An apparatus for ultrasound irradiation of a body part (208) includes a first ultrasound transducer (216), and a second ultrasound transducer (212) mounted oppositely, and is configured: a) such that at least two ultrasound receiving elements, for determining a relative orientation of the first to the second transducer, are attached to the first transducer; b) for a beam, from the first transducer, causing cavitation, and/or bubble destruction of systemically circulating microbubbles, within the body part; or c) both with the attached elements and for the causing. The apparatus registers, with said first transducer, the second transducer, by using as a reference respectively the features a) and/or b). A detachable subsystem includes either a therapy or imaging transducer, to form a combination imaging and therapy system, the subsystem being configured for removable coupling to correspondingly an imaging or therapy subsystem comprising a head frame (204) to which is mounted an imaging or therapy transducer, the imaging or therapy subsystem for registering the imaging or therapy transducer, one to the other, by the above method.

It has been known for many years that ultrasound in combination with thrombolytic drugs, in particular tissue plasminogen activator (tPA) can aid in the dissolution of blood clots that cause ischemic stroke. However, tPA has many side effects and can be deadly when used in a hemorrhagic (bleeding) stroke patient and so requires a CT to rule out hemorrhage before its use. Ultrasound in combination with microbubble contrast agents has also been shown to lyse blood clots with potentially fewer adverse effects. This effect is commonly referred to as sonothrombolysis (STL).
Transcranial imaging has long been used to diagnose cerebrovascular diseases such as stroke with diagnostic ultrasound systems. Strokes nearly always occur on one side of the brain or the other. The most common clinical diagnosis of stroke is weakness on one side, implying a stroke on the opposite side since the right side of the brain controls motor function on the left side of the body and vice versa. Approximately 70% of all ischemic strokes occur in the middle cerebral artery (MCA), a major vessel, and strokes here are especially devastating. The MCA is located behind the temporal bone (at a depth of approximately 3-5 cm), the thinnest part of the skull and hence the least attenuating for ultrasound.
Commonly-assigned U.S. Patent Publication No. 2010/0160779 to Browning et al. (hereinafter "the Browning application"), the entire disclosure of which is incorporated herein by reference, discloses a headset into which are mounted transducers for STL.

Transducer placement and registration for image-guided sonothrombolysis


A device for actuating at least one throttle valve of an internal combustion engine is provided. When the throttle valve opening angles are small, the throttle valve and the actuating device are positively coupled, and when the throttle valve opening angles are large, the throttle valve and the actuating device are form lockingly coupled in the closing direction, but are only conditionally coupled in the opening direction, such that the throttle valve can be brought into operation for smaller throttle valve opening angles.

The invention relates to a device for actuating at least one throttle valve of an internal-combustion engine, having an actuating device, such as a throttle twist grip, a stop, which may be swiveled about an axis via the actuating device, a driving device corresponding with the stop, and a throttle valve, which may be swiveled by means of the driving device. The stop limits a movement of the throttle valve in an opening direction. The stop is acted upon by a spring in the closing direction of the throttle valve. The driving device follows the stop while being acted-upon by the spring. An adjusting device is provided for a controlled throttle valve intervention.
Actuating devices of this type permit a throttle valve intervention in the closing direction superimposed upon the driver's actuation intention. In this context, reference is made to German Patent document DE 40 11 182 A1.
For example, in the case of a motorcycle, when the throttle twist grip is operated by the driver, a swiveling of a cable pulley takes place by way of a Bowden cable, which cable pulley has a stop, which can be swiveled by means of the cable either indirectly or directly. Acted upon by spring force, the cable pulley is prestressed in the closing direction. If required, by the use of additional kinematic transmission members, the stop corresponds with a driving device and actuates a throttle valve in the opening direction, which throttle valve is arranged on a shaft.
If the throttle twist grip is not operated or is operated less, the cable pulley, while being acted upon by spring force, swivels in the closing direction into the corresponding position defined by the driver. The driving device—also while being acted upon by a spring force—following the stop.
According to a control device, a throttle valve intervention takes place as a function of a plurality of input values in that an adjusting device acts upon the throttle valve in the closing direction. In this case, the driving device lifts off the stop, so that the intervention is not noticeable on the driver side at the throttle twist grip.
Such a throttle valve intervention can take place, for example, with respect to a limiting of the maximal vehicle speed, of the internal-combustion engine torque or, for reasons of acoustics, also before the background of an optimized load cycle.
However, it was found that the uncoupling of the stop and the driving device is problematic, particularly in the lower load range. In the case of small throttle valve angles, a good apportioning capability is required, which does not exist because the driving device follows the stop only slightly because of the spring force and, particularly in the lower load range, the throttle valve is extremely loaded by low pressure.
An aspect of the invention is to cost-effectively provide an actuating device of the above-mentioned type by the use of simple devices, which actuating device is operationally reliable and permits a good apportioning of the internal-combustion engine power also in a lower load range.
This present invention meets this need by providing a device for actuating at least one throttle valve of an internal-combustion engine. The device includes an actuating device, such as a throttle twist grip, a stop, which may be swiveled about an axis by use of the actuating device, a driving device corresponding with the stop, and a throttle valve, which may be swiveled by use of the driving device. The stop limits movement of the throttle valve in the opening direction, and is acted upon by a spring in the closing direction of the throttle valve. The driving device follows the stop while being acted-upon by the spring. An adjusting device is provided for the controlled throttle valve intervention, wherein the stop and the driving device may be mutually coupled in a form-locking manner. According to the basic idea, the stop and the driving device can be formlockingly coupled with one another.
Particularly preferable embodiments and further developments of the invention are described and claimed herein.
According to a particularly preferable embodiment, a coupling of the stop and the driving device takes place as a function of the throttle valve opening angle. That is, below a predetermined throttle valve opening angle (in the case of small throttle valve opening angles), the stop and the driving device are mutually coupled and, above the predetermined throttle valve opening angle (in the case of small throttle valve opening angles), the stop and the driving device are uncoupled.
In an embodiment in which the stop is assigned to a cable pulley, which may be operated by way of a Bowden cable, the Bowden cable covers a partial circumference of the cable pulley, and the driving device is arranged to be axially spaced from the cable pulley. A lever element is expediently provided for connecting the cable pulley and the driving device. The lever element may be operated by means of the Bowden cable. If required, more than a partial circumference of the cable pulley may also be covered by the Bowden cable. It is important that the Bowden cable lifts tangentially off the cable pulley in a transition area. The driving device operates a shaft arranged coaxially with respect to the cable pulley axis.
It is very advantageous for the lever element to be assigned to the cable pulley and to be swivel able together with the latter about the cable pulley axis.
According to a particularly preferable embodiment of the invention, the lever element has a first cable-pulley side end area and a second driving-device-side end area. Expediently, the first end area of the lever element, as a function of the position of the cable pulley, is assigned to the partial circumference of the cable pulley, which is covered by the Bowden cable or is not covered by the Bowden cable.
Advantageously, in the covered partial circumference of the cable pulley, the Bowden cable acts upon the first end area of the lever element such that the lever element is operated in the engaging direction, the second end area being connected with the driving device. In the uncovered partial circumference of the cable pulley, the first end area of the lever element is released, so that the lever element is disengaged while being acted upon by spring force.
The driving device expediently has a recess corresponding with the second end area of the lever element, for the form-locking connection with the lever element.
Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings.

Device for actuating a throttle valve of an internal combustion engine

Bayerische Motoren Werke Aktiengesellschaft


A semiconductor memory device which employs a hierarchical word-decode scheme for word selection includes sub-word lines provided for each of column blocks, a control circuit selecting one of the column blocks corresponding to a currently accessed column address in a first case where a currently accessed row address is different from a successively accessed row address, and selecting all of the column blocks in a second case where the currently accessed row address is the same as the successively accessed row address, and a sub-word decoder selectively activating the sub-word lines with respect to all of one or more column blocks selected by the control circuit.

1. Field of the Invention
The present invention generally relates to semiconductor memory devices, and particularly relates to a semiconductor memory device which employs a hierarchical word-decode scheme.
2. Description of the Related Art
The hierarchical word-decode scheme employs a hierarchical structure of word lines in which two types of word lines, i.e., main-word lines and sub-word lines, are used for word selection. A typical material used for word lines is polysilicon. Unfortunately, polysilicon has a relatively high resistance for wiring material, causing a significant delay to signals propagating therethrough. A conventional technique to counter this is to establish contact at predetermined intervals between polysilicon word lines and aluminum wiring lines arranged in parallel to the polysilicon word lines, thereby reducing a resistance of the word lines. In order to increase circuit density, however, intervals between the wiring lines needs to be shortened, but it is difficult to implement a pattern of aluminum wiring lines having the same pitch as polysilicon wiring lines. The hierarchical word-decode scheme obviates this problem by dividing polysilicon word lines into sub-word lines having tolerable delays and by using aluminum for main-word lines to achieve sufficiently small delays.
FIG. 1 is an illustrative drawing showing a word-line structure according to a related-art hierarchical word-decode scheme. A main-word decoder 201 decodes a row address to select one of main-word lines 213, and turns the selected main-word line to HIGH. The main-word lines 213 are provided on a wiring layer. In a different wiring layer, four sub-word lines 214 are laid out generally under the main-word lines 213. The sub-word lines 214 are connected to four types of sub-word decoders 209 through 212, respectively. The sub-word decoders of the same type are arranged in a row perpendicular to the extension of the main-word lines 213.
A sub-word-decoder selecting circuit 203 selects one type of sub-word decoder from the four types of the sub-word decoders 209 through 212 via the sub-word-decoder selection lines 215. The selected type of the sub-word decoders connects the main-word lines 213 to the sub-word lines 214. As a result, only one of the four sub-word lines 214 connected to the selected one of the main-word lines 213 becomes HIGH when this sub-word line 214 is selected by the sub-word-decoder selecting circuit 203. This achieves a hierarchical word selection. In the case of data-read operations, for example, data stored in memory-cell arrays 207 is read by sense amplifiers of sense-amplifier blocks 204 only with respect to the selected word.
The memory-cell arrays 207 are arranged in a plurality of column blocks along a column direction (horizontal direction in the figure) as well as in a plurality of row blocks along a row direction (vertical direction in the figure). FIG. 1 only shows a configuration of one row block. This row block is selected when a row-block-selection circuit 202 selectively operates the sense-amplifier blocks 204 of his row block. In general, all the sense-amplifier locks 204 are operated with respect to a selected row lock.
The operation described above is generally referred to as a RAS (row address strobe) operation. Following this RAS operation, a CAS (column address strobe) operation is performed to read data from the semiconductor memory device. That is, a column decoder 217 selectively activates one of the column-selection lines 218 corresponding to an indicated column address so as to select a sense amplifier from one of the sense-amplifier blocks 204, thereby allowing data to be read from the selected sense amplifier.
In semiconductor devices, it is preferable to reduce power consumption as much as possible. In order to meet this demand, a column address may be supplied by the time a row access is performed, so as to allow sense amplifiers to operate only with respect to a column block of a selected column address.
FIG. 2 is an illustrative drawing showing a configuration which activates only a selected column block in the hierarchical word-decode scheme.
In the configuration of FIG. 2, all the sense-amplifier blocks 204 are not driven, but only one of the sense-amplifier blocks 204 is operated with respect 20 to a selected column address. A column-block-selection circuit 208 is provided for this purpose.
Before a row access is performed, a column address is supplied to the device, and the column-block-selection circuit 208 selects a column block corresponding to an indicated column address. Column-block-selection lines 216 extend from the column-block-selection circuit 208, and are connected to sense-amplifier-control circuits 205 and sub-word-decoder-control circuits 206. The sense-amplifier-control circuits 205 drive only one of the sense-amplifier blocks 204 selected by the column-block-selection circuit 208 in a selected row block when the row-block-selection circuit 202 selects this row block. The sub-word-decoder-control circuits 206 supply selection signals from the sub-word-decoder selecting circuit 203 to the sub-word decoders 209 through 212 only in the column block selected by the column-block-selection circuit 208.
In this manner, data access is made to a memory-cell array 207 of a selected column with respect to a selected row block, and one of the sense-amplifier blocks 204 is operated only with respect to the selected column block. This achieves a reduction in the operation load of the circuits relating to the RAS operation, and, at the same time, achieves a reduction in power consumption.
When the RAS operation is performed by the unit of a column block as shown in FIG. 2, however, a speed limit is placed on the CAS operation. In the configuration of FIG. 1, the sub-word lines 214 are selectively activated with respect to all the column blocks, and the sense-amplifier blocks 204 are activated for all the column blocks. As long as successive accesses are made to the same row address, data can be consecutively read from different column addresses of the sense-amplifier blocks 204 by successively selecting the column-selection lines 218. In the configuration of FIG. 2, on the other hand, each time data is read from a column block, a selective activation needs to be performed with respect to the main-word lines 213 and the sub-word lines 214. That is, the RAS operation is necessary at every turn even when the same row address continues to be accessed.
Even though the RAS operation in the configuration of FIG. 2 has a greater speed than the RAS operation of FIG. 1 because of the column-block-wise access, there is a need to carry out the RAS operation each time a column block is accessed. The configuration of FIG. 2 thus suffers a reduction in operation speed when a total of the RAS operation and the CAS operation is taken into consideration, compared to the configuration of FIG. 1.
Accordingly, there is a need for a semiconductor memory device which can achieve a high speed operation while performing column-block-wise access to reduce power consumption.

Semiconductor memory device with row access in selected column block


In a sunroof system (3) for a vehicle using a push-pull cable (22) for actuating a sunroof panel (4), the push-pull cable is received in a drive pipe (25), and a sunroof frame (12) is provided with a drive pipe retaining feature (16, 18). Therefore, the drive pipe may be made of flexible material, and firmly held in place by the pipe retaining feature even when the push-pull cable is subjected to significant tensile and compressive load. The pipe retaining feature may include a pipe retaining groove (16) for receiving the drive pipe and clips (18) for resiliently retaining the drive pipes in the pipe retaining groove.

The present invention relates to a drive system for a closure member configured to selectively close an opening of a vehicle roof, and in particular to an automotive sunroof system.
In a typical automotive sunroof system, a pair of side frames each fitted with a guide rail extend in a fore-and-aft direction on either side of a roof opening. Each side frame has a front end adjacent to a front edge of the roof opening and a rear end extending further rearward from a rear edge of the roof opening. A pair of sliders supporting a slide panel are slidably supported by the corresponding guide rails, and to each slider is connected an end of a Bowden or push-pull cable which is configured to be pushed and pulled as required by an electric motor located centrally in a front frame extending along the front edge of the roof opening. Thereby, the slide panel can be moved in a fore-and-aft direction between a closed position fully closing the roof opening and an open position fully exposing the roof opening.
The push-pull cable typically comprises an inner wire including a steel core wire and an additional outer wire wrapped spirally around the core wire, and, optionally, a sheath pipe or a housing that slidably receives the inner wire. The push-pull cable is normally held in position to the corresponding side frame by using cable guides integrally formed in the side frame, and extends substantially linearly along the length of the side frame. A relatively rigid drive pipe made of steel extends from the front end of each side from to a drive gear of the electric motor, and an idle pipe extends from the drive gear away from the drive pipe so that the section of the push-pull cable extending from the front end of the side panel past the drive gear of the electric motor may be guided without any significant deflection in spite of the significant tension and compression that is required to be transmitted by the push-pull cable.
Such a drive pipe and idle pipe are required to be bent in a complex configuration, and this contributed to an increase in the cost of the sunroof system. Japanese patent No. 3043589 (patent document 1) discloses an automotive sunroof system including a pair of drive pipes that are disposed on a common plane and a pair of idle pipes that are made of relatively flexible plastic material. Thereby, the work required for bending the drive pipes can be simplified, and the generation of noises due to the collision between the drive pipes and idle pipes that can be caused by the vibrations of the vehicle can be avoided.
Japanese patent No. 3994815 (patent document 2) discloses an automotive sunroof system in which a front frame made of plastic material is integrally molded with guide pipe portions for receiving the push-pull cable therein. This prior invention allows the number of component parts to be reduced.
According to the invention disclosed in patent document 1, the drive pipes are made of steel, and the need for bending steel pipes prevents the reduction in the manufacturing cost and weight. Because each drive pipe is required to protrude ahead of the front frame for the purpose of avoiding a sharp bending of the drive pipe, the protruding parts of the drive pipes are prone to inadvertent deformation during the handling of the sunroof assembly, and any deformation of the drive pipes may ruin the whole drive system of a sunroof system.
In the case of the sunroof system disclosed in patent document 2, the number of component parts can be reduced owing to the elimination of the drive pipes, but a highly complex die assembly is required for molding the front frame, and this increases the manufacturing cost. Furthermore, because the guide pipe portions cannot be molded so as to entirely surround the push-pull cables, a measure is required to prevent grease from dripping from the guide pipe portions. It is also difficult to entirely eliminate noises that are caused by the sliding contact between the cable and guide pipe portions.
The guide pipe portions are typically given with a highly complex configuration, and this tends to cause poor dimensional and geometrical precision. If there are burrs in the guide pipe portions, the sliding engagement between the burrs and cables cause noises.


A spike, drivable into the trunk of a tree, includes a hollow body which provides a storage chamber for a water soluble compound such as a pesticide or fertilizer. The spike has a generally pointed first end which facilitates driving the spike into a tree trunk. The hollow body is equipped with bleed apertures near the pointed end, so that when the spike is driven into the trunk of a tree, the storage chamber is coupled to the vascular system thereof. The spike is supplied with a resilient sheath that seals the bleed apertures during shipping and handling. As the spike is driven into a tree trunk, the sheath is peeled off the body, thereby exposing the bleed apertures to the tree""s vascular tissue and forming a gasket between the spike body and the aperture created by driving the spike into the trunk.

1. Field of the Invention
This invention relates to devices for introducing a water soluble compound, such as a pesticide or fertilizer, into the vascular system of plants.
2. Description of the Prior Art
The injection of nutrients, pesticides and dyes into the vascular system of trees and plants has long been known in the art, as evidenced by the issuance of more than a dozen U.S. patents related methods and apparatus since the beginning of the twentieth century. For example, U.S. Pat. No. 952,245 to Levi S. Gardner discloses a process for coloring the wood of living trees by injecting dyes into their vascular systems. U.S. Pat. No. 2,044,063 to Arnold V. Dahlberg, is an example of a process for fertilizing trees and shrubs which bypasses the natural root system by introducing a nutrient solution directly into the cambium layer. More recent patents include U.S. Pat. No. 3,286,401 to James J. Mauget for a pressurized plant injection device and U.S. Pat. No. 4,989,366 to Terry A. DeVlieger for a gravity-feed fluid injection device for trees.
During the past decade, the world economy has experienced explosive economic growth. That growth has resulted in greatly increased demand for paper and lumber. Increased demand and more restrictive logging directives recently promulgated by the U.S. Forest Service have resulted in a doubling of the price of lumber during the same period. Sadly, at this time of increasing demand for timber, whole forests often die from insect infestations. While gypsy moths destroy hardwood trees, bark beetles lay waste to stands of Douglas firs. Annual losses to insect pests total in the billions of dollars.
The spraying of insecticides on forests has several major drawbacks. First, the insecticides are generally non-selective. Thus, both harmful and beneficial insects are killed. Second, aerial spraying of forests is in mountainous regions is quite hazardous. Third, pesticides are expensive, and aerial spraying coats everything, along with the trees. Fourth, much of the sprayed liquid ends up in streams and rivers, with deleterious consequences for animal life living on land and in water.
Though many of the existing injection methods and apparatus would work for injecting pesticides into the vascular tissue of trees, the known methods and devices are either too complex or too expensive to be used to treat entire forests. What is needed is a simple, inexpensive device which can be rapidly installed in the trunks of trees and which can be used to distribute insecticide throughout the vascular system of the tree so that insect pests that feed on parts of the tree will die.
The present invention includes a spike having a hollow body which provides a storage chamber for a water soluble compound such as a pesticide, fungicide, fertilizer, or any other aqueous solution used for the intravascular treatment of trees. The spike has a generally pointed end which can be driven into the trunk of tree. The hollow body is equipped with bleed apertures near the pointed end, so that when the spike is driven into the trunk of a tree, the storage chamber is coupled to the vascular system thereof. The spike is supplied with a resilient sheath that seals the bleed apertures during shipping and handling. As the spike is driven into a tree trunk, the sheath is peeled off the body, thereby exposing the bleed apertures to the tree""s vascular tissue and forming a gasket between the spike body and the aperture created by driving the spike into the trunk.
For a preferred embodiment of the invention, the spike includes a generally elongated, hollow body fabricated from a section of steel tubing. A hammer-drivable head, also made of steel, is welded or adhesively bonded to one end. The head may be either stamped, cast or machined. A pointed end piece, which may be either machined or cast, is welded or adhesively bonded to the opposite end. Bleed apertures are made in the tube wall near the pointed end and the spike is dipped in a solvated liquid polymeric compound. Once the solvent has evaporated, the polymeric compound becomes the resilient sheath, which seals the bleed apertures. When so assembled, a sealed chamber is formed within the tubing between the hammer drivable head and the point. The chamber can be most easily filled with a water soluble solution either by adhesively installing the hammer-drivable head last or by providing an aperture within the head which can be plugged after filling the chamber. For a preferred method of use, the spike is driven into the trunk near the base of the tree until the bleed apertures are positioned within the sapwood. In addition to sealing the fertilizer and/or pesticide containing solution, the sheath serves as a gasket once the spike is driven into a tree trunk, forming a seal which helps to prevent leaks of the solution to the exterior surface of the tree trunk.
If it is deemed important that the wood of the tree not be stained, the spike may be fabricated from stainless steel or heat-treated aluminum.
Alternative embodiments of the invention are also contemplated. For example, the spike may be injection molded from polymeric materials such as polyesters, acrylics, and epoxies, which are reinforced with structural fibers formed from glass, carbon, metal, or similar materials. As an ecological measure, the tree spike may even be cast from fiber-reinforced concrete. For tree spikes manufactured from polymeric materials or fiber-reinforced concrete, it may be preferable to drill, in the tree trunk, a hole having a diameter slightly smaller than that of the spike, so that an interference fit may be achieved without utilizing the spike to create the hole.
In order to rapidly treat large numbers of trees, the spike may be driven into tree trunks using a gun powered by pressurized air or explosive charges.

Perforated hollow spike for introducing a water soluble compound into a tree""s vascular system


A method is performed by a node configured to implement an Operation, Administration, and Maintenance (OAM) protocol for rapid link failure detection. The node receives peer OAM packets sent by a peer node over a link at a peer periodic interval. While in a first mode of the OAM protocol, the node determines whether the peer node is reachable based on the peer OAM packets, sends OAM packets to the peer node at a periodic interval to indicate to the peer node that the node is reachable, and responsive to detecting a critical condition of the node that impairs the sending the OAM packets, transitions to a second mode of the OAM protocol. While in the second mode, the node adds, to the peer OAM packets, a code to indicate the critical condition, and reflects the peer OAM packets with the code back to the peer node.

In a network, a bidirectional forwarding detection (BFD) protocol (referred to as simply "BFD") may be used to detect network reachability failures between peer nodes in the network on behalf of higher level routing protocols. The routing protocols, such as Open Shortest Path First (OSPF)/Intermediate System to Intermediate System (ISIS), and the like, use BFD to detect peer reachability failures quickly, and then take alternate paths to minimize any traffic loss in the network. The peer nodes exchange BFD "Hellos" in millisecond intervals to detect the reachability failures quickly. Unfortunately, BFD can give false alarms, i.e., indicate peer reachability failures, even when reachability is sound. The false alarms may occur when a peer node cannot timely service is local BFD timers that trigger sending of the BFD Hellos due to reasons unrelated to reachability between the peer nodes. The BFD false alarms can trigger what is referred to as "churn" in the overlaying routing protocols, which should be avoided.

Event-triggered adaptiveness to toggle timers/modes in fast-detection OAM protocols


A method for forming a self-aligned, recessed channel, MOSFET device that alleviates problems due to short channel and hot carrier effects while reducing inter-electrode capacitance is described. A thin pad oxide layer is grown overlying the substrate and a gate recess, followed by deposition of a thick silicon nitride layer filling the gate recess. The top surface is planarized exposing the pad oxide layer. An additional oxide layer is grown, thickening the pad oxide layer. A portion of the silicon nitride layer is etched away and additional oxide layer is again grown. This forms a tapered oxide layer along the sidewalls of the gate recess. The remaining silicon nitride layer is removed. The oxide layer at the bottom of the gate recess is removed and a gate dielectric layer is grown. Gate polysilicon is deposited filling the gate recess. S/D implantations, metallization, and passivation complete fabrication of the device.

(1) Field of the Invention
The invention generally relates to a method of fabricating a semiconductor device and, more particularly, to a method of fabricating a field-effect transistor (FET) having a recessed gate structure in the manufacture of integrated circuits.
(2) Description of Prior Art
A device prevalent in high-speed integrated circuits is the so-called metal-oxide-semiconductor field effect transistor (MOSFET). A MOSFET comprises three electrodes: a source, a drain and a gate. The heavily doped source and drain (S/D) regions are separated by a lightly doped channel. If the S/D are n-type material, then the channel is p-type and the device is an NMOS transistor. Conversely, if the S/D are p-type material, then the channel is n-type and a PMOS transistor results. The gate electrode is positioned over, but electrically insulated from the channel. By applying a voltage to the gate electrode, the conductivity of the channel is affected, thus a voltage on the gate can control the current between the source and drain. By implanting dopant ions into the channel, the threshold or "turn-on" gate voltage can be tailored to the required level.
As integrated circuit device dimensions are reduced, parasitic effects become a challenge. In MOSFET devices, as the distance between the source and drain (channel length) is reduced, punch-through, hot-carrier effect, and interelectrode capacitance become factors that degrade performance.
As the channel length is decreased, a voltage applied to the drain electrode can result in conduction between the source and drain without a voltage applied to the gate. This punch-through effect reduces the control the gate electrode has over the drain current. Typically, a punch-through implantation is performed (along with the threshold adjust implantation) prior to formation of any of the gate structure to counter the effects of the short channel.
To reduce the hot carrier effect, the S/D regions are formed with two dopant levels. Typically, lightly doped S/D regions are formed by ion implantation using the gate as a mask. This is followed by the formation of gate sidewall spacers to, in effect, widen the gate mask. This is followed by a second more heavily doped S/D implantation. The presence of a lightly doped S/D concentration near the gate electrode minimizes the hot carrier effect. Alternately, a lightly doped envelope for the heavily doped S/D junctions may be formed by a faster diffusing dopant ion implantation with a lower dose, followed by a heavy ion implantation at a higher dose.
Capacitance between the drain and substrate is inversely proportional to the width of the depletion region between them. For a specific S/D dopant concentration, the depletion region width decreases as the substrate dopant concentration increases. Thus, as the punch-through implantation increases the substrate dopant concentration, the depletion region width shrinks, and the drain capacitance increases. This increase in drain capacitance limits the speed at which the device and the integrated circuit will switch.
One method of reducing the aforementioned parasitic effects is to use a device with a recessed channel. The recessed channel reduces punch-through, and in some cases, the punch-through implantation step is eliminated and capacitance is reduced. Several methods of forming recessed channels have been described. U.S. Pat. No. 5,814,544 to Huang teaches a method of forming a recessed channel where a silicon nitride layer with a gate opening is patterned. Mask oxide is then grown in the exposed gate opening consuming some of the silicon. The S/D implantation is performed using the mask oxide in the gate opening as a mask. The oxide is then removed leaving a recessed channel area. U.S. Pat. No. 5,599,728 to Hu et al. teaches a method of forming a recessed gate by forming a trench in a silicon nitride spacer. A wet oxidation is performed creating the recessed gate. U.S. Pat. No. 5,610,090 to Jo teaches a method incorporating reactive ion etching (RIE) to form a non-symmetrical recessed gate. U.S. Pat. No. 5,270,228 to Ishikawa teaches a method of forming a two-level recessed gate using a single lithographic and etch step.

Process flow for a performance enhanced MOSFET with self-aligned, recessed channel

Chartered Semiconductor Manufacturing Ltd.


A novel gene of Bifidobacteria and the polypeptides encoded thereby. In particular, a gene belonging to the Serpin superfamily and its use in the production of bacterial Serpins is provided. Also provided are vectors, host cells, and methods for producing bacterial Serpin polynucleotides and/or polypeptides.

The present invention pertains to a novel gene of Bifidobacteria and to the polypeptides encoded thereby. In particular, the present invention pertains to a gene belonging to the Serpin superfamily and its use in the production of bacterial Serpins. Also provided are vectors, host cells, and methods for producing bacterial Serpin polynucleotides and/or polypeptides.
Lactic acid bacteria have been utilized for the preservation and preparation of food material for long time taking benefit of the low pH and the action of products generated during the fermentative activity thereof. In addition, Lactic acid bacteria are involved in the production of a variety of different food products, such as cheese or yogurt.
Quite recently lactic acid bacteria, in particular Lactobacilli and Bifidobacteria, have attracted a great deal of attention in that some strains have been found to exhibit valuable properties to man and animals upon ingestion. These strains, which are generically designated probiotics, have been found to be capable to survive the severe environmental conditions prevailing in the gastric tract and be able to at least transiently colonize the intestinal mucosa, where they bring about positive effects for the living beings having incorporated them.
In EP 0 768 375 such a probiotic strain of the genus Bifidobacterium is disclosed, which is capable to become implanted in the intestinal flora. This Bifidobacterium is reported to assist in the immuno-modulation of the host, being able to competitively exclude adhesion of pathogenic bacteria to intestinal cells, thus supporting the maintenance of the individual's health.
Further, in EP 0 577 903 reference is made to the use of a lactic acid bacteria having the ability of replacing Heliobacter pylori, the acknowledged cause for the development of ulcer.
Also, in WO 97/00078 a specific lactobacillus strain, termed Lactobacillus GG (ATCC 53103), is disclosed as such a probiotic. The microorganism may be employed for preventing or treating food induced hypersensitivity reactions.


The brassiere with adjustable spacing between cups includes an elastic band adapted for releasable mounting about a user's torso and a pair of shoulder straps secured thereto. A pair of fabric cups are secured to the elastic band for supporting the user's breasts. A lower portion of each cup has a channel defined therein and an open end. Each end of an elongate, flexible support wire or member is slidably disposed within a respective one of the channels. Additionally, a pair of flaps are respectively secured to the pair of fabric cups. Each of the flaps has a free end for selective positioning adjacent a respective open end of each of the channels. The free ends may be secured together such that when the flaps are secured, the support wire allows the spacing between the cups to decrease, thus providing additional inward and upward support for the user's breasts.

1. Field of the Invention
The present invention relates to undergarments, and particularly to a brassiere with adjustable spacing between cups to enhance the user's cleavage.
2. Description of the Related Art
The use of brassieres with an underwire to support a woman's breasts is well known in the art. Recently, attempts have been made to enhance the cleavage and appearance of a woman's breasts by pushing up and pushing in on the individual breasts using "push-up" cups, by adding push-up inserts into the brassiere, or by pulling brassiere cups together via straps or the like, thereby enhancing the perceived size of the breasts, as well as the cleavage formed therebetween.
Breasts may be pulled together laterally for the purposes of enhancing cleavage. However, conventional push-up brassieres do not work well with breast implants, as the implant itself tends not to be pushed either upward or inward by the push-up brassiere. When women have breast implants, the breast implant is typically placed underneath the pectoral muscles. As a result, the breast implants are separated from one another and expose the breastbone. To create cleavage for implanted breasts, the breast implants need additional force to be pushed over the breastbone to create a desirable cleavage effect. Typically, push-up brassieres do not provide this additional force.
Thus, a brassiere with adjustable spacing between cups solving the aforementioned problems is desired.

Brassiere with adjustable spacing between cups


A method and computer program for managing and presenting a visual history of web pages accessed by a user. This method and computer program is able to create a screen of thumbnail snapshots of web pages for presentation to a user. These thumbnail snapshots are reduced images of the actual web pages themselves that the user has visited. Associated with each thumbnail snapshot is a universal resource locator for the web page. The history of the web pages visited may be displayed in a toolbar which is scrollable.

With the explosion in Internet access and usage individuals have discovered that they may now receive a large amount of information in their homes and offices almost immediately from any number of sources. These sources include everything from the latest news, weather, and sports to stocks, bond and commodity prices. Currently, a typical Internet user would have a browser installed in his local computer or server such as Internet Explorer™ or Netscape™. Using this browser, the user would access an Internet service provider (ISP), such as America-On-Line (AOL™), via a modem over the local public switched telephone network (PSTN). Once logged onto the Internet server, the user may utilize one of the many search engines, such as Yahoo™ or Lycos™, to specify search terms. The user may also use a web crawler, spider or robot to attempt to find a product, service or information desired. The search engine or web crawler would then respond with a list of web sites which matched the search terms the user provided. The user would then log onto a web site and view the products or services available for sale or receive the information desired. Further, if the user discovers a web site he prefers, the user may store the universal resource locator (URL) in a favorites' directory for later quick access. This storage of the URL in a favorites directory is often referred to as bookmarking the entry and the entry is then referred to as a bookmark. In addition to bookmarks, the browser may keep in a history of the web pages visited by storing each URL accessed. Thereafter, the user may revisit the web page by accessing the favorites directory and searching for a title for the web page associated with a URL. However, once some number of bookmarks has been accumulated, the user may find it difficult to identify the bookmark desired based on the title alone. Further, in some instances the designers of the web page may not necessarily create a title for a web page as in the case of purely graphic web pages. Therefore, the user may be forced to try and recognize the bookmark using solely the URL. The user under the circumstances would find it frustrating to look through a large number of bookmarks by title and URL to identify the web page desired. In addition, the user may often are need to access several web pages before discovering the bookmark associated with the desired web page. This also applies to the history file. A user or system administrator would often have to access the web site to determine the nature of the content therein.
To overcome this problem of inadequate description of bookmarks Nielsen in U.S. Pat. No. 5,963,964, issued on Oct. 5, 1999, the contents of which are incorporated herein by reference, proposes substituting a thumbnail snapshot of the web page itself for the title or the URL used as a bookmark. However, in the case of a history file, it is still necessary to open the file and access the history by time period.
Therefore, what is needed are a system and method in which a history of web pages accessed may be organized for presentation as web pages so that they may be easily discovered and accessed by a user. The system and method should further present to the user the history of web page access as thumbnail snapshots. Further, this system and method should display these thumbnail snapshots to the user in such a fashion that the user may identify the web page of interest and access it quickly.

System and method for visual history presentation and management


Authenticating users for mobile transactions conducted over mobile phones. In general, the present invention makes it possible to securely authenticate a rural user (using the unique user ID from the uWallet, the client certificate in the mobile phone of the rural user and PIN code/password provided by the rural user) and then permit mobile banking transactions over the mobile phone. Both participating individuals employ their individual mobile phones and secure USB/Bluetooth based mobile banking devices (the uWallet) to authenticate themselves and conduct monetary transactions (funds transfer, mobile payments, etc.).

1. Technical Field
The present invention relates generally to a conducting monetary transactions using a mobile device and particularly to a solution wherein a user can conduct secure transactions after using a USB-based memory stick for authentication, authorization and security.
2. Related Art
Mobile devices are becoming ubiquitous. People in urban areas carry them and so do people living in rural communities. Most people working in remote locations use mobile phones to stay in touch with their family, customers and take phone calls throughout the day.
Urban-oriented banks and financial institutions in the developing world, such as India, perceive business prospects in shifting focus to the rural sector. The rural Indian market, for example, a hitherto much neglected one, is now emerging as a large pool of high net worth individuals, traders, entrepreneurs, processing industries, marketing and warehousing agencies, market intermediaries, professionals, educational institutions, plantations and so on provides a wide range of business avenues and market for these institutions to diversify the risks and also seek growth.
Despite decades of effort and experimentation in banking; the organised financial sector is still not able to meet the credit gap in the rural sector. It took time for banks to realise the potential of the rural markets. Lack of infrastructure in the rural areas and the focus in the urban sector were the reasons. Directed and subsidised lending, cumbersome procedures, delay in sanctioning loans and lack of statutory backing for recoveries were major impediments to the growth of banking in the rural sector. In view of this, there is great need for technology to provide support to the rural populace via an easy mode of access to bank accounts and credits besides, a need to offer the banking sector an easy reach with minimal infrastructure. The situation is similar in other communities in the world, where commercial banking has made little inroads.
One of the main problems in rural places (villages, small towns, etc.) in the world is the lack of bank branches, ATM machines or other type of financial organizations in proximity to the rural communities. In addition, credit cards are of limited use as there are no departmental stores that accept credit cards or debit cards. Small rural stores do not have point-of-sale devices that are typically used for swiping credit cards and other type of cards to conduct purchases, etc.
Accordingly, the present invention addresses the need for rural people to conduct banking operations, access banking services, make payments to each other, send funds to each other, etc. despite the lack of traditional banking facilities such as ATM machines, banking counters and point-of-sale devices. The present invention enables easy & secure/payment, from even remote rural areas where a mobile telephone network is in place, and without the need for any additional infrastructure costs to the users and the banks. In most rural places in the world, very few ATMs or bank facilities are in proximity to rural people. Very few rural people have bank accounts. In addition, very few point-of-sale (POS) devices are available or used in small stores and places of business. There is a need for simple-to-operate secure financial transaction means. There is also a need to support farmer-to-farmer transactions in rural places where there are no ATM machines available and no banking counters, etc. There is also a need to maintain records of transactions made by rural people as they buy and sell produce.
The present invention also addresses the need to identify an individual properly during mobile transactions, in general. Mobile phones can be stolen and misused, user passwords can be stolen, PIN codes can be hacked (or guessed), etc. Thus, the identity of a user of a mobile phone needs to be properly ascertained and verified. The present invention addresses the "user identity" issue thereby making mobile transactions safer and more secure.
There are a few examples of technology where the mobile telephone network has been used for some types of mobile transactions. The Obopay system requires setting up accounts at Nokia stores and similar outlets initially by a user, and it involves associating a credit card with the user account for subsequent transactions. This makes it harder for rural people, especially those without a credit card, to participate. Once a credit card is associated, subsequent charges made for mobile purchases are conducted via the credit card. The Obopay system can be a burden on the rural user in India, as a network of Nokia stores or similar outlets may not be easily available. The Beam Card requires purchase of Beam Gift cards that are used as pre-paid cards for purchases by users. Beam does not provide mobile banking support, nor adhoc payment from one user to another when the users have not yet setup some kind of account or registered with them—rather it provides gift card purchases and payment against such gift cards. The Done card system used by OSS is also based on gift cards being purchased, often limited to small amounts (cannot be larger than a threshold such as Rs 10000) which limits what a person can do (cannot purchase two large bags of cement or two bags of fertilizers, or even a plane ticket to Delhi from Chennai). The whole gift-card based approach is rather limiting, in that the person has to track down a place where such giftcards are sold, which are often not in the proximity/vicinity of a user. Thus these are unsuitable for rural places.
In general, USB based memory devices are used by people to store their data or transfer data from PCs. The SanDisk miniSD card is slightly smaller than a full size SD card. Originally designed for the mobile phones, this card is used broadly in portable devices. Users plug this miniSD card into mobile phones, often after unplugging their batteries to gain access to a slot or adapter, and such users use the miniSD card to store songs, download videos, etc. Similar microSD cards are also available in the market. Very few if any memory stick manufacturers sell USB based memory sticks that can be tethered to a few mobile phones to store songs that are downloaded by a user. Mini USB ports on mobile devices are primarily used by users to connect to PCs and manage their contact lists, etc.
RFIDs are available to tag retail and wholesale products for sale. In general, a merchant or salesperson with a specialized RFID reader scans such a product (with an RFID tag) and conducts a stocking operation or some such related warehousing and tracking operation. RFID tags are expected to revolutionize tracking of goods and retail sales of goods.
Rural people do not carry credit cards/debit cards and point-of-sale devices are usually unavailable in stores found in rural areas, therefore credit card/debit cards (even if one possesses them) are rendered useless. Access to ready cash is also limited as rural areas (in India or in other rural communities all over the world) do not have reliable ATM machines. The other issue is that authentication of the user in an Indian rural setting via the traditional methods is a problem. Besides, there is a real problem of rural people being excluded from financial systems and the modern innovations in the banking sector, due to their lack of knowledge and limited access to financial education. The present invention addresses all of these problems faced by rural people (in India and other places) by providing a very simple, easy and very secure solution that would have a phenomenal reach with negligible costs to the user.
In view of the foregoing considerations, it is clear that there is a need for an improved system and method for financial transactions between people in rural communities, where there are very few (or none) ATM machines, banks, or modern point-of-sale devices.

Mobile monetary transactions and banking for rural populations


This invention relates to compounds of the formula

This invention relates to novel hygromycin A prodrugs that are useful as antibacterial and antiprotozoal agents in mammals, including man, as well as in fish and birds. This invention also relates to pharmaceutical compositions containing the novel compounds and to methods of treating bacterial and protozoal infections in mammals, fish and birds by administering the novel compounds to mammals, fish and birds requiring such treatment. The hygromycin prodrugs of this invention possess an advantage over the parent drugs in terms of efficacy, formulation, solubility, side effects or stability.
Hygromycin A is a fermentation-derived natural product first isolated from Streptomyces hygroscopicus in 1953. As an antibiotic, hygromycin A possesses activity against human pathogens and is reported to possess potent in vitro activity against Serpulina (Treponema) hyodysenteriae which causes swine dysentery. Several references refer to semisynthetic modifications of hygromycin A, including the following: derivatization of the 5xe2x80x3 ketone of hygromycin A to the 2,4-dinitrophenylhydrazone is referred to in K. Isono et al., J. Antibiotics 1957, 10, 21, and R. L. Mann and D. O. Woolf, J. Amer Chem. Soc. 1957, 79, 120. K. Isono et al., ibid., also refer to the thiosemicarbazone at 5xe2x80x3; reduction of the 5xe2x80x3 ketone of hygromycin A to the 5xe2x80x3 alcohol is referred to in R. L. Mann and D. O. Woolf, ibid., as well as in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533 and S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 295; furanose analogues are referred to in B. H. Jaynes et al., Bioorg. Med. Chem. Lett. 1993, 3, 1531, and B. H. Jaynes et al., J. Antibiot. 1992, 45, 1705; aromatic ring analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1993, 3, 289, and C. B. Cooper et al., Bioorg. Med. Chem. Lett. 1997, 7, 1747; enamide analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 533; aminocyclitol analogues are referred to in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1015, and in S. J. Hecker et al., Bioorg. Med. Chem. Lett. 1992, 2, 1043. The hygromycin A derivatives of the present invention possess activity against both gram-negative and gram-positive bacteria and protozoa.
The present invention relates to compounds of the formula
or the pharmaceutically acceptable salts thereof; wherein
a is 0 or 1;
b is 0, 1, 2 or 3;
R1 is hydrogen or hydroxy;
R2 is methyl;
R3 is (C6-C10)aryl optionally substituted by one to three groups independently selected from hydrogen, halo, (C1-C6)alkoxy, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, nitro, (C1-C6)alkoxy, (C1-C6)alkoxyC(O), (C1-C6)alkylaminoC(O), (C6-C10)aryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl or (C1-C6)alkyl optionally substituted by one to three fluoro;
X is (R4O)2P(O)xe2x80x94, (R4O)S(O)nxe2x80x94, (C6-C10)arylC(O), (C2-C9)heteroarylC(O), (C2-C9)heterocycloalkylC(O), (R7)2N(CHR5)C(O)xe2x80x94, R6pyridinium(C1-C6)acyl, (R8)3N+(C1-C1-C6)acyl, (C1-C6)acyl, (C6-C10)aryl(C1-C3)acyl, (C2-C9)heteroaryl(C1-C3)acyl and (C2-C9)heterocycloalkyl(C1-C3)acyl;
wherein n is 1 or 2;
R4 is hydrogen, (C1-C5)alkyl, (C6-C10)aryl or an alkaline metal;
R5 is hydrogen, (C1-C6)alkyl optionally substituted by hydroxy, aminoC(O)xe2x80x94, thio, methylthio, carboxy or amino; (C6-C10)aryl optionally substituted by hydroxy; or (C2-C9)heteroaryl;
R6 is hydrogen, halo, nitro, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, hydroxy, (C1-C6)alkoxy, (C1-C6)alkyoxyC(O) or (C1-C6)alkylaminoC(O);
R7 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl or (C6-C10)aryl(C1-C6)alkyl;
R8 is hydrogen or (C1-C6)alkyl;
Y is CH or N, wherein the wavy bond symbol linking Y and (CH2)a designates a single bond in either the xe2x80x9cZxe2x80x9d or xe2x80x9cExe2x80x9d configuration relative to the furanyl ring;
Z is oxygen or NR12 wherein R12 is hydrogen, (C1-C6)alkyl or (C6-C10)aryl;
with the proviso that when Y is CH, a is 1; and
with the proviso that when Y is nitrogen, a is zero.
The term xe2x80x9chaloxe2x80x9d, as used herein, unless otherwise indicated, includes fluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloro and bromo.
The term xe2x80x9calkylxe2x80x9d, as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight or branched moieties. Said alkyl group may include one or two double or triple bonds. It is understood that for said alkyl group to include a carbonxe2x80x94carbon double or triple bond at least two carbon atoms are required in said alkyl group.
The term xe2x80x9calkoxyxe2x80x9d, as used herein, includes O-alkyl groups wherein xe2x80x9calkylxe2x80x9d is defined above.
The term xe2x80x9carylxe2x80x9d, as used herein, unless otherwise indicated, includes an organic radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as phenyl or naphthyl, and also benzyl.
(C2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, chromanyl, etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon or a sp3 hybridized nitrogen heteroatom.
(C2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyridinyl, benzo[b]thiophenyl, 5, 6, 7, 8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazinyl; etc. One of ordinary skill in the art will understand that the connection of said (C2-C9)heterocycloalkyl rings is through a carbon atom or a sp3 hybridized nitrogen heteroatom.
The phrase xe2x80x9cpharmaceutically acceptable salt(s)xe2x80x9d, as used herein, unless otherwise indicated, includes salts of acidic or basic groups which may be present in the compounds of the present invention. The compounds of the present invention that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds of are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts. The compounds of the present invention that include a basic moiety, such as an amino group, may form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
Preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen and b is 1. In an embodiment, the preferred compounds include those wherein R1 is hydroxy, X is (R4O)2P(O)xe2x80x94 and R4 is hydrogen or alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydrogen, X is (R4O)2P(O)xe2x80x94 and R4 is hydrogen or alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydroxy and X is (R4O)S(O)nxe2x80x94, wherein n is 2 and R4 is hydrogen or alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydrogen and X is (R4O)S(O)nxe2x80x94, wherein n is 2 and R4 is hydrogen or alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydroxy and X is R6pyridinium(C1-C3)acyl, wherein n is 2 and R4 is hydrogen or alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydrogen and X is R6pyridinium(C1-C3)acyl, wherein n is 2 and R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is CH, a is 1, Z is oxygen and b is zero. In an embodiment, the preferred compounds include those wherein R1 is hydroxy, X is (R4O)2P(O)xe2x80x94 and R4, is hydrogen or formula alkaline metal. In another embodiment, the preferred compounds include those wherein R1 is hydrogen, X is (R4O)2P(O)xe2x80x94 and R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is CH, a is 1, Z is oxygen, b is zero and X is R6pyridinium(C1-C3)acyl or (R4O)S(O)nxe2x80x94, wherein n is 2 and R4 is hydrogen or alkaline metal. In an embodiment thereof, R1 is hydroxy. In another embodiment thereof, R1 is hydrogen.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydroxy and X is (R4O)S(O)nxe2x80x94 wherein n is 2 and R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is CH; a is 1, Z is oxygen, b is zero, R1 is hydroxy and X is (R4O)2P(O)xe2x80x94 wherein R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydrogen and X is (R4O)2P(O)xe2x80x94 wherein R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydrogen and X is (R4O)S(O)nxe2x80x94 wherein n is 2 and R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is CH; a is 1, Z is oxygen, b is zero, R1 is hydroxy and X is (R4O)2P(O)xe2x80x94 wherein R4 is hydrogen or alkaline metal.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydroxy and X is R6pyridinium(C1-C3)acyl.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydrogen and X is R6pyridinium(C1-C3)acyl.
Other preferred compounds of formula I include those wherein Y is CH; a is 1, Z is oxygen, b is zero, R1 is hydroxy and X is R6pyridinium(C1-C3)acyl.
Other preferred compounds of formula I include those wherein Y is nitrogen, a is zero, Z is oxygen, b is 1, R1 is hydrogen and X is R6pyridinium(C1-C3)acyl.
Other preferred compounds of formula I include those wherein Y is CH; a is 1, Z is oxygen, b is zero, R1 is hydroxy and X is R6pyridinium(C1-C3)acyl.
Specific preferred compounds of formula I including the following:
Phosphoric acid mono-(2-(5-(1-(3-chloro-benzyloxy-Z-imino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester;
Phosphoric acid mono-(2-(5-(1-(3-chloro-4-fluoro-benzyloxy-E-imino)-ethyl)-3,4-dihydroxy-tetrahydro-furan-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester;
Phosphoric acid mono-(2-(5-(1-(3-chloro-benzyloxy-E-imino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester;
Phosphoric acid mono-(2-(5-(1-(3-fluoro-benzyloxy-E-imino)-ethyl)-4-hydroxy-tetrahydro-furan-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester;
Phosphoric acid mono-(2-(5-(3-(2-chloro-4-fluoro-phenoxy)-1-methyl-propenyl)-3,4-dihydroxy-tetrahydrofuran-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester; and
Phosphoric acid mono-(2-(5-(3-(2-chloro-4-fluoro-phenoxy)-1-methyl-propenyl)-4-hydroxy-tetrahydrofuran-2-yloxy)-5-(2-(4,6,7-trihydroxy-hexahydro-benzo(1,3)dioxol-5-ylcarbamoyl)-propenyl)-phenyl) ester.
The invention also relates to a method of preparing a compound of formula I as defined above, which comprises treating a compound of formula II (see, e.g., Scheme 1) in the presence of about 1 equivalent of base, with an agent comprising about 1 equivalent of an anhydride or an acylating agent of the formula R9C(O)L or a phosphorylating agent of the formula ((R4O)2PO)2O, (R4O)2P(O)Cl, or (R4O)2P(O)Br or a sulfonating agent of the (R4O)S(O)2Cl or (R4O)S(O)3 or an amino acylating agent having the formula R10R7N(CHR5)C(O)Cl or R10R7N(CHR5)C(O)Br; wherein R9 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, R6pyridinium(C1-C6)alkyl or (R8)3N+(C1-C6)alkyl; wherein R10 is a suitable protecting group; wherein L is chloro, bromo or imidazole; provided that sulfonation with (R4O)S(O)2Cl or (R4O)S(O)3 is followed by hydrolysis to yield the compound of formula I; and provided that following treatment with an amino acylating agent, R10 is removed to provide the compound of formula I. In an embodiment, R10 is carbobenzyloxy or tert-butoxycarbonyl.
The invention also relates to a pharmaceutical composition for the treatment of a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In an embodiment thereof, the composition comprises a compound of formula I wherein Y is nitrogen, a is zero, Z is oxygen and b is one. In another embodiment thereof, the composition comprises a compound of formula I wherein Y is CH, a is one, Z is oxygen and b is zero. In still further embodiments thereof, the composition comprises any one of the preferred compounds of formula I. In yet another embodiment, the composition comprises at least one of the specific preferred compounds of formula I as set forth above. In another embodiment, the composition further comprises another antibiotic. Examples of suitable other antibiotics include, but are not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides.
The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administering to said mammal, fish or bird a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof. In an embodiment of the method, the compound of formula I comprises the compound wherein Y is nitrogen, a is zero, Z is oxygen and b is one. In another embodiment of the method, the compound of formula I comprises the compound wherein Y is CH, a is one, Z is oxygen and b is zero. In still further embodiments of the method, the compound comprises any one of the preferred compounds of formula I. In yet another embodiment of the method, the compound comprises at least one of the specific preferred compounds of formula I as set forth above.
The invention also relates to a method of treating a disorder selected from a bacterial infection, a protozoal infection, and disorders related to bacterial infections or protozoal infections, in a mammal, fish, or bird which comprises administering to the mammal, fish or bird a combination comprising a compound of formula I and another antibiotic, wherein the amounts of the compound and of the other antibiotic are together therapeutically effective in treating the disorder. In further embodiments, the compound of the invention may administered prior to, with or after the other antibiotic. Examples of suitable other antibiotics include, but are not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides.
The term xe2x80x9ctreatingxe2x80x9d, as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term xe2x80x9ctreatmentxe2x80x9d, as used herein, refers to the act of treating, as xe2x80x9ctreatingxe2x80x9d is defined immediately above.
As used herein, unless otherwise indicated, the terms or phrases xe2x80x9cbacterial infection(s)xe2x80x9d, xe2x80x9cprotozoal infection(s)xe2x80x9d, and xe2x80x9cdisorders related to bacterial infections or protozoal infectionsxe2x80x9d include the following: pneumonia, otitis media, sinusitus, bronchitis, tonsillitis, and mastoiditis related to infection by Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, Enterococcus faecalis, E. faecium, E. casselflavus, S. epidermidis, S. haemolyticus, or Peptostreptococcus spp.; pharyngitis, rheumatic fever, and glomerulonephritis related to infection by Streptococcus pyogenes, Groups C and G streptococci, Corynebacterium diphtheriae, or Actinobacillus haemolyticum; respiratory tract infections related to infection by Mycoplasma pneumoniae, Legionella pneumophila, Streptococcus pneumoniae, Haemophilus influenzae, or Chlamydia pneumoniae; blood and tissue infections, including endocarditis and osteomyelitis, caused by S. aureus, S. haemolyticus, E. faecalis, E. faecium, E. durans, including strains resistant to known antibacterials such as, but not limited to, beta-lactams, vancomycin, aminoglycosides, quinolones, chloramphenicol, tetracyclines and macrolides; uncomplicated skin and soft tissue infections and abscesses, and puerperal fever related to infection by Staphylococcus aureus, coagulase-negative staphylococci (i.e., S. epidermidis, S. hemolyticus, etc.), Streptococcus pyogenes, Streptococcus agalactiae, Streptococcal groups C-F (minute-colony streptococci), viridans streptococci, Corynebacterium minutissimum, Clostridium spp., or Bartonella henselae; uncomplicated acute urinary tract infections related to infection by Staphylococcus aureus, coagulase-negative staphylococcal species, or Enterococcus spp.; urethritis and cervicitis; sexually transmitted diseases related to infection by Chlamydia trachomatis, Haemophilus ducreyi, Treponema pallidum, Ureaplasma urealyticum, or Neiserria gonorrheae; toxin diseases related to infection by S. aureus (food poisoning and toxic shock syndrome), or Groups A, B, and C streptococci; ulcers related to infection by Heicobacter pylori; systemic febrile syndromes related to infection by Borrelia recurrentis; Lyme disease related to infection by Borrelia burgdorferi; conjunctivitis, keratitis, and dacrocystitis related to infection by Chlamydia trachomatis, Neisseria gonorrhoeae, S. aureus, S. pneumoniae, S. pyogenes, H. influenzae, or Listeria spp.; disseminated Mycobacterium avium complex (MAC) disease related to infection by Mycobacterium avium, or Mycobacterium intracellulare; infections caused by Mycobacterium tuberculosis, M. leprae, M. paratuberculosis, M. kansasii, or M. chelonei; gastroenteritis related to infection by Campylobacter jejuni; intestinal protozoa related to infection by Cryptosporidium spp.; odontogenic infection related to infection by viridans streptococci; persistent cough related to infection by Bordetella pertussis; gas gangrene related to infection by Clostridium perfringens or Bacteroides spp.; and atherosclerosis or cardiovascular disease related to infection by Helicobacter pylon or Chlamydia pneumoniae.
Those compounds of the present invention that are acidic in nature are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline earth metal salts and, particularly, the calcium, magnesium, sodium and potassium salts of the compounds of the present invention.
The compounds of the present invention have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. This invention relates to the use of all optical isomers and stereoisomers of the compounds of the present invention, and mixtures thereof, and to all pharmaceutical compositions and methods of treatment that may employ or contain them. In this regard, the invention includes both the E and Z isomers or configurations.
In particular, in this application a wavy bond symbol

emanating from an sp2 hybridized C or N (Y of formula I) designates a single bond in either the Z and E configuration relative to the highest priority substituent of the adjacent sp2 hybridized C atom, i.e., relative to the furanyl ring. The compounds of formula I may also exist as tautomers. This invention relates to the use of all such tautomers and mixtures thereof.
The subject invention also includes isotopically-labelled compounds, and the pharmaceutically acceptable salts thereof, which are identical to those recited in formula I, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 35S, 18F, and 36Cl, respectively. Compounds of the present invention, prodrugs thereof, and pharmaceutically acceptable salts of said compounds or of said prodrugs which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically-labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of formula I of this invention and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated a, b, X, Y, Z, R1, R2, R3, R4 in the reaction Schemes and the discussion that follow are defined as above.
In reaction 1 of Scheme 1, the compound of formula II is converted to the corresponding compound of formula III by reacting II, in the presence of about 1 equivalent of base, such as sodium hydride or potassium hydride, with either 1 equivalent or slightly more than 1 equivalent of (a) an anhydride compound of the formula, (R9C(O))2O, or (b) an acylating agent of the formula, R9C(O)L, wherein R9 is hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heteroaryl(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, R6pyridinium(C1-C6)alkyl or (R8)3N+(C1-C6)alkyl; and L is chloro, bromo or imidazole. The reaction is stirred in an aprotic solvent, such as tetrahydrofuran, at a temperature range between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about xe2x88x925xc2x0 C., for a time period between about 30 minutes to about 24 hours, preferably about 2 hours.
In reaction 1 of Scheme 2, the compound of formula II is converted to the corresponding compound of formula IV by reacting II, in the presence of about 1 equivalent of base, such as sodium hydride or potassium hydride, with either one equivalent or slightly more than one equivalent of (a) a compound of the formula, ((R4O)2PO)2O, or (b) a phosphorylating agent of the formula, (R4O)2P(O)L, wherein L is chloro or bromo. The reaction is stirred in an aprotic solvent, such as tetrahydrofuran, at a temperature range between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about 18xc2x0 C., for a time period between about 30 minutes to about 24 hours, preferably about 2 hours.
In reaction 1 of Scheme 3, the compound of formula II is converted to the corresponding compound of formula V, wherein n is 1, by reacting II, in the presence of about one equivalent of a base, such as sodium hydride or potassium hydride, with one equivalent or slightly more than one equivalent of thionyl chloride. The resulting compound is then treated with a dilute aqueous base (such as NaHCO3). The compound of formula II is converted to the corresponding compound of formula V, wherein n is 2, by reacting II, in the presence of about one equivalent of base, such as sodium hydride or potassium hydride, with either one or slightly more than one equivalent of a sulfuryl chloride or sulfur trioxide, i.e., (R4O)SO2Cl or (R4O)SO3. The intermediate from the sulfuryl chloride is then hydrolyzed by treating with a dilute aqueous base such as NaHCO3. Each reaction is stirred in an aprotic solvent, such as tetrahydrofuran, at a temperature range between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about 0xc2x0 C., for a time period between about 30 minutes to about 24 hours, preferably about 2 hours, followed by the addition of water or a saturated sodium bicarbonate solution at 0xc2x0 C. and stirred to an additional time period between about 30 minutes to about 2 hours.
In reaction 1 of Scheme 4, the compound of formula II is converted to the corresponding compound of formula VI by reacting II, in the presence of about one equivalent of a base, such as sodium hydride or potassium hydride, with slightly more than one equivalent of a compound of the formula, R10R7Nxe2x80x94CHR5xe2x80x94C(O)xe2x80x94L, wherein R10 is carbobenzyloxy or tert-butoxycarbonyl and L is chloro, bromo or imidazole. The reaction is stirred in an aprotic solvent, such as tetrahydrofuran, at a temperature range between about xe2x88x9220xc2x0 C. to about 50xc2x0 C., preferably about 0xc2x0 C., for a time period between about 30 minutes to about 24 hours, preferably about 8 hours. Removal of the R10 protecting group from the compound so formed to give the corresponding compound of formula VI is carried out under conditions appropriate for that particular R10 protecting group in use which will not affect other functional groups. Such conditions include: (a) transfer hydrogenation using 1,4-cyclohexadiene and 10% palladium on carbon under inert atmosphere when R10 is carbobenzyloxy or (b) trimethylsilyl, trifluoromethylsulfonate and diisopropylethylamine when R10 is tert-butoxycarbonyl.
The compounds of the present invention have asymmetric carbon atoms. Compounds having a mixture of isomers at one or more centers will exist as diastereomeric mixtures, which can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to those skilled in the art, for example, by chromatography or fractional crystallization. All such isomers, including diastereomer mixtures, are considered as part of the invention.
The compounds of the present invention that are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate the compound of the present invention from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the basic compounds of this invention are readily prepared by treating the basic compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained. The desired acid salt can also be precipitated from a solution of the free base in an organic solvent by adding to the solution an appropriate mineral or organic acid.
Those compounds of the present invention that are acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of the present invention. Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired alkali metal alkoxide or metal hydroxide, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide or metal hydroxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
The antibacterial activity of the compounds of the present invention against bacterial pathogens is demonstrated by the compound""s ability to inhibit growth of defined strains of pathogens.
The assay, described below, employs conventional methodology and interpretation criteria and is designed to provide direction for chemical modifications that may lead to compounds with antibacterial activity against susceptible and drug-resistant organisms including, but not limited to, beta-lactam, macrolide and vancomycin resistance. In the assay, a panel of bacterial strains is assembled to include a variety of target pathogenic species, including representatives of antibiotic resistant bacteria. Use of this panel enables the chemical structure/activity relationship to be determined with respect to potency and spectrum of activity. The assay is performed in microtiter trays and interpreted according to Performance Standards for Antimicrobial Disk SusceDtibility Testsxe2x80x94Sixth Edition; Approved Standard, published by The National Committee for Clinical Laboratory Standards (NCCLS) guidelines; the minimum inhibitory concentration (MIC) is used to compare strains. Compounds are initially dissolved in dimethylsulfoxide (DMSO) as stock solutions. The compound of Example 1 exhibits antibacterial activity in the microtiter assay described above.
The activity of the compounds of the present invention also may be assessed in accord with Steers replicator technique which is a standard in vitro bacterial testing method described by Steers et al., Antibiotics and Chemotherapy 1959, 9, 307.
The in vivo activity of the compounds of the present invention can be determined by conventional animal protection studies well known to those skilled in the art, usually carried out in rodents. According to one in vivo model, compounds are evaluated for efficacy in mouse models of acute bacterial infection. An example of one such in vivo system is provided as follows. Mice (CF1 mixed sex mice; 18-20 g) are allotted to cages upon their arrival, and allowed to acclimate 1-2 days before being placed in a study. The acute infection is produced by intraperitoneal inoculation of bacteria (Staphylococcus aureus strain 01A1095) suspended in 5% sterile hog gastric mucin. The inoculum is prepared by: growing the culture overnight at 37xc2x0 C. on blood agar, harvesting the resulting surface growth with sterile brain heart infusion broth, and adjusting this suspension to a turbidity that when diluted 1:10 into 5% sterile hog gastric mucin would produce 100% lethality.
Mice (10 per group) are treated subcutaneously, at 0.5 hour and 4 hours after challenge. Appropriate non-treated (infected but not treated) and positive (vancomycin or minocycline, etc.) controls are included in each study. Percent survival is recorded after a 4-day observation period; the PD50 (mg/kg/dose calculated to protect 50% of infected animals) is determined by the probit method.
A similar assay was used to evaluate the compounds of Example 1 and Example 3 in a mouse peritonitis infection model vs. a susceptible strain of Staphylococcus aureus (Pfizer designation 01A1146). Mice were challenged intraperitoneally with 1.5xc3x97105 cfu (LD100) of S. aureus suspended in 10% hog gastric mucin. The compound (100, 50, 25 and 12.5 mg/kg) was given at 0.5 and 4 hrs. post-challenge using a subcutaneous route of drug administration for both the compound (ester) and its precursor hydroxy or xe2x80x9cparentxe2x80x9d compound. The dosage forms for the compounds were prepared in a 20% xcex2-cyclodextrin or H2O vehicle and the parent compound was prepared only in 20% xcex2-cyclodextrin. Survivors were recorded over a 5 day period and PD50 values were estimated from survival data on day 5 using non-linear regression techniques. The compounds of Example 1 and Example 3 provided protection against the infection in this assay with PD50 values within the above dosage range. These examples serve only to illustrate the antibacterial activity of the compounds of the invention, and no limitations are to be inferred from the examples provided.
The compounds of the present invention, and the pharmaceutically acceptable salts thereof (hereinafter xe2x80x9cthe active compoundsxe2x80x9d), may be administered through oral, parenteral, topical, or rectal routes in the treatment of bacterial and protozoal infections. In general, these compounds are most desirably administered in dosages ranging from about 0.2 mg per kg body weight per day (mg/kg/day) to about 200 mg/kg/day in single or divided doses (i.e., from 1 to 4 doses per day), although variations will necessarily occur depending upon the species, weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 3 mg/kg/day to about 60 mg/kg/day is most desirably employed. Variations may nevertheless occur depending upon the species of mammal, fish or bird being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active compounds may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by the routes previously indicated, and such administration may be carried out in single or multiple doses. More particularly, the active compounds may be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc. Moreover, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active compounds are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration, the active compound may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
For parenteral administration, solutions of an active compound in either sesame or peanut oil or in aqueous ethanol or propylene glycol may be employed. Use of a cyclodextrin derivative such as xcex2-cyclodextrin sulfobutyl ether, sodium salt (see U.S. Pat. No. 5,134,127) may also be advantageous. The aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques known to those skilled in the art.
Additionally, it is also possible to administer the active compounds of the present invention topically and this may be done by way of creams, jellies, gels, pastes, patches, ointments and the like, in accordance with standard pharmaceutical practice.
For administration to animals other than humans, such as cattle or domestic animals, the active compounds may be administered in the feed of the animals or orally as a drench composition.
The active compounds may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.
The active compounds may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide phenyl, polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysine substituted with palmitoyl residues. Furthermore, the active compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in this art. For examples, see Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 18th Edition (1990).

Abstract: and to pharmaceutically acceptable salts and solvates thereof, wherein a, b, X, Y, Z, R1, R2, and R3 are as defined herein. The compounds of formula I are antibacterial and antiprotozoal agents useful for treating various bacterial and protozoal infections and disorders related to such infections. The invention also relates to pharmaceutical compositions containing the compounds of formula I, to methods of treating bacterial and protozoal infections by administering the compounds of formula I, and to methods for preparing compounds of formula I.


A process for the preparation of a compound of formula (VI), optionally in enantiomerically-enriched form (R or S), comprises chemoselective reduction of a novel compound of formula (V), wherein Ar.sup.1 and Ar.sup.2 are independently selected from optionally-substituted aromatic or heteroaromatic groups having upto 20 C atoms, Ak is C.sub.1-20 alkyl, and R is H or C.sub.1-20 alkyl. ##STR1##

Verapamil (I) is presently in clinical use as the racemate and is used extensively for the treatment of hypertension. The opposite enantiomers of verapamil have different biological activities. The (S)-enantiomer (levoverapamil) has the majority of the calcium channel antagonist activity (DE-A-2059923) whilst the (R) -enantiomer (dextroverapamil) differs in having sodium channel and other cell-pump actions in addition to higher bioavailability, with slower clearance rate. These differences may be of clinical significance, for example, the (R) -enantiomer may be of benefit for the reversal of multidrug resistance in cancer chemotherapy (see Eliason, Int. J. Cancer (1990) 46: 113); in this case hypotensive action by admixture with the (S) -enantiomer would be undesirable.
Thus there is a requirement for efficient manufacturing processes to produce single enantiomer or enantiomerically-enriched forms of the compound verapamil and analogues thereof. This is a challenging endeavour since construction of the quaternary chiral centre with high asymmetric induction is difficult. Several synthetic routes to such compounds have been published but for a variety of reasons most are unsuitable for preparation on a large scale.
For example, the synthesis of (S) -verapamil commencing from (S) -1,2-propanediol entails 11 steps, only 3 of which are used to create permanent skeletal bonds; see Theodore and Nelson, J. Org. Chem. (1987) 52: 1309. Of the shorter routes proceeding via classical resolution are processes disclosed in WO-A-9729081, which involve resolution of 4-cyano-4-(3,4-dimethoxyphenyl)-5-methyl hexanoic acid (II; verapamilic acid). Such processes are potentially advantageous over the resolution of verapamil itself (disclosed in DE-A-3723684 and WO-A-9316035) due to better atom utilisation and lower waste levels. Literature methodology for the conversion of enantiomerically-enriched (II) to verapamil (1), and corresponding processes for analogues, invariably entails reduction of (II) to either the enantiomerically-enriched alcohol (III) or the enantiomerically-enriched aldehyde (IV).
Proceeding via alcohol (III) involves conversion to either an O-sulphonyl derivative or an alkyl halide, and subsequent amination to verapamil (I), which may require elevated temperatures (see GB 1367677), prolonged reaction times (see Theodore and Nelson, as above), or the use of the hazardous solvent hexamethylphosphoramide (see U.S. Pat. No. 4,940,780). Proceeding via aldehyde (IV), an a large scale from (II), requires two operations, either reduction-oxidation via alcohol (III) or acid chloride formation, and then a Rosenmund reaction. Racemic analogues of (IV) are available without recourse to this awkward adjustment of oxidation levels, but the protocols used, for instance as described in DE-A-2631222, are not suitable for preparing enantiomerically-enriched compounds.
For the above reasons it is desirable to establish a more streamlined protocol for the conversion of enantiomerically-enriched (II) to enantiomerically-enriched verapamil (I).