A method of operating a call management system enables a subscriber to acknowledge a call, without taking the call. When the system receives the call, it identifies the called subscriber, obtains caller information, and presents the caller information to the subscriber when notifying the subscriber of the pending call. Caller information is information relating to the caller or to the call, such as the caller's name and telephone number. If the subscriber chooses to acknowledge the call, the system records an acknowledgement message from the subscriber. The system then plays the acknowledgement message to the caller. After playing the acknowledgement message, the system offers the caller an opportunity to leave a message for the subscriber. The system may allow such message exchange between the caller and subscriber to continue, enabling the subscriber to acknowledge the caller's additional messages, and the caller to leave messages in response to the acknowledgements.

Even with the relatively recent proliferation of email, instant messaging, and similar communication technologies, telephone services remain important to an average person or business. Indeed, it appears that the number of individual telephone lines in use is constantly increasing. The number and sophistication of feature functions available from both telephone systems and telephone service providers also continue to increase. Call answering, voice messaging, and automated attendant (auto attendant) are some of the more popular feature functions commonly offered by telephone systems and service providers.
An auto attendant system typically answers the incoming calls, greets the callers, and transfers the calls to selected extensions. Some auto attendant systems interact with the callers using, for example, dual tone multi-frequency (DTMF or touch-tone) key input. Other auto attendant systems accept voice input, which they process using automatic speech recognition. Still other systems can receive and process both DTMF and voice input. Representative auto attendant systems of all three types can support call screening. For example, an auto attendant system can request a caller to identify himself (or herself, as the case may be), record the caller's response, play the response to the called party, and allow the called party to accept or reject the call.
An auto attendant system's functionality can be further extended with a so-called "locate" feature, which allows the caller to reach the called party-subscriber at one or more programmable telephone numbers, such as the subscriber's home or mobile telephone numbers. CallXpress™ Call Manager product of the assignee of this invention and other products further extended this functionality to graphical user interface (GUI) screen pop-ups, and added other identification means, such as using the automatic number identification (ANI) number of a call to look up a name in a contact database in order to pop-up the caller's name on the subscriber's screen.
When the called party-subscriber chooses not to take the call, the caller generally does not have a simple and easy way to find out when the called party gets the message. This can be frustrating for the caller. This can also be annoying for the called party, because the call is terminated without giving the called party an opportunity to respond to the call, except by actually taking the call.
To increase the number of options available to the called party, some call processing systems allow the called party to prerecord a number of outgoing messages. The system can select a specific outgoing message based, for example, on the caller identification, on the time of day, on the date, day of the week, or a combination of these and similar variables.
This feature may also allow the called party to prerecord a detailed personalized message for a particular caller, and store the message in a voice mailbox assigned to the caller. After a call is received and the particular caller is identified, the caller can be routed to the mailbox to receive the personalized message. Based on the nature of the prerecorded message, the caller may, for example, call again at a later time, leave a detailed message for the called party, or simply hang up.
Providing prerecorded personalized messages may be an improvement on the art, but the caller is still left without knowledge of when the called party hears the caller's message. Moreover, because the messages are prerecorded, they do not provide the called party an opportunity to respond to the specific call, except by taking the call; the caller can thus receive a stale message or a message irrelevant under the circumstances. Another potential problem with this scheme is caller misidentification, which may cause a prerecorded message to be played to an unintended recipient.
Quite often situations arise when the called party would prefer to acknowledge the call by providing information that is not carried by a prerecorded message, without, however, engaging in a conversation with the caller. For example, the called party may be busy attending a meeting or engaging in other important matters, but still would like the caller to know that the called party knows about the call. Furthermore, the called party may want to provide the caller with additional information while the caller is still on the telephone, without, however, speaking with the caller. Depending on the circumstances, the called party may also wish to receive the caller's response to the personalized acknowledgement message.

Apparatus and method for personalized call acknowledgement

Applied Voice & Speech Technologies, Inc.


The invention relates to a knife assembly for slicing woodwool, comprising a knife with a chip surface (1), a clearance surface (2) and a cutting edge (3), defined by the intersection between both surfaces. The knife assembly is characterized by guiding ribs (4) extending perpendicularly to the cutting edge (3) and joining the chip surface (1) with an end (5) that substantially coincides with the cutting edge (3) and with the guiding surface joining said end and rising there towards. The guiding ribs (4) can be formed integrally with the knife.

Woodwool (which also means "flakes" and alike) for packaging purposes and as base material for, among others, insulating cement-bonded building boards is mainly sliced using carriage planing machines. Because for the production of woodwool generally waste material of sawing mills and second rated logs are used, of which the growing fibres (the grain of the wood) mostly are not straight and because the wood often contains a lot of knots, in practice preferably only one planing knife is used. In this case the wood is clamped manually in a somewhat inclined position above the carriage of the carriage planing machine, such that during the cutting stroke the planing knife averagely cuts more "into" than "out of" the growing fibres.
For determining the width of the woodwool several measures can be taken. It is possible, that ahead of the planing knife a series of sharpenable or exchangeable width knives (so-called spurs) are mounted. Sharpenable width knives however have the disadvantage that after use they have to be collected, sorted out, sharpened individually, bundled and positioned again very carefully in the planing machine. This is labour intensive and an accurate setting is difficult. Therefore there are also solutions, according to which sets of pre-machined bundled not-sharpenable small and thin width knives are applied for one-time use. However a disadvantage thereof are the cost, whereas these small width knives are easily damaged or broken. For replacement the production of woodwool then has to be interrupted. Further the setting relative to the planing knife and relative to the wood block to be processed causes problems. Width knives extending too far above the planing knife produce a lot of dust in the woodwool, because they do not always precisely follow the same path in carriage planing machines during the forward and during the backward stroke, and because they do not cut grooves at exactly the same position as width knives mounted ahead of the successive planing knife in rotating planing machines. This disadvantage is increased by transversal movements of the wood and/or the carriage.
All types of width knives have the disadvantage that while planing narrow woodwool the space between the width knives becomes that small that woodwool fibres get entangled and the interspaces between the knives get jammed up. As a result the slicing operation has to be stopped in order to be able to clean the width knives. This phenomenon renders it impossible to slice narrow woodwool using width knives, as is desired for packaging purposes or for aesthetically high quality cement-bonded ceiling panels.
In view of the above one has searched for other possibilities for determining the width of the woodwool fibres. These possibilities are provided in the form of so-called comb or profiled knives, as illustrated in U.S. Pat. No. 2,576,190. However, it is a disadvantage of these profiled knives that they cannot or hardly be used for second choice wood, showing cracks, knots and irregularly extending growing fibres. The projecting high wood ribs formed by planing already break before the following cutting edges can slice a second series of woodwool strands at that location. The strips being cut by the tooth points of these profiled knives often follow in an uncontrolled way the irregularly extending growing fibres, such that large pieces break loose from the wood block. Further splinters and, in the case of narrow woodwool, the fibres are clamped into the deep grooves of the profiled knives, whereas sometimes the high small teeth of the profiled knives can break off on hard knots in the wood.
An other alternative is shown by European patent application 19,614, according to which a profiled knife and a flat knife are positioned behind each other. In this case for example a profiled knife with alternating 4 mm wide teeth and 4 mm wide recesses and a following flat knife are used for slicing 4 mm wide woodwool fibres, for example. Using this combination the slicing operation occurs with both knives using the point of the knife and the profiled knife is positioned slightly higher than the smooth knife, such that by means of the profiled knife strands of woodwool are sliced creating grooves in the wood block. These grooves are somewhat deeper than the desired thickness of the woodwool. Next using the flat knife subsequent woodwool fibres having the desired thickness are sliced from the ripples shaped thus. Meanwhile the grooves planed into the wood block by means of the profiled knife still partially remain.
Positioning a profiled knife and a smooth knife behind each other in correspondence with this publication offers the advantage, that the wood can be clamped in a slightly sloping manner, such that both knives in average cut "into" the growing fibre, but an important disadvantage is that with second choice wood, comprising knots and irregular fibre directions, it cannot be avoided that both knives slice irregularly thick fibres and often even splice off slices from the wood block instead of separate woodwool fibres with constant thickness and width. Such undesired phenomenons occur more often when the woodwool fibres to be produced have to be narrow, and slicing regularly shaped very fine woodwool is not possible at all.
Generally it may be noted, that an important disadvantage of the use of profiled knives is, that the side edges of the produced woodwool is ripped out of the grooves by means of the profiled knife instead of cut out. As a result at these side edges of the woodwool fibres frills and hairs are formed, which moreover disengage easily and create a lot of wood dust. Therefore the woodwool fibres, which are subsequently sliced during a successive step (for example by means of a smooth knife) from the remaining ripples neither comprise smoothly cut side edges.
As noted before the width of the woodwool varies because it is dependent upon the presence of, for example, dryness cracks, knots and the path of the growing fibres of the wood at the location of the tooth points of the profiled knives. Therefore the width of the fibres cannot be controlled and is not constant.
The problems mentioned before will increase in magnitude when the quality of the wood is less and the woodwool to be produced has to be narrow, such as if it has to be used for packaging purposes or in decorative ceiling panels, where slices, splinters, hairs and dust are unacceptable.
From the foregoing it has to be concluded that none of the techniques available at the present renders it possible to produce optimally shaped, regular woodwool.
It is an object of the invention to provide a solution.

Knife assembly and apparatus for slicing woodwool

Bau- und Forschungsgesellschaft Thermoform AG


An electromagnetically complete field vector field probe has a set of three dipoles extending along three mutually perpendicular axes, and three loops situated in mutually orthogonal planes defined by different pairs of said axes. The dipoles and loops are all disposed about a common center. Each dipole has a central element and two end elements, separated by gaps. Each loop has four conducting elements each extending from a point adjacent to one of the three axes to a point adjacent to another of the three axes. The conducting elements of each loop are separated from one another by gaps at the axes, so that each gap of each loop is substantially coincident with a gap of another loop and with a gap of a dipole. Coaxial lines extending through the central conducting elements of the dipoles are connected directly to the ends of the loop elements and need not extend through parts of the loop elements themselves. Each loop is connected to a corresponding magnetic field output port through an additive network having eight inputs, each input being connected to a different end of an element of the loop.

At VHF frequencies, it is possible to achieve acceptable direction finding accuracy using an interferometer comprising two dipole elements spaced from each other by one wavelength. However, at HF frequencies, i.e. frequencies in the range of approximately 2-30 Mhz., interferometry is not a practical way to achieve highly accurate direction finding, in part because the required element spacing is prohibitively large. Most other direction finding antennas usable in the HF range are comparatively inaccurate.
One type of device which is able to achieve high accuracy in the HF range is the field probe. A field probe is a device which measures one or more components of an electromagnetic field. Direction finding, by means of a field probe, is fundamentally a process of comparing amplitudes of field components, as detected by two or more antennae having different antenna patterns.
A time-varying electromagnetic field is completely characterized at any point in space, in Cartesian coordinates, by six vector quantities: the electric field parallel to the x axis (E.sub.x), the electric field parallel to the y axis (E.sub.y), the electric field parallel to the z axis (E.sub.z), the magnetic field parallel to the x axis (H.sub.x), the magnetic field parallel to the y axis (H.sub.y), and the magnetic field parallel to the z axis (H.sub.z).
An electromagnetically complete field probe resolves the electric and magnetic field components of an electromagnetic wave into their orthogonal components E.sub.x, E.sub.y, E.sub.z, H.sub.x, H.sub.y and H.sub.z. By applying known, model-based "superresolution" algorithms to the output of the field probe, direction finding accuracies comparable to those achievable by interferometry can be realized.
Preferably, in the interest of transportability and cost, and in the interest of measurement accuracy as well, the field probe is electrically small, i.e. its element lengths and spacings are only small fraction of the wavelength of the received signal. An electrically small antenna is inefficient. However, in the HF range, external noise, rather than internal noise, is the primary noise problem. Since external noise and signal strength vary together in dependence on antenna efficiency, it is possible to compensate for the inefficiency of a small antenna by amplification, without seriously affecting the signal to noise ratio (S/N). Thus, the size of an electromagnetic field probe can be reduced until a point is reached at which there is a serious degradation in the overall signal to noise ratio. A practical probe suitable for use in the HF range can have a maximum dimension no more than approximately two meters.
One form of prior art electromagnetically complete field probe comprises a three mutually perpendicular dipoles and three mutually perpendicular loops, all symmetrical about a common center point. The dipoles measure the electric field components E.sub.x, E.sub.y and E.sub.z, while the loops measure the magnetic field components H.sub.x, H.sub.y and H.sub.z.
Each dipole is in a special configuration and comprises an intermediate conductor extending through the center of the array, and two end conductors, one on each end of the array. For example, the dipole for measuring E.sub.x has an intermediate conductor and two end conductors, all extending along the x axis. The end conductors are separated from the intermediate conductors by gaps, and electrical connections are from the gaps, through a four-port hybrid junction to an x-axis electric field (E.sub.x) output port. The E.sub.y and E.sub.z dipoles are similarly constructed and connected to output ports.
The loops are situated respectively in the y-z, x-z and x-y planes. Each loop comprises four elements, each element corresponding to the side of a rectangle. Electrical connections are made to the elements at gaps formed at the corners of the rectangle. The electrical connections for each loop are made, through an array of four-port hybrid junctions to an output port. Thus the loop in the y-z plane is connected to an H.sub.x output port; the loop in the x-z plane is connected to an H.sub.y output port; the loop in the x-y plane is connected to an H.sub.z output port.
Although the electromagnetically complete field probe is used as a receiving antenna, its operation can be most easily understood by treating each dipole and loop as a transmitting antenna.
A voltage applied to the x-axis electric field port would induce a current distribution in the intermediate conductor and end conductors of the x-axis dipole. Similar voltages applied to the y-axis and z-axis electric field ports would induce current distributions in the corresponding dipoles. Thus, by the theorem of electromagnetic reciprocity, when the probe is subjected to an incident electromagnetic field, the electric field output ports provide voltages proportional to the electric field components along the axes of their corresponding dipoles.
In a similar way, a voltage applied to the x-axis magnetic field port (H.sub.x) would excite voltages at the corners of the loop in the y-z plane which induce a current distribution in the elements of the loop. Likewise, a voltage applied to the y-axis magnetic field port (H.sub.y) would induce a current distribution in the elements of the loop in the x-z plane, and a voltage applied to the z-axis magnetic field port (H.sub.z) would induce a current distribution in the elements of the loop in the y-z plane.
The arrangement of elements in the electromagnetically complete field probe substantially eliminates the effects of mutual coupling between elements. For example, viewing the loops and dipoles of the device once more as transmitting antennae, if the loop in the x-y plane is excited, currents would be induced in elements of the x and y-axis dipoles. However, because the loop is excited at each of its corners, the current distribution in the loop is nearly balanced. Therefore, in each element of the x and y axis dipoles, currents induced by mutual coupling with the loop in the x-y plane oppose and cancel one another.
One of the problems with the prior field probe, as described above, is that it is physically difficult to connect the magnetic field ports to the corners of the three loops. Another problem is that, in the transmitting antenna model of the device, exact balancing and cancellation of induced currents is not achieved. Correspondingly, in the field probe, unbalanced conditions exist, which adversely affect the accuracy of measurement.

Field probe for measuring vector components of an electromagnetic field


A security device for a utility shutoff valve and a tool for inserting and removing the security device. The security device and tool are utilized for water and gas shutoff valves located underground that are accessed through a vertical access pipe. The invention is a cylindrical plug which is placed inside the access pipe, resting on top of the valve. The plug includes a grip resistant dummy valve handle which, when turned, causes the plug to rotate without having any effect on the valve. The plug is also very difficult to remove without the insertion/removal tool, comprising an inverted cup with a long handle, wherein the inside of the cup is lined with horizontal steel bristles. When the cup is placed over the top of the plug, the bristles enter corresponding holes in the dummy valve handle, allowing the plug to be lifted.

1. Field of the Invention
The present invention relates to devices for securing valves from unauthorized tampering, more specifically, a dummy plug having a simulative valve handle which sits on top of and camouflages the functioning valve, and, a specialized steel-bristled tool for inserting and removing the plug.
2. Description of Related Art
Other inventors have attempted to develop satisfactory ways to prevent unauthorized tampering with water, gas, or other utility valves. One early example is English Pat No. 589,268, issued to James Laidlaw, disclosing a cover which could only be unscrewed by the use of a special key or tool. More recently, John R. Saporito disclosed in U.S. Pat. No. 3,797,286 a plug wherein a bolt locks the plug inside an access pipe, requiring a key to unlock it. Mr. Saporito's invention requires drilling a hole in the access pipe to accept the bolt. French Pat. No. 2,380,381 discloses another attempt to limit access to valves. Jeffrey G. Thomas and Lucas Brito describe in U.S. Pat. No. 5,234,029 a bracket which fits inside the access pipe, with the edges underneath a ledge in the pipe. An eyebolt is attached to the bracket, and passes through a hole in the pipe's cover. Placing a padlock through the eyehole locks the cover in place. This invention requires an access pipe with the appropriate ledge for the bracket.
Similar ideas have also been used for different applications, such as the refrigerant valve safety cap disclosed in U.S. Pat. No. 5,597,010, which was issued to John W. Hoffman. The cap screws down over the top of the valve access port. Unscrewing the valve requires a special tool wherein the end comprises several pegs dimensionally and positionally suited to fitting into several asymmetrically spaced holes on the top of the cap.
At least three inventors directed their ideas toward securing fire hydrant valves. U.S. Pat. No. 3,453,655, issued to Carlos M. Quinones, discloses an irregularly shaped nut wherein a bolt extends from the nut and engages a hole in a wall surrounding the nut. When the proper tool engages the nut, the bolt is withdrawn, allowing the nut to be turned. Albert B. Kopesky described in U.S. Pat. No. 4,620,428 an internal cylinder which attaches over the valve's nut, and an external cylinder which rotates freely with respect to the internal cylinder. Both the internal cylinder and the opening tool contain magnets. When the proper tool is used, the internal cylinder's magnet raises to engage the outer cylinder, causing both cylinders and the nut to rotate together. More recently, U.S. Pat. No. 5,596,893, issued to Henry J. Stehling et al., discloses an improved version of the same concept. All three of these inventions require modification to the valve to be protected. To retrofit an entire region with special replacement valves would result in a prohibitive and unnecessary cost to the utility users in such region.
William A Miskiewiez described in U.S. Pat. No. 5,664,597 a cover for fire hydrants. Although the cover is primarily directed to keeping fire hydrants visible and accessible in heavy snow, it generally describes the purpose of preventing unauthorized access to a hydrant. However, the current invention is directed towards preventing someone from finding a valve, teaching away from the '597 device which enables a user to find the hydrant.
Additional inventions were directed towards making it easier to open utility valves. U.S. Pat. No. 5,456,278, issued to Jeffrey B. Morris et al., discloses a folding bar designed to provide the appropriate reach and leverage to operate both gas and water valves. U.S. Pat. No. 5,638,590, issued to Peter Silano, discloses a tool for removing and replacing the operating nuts on underground valves. Lastly, U.S. Pat. No. 5,671,772, issued to William Charles Bliss, describes a telescoping access pipe.
None of the above inventions and patents, taken either singly or in combination, is seen to describe the instant invention as claimed.

Security device for utility shutoff valve


A personal fall limiter arrangement having a user connection arrangement, including: a body attached to at least a portion of the frame and having a recess configured to receive at least a portion of a user connector; at least one tab pivotally attached to a first portion of the body; and at least one biasing member engaged with the at least one tab and configured to urge the at least one tab towards a locked (or closed) position; wherein, in operation, the at least one tab is pivotal between: (1) an open position to permit passage of at least a portion of the user connector into or out of the recess; and (2) the locked position to prevent passage of at least a portion of the user connector out of the recess.

1. Field of the Invention
The present invention relates generally to fall protection systems and arrangements for ensuring the safety of users during and after a fall event, and in particular to a personal fall limiter arrangement and user connection arrangement therefore for use in conjunction with other safety equipment.
2. Description of the Related Art
As is known in the art, a variety of activities, workplace functions, and emergency situations require additional safety measures and systems. In particular, such activities, functions, and situations include, without limitation, climbing, construction, and rescue situations. In order to provide safety to the person involved in the activity, function, and situation, certain safety equipment is utilized. For example, a person often wears a full body harness or safety belt that is removably attachable and is formed using one or more lengths of straps. As also is known, such harnesses or belts include a connector attached thereto, such as a D-ring or the like. It is this D-ring or connector that is attached to other safety equipment and arrangements, such as a personal fall limiter.
A personal fall limiter arrangement, such as a self-retracting lanyard, normally includes a hub rotatably attached to a frame, and a braking assembly operable to brake the rotation of the hub. A line, such as a synthetic strap or cable, is attached to and wound around the hub. The free end of the line is formed with a loop to which some connector is attachable. This connector may be, for example, a snap-hook, a carabiner, or the like. This connector is then attached to some secure point on a structure or other secure area. While not necessary, such arrangements may also include one or more springs that continually urge the line back around the hub to remove any slack in the line.
Further, the personal fall limiter arrangement includes or is attached either directly to the strap of the harness or belt, or more often, to the user connector, e.g., the D-ring. In this manner, the personal fall limiter arrangement is securely connected between the user's harness or belt and some secure point. Accordingly, in the event of a fall, the line will pay out of the arrangement, and the braking assembly will safely brake the line so as to relieve or minimize the forces of the fall event on the user. As is known, such a brake assembly may include a pawl-and-sperrad arrangement, or some other structural interrelationships to effectively slow the pay out of the line and protect the user.
One example of a known personal fall limiter arrangement is the "Safety Retractable Lanyard" of Ultra-Safe Inc. This arrangement includes a removably attachable connector in the form of a clip that can be threaded open and closed around the D-ring. However, this connector is long and, therefore, in a fall event may move and strike the user's back, neck, or head. In addition, this connector includes multiple connection points and, therefore, multiple possible failure points.
Other personal fall limiter arrangements include integrated user connection arrangements that utilize complicated mechanical structures. Such connection arrangements may also be attached directly to the harness or belt (i.e., not to a separate D-ring). However, the use of such complicated mechanical structures also lead to many failure points and other mechanical failures. Still further, the operation of such mechanical structures is not intuitive, and may even lead to partial closing of the connection points (yet another source of safety concerns with such arrangements). One example of such an arrangement is the self-retracting lifeline shown in U.S. Patent Publication No. US 2007/0151805.
Accordingly, there remains a need in the art for improved personal fall limiter arrangements that provide enhanced safety to the user. Further, there is a need in the art for improved user connection arrangements that safely attach a personal fall limiter arrangement, or other similar device, to the harness or belt of the user.

Personal fall limiter arrangement and user connection arrangement therefor


A probability estimation table reading apparatus includes a memory part for storing a probability estimation table, the table defining, for each address value, a switch data value, a probability estimate data value, an LPS data value indicative of a next address when a more probable symbol occurs and an MPS data value indicative of a next address when a less probable symbol occurs, and a control part for reading out each the LPS data value and MPS data value for a current address value of the stored table, so that next address values required by an arithmetic coder to perform arithmetic coding data compression, can be generated. Each of the LPS data value in the stored table stored in the memory part has been replaced by the difference between a current address value and a next address value indicated by a standard LPS data value for the current address value, and each of the MPS data value has been replaced by the difference between the current address value and a next address value indicated by a standard MPS data value for the current address value.

The present invention generally relates to a probability estimation table apparatus, and more particularly to an apparatus for reading a probability estimation table for use in an arithmetic coder as well as an apparatus for generating the probability estimation table stored in a memory of the probability estimation table reading apparatus.
The ISO/IEC International Standard of Coded Representation of Picture and Audio Information (Early Draft, WG9-S1R2, Dec. 14, 1990, the standard number being still not assigned) defines a method for compression encoding a bi-level image, and recommends a standard probability estimation table adaptive to the arithmetic coding data compression. The standardization of this technology is under way, and some prototypes of arithmetic coders for carrying out the arithmetic coding data compression have been proposed. However, there is still not a useful mechanism for outputting a next index, required for compression encoding an image, by using the standard probability estimation table.
FIGS. 1A and 1B show the standard probability estimation table recommended by the above mentioned international standard. The probability estimation table is called the Qe table. For each possible value of the index CX there is stored a 1-bit value MPS (CX) and a seven-bit value ST (CX), which together completely express the adaptive probability estimate associated with that particular index. An index CX is used to identify the index of the state of the coder for coding a current pixel.
In the standard Qe table in FIGS. 1A and 1B, four arrays are indexed by the index (CX). The MPS is the estimated most likely color for a pixel PIX in a symbol sequence. The Qe Value is a 15-bit value of the LPS interval size, which can be interpreted to be a probability based on a prescribed equation.
The arrays N/I-LPS (Next Index-LPS) and N/I-MPS (Next Index-MPS) are 7-bit values of next indexes giving, respectively, the next Qe state for an observation of the LPS and the MPS. The movement given by the N/I-MPS only occurs if in addition to observing the MPS, a renormalization also occurs. When the movement given by the N/I-LPS occurs, there will also be an inversion of MPS (CX) if the SWITCH (CX) value is 1. The array SWITCH is a 1-bit value of the MPS/LPS switch. A Qe table reading apparatus requires a memory (for example, a ROM) for storing the above mentioned standard Qe table. Since the 1-bit data of the switch and the 15-bit data of the Qe-Value are fixed and cannot be changed, a memory space of at least 112 14-bit words is required for storing the LPS data and the MPS data of the standard Qe table. However, memory chips currently available to the manufacturers at a low cost are multi-purpose 8-bit ROMs. There is a problem in that it is necessary to use a 16-bit memory chip for storing the standard Qe table with space of at least 112 14-bit words, thus increasing the manufacturing cost.


A walking assistance device having a leg link connected to a load transmit portion via a first joint and to a foot attachment portion via a second joint, and having an intermediate third joint moving such that a distance between the first joint and the second joint is variable; a drive source for the third joint; and a battery for the drive source. When in an upstanding position, force in the forward-backward direction is prevented from acting on the load transmit portion to enhance stability. Also, a moment of inertia of the leg link is decreased to curtail a load applied to the leg of the user. The drive source and the battery are located at positions higher than the third joint, and when the user is in an upstanding position, a plane passing through the second joint lies between the drive source and the battery.

1. Field of the Invention
The present invention relates to a walking assistance device for assisting a user in walking.
2. Description of the Related Art
Conventionally, as a type of walking assistance device, there is known one including a trunk attachment portion which is attached to a user's trunk, a thigh attachment portion which is connected to the trunk attachment portion via a hip joint portion corresponding to a human hip joint and attached to a thigh of a user's leg, a crus attachment portion which is connected to the thigh attachment portion via a knee joint portion corresponding to a human knee joint and attached to the crus of the user's leg, and a foot attachment portion which is connected to the crus attachment portion via an ankle joint portion corresponding to a human ankle joint and attached to a user's foot, wherein a drive source for driving each of the joint portions is provided coaxially with the respective joint portion (refer to Japanese Patent Laid-Open No. 2003-220102, for example). This type of walking assistance device is capable of assisting the user in walking by applying an assist moment from the drive source for driving the hip joint portion to the user's thigh via the thigh attachment portion, applying an assist moment from the drive source for driving the knee joint portion to the user's crus via the crus attachment portion, and applying an assist moment from the drive source for driving the ankle joint portion to the user's foot via the foot attachment portion.
The above-mentioned conventional walking assistance device is capable of assisting all movements of the user's thigh, crus, and foot. However, the user experiences a considerably constrained feeling as the thigh and the crus are restrained by the thigh attachment portion and the crus attachment portion. In addition, it is necessary to provide the drive sources for driving the joint portions such as the hip joint portion, the knee joint portion, and the ankle joint portion, respectively, which increases the cost disadvantageously.
In order to solve the above disadvantages, it is conceivable to provide a walking assistance device including a load transmit portion; a foot attachment portion attached to the user's foot; a leg link connected to the load transmit portion via a first joint portion located at an upper end thereof and connected to the foot attachment portion via a second joint portion located at a lower end thereof, and having a middle third joint portion which operates in such a way that a distance between the first joint portion and the second joint portion is variable; a drive source to drive the third joint portion, wherein a force generated for the leg link from the third joint portion driven by the drive source is transferred to the user's trunk via the load transmit portion. According thereto, the walking assistance device can assist walking by alleviating the load on the user's leg by means of the force from the leg link transferred to the user's trunk via the load transmit portion. Furthermore, it is possible to relieve the user of the constrained feeling by making the leg link free from the user's leg.
Meanwhile, it is also necessary to provide a battery for the drive source in the walking assistance device. Generally, it is conceivable that the battery is housed in a back pack shouldered by the user. However, this solution resultantly impairs the alleviation effect on the constraint feeling of the user. Therefore, it is desirable to provide a walking assistance device including a drive source for a third joint portion and a battery for the drive source without being shouldered in a back pack by the user.
However, in the above-mentioned case, since the drive source and the battery are both heavy loads, when the user stands upright, divergence of the center of gravity of the drive source and the battery to either a forward direction or a backward direction with respect to a frontal plane (a plane which is vertical and parallel to a transverse direction) passing through the lower second joint portion of the leg link generates a forward or backward tilt moment to the leg link with respect to the second joint portion as the center, which causes a forward or backward pushing force applied to the load transmit portion. Further, the moment of inertia around the first joint portion of the leg link may become great according to the disposed height of the drive source and the battery, which thereby increases a load applied to the free leg due to the moment of inertia of the leg link when a free leg of the user (a leg whose foot is off from the ground) swings forward.


It is recognized that an attached USB memory is an unanalyzable USB memory. Then, disconnect setting is made. A USB connection process is performed. A PC is instructed through a connection line to establish USB connection. The PC recognizes that the attached device is a USB-connected MFP. The PC acquires data control information of the MFP. The MFP then transfers, through the connection line, the data control information output from the USB memory.

1. Field of the Invention
The present invention relates to an information processing system including an image input and output apparatus having a USB (Universal Serial Bus) connector to which a USB device can be attached, and an information processing apparatus connected through a network.
2. Description of the Related Art
In recent years, a memory card and the like serving as a removable external storage device for storing image data and the like have widely been used in a widely used portable information terminal (PDA) (Personal Data Assistance), a digital camera and the like.
In addition, a multi-function peripheral (MFP) serving as an image input and output apparatus capable of forming an image based on image data stored in the external storage device has come into wide use.
Meanwhile, a USB memory has widely been used as a removable external storage device in recent years, and data security measures have recently become important. As one exemplary measure, a USB memory having not only a data area but also an application area and capable of storing date in the data area using an encryption application and the like stored in the application area has been introduced.
For example, a USB memory complying with U3® specifications proposed by SanDisk® Corporation (hereinafter also referred to as a U3® memory) is available.
In many cases, the application of the U3® memory as described above is adapted to a general-purpose operating system (OS) (for example, Windows®) generally used in a personal computer (PC), but not adapted to an embedded OS (for example, VxWorks®) incorporated in the MFP.
Therefore, even when the U3® memory is attached to the connector terminal of the USB provided in the MFP, the MFP cannot recognize the application stored in the U3® memory, and therefore, cannot control the U3® memory.
In this regard, Japanese Laid-Open Patent Publication No. 2006-015532 discloses a scheme by which the peripheral control software is downloaded through a network from the service site to allow recognition of the USB devices (for example, U3® memory and the like) corresponding to peripherals that cannot be recognized.
However, in order to allow the USB devices to be controlled, this scheme requires the peripheral control software to be provided in the service site depending on the OS. This poses a problem of a significant increase in cost in the case where updates are frequently performed.

Information processing system capable of recognizing and accessing removable external storage device in simple scheme, method for controlling information processing system, and image input and output apparatus

Konica Minolta Business Technologies, Inc.


The present application describes novel lactams and derivatives thereof of formula I:

This invention relates generally to novel lactam inhibitors of matrix metalloproteinases, TNF-xcex1, and aggrecanase, pharmaceutical compositions containing the same, and methods of using the same.
There is now a body of evidence that metalloproteinases (MP) are important in the uncontrolled breakdown of connective tissue, including proteoglycan and collagen, leading to resorption of the extracellular matrix. This is a feature of many pathological conditions, such as rheumatoid and osteoarthritis, corneal, epidermal or gastric ulceration; tumor metastasis or invasion; periodontal disease and bone disease. Normally these catabolic enzymes are tightly regulated at the level of their synthesis as well as at their level of extracellular activity through the action of specific inhibitors, such as alpha-2-macroglobulins and TIMP (tissue inhibitor of metalloproteinase), which form inactive complexes with the MP""s.
Osteo- and Rheumatoid Arthritis (OA and RA respectively) are destructive diseases of articular cartilage characterized by localized erosion of the cartilage surface. Findings have shown that articular cartilage from the femoral heads of patients with OA, for example, had a reduced incorporation of radiolabeled sulfate over controls, suggesting that there must be an enhanced rate of cartilage degradation in OA (Mankin et al. J. Bone Joint Surg. 52A, 1970, 424-434). There are four classes of protein degradative enzymes in mammalian cells: serine, cysteine, aspartic and metalloproteinases. The available evidence supports that it is the metalloproteinases which are responsible for the degradation of the extracellular matrix of articullar cartillage in OA and RA. Increased activities of collagenases and stromelysin have been found in OA cartilage and the activity correlates with severity of the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly identified metalloproteinase enzymatic activity) has been identified that provides the specific cleavage product of proteoglycan, found in RA and OA patients (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22).
Therefore metalloproteinases (MP) have been implicated as the key enzymes in the destruction of mammalian cartilage and bone. It can be expected that the pathogenesis of such diseases can be modified in a beneficial manner by the administration of MP inhibitors, and many compounds have been suggested for this purpose (see Wahl et al. Ann. Rep. Med. Chem. 25, 175-184, AP, San Diego, 1990).
Tumor necrosis factor (TNF) is a cell associated cytokine that is processed from a 26 kd precursor form to a 17 kd active form. TNF has been shown to be a primary mediator in humans and in animals, of inflammation, fever, and acute phase responses, similar to those observed during acute infection and shock. Excess TNF has been shown to be lethal. There is now considerable evidence that blocking the effects of TNF with specific antibodies can be beneficial in a variety of circumsatnces including autoimmune diseases such as rheumatoid arthritis (Feldman et al, Lancet, 1994, 344, 1105) and non-insulin dependent diabetes melitus. (Lohmander L. S. et al. Arthritis Rheum. 36, 1993, 1214-22) and Crohn""s disease (MacDonald T. et al. Clin. Exp. Immunol. 81, 1990, 301).
Compounds which inhibit the production of TNF are therefore of therapeutic importance for the treatment of inflammatory disorders. Recently it has been shown that a matrix metalloproteinase or family of metalloproteinases, hereafter known as TNF-convertases (TNF-C), as well as other MP""s are capable of cleaving TNF from its inactive to active form (Gearing et al Nature, 1994, 370, 555). This invention describes molecules that inhibit this conversion and hence the secretion of active TNF-xcex1 from cells. These novel molecules provide a means of mechanism based therapeutic intervention for diseases including but not restricted to septic shock, haemodynamic shock, sepsis syndrom, post ischaemic reperfusion injury, malaria, Crohn""s disease, inflammatory bowel diseases, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic diseases, cachexia, graft rejection, cancer, diseases involving angiogenesis, autoimmune diseases, skin inflammatory diseases, osteo and rheumatoid arthritis, multiple sclerosis, radiation damage, hyperoxic alveolar injury, periodontal disease, HIV and non-insulin dependent diabetes melitus.
Since excessive TNF production has been noted in several disease conditions also charactarized by MMP-mediated tissue degradation, compounds which inhibit both MMPs and TNF production may also have a particular advantage in diseases where both mechansisms are involved.
There are several patents which disclose hydroxamate and carboxylate based MMP inhibitors.
WO95/09841 describes compounds that are hydroxamic acid derivatives and are inhibitors of cytokine production.
EP 574,758 A1 illustrates hydroxamic acid derivatives as collagenase inhibitors having the general formula:
GB 2 268 934 A and WO 94/24140 claim hydroxamate inhibitors of MMPs as inhibitors of TNF production.
WO 97/32846 depicts hydroxamic acid derivatives as MMP inhibitors having the general formula:
wherein X and Y are carbon or nitrogen, and R3 and R4 can be a variety of groups including amides, aryls, heterocycles and cycloalkyls. Compounds of this sort are not considered to be part of the present invention.
The compounds of the current invention act as inhibitors of MMPs, aggrecanase and/or TNF. These novel molecules are provided as anti-inflammatory compounds and cartilage protecting therapeutics. The inhibiton of aggrecanase, TNF-C, and other metalloproteinases by molecules of the present invention indicates they are anti-inflammatory and should prevent the degradation of cartilage by these enzymes, thereby alleviating the pathological conditions of osteo- and rheumatoid arthritis.
Accordingly, one object of the present invention is to provide novel lactams which are useful as metalloprotease inhibitors or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel lactams for use in therapy.
It is another object of the present invention to provide the use of novel lactams for the manufacture of a medicament for the treatment of an inflammatory disorder.
It is another object of the present invention to provide the use of novel lactams for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I):
or pharmaceutically acceptable salt or prodrug forms thereof, wherein A, B, R1, R2, R3, and R4 are defined below, are effective metalloprotease inhibitors.
[1] Thus, in an embodiment, the present invention provides a novel compound of formula I:
or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein;
A is selected from COR5, xe2x80x94CO2H, C(RRxe2x80x2)CO2H, xe2x80x94CO2R6, xe2x80x94CONHOH, xe2x80x94C(RRxe2x80x2)CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94NHRa, xe2x80x94N(OH)C(O)R5, xe2x80x94SH, xe2x80x94CH2SH, xe2x80x94SONHRa, SN2H2Ra, PO(OH)2, and PO(OH)NHRa;
ring B is a 4-8 membered cyclic amide containing from 0-3 additional heteroatoms selected from O, NRa, and S(O)p, 0-1 additional carbonyl groups and 0-1 double bonds;
R1 is Uxe2x80x94Xxe2x80x94Yxe2x80x94Zxe2x80x94Uaxe2x80x94Xaxe2x80x94Yaxe2x80x94Xbxe2x80x94Za;
U is absent or is selected from: NRa, C(O), C(O)O, C(O)NRa, NRaC(O), NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
X is absent or selected from C1-10 alkylene, C2-10 alkenylene, and C2-10 alkynylene;
Y is absent or selected from O, NRa, S(O)p, and C(O);
Z is absent or selected from a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)O, OC(O), C(O)NRa, NRaC(O), OC(O)O, OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)p, S(O)pNRa, NRaS(O)p, and NRaSO2NRa;
Xa is absent or selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Ya is absent or selected from O, NRa, S(O)p, and C(O);
Xb is absent or selected from C1-10 alkylene, C2-10 alkenylene, C2-10 alkynylene;
Za is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rc and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
provided that:
(a) when U is absent, X and Y are absent; and,
(b) R1 is other than unsubstituted alkyl, alkylene-Z, alkylene-Za, alkylene-amino-Z, alkylene-amino-Za, alkylene-amino-Z-Za, and alkylene-amino-Z-alkylene-Za;
R2 is selected from H, Qxe2x80x2, C1-10 alkylene-Qxe2x80x2, C2-10 alkenylene-Qxe2x80x2, C2-10 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, and (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2;
R, at each occurrence, is independently selected from H, CH3, CH2CH3, CH(CH3)2, CHxe2x95x90CH2, CHxe2x95x90CHCH3, and CH2CHxe2x95x90CH2;
Rxe2x80x2, at each occurrence, is independently selected from H, CH3, CH2CH3, and CH(CH3)2;
Qxe2x80x2 is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x3NHQ, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)ORa, and (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rNHC(O)(CRRxe2x80x2)rNHC(O)ORa,
Q is selected from H, a C3-13 carbocyclic residue substituted with 0-5 Rb and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
R4 is selected from H, C1-10 alkylene-H, C2-10 alkenylene-H, C2-10 alkynylene-H, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2OC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94H, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94H, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94H;
alternatively, R3 and R4 combine to form a C3-13 carbocyclic residue substituted with Rc and 0-3 Rb or a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with Rc and 0-3 Rb;
Ra, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x2, at each occurrence, is independently selected from H, C1-4 alkyl, phenyl and benzyl;
Raxe2x80x3, at each occurrence, is independently selected from H, C1-4 alkyl, benzyl, C3-7 carbocyclic residue, or a 5 to 6 membered heteroaromatic ring containing 1-4 heteroatoms selected from the group consisting of N, O, and S;
alternatively, Ra and Raxe2x80x2 taken together with the nitrogen to which they are attached form a 4, 5, or 6 membered ring containing from 0-1 additional heteroatoms selected from the group consisting of N, O, and S;
Rb, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, and CF2CF3;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, NRaC(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, xe2x80x94CH(xe2x95x90NOH), xe2x80x94C(xe2x95x90NOH)CH3, (CRRxe2x80x2)sO(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sS(O)p(CRRxe2x80x2)sxe2x80x2Rd, (CRRxe2x80x2)sNRa(CRRxe2x80x2)sxe2x80x2Rd, phenyl, and a 5-14 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S;
R5, at each occurrence, is selected from H, C1-10 alkyl substituted with 0-2 Rb, and C1-8 alkyl substituted with 0-2 Rd;
Rd, at each occurrence, is independently selected from phenyl substituted with 0-3 Rb, biphenyl substituted with 0-2 Rb, naphthyl substituted with 0-3 Rb and a 5-10 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
R6, at each occurrence, is selected from phenyl, naphthyl, C1-10 alkyl-phenyl-C1-6 alkyl-, C3-11 cycloalkyl, C1-6 alkylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxycarbonyloxy-C1-3 alkyl-, C2-10 alkoxycarbonyl, C3-6 cycloalkylcarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyloxy-C1-3 alkyl-, C3-6 cycloalkoxycarbonyl, phenoxycarbonyl, phenyloxycarbonyloxy-C1-3 alkyl-, phenylcarbonyloxy-C1-3 alkyl-, C1-6 alkoxy-C1-6 alkylcarbonyloxy-C1-3 alkyl-, [5-(C1-5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl]methyl, (5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyl, xe2x80x94C1-10 alkyl-NR7R7a, xe2x80x94CH(R8)OC(xe2x95x90O)R9, xe2x80x94CH(R8)OC(xe2x95x90O)OR9, and
R7 selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R7a is selected from H and C1-10 alkyl, C2-6 alkenyl, C3-6 cycloalkyl-C1-3 alkyl-, and phenyl-C1-6 alkyl-;
R8 is selected from H and C1-4 linear alkyl;
R9 is selected from H, C1-8 alkyl substituted with 1-2 Re, C3-8 cycloalkyl substituted with 1-2 Re, and phenyl substituted with 0-2 Rb;
Re, at each occurrence, is selected from C1-4 alkyl, C3-8 cycloalkyl, C1-5 alkoxy, phenyl substituted with 0-2 Rb;
p, at each occurrence, is selected from 0, 1, and 2;
r, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
rxe2x80x2, at each occurrence, is selected from 0, 1, 2, 3, 4, and 5;
rxe2x80x3, at each occurrence, is selected from 1, 2, and 3;
s, at each occurrence, is selected from 0, 1, 2, and 3; and,
sxe2x80x2, at each occurrence, is selected from 0, 1, 2, and 3.
In a preferred embodiment, the present invention provides a compound wherein;
A is selected from COR5, xe2x80x94CO2H, CH(R)CO2H, xe2x80x94CONHOH, CH(R)CONHOH, xe2x80x94CONHOR5, xe2x80x94CONHOR6, xe2x80x94N(OH)COR5, xe2x80x94SH, and xe2x80x94CH2SH;
ring B is a 4-7 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
U is absent;
X is absent;
Y is absent;
Z is selected from a C5-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), OC(O)NRa, NRaC(O)O, NRaC(O)NRa, S(O)pNRa, and NRaS(O)p;
R2 is selected from H, Qxe2x80x2, C1-5 alkylene-Qxe2x80x2, C2-5 alkenylene-Qxe2x80x2, C2-5 alkynylene-Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rQxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2C(O)O(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2;
Qxe2x80x2 is selected from H, phenyl substituted with 0-3 Rb and a 5-6 membered heteroaryl system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
R3 is selected from H, Q, C1-10 alkylene-Q, C2-10 alkenylene-Q, C2-10 alkynylene-Q, (CRRxe2x80x2)rxe2x80x2O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rC(O)(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rQ, (CRRxe2x80x2)rxe2x80x2C(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)O(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2S(O)p(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2SO2NRa(CRRxe2x80x2)rxe2x80x94Q, (CRRxe2x80x2)rxe2x80x2NRaSO2(CRRxe2x80x2)rxe2x80x94Q, and (CRRxe2x80x2)rxe2x80x2NRaSO2NRa(CRRxe2x80x2)rxe2x80x94Q;
R, at each occurrence, is independently selected from H, CH3, and CH2CH3;
Rxe2x80x2, at each occurrence, is independently selected from H and CH3;
Q is selected from H, a C3-10 carbocyclic residue substituted with 0-5 Rb and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb; and,
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Raxe2x80x3, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S.
In a more preferred embodiment, the present invention provides a compound wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, CH(R)CONHOH, xe2x80x94CONHOR5, and xe2x80x94N(OH)COR5;
ring B is a 4-6 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
Z is absent or selected from a C5-6 carbocyclic residue substituted with 0-3 Rb and a 5-9 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb;
Ua is absent or is selected from: O, NRa, C(O), C(O)NRa, NRaC(O), and S(O)pNRa;
Xa is absent or C1-10 alkylene;
R2 is selected from H, C1-5 alkylene-Qxe2x80x2, (CH2)rxe2x80x2(CH2)rxe2x80x94Qxe2x80x2, (CH2)rxe2x80x2NRa(CH2)rQxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)(CRRxe2x80x2)rQxe2x80x2, (CH2)rxe2x80x2C(O)NRa(CH2)rxe2x80x94Qxe2x80x2, (CRRxe2x80x2)rxe2x80x2NRaC(O)NRa(CRRxe2x80x2)rxe2x80x94Qxe2x80x2, and (CH2)rxe2x80x2C(O)(CH2)rxe2x80x94Qxe2x80x2;
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-9 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S; and,
Q is selected from H, a C5-6 carbocyclic residue substituted with 0-5 Rb and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rb.
In an even more preferred embodiment, the present invention provides a compound wherein;
A is selected from xe2x80x94CO2H, CH2CO2H, xe2x80x94CONHOH, and xe2x80x94N(OH)CHO;
ring B is a 4-5 membered cyclic amide containing from 0-2 additional heteroatoms selected from O, NRa, and S(O)p, and 0-1 additional carbonyl groups and 0-1 double bonds;
X is absent or selected from C1-4 alkylene, C2-4 alkenylene, and C2-4 alkynylene;
Z is absent or selected from phenyl substituted with 0-3 Rb and a 5-9 membered aromatic heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-3 Rb;
Xa is absent or C1-4 alkylene;
Ya is absent or selected from O and NRa;
Za is selected from H, a C5-10 carbocyclic residue substituted with 0-5 Rc and a 5-10 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S and substituted with 0-5 Rc;
R4 is selected from H, C1-4 alkylene-H, (CH2)rxe2x80x2O(CH2)rxe2x80x94H, and (CH2)rxe2x80x2NRa(CH2)rxe2x80x94H; and,
Rc, at each occurrence, is independently selected from C1-6 alkyl, ORa, Cl, F, Br, I, xe2x95x90O, CN, NO2, NRaRaxe2x80x2, C(O)Ra, C(O)ORa, C(O)NRaRaxe2x80x2, S(O)2NRaRaxe2x80x2, S(O)pRa, CF3, CF2CF3, and a 5-6 membered heterocyclic system containing from 1-4 heteroatoms selected from the group consisting of N, O, and S.
In a preferred embodiment, the present invention provides a compound wherein;
(xcex1S,3R)-xcex1-[(2,2-dimethyl-1-oxopropyl)amino]-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
1,1-dimethylethyl [2-(hydroxyamino)-(1S)-1-[1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-oxoethyl]carbamate;
(xcex1S,3R)-xcex1-amino-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
(xcex1S,3R)-xcex1-(acetylamino)-N-hydroxy-1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-3-pyrrolidineacetamide;
N-[2-(hydroxyamino)-(1S)-1-[1-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-oxoethyl]-4-morpholinecarboxamide;
1,1-dimethylethyl [(1S)-1-[1-[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]-2-oxo-(3R)-3-pyrrolidinyl]-2-(hydroxyamino)-2-oxoethyl]carbamate;
(xcex1S,3R)-xcex1-amino-1-[4-[(2,6-dimethyl-4-pyridinyl)methoxy]phenyl]-N-hydroxy-2-oxo-3-pyrrolidineacetamide;
methyl (1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethylcarbamate;
butyl (1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethylcarbamate;
N-[(1S)-2-(hydroxyamino)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-oxoethyl]benzamide;
(2S)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-2-(1H-pyrrol-1-yl)ethanamide;
(2S)-2-(dimethylamino)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethanamide;
(2R)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)propanamide;
(2S)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)propanamide;
(2R)-N-hydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)pentanamide;
(2S)-N,2-dihydroxy-2-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethanamide;
(1S)-1-{(3R)-1-[4-(benzyloxy)phenyl]-2-oxopyrrolidinyl}ethyl(hydroxy)formamide;
hydroxy[(1S)-1-((3R)-1-{4-[(2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)ethyl]formamide;
(2R,S)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypentanamide;
(2S,R)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypentanamide;
(2S,R)-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypropanamide;
(2S,R)-((3S,R)-3-(dimethylamino)-1-{f4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxypropanamide; and,
2-((3S,R)-3-amino-1-{4-[2-methyl-4-quinolinyl)methoxy]phenyl}-2-oxopyrrolidinyl)-N-hydroxyacetamide;
or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method for treating or preventing an inflammatory disorder, comprising: administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as rheumatoid arthritis, osteoarthritis, periodontitis, gingivitis, corneal ulceration, solid tumor growth and tumor invasion by secondary metastases, neovascular glaucoma, multiple sclerosis, or psoriasis in a mammal, comprising: administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides a novel method of treating a condition or disease wherein the disease or condition is referred to as fever, cardiovascular effects, hemorrhage, coagulation, cachexia, anorexia, alcoholism, acute phase response, acute infection, shock, graft versus host reaction, autoimmune disease or HIV infection in a mammal comprising administering to the mammal in need of such treatment a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt form thereof.
In another embodiment, the present invention provides novel lactams of formula I for use in therapy.
In another embodiment, the present invention provides the use of novel lactams of formula I for the manufacture of a medicament for the treatment of an inflammatory disorder.
In another embodiment, the present invention provides the use of novel lactams of formula I for the manufacture of a medicament for the treatment of a condition or disease mediated by MMPs, TNF, aggrecanase, or a combination thereof.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Geometric isomers of double bonds such as olefins and Cxe2x95x90N double bonds can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated. All processes used to prepare compounds of the present invention and intermediates made therein are considered to be part of the present invention.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced. Keto substituents are not present on aromatic moieties. When a ring system (e.g., carbocyclic or heterocyclic) is said to be substituted with a carbonyl group or a double bond, it is intended that the carbonyl group or double bond be part (i.e., within) of the ring.
The present invention is intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include C-13 and C-14.
When any variable (e.g., Rb) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Rb, then said group may optionally be substituted with up to two Rb groups and Rb at each occurrence is selected independently from the definition of Rb. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. C1-10 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkyl groups. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and s-pentyl. xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)). Examples of haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl. xe2x80x9cAlkoxyxe2x80x9d represents an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. C1-10 alkoxy, is intended to include C1, C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkoxy groups. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, s-butoxy, t-butoxy, n-pentoxy, and s-pentoxy. xe2x80x9cCycloalkylxe2x80x9d is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, or cyclopentyl. C3-7 cycloalkyl, is intended to include C3, C4, C5, C6, and C7 cycloalkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl and propenyl. C2-10 alkenyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkenyl groups. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl and propynyl. C2-10 alkynyl, is intended to include C2, C3, C4, C5, C6, C7, C8, C9, and C10 alkynyl groups.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, and sulfate.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, and tetrahydronaphthyl.
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. A nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heterocycle is not more than 1. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d or xe2x80x9cheteroarylxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and 1, 2, 3, or 4 heterotams independently selected from the group consisting of N, NH, O and S. It is to be noted that total number of S and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-thiazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, and xanthenyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; and alkali or organic salts of acidic residues such as carboxylic acids. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, and isethionic.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
xe2x80x9cTherapeutically effective amountxe2x80x9d is intended to include an amount of a compound of the present invention or an amount of the combination of compounds claimed effective to inhibit a MMP related disorder in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984), occurs when the effect (in this case, inhibition of a MMP) of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased inhibitory effect, or some other beneficial effect of the combination compared with the individual components.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereon as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All references cited herein are hereby incorporated herein in their entirety by reference.
The novel compounds of this invention may be prepared using the reactions and techniques described in this section. The reactions are performed in solvents appropriate to the reagents and materials employed and are suitable for the transformations being effected. Also, in the description of the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
A variety of compounds of formula (I) wherein ring B is pyrrolidinone or piperidinone can be prepared by methods described in Scheme 1. Carboxylic acid 1 can be converted to 3 under several sets of literature conditions. One example is activation of 1 with trimethylacetyl chloride followed by treatment with 2. Alkylation of 3 with methyl bromoacetate or t-butyl bromoacetate provides 4a or 4b, respectively. 4a and 4b are converted to aldehydes 5a and 5b by oxidative degradation, such as ozonolysis, or dihydroxylation (OSO4) followed by cleavage with NaIO4. The desired pyrrolidinone 7a and piperidinone 7b are synthesized upon treatment of aldehyde 5 and appropriately functionalized amine 6 with zinc in acetic acid at elevated temperature. Alternatively, 5 and 6 are first coupled to form imine in toluene at reflux, then reduced with reducing agent such as sodium triacetoxyborohydride, and finally cyclized at elevated temperature. As another alternative route to 7b, 4b is hydrolyzed to give carboxylic acid 8. 8 is coupled to an appropriately substituted amine 6 by methods well described in the literature for making amide bonds, such as BOP-Cl in THF, to give compound 9. Following oxidative cleavage as described previously, the resultant aldehyde 10 is treated with reducing agents such as triethylsilane in the presence of acids such as trifluoroacetic acid to provide 7b.
The methyl ester of 7 (R11=Me) is converted to hydroxamic acid 11 by treatment with hydroxylamine under basic conditions such as KOH or NaOMe in solvents such as methanol (Scheme 2). The methyl ester 7 (R11=Me) can also be converted to O-benzyl protected hydroxamic acid with O-benzylhydroxylamine under similar conditions or using Weinreb""s trimethylalluminum conditions (Levin, J. I.; Turos, E.; Weinreb, S. M. Syn. Commun. 1982, 12, 989) or Roskamp""s bis[bis(trimethylsilyl)amido]tin reagent (Wang, W.-B.; Roskamp, E. J. J. Org. Chem. 1992, 57, 6101). The benzyl ether is removed by methods well known in the literature such as hydrogenation using palladium on barium sulfate in hydrogen, to give compound 11. Alternatively, 11 can be prepared through the carboxylic intermediate 12. Carboxylic acid 12 is converted to 11 via coupling with hydroxylamine or O-benzylhydroxylamine followed by deprotection.
A variety of compounds of formula (I) wherein ring B is pyrrolidinone or piperidinone and R3 is alkyl can be prepared by methods described in Scheme 3. Following known literature procedure (Becket, R. P.; Crimmins, M. J.; Davis, M. H.; Spavold, Z. Synlett 1993, 137), intermediate 8 from Scheme 1 is converted to anti-succinate 14 via alkylation and epimerization. Following esterification and olefin cleavage, the aldehyde 16 is converted to lactam 17 following conditions as described previously. Ester 17 is converted to the hydroxamic acid following the sequences outlined in Scheme 2.
A variety of compounds of formula (I) wherein ring B is imidazolinone or piperazinone can be prepared by methods described in Scheme 4. Esterification of D-aspartic acid 18 and alkylation provide anti-alkylated product 20. Cleavage of benzyl ester, coupling with appropriately functionalized amine 6 under conditions described previously and unmasking of the amino group gives 23. The imidazolinone ring formation is achieved with formaldehyde in solvent such as toluene at elevated temperature. The piperazinone analogues can be synthesized from common intermediate 21. Following coupling with appropriately functionalized amine 25 and olefin cleavage, the aldehyde 27 is converted to piperazinone 28 following conditions as described previously. The secondary amine center of 28 is further functionalized as tertiary amines, amides, sulfonamides, carbamates, ureas, or sulfonylureas (29). Esters 24, 28 and 29 are converted to the hydroxamic acids following the sequences outlined in Scheme 2.
A variety of compounds of formula (I) wherein R3 is an amino derivative can be prepared by methods described in Scheme 5. L-Aspartic acid 30 is converted to 32 following similar sequence described earlier. Oxidative cleavage of 32 yields aldehyde 33 (n=1), an intermediate for pyrrolidinones. The corresponding intermediate for piperidinones, 33 (n=2), is synthesized by hydroboration with agents such as 9-BBN and oxidation following methods well described in the literature, such as Swern oxidation. 33 is converted to 34 following conditions described previously. After removal of BOC group, The primary amine center of 35 is further functionalized as secondary or tertiary amines, amides, sulfonamides, carbamates, ureas, or sulfonylureas (36 and 37). Esters 34-37 are converted to the hydroxamic acids following the sequences outlined in Scheme 2.
A variety of compounds of formula (I) wherein R3 is OR can be prepared by methods described in Scheme 6. Frater alkylation of dimethyl malate (38) establishes the anti configuration. 39 is converted to 41 using chemistry described previously. The hydroxyl group in 41 is functionalized as ethers, esters, carbonates or urethanes (42). Esters 41-42 are converted to the hydroxamic acids following the sequences outlined in Scheme 2.
A variety of compounds of formula (I) wherein A is xe2x80x94NH(OH)C(O)H can be prepared by methods described in Scheme 7. Frater alkylation, and Wenreib amide formation with O-t-butylhydroxylamine give 45. xcex2-Lactam formation is done by mesylate formation and base-induced lactamization. TMSCl mediated methanolysis followed by N-formylation provide 49. Following sequence analogous to that described in previous schemes, lactam 51 is obtained. Hydrolysis of t-Butyl group in 51 completes the synthesis.
A variety of compounds of formula (I) wherein R1 is functionalized phenyl group can be prepared by methods described in Scheme 8. Intermediate 53, available from schemes described previously, is converted to phenol 54 by hydrogenolysis. 54 is used as common intermediates for structure diversification. Reaction of 54 with R11xe2x80x94X provides 55, an alternative is the reaction of 54 with R11xe2x80x94OH under Mitsunobu conditions to produce 55. R10 can be appended directly to the aromatic ring by converting 54 to an aryl triflate then reaction with an organometallic in the presence of a palladium (0) catalyst to give 56. 54 can also be reacted with acyl halides or isocyanates to afford 58. Biaryl ethers 57 can be produced by treatment of 54 with aryl boronic acids in the presence of a copper catalyst. Esters 55-58 are converted to the hydroxamic acids following the sequences outlined in Scheme 2.
A variety of compounds of formula (I) wherein R2 is an amino derivative can be prepared by methods described in Scheme 9. Protecting group manipulations on 59 give 61. Allylation and esterification gives 63. 63 is converted to lactam 65 following previously described sequences. Allylation and hydrogenation provide phenol 67. 67 can be functionalized following scheme 8 and converted to hydroxamic acid following scheme 2.
Aternatively, phenol 67 can be prepared following scheme 10. Allylation of 60 gives 68 with the desired anti configuration. Following hydrogenation, 69 is further allylated and protected as methyl ester. 70 is then converted to phenol 67 following previously described sequences.
One diastereomer of a compound of Formula I may display superior activity compared with the others. Thus, the following stereochemistries are considered to be a part of the present invention.
When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Steven D. Young, et al, Antimicrobial Agents and Chemotheraphy, 1995, 2602-2605. A chiral compound of Formula I may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Andrew S. Thompson, et al, Tert. lett. 1995, 36, 8937-8940).
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.

Lactam inhibitors of matrix metalloproteinases, TNF-xcex1 and aggrecanase

Abstract: or pharmaceutically acceptable salt forms thereof, wherein ring B is a 4-8 membered lactam containing from 0-3 additional heteroatoms selected from N, O, and S, which are useful as inhibitors of matrix metalloproteinases, TNF-xcex1, and aggrecanase.