediates in the synthesis of compounds of the formula I.
In the above compounds of formulas II to IV, M is chloro, bromo, iodo, xe2x80x94OSO2CF3 or ZR5; P is NH, CHCN or CHCOO(C1-C4 alkyl); Q is amino, xe2x80x94(C1-C2 alkyl)CH[COO(C1-c4alkyl)]2, (C2-C3 alkyl)-CN, hydroxy or mercapto, and A, B, D, E, K and G are defined as above.
Methods of preparing the compounds and compositions of this invention are described below. In the discussion and reaction schemes that follow, R1 through R14, R12, A, B, D, E, K, G. Z, T, M, P, Q, and U, the dashed lines and structural formulas I, II, III, and IV, unless otherwise indicated, are defined as above.
Compounds of the formula I may be prepared by reacting a compound of the formula 11 with the corresponding compound of the formula R5ZH. This reaction is generally carried out with or without a solvent, in the presence of a base, at a temperature from about 0xc2x0 C. to about 270xc2x0 C., at a pressure from about 14 psi to about 300 psi. Suitable solvents include organic solvents such as tetrahydrofuran (THF), acetonitrile, N,N-dimethylformamide (DMF), dimethylsulfoxide (DMS0), acetone, C2-C15 alcohols, chloroform, dioxane, chlorobenzene, benzene, toluene, xylene, sulfolane, pyridine, quinoline, 2,4,6-trimethylpyridine, acetamide, di-(C1-C2)alkylacetamide, and 1-methyl-2-pyrrolidinone (NMP).
When Z is NH, an excess of R5ZH, may be used both as the reagent and as the base. Examples of bases other than R5ZH that may be used include potassium carbonate, sodium hydride, potassium hydride, sodium (C1-C4) alkoxides, potassium (C1-C4) alkoxides, sodium, sodium amide, tri-[(C1-C4) alkyllamines, organolithium or organosodium compounds such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylimide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide, and organometallic bases such as Grignard reagents. This reaction is generally carried out in an appropriate solvent (e.g., THF, dioxane, sulfolane, DMSO, toluene, DMF or NMP, with or without an additional catalyst such as a copper halide, oxide or sulfate e.g., Cul, CuBr, Cu2O, CuCl, CuSO4 Cu2. CuBr2, CuCl2 or Cu(O)), a Pd(O) salt such as Pd(PPH3)4, a Pd(II) salt such as Pd(OAc)2 (wherein OAc is acetate) with racemic or (R)xe2x80x94 or (S)-2,2-bis(diphenylphosphino)-1,1-binaphthyl (BINAP), at temperature from about room temperature to about 270xc2x0 C.
When Z is oxygen or sulfur, a base that is capable of deprotonating R5ZH may be used, such as potassium carbonate, sodium carbonate, sodium, sodium amide, an alkali metal hydride such as sodium or potassium hydride, a sodium (C1-C4 alkoxide), a potassium (C1-C4 alkoxide), sodium amide, a tri-[(C1-C6)alkyl]amide or an organometallic base such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide. The reaction temperature can range from about 0xc2x0 C. to about 180xc2x0 C. and is preferably from about 50xc2x0 C. to about 140xc2x0 C. Suitable solvents include DMSO, THF, sulfolane, dioxane and NMP.
When Z is CHCN or CHCOO(C1-C4 alkyl), a base that is capable of deprotonating R5ZH may be used, such as an alkali metal hydride (e.g., sodium or potassium hydride), a sodium (C1-C4 alkoxide) or an organometallic base such as n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium bis(trimethylsilyl)amide, in an appropriate solvent, e.g., THF, DMSO, dioxane, methylene chloride, chloroform, toluene, xylene, benzene or a C1-C6 alkanol.
When Z is CR13CN, compounds of formula I may be prepared by reacting the corresponding compounds wherein Z is CHCN first with a base such as an alkali metal hydride such as sodium or potassium hydride, n-butyllithium, s-butyllithium, t-butyllithium, lithium diisopropylamide, lithium bis(trimethylsilyl)amide or sodium diisopropylamide, and then with a compound of the formula R13L wherein L is a leaving group such as iodo, chloro, bromo, mesylate (OMs) or tosylate (OTs).
Compounds of the formula I wherein Z is CHR13 may be prepared by acid hydrolysis (using, e.g., 85% phosphoric acid) of the corresponding compounds wherein Z is CR13CN, followed by decarboxylation upon heating in an oil bath at a temperature from. about 120xc2x0 C. to about 180xc2x0 C. Further alkylation in the presence of base and a compound of the formula and R14L, wherein L is defined as above, will provide the corresponding compounds of formula I wherein Z is CR13R14.
When Z is N(C1-C4 alkyl), compounds of the formula I may be prepared by reacting the corresponding compounds wherein Z is NH first with a base and then with a compound of the formula (C1-C4 alkyl)-L, wherein L is defined as above. Bases such as lithium diisopropylamide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide may be used. Suitable solvents include THF, methylene chloride (CH2Cl2), DMSO, DMP, NMP and dioxane. The reaction temperature may range from about 20xc2x0 C. to about 150xc2x0 C., and is preferably from about room temperature to about 100xc2x0 C.
Compounds of formula I wherein D is carbon and B is xe2x80x94NR1R2, xe2x80x94OCHR1R2 or xe2x80x94SCHR1R2 may be prepared by reacting the corresponding compounds of formula III, wherein U is chloro, bromo or iodo, with a compound of the formula BH in the presence of a base, using methods analogous to those described above for the conversion of compounds of the formula II into compounds of the formula I.
Compounds of formula I wherein D is carbon and B is xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, xe2x80x94CR2R10NHR1, xe2x80x94CR2R10OR1, xe2x80x94CR2R10SR1 or xe2x80x94COR2 may be prepared by reacting the corresponding compounds of formula III, wherein U is cyano, with a Grignard reagent containing the desired R2 group to form a compound of the formula I wherein B is COR2. Further reaction of this compound with a Grignard reagent containing the desired R1 group will yield the compound of formula I wherein B is xe2x80x94CR1 R2(OH).
Compounds of the formula I wherein B is xe2x80x94CR1R2R11, or xe2x80x94C(Cxe2x95x90CR2R11)R1 may be prepared using conventional methods well known to those skilled in the art. For example, reaction of compounds of the formula I wherein B is xe2x80x94C(OH)R1 R2 with an acid such as concentrated sulfuric acid in acetic acid, or a Burgess inner salt (such as (carboxysulfamoyl)triethylammonium hydroxide methyl ester) will yield a compound of the formula I wherein B is xe2x80x94C(xe2x95x90CR2R11)R1. Hydrogenation of a compound of the formula I wherein B is xe2x80x94C(xe2x95x90CR2R11)R1 using a Pd/C (palladium on carbon) or platinum oxide catalyst, using standard methods well known in the art, will yield a compound of formula I wherein B is xe2x80x94CHR1R2. Reaction of compounds in formula I wherein B is xe2x80x94CR1R2(OH) with diethylaminosulfur trifluoride or triphenylphosphine/carbon tetrachloride will afford a compound of formula I wherein B is xe2x80x94CR1R2F or xe2x80x94CR1R2Cl, respectively.
Reduction of compounds of the formula I wherein B is xe2x80x94COR2 with sodium borohydride in a reaction inert solvent such as a (C1-C4 alcohol), THF or dioxane, preferably methanol, at a temperature from about room temperature to about 100xc2x0 C, preferably from about room temperature to about 60xc2x0 C., will yield a compound of the formula I wherein B is xe2x80x94CHR2OH. Alkylation of the xe2x80x94CHR2OH group with an alkyl halide (such as an alkyl iodide) in the presence of a base (such as sodium hydride, potassium hydride or sodium or lithium bis(trimethylsilyl)amide) at about room temperature will afford the corresponding compound of formula I wherein B is xe2x80x94CHR2OR1. Compounds of formula I wherein B is xe2x80x94CR2R10NHR1 may also be prepared by a conventional methods well known in the art, such as reductive amination of the corresponding compounds of formula I wherein B is xe2x80x94COR2 with an appropriate amine and reducing agent (e.g., sodium cyanoborohydride or sodium triacetoxylborohydride) in an appropriate solvent (e.g., a lower alkanol or acetic acid).
Compounds of the formula ill wherein U is CN may be prepared by reacting the corresponding compounds of the formula lIl wherein U is chloro, bromo, iodo, or xe2x80x94OCOCF3 with potassium cyanide or copper cyanide in dimethylsulfoxide, THF, methylene chloride, toluene or DMF, with or without a Pd(0) or Pd(II) catalyst, at a temperature from about room temperature to about 180xc2x0 C., preferably at about the reflux temperature.
Compounds of the formula Ill wherein U is chloro, bromo, iodo, or xe2x80x94OCOCF3 may be prepared from the corresponding compounds of the formula III wherein U is hydroxy or amino. Compounds of the formula III wherein U is halo, or xe2x80x94OCOCF3 may be prepared by reacting a compound of the formula III wherein U is amino with a compound of the formula (C1-C5 alkyl)-O-Nxe2x95x90O and a copper (II) halide in an appropriate solvent such as acetonitrile, acetone, toluene, methylene chloride or dichloroethane, at a temperature from about room temperature to about the reflux temperature. This reaction is preferably carried out in acetonitrile at the reflux temperature.
Compounds of formula III wherein U is chloro or bromo may be prepared by reacting the corresponding compounds of the formula III wherein U is hydroxy with a compound of the formula POX3, wherein X is chloro or bromo, with or without di-(C1-C4alkyl)aniline. This reaction may be conducted neat or in a solvent such as dimethylformamide, dichloroethane or methylene chloride, at a temperature from about 100xc2x0 C. to about 180xc2x0 C. Compounds of formula III wherein U is xe2x80x94OTf (wherein Tf is triflate) may be prepared by reacting the corresponding compounds of the formula III wherein U is OH with Tf2O in the presence of a base such as tri-(C1-C4 alkyl) amine or pyridine or an appropriate pyridine derivative (e.g., dimethylaminopyridine) in an appropriate solvent such as methylene chloride, DMF, DMSO, chloroform, or THF. Reaction of compounds of formula III wherein U is OTf with a compound of the formula KX, NaX or CuX (wherein X is chloro, bromo or iodo) in an appropriate solvent such as DMF, dimethylacetamide, N-methyl-pyrrolidone (NMP), or DMSO at temperature between about room temperature and about 180xc2x0 C. will yield compounds of the formula III wherein U is chloro, bromo or iodo.
Compounds of formula I, II, and III, wherein Z and R5 are defined as above for formula I and R3 is xe2x80x94O-(C1-C4) alkyl or xe2x80x94S-(C1-C4) alkyl (hereinafter R20) may be prepared by reacting the corresponding compounds of the formula I, wherein R3 is chloro, bromo, OTs or iodo, with a nucleophile of the formula R20H, wherein R20H is a (C1-C6)alkanol or a (C1-C6)alkane thiol, optionally in the presence of an organic or inorganic base. Suitable bases include sodium, sodium hydride, potassium hydride, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and sodium diisopropylamide. Compounds of the formula I wherein R3 is fluoro may be prepared by reacting the corresponding compounds wherein R3 is chloro, bromo, iodo, xe2x80x94OCOCF3, or xe2x80x94OSO2CF3 with tetrabutylammonium fluoride, potassium fluoride or another suitable fluoride agent, using standard methods well known to those skilled in the art.
Compounds of formula I wherein G is O, S, or NR8 may be prepared from compounds of formula IV-a, as illustrated in Scheme 1. Referring to Scheme 1, compounds of the formula IV-b may be prepared by reacting the appropriate compound of the formula IV-a, wherein B is xe2x80x94CR1R2R10, xe2x80x94C(xe2x95x90CR2R11)R1, CR1R10OR1, CR2R10SR1 or COR2; Y is O, S, NR8; and A is CR7 or N, with an acyl halide such as L-(CH2)nxe2x80x94COX (wherein X is chloro, bromo, iodo, mesylate, tosylate, triflate or OCOCF3; and L is chloro, bromo, iodo, hydroxy, mesylate, tosylate, triflate or OCOCF3), or an anhydride (such as [C1-C4alkyl)CO]2O) in the presence of a base such as a tri-(C1-C4 alkyl)amine, pyridine or a substituted pyridine, in an appropriate solvent such as methylene chloride, chloroform, THF, DMSO, dioxane, ether, dimethoxyethane, at a temperature from about 0xc2x0 C. to about 180xc2x0 C., preferably from about room temperature and about 60xc2x0 C.
Compounds of formula la may be prepared by reacting the corresponding compounds of the formula IV-b with a base. Suitable bases for use in this reaction include sodium, sodium hydride, potassium hydride, lithium diisopropylamide, butyl lithium, lithium bis(trimethylsilyl)amide, sodium diisopropylamide or sodium or potassium carbonate. Alkylation of the resulting compounds of the formula Ia with a base, followed by quenching with alkyl halide in an appropriate solvent such as ether, THF, methylene chloride, dioxane, benzene, toluene, or dimethoxyethane (DME), with or without hexamethylphosphoramide (HMPA), at temperature from about xe2x88x9278xc2x0 C. to about room temperature, will afford the corresponding compounds of the formula Ic. Suitable bases for use in this reaction include lithium diisopropyilnide, lithium bis(trimethylsilyl)amide, sodium diisopropylamide, and butyl lithium. Reduction of compounds of the formula I-a or I-c with a reducing agent such as borane methyl sulfide complex (BH3xe2x80xa2DMS), borane (BH3), borane THF complex (BH3xe2x80xa2DMS), diisobutylaluminum hydride or lithium aluminum hydride will yield the corresponding compounds of the formula I-b or I-d, respectively.
Compounds of formula I wherein G is carbon may be prepared from compounds of formula IV-c, as illustrated in Scheme 2. Referring to scheme 2, compounds of formula 1-e may be prepared by cyclization of compounds of formula IV-c wherein Q is (C1-C2 alkyl)CR4(COOC1-C4 alkyl)2, (C1-C2 alkyl)CR4(COOC1-C4 alky), (C1-C2 alkyl)CR4(CN)2, (C1-C2 alkyl)CR4(CN) or (C1-C2 alkyl)CR4COOH using standard methods for amide formation that are well known in the literature. Such methods include acid cyclization (such as: (a) heating in 40-85% phosphoric acid at a temperature from about 100xc2x0 C. to about 150xc2x0 C.; (b) heating in aqueous acetic acid/hydrochloric acid; or (c) base hydrolysis; followed by decarboxylation and then amide cyclization). Compounds of formula I-f may be obtained by reduction of the corresponding compounds of the formula I-e using the methods analogous to those described above for conversion of compounds of the formula I-a into those of the formula I-b.
Compounds of formula IV-c wherein Q is (C1-C2 alkyl)CR4(COOC1-C4 alkyl)2 or (C1-C2 alkyl)CR4(CN)2 can be prepared by reaction of a compound of the formula Naxe2x80x94, Kxe2x80x94 or Lixe2x80x94CR4(COOC1xe2x80x94C4 alkyl)2 or Naxe2x80x94, Kxe2x80x94 or Lixe2x80x94CR4(CN)2 with a compound in formula IV-c wherein Q is CHR8X or CHR8CHR4X (wherein X is chloro, bromo or iodo), at a temperature between about 0xc2x0 C. and about 150xc2x0 C., preferably between about 10xc2x0 C. to about 60xc2x0 C., in an appropriate solvent such as THF, DMSO, DMF, a (C1-C5 alkyl)-alcohol, acetonitrile, acetone, toluene, NMP or dimethyl acetamide. The preferred solvent is DMSO. Other compounds of formula IV may be prepared by methods analogous to those described in World Patent Application WO 95/33750, which designates the United States and which was published on May 18, 1995. This application is incorporated herein by reference in its entirety.
Compounds of formula I wherein E is CR6, G is CR8, D is nitrogen and K is oxygen may be prepared by reacting compounds of the formula IV-c wherein Q is CHR8OH with aqueous formaldehyde or R6CHO in an appropriate solvent such as benzene, toluene, xylene, a C1-C5 alkyl alcohol or acetonitrile, in the presence of acid catalyst such as p-TsOH, H2SO4 or HCl, at a temperature from about room temperature to about 160xc2x0 C., preferably at about the reflux temperature. Toluene or benzene is preferred solvent.
Compounds of formula IV-c may be prepared by the methods described in World Patent Application WO 95/33750, which designates the United States and was published on May 18,1995.
The acid addition salts of compounds of the formula can be prepared in a conventional manner by treating a solution or suspension of the corresponding free base with one chemical equivalent of a pharmaceutically acceptable acid. Conventional concentration or crystallization techniques can be employed to isolate the salts. Illustrative of suitable acids are acetic, lactic, succinic, maleic, tartaric, citric, gluconic, ascorbic, benzoic, cinnamic, fumaric, sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, sulfamic, sulfonic acids such as methanesulfonic, benzene sulfonic, p-toluenesulfonic, and related acids.
The compounds of formula I and their pharmaceutically acceptable salts (hereinafter referred to, collectively, as xe2x80x9cthe active compounds of this inventionxe2x80x9d) may be administered alone or in combination with pharmaceutically acceptable carriers, in either single or multiple doses. Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents The pharmaceutical compositions formed by combining the novel compounds of formula I and pharmaceutically acceptable carriers can then be readily administered in a variety of dosage forms such as tablets, powders, lozenges, syrups, injectable solutions and the like. These pharmaceutical compositions can, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. Thus, for purposes of oral administration, tablets containing various excipients such as sodium citrate, calcium carbonate and calcium phosphate may be employed along with various disintegrants such as starch, methylcellulose, alginic acid and certain complex silicates, together with binding agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules. Preferred materials for this include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the essential active ingredient therein may be combined with various sweetening or flavoring agents, coloring matter or dyes and, if desired, emulsifying or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin and combinations thereof.
For parenteral administration, solutions containing an active compound of this invention or a pharmaceutically acceptable salt thereof in sesame or peanut oil, aqueous propylene glycol, or in sterile aqueous solution may be employed. Such aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. The sterile aqueous media employed are all readily available by standard techniques known to those skilled in the art.
The effective dosages for the active compounds of this invention will depend on the intended route of administration and factors such as the age and weight of the patient, as generally known to a physician. The dosages will also depend on the particular illness to be treated. For instance, the daily dosage for stress-induced illnesses, inflammatory disorders, Alzheimer""s disease, gastrointestinal diseases, anorexia nervosa, hemorrhagic stress and drug and alcohol withdrawal symptoms will generally range from about 0.1 to about 50 mg/kg body weight of the patient to be treated.
Methods that may be used to determine the CRF antagonist activity of the active compounds of this invention and their pharmaceutically acceptable salts are described in Endocrinology, 116, 1653-1659 (1985) and Peptides, 10, 179-188 (1985). The binding activities for compounds of the formula I, expressed as IC50 values, generally range from about 0.5 nanomolar to about 10 micromolar. Methods that can be used to determine the CRF binding protein inhibiting activity of compounds of the formula I can be determined using the method described in Brain Research, (1997), 745 (1,2), 248-255.
The present invention is illustrated by the following examples. It will be understood, however, that the invention is not limited to the specific details of these examples. Melting points are uncorrected. Proton nuclear magnetic resonance spectra (1H NMR) and C13 nuclear magnetic resonance spectra (C13 NMR) were measured for solutions in deuterochloroform (CDCl3) and peak positions are expressed in parts per million (ppm) downfield from tetramethylsilane (TMS). The peak shapes are denoted as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad.

Substituted pyrido-or pyrimido-containing 6,6-  or 6,7-bicyclic derivatives


A tensioner for maintaining engagement of a conveyor belt cleaner, including one or more scraper blades mounted on a rotatable support frame, with a conveyor belt. The tensioner includes a mounting member attached to the support frame for conjoint rotation therewith, a biasing member attached to the mounting member, and an actuator attached to the biasing member. Operation of the actuator stores a biasing force within the biasing member which in turn rotates the scraper blades into full-face engagement with the conveyor belt. As the scraper blades wear, the biasing member continues to rotate the blades into full-face engagement with the conveyor belt with a biasing force that changes in magnitude. The scraper blades include a blade face having an area which changes as the blades wear, in order to maintain a substantially constant contact pressure between the blades and the conveyor belt as the blades wear.

The present invention relates to a conveyor belt cleaner and tensioning arrangement, and in particular to a conveyor belt cleaner and tensioning arrangement wherein the scraper blades of the conveyor belt cleaner have a blade face which provides initial and subsequent full-face contact with the conveyor belt and wherein the scraper blades maintain a substantially constant cleaning angle with the surface of the conveyor belt and engage the conveyor belt with a substantially constant scraping pressure during the wear life of the scraper blades.
Conveyor mechanisms utilize an endless conveyor belt to transport bulk material, such as sand, gravel, coal and other bulk materials, from one location to another. Such a conveyor utilizes a rotating drum at each end of the moving belt. As the bulk material is discharged from the moving conveyor belt, a portion of the bulk material often remains adhered to the outer surface of the conveyor belt. Conveyor belt cleaners, including one or more scraper blades, are used to scrape the adherent material from the belt on its return run and thereby clean the belt. The scraper blades of a conveyor belt cleaner are removably attached to a rotatable cross shaft that extends transversely across the width of the conveyor belt. A tensioning device is attached to the cross shaft and applies a rotational biasing force to the cross shaft which in turn rotates the tips of the scraper blades into scraping engagement with the conveyor belt.
Scraper blades made for contacting the belt on the curvature of the discharge pulley were previously made such that just the scraping edge of the blade face surface initially engaged the conveyor belt, rather than the entire or full blade face surface, when installed. This edge contact type of blade design cleans with high efficiency when new, but after the blade wears for a short period of time cleaning effectiveness is lost. Scraper blades that provide full-face contact between the face surface of the blade and the conveyor belt, such as those of the present invention, can be designed to maintain constant cleaning efficiency over their wear life. Full-face contact blades extend the life of the scraper blade, particularly on high speed conveyors because a full-face contact blade has more mass to absorb the heat of friction generated with the rotating belt. Full-face blades reduce a problem known as feathering which occurs with primary cleaner blades when just the scraping edge engages the belt.
The present invention also enables a scraper blade to operate with a substantially constant cleaning angle and scraping pressure. The tips of primary scraper blades engage the curved surface of the conveyor belt at the head pulley of the conveyor and form a cleaning angle between the conveyor belt surface and the front surface of the scraper blade at the scraping edge of the front surface. The tip of each scraper blade also includes a scraping surface that engages the surface of the conveyor belt. The scraping surface engages the surface of the conveyor belt with a scraping pressure that is approximately equal to the scraping force with which the scraper blade engages the conveyor belt divided by the area of the scraping surface of the scraper blade.
During operation, the scraping edge and the scraping surface of each scraper blade wears due to its scraping engagement with the moving conveyor belt coated with abrasive bulk solids. The tensioner rotates the cross shaft and the scraper blades to maintain the scraper blades in biased scraping engagement with the conveyor belt. As the scraper blades wear and are rotated into continuing engagement with the conveyor belt, the orientation of the scraper blades with respect to the conveyor belt changes, which typically causes a change in the cleaning angle between the surface of the conveyor belt and the front surface of the scraper blade at the scraping edge, and a change in the scraping pressure with which the scraper blade engages the conveyor belt. In order to maintain optimum cleaning of the surface of the conveyor belt, and to achieve maximum scraper blade life and performance, the cleaning angle between the scraper blades and the conveyor belt surface, and the scraping pressure with which the scraper blades engage the conveyor belt, should remain substantially constant during the wear life of the scraper blades as the scraper blades wear and are rotated into continuing engagement with the conveyor belt. One approach to partially solving this problem is shown in U.S. Pat. No. 4,917,231 owned by the applicant herein.

Constant angle and pressure conveyor belt cleaner and tensioner


A method and program product includes assigning a first location of at least one embedded device. The embedded device includes at least one sensor and is associated with a one joint capable of movement. The first location is captured by the sensor. A second location of the at least one embedded device is assigned. The second location being captured by observation of the embedded device by at least one external sensor. A pose correspondence between the first location and the second location is established using a model of the joint. The sensor is calibrated by tracking a change in a pose captured by the external sensor and a change in a pose captured by the one sensor as the joint moves.

The following background information may present examples of specific aspects of the prior art (e.g., without limitation, approaches, facts, or common wisdom) that, while expected to be helpful to further educate the reader as to additional aspects of the prior art, is not to be construed as limiting the present invention, or any embodiments thereof, to anything stated or implied therein or inferred thereupon.
Various types of sensors including gyroscopes and accelerometers are increasingly being embedded in devices and placed on joints of humans and robots to measure some local information, for example position of joints, velocity of motion, and angles between joints. Typically, sensors require calibration to map raw readings to actual measurements in physical units. External sensors, such as Kinect, capture three dimensional depth and RGB color information.
The following is an example of a specific aspect in the prior art that, while expected to be helpful to further educate the reader as to additional aspects of the prior art, is not to be construed as limiting the present invention, or any embodiments thereof, to anything stated or implied therein or inferred thereupon. A system includes a sensor array which longitudinally spans a body joint in order to measure movement of that body joint. This sensor array can further include a first accelerometer which is proximal to the body joint and a second accelerometer which is distal to the body joint.
By way of educational background, another aspect of the prior art generally useful to be aware of is that a system includes a wearable joint-action sensor that detects actions of a joint that links a first body segment to a second body segment by using a proximity sensor worn on the first body segment to detect a separation between the proximity sensor and the first and/or second body segment.
By way of educational background, another aspect of the prior art generally useful to be aware of is that a system includes a wearable device having feedback characteristics including a compliant article arranged to extend over an anatomical portion of a wearer and for providing a user with information regarding range of motion parameters of a joint and/or to condition users to maintain proper joint orientations. Sensors provided with the wearable device detect the orientation of the joint and send signals to a processor for analysis.
By way of educational background, another aspect of the prior art generally useful to be aware of is that a system for monitoring joint position following introduction of a joint prosthesis in a patient includes a first angular movement sensor positioned adjacent a first side of a bodily joint of a patient and a second angular movement sensor positioned adjacent a second, opposite side of the bodily joint. A receiver can receive data from the angular movement sensors.
In view of the foregoing, it is clear that these traditional techniques are not perfect and leave room for more optimal approaches.
Unless otherwise indicated illustrations in the figures are not necessarily drawn to scale.

Method and program product for multi-joint tracking combining embedded sensors and an external sensor


This disclosure discusses systems, methods, and apparatus for dynamically scaling a clock frequency of an I/O interface to a non-volatile storage device. The scaling can be based on monitoring an idle time on the I/O interface, a priority of one or more applications having read/write requests queued for dispatch to the I/O interface, a load of the queued read/write requests on the I/O interface or a combination of priority and load. Such variables can be compared to thresholds in a frequency governor.

1. Field
The present disclosure relates generally to computing device storage, and more specifically to non-volatile storage devices.
2. Background
Dynamic clock-voltage scaling (DCVS) schemes can be used to reduce power consumption by reducing clock frequency and/or voltages. So far, DCVS has typically only been applied to memory and processor subsystems. Yet, storage devices (e.g., peripheral and internal storage drives) and their input-output (I/O) subsystems also have significant impact on device power consumption. Current research has looked at power reduction schemes for disk-based storage—schemes which are not applicable to non-volatile storage devices (e.g., embedded Multi-Media cards (eMMC), Secure Digital (SD), and other Solid-State Devices (SSD)), which are common in embedded systems like handheld devices including smartphones, tablets, and ultrabooks, to name a few. At the same time, clock frequency of these I/O subsystems is on the rise, and with these increased frequencies comes even greater power consumption. There is thus a need in the art to reduce power consumption in I/O subsystems.

Dynamic load and priority based clock scaling for non-volatile storage devices