A photographic device includes a base, a camera lens module, a circuit component and multiple light-emitting components. The base has an installation surface. The camera lens module is movably installed on the installation surface of the base. The circuit component is installed on the installation surface of the base. The light-emitting components are electronically disposed on the circuit component. At least two of the light emitting components have different optical axis directions.

1. Technical Field
The disclosure relates to an optical component, more particularly to a photographic device.
2. Related Art
Generally speaking, the surveillance cameras are widely applied in several areas. For example, the surveillance cameras can be installed in a factory, a store, a building, a gateway or a passage of a house, a place needed to be supervised, or a place that is off the beaten track. Thereby, the incident can be recorded as evidence or for the purpose of the investigation if needed. Hence, the surveillance cameras can threaten the criminals to prevent them from committing crimes so that public order can be improved.
The fixed dome camera with infrared light, which are available on the current market, has a problem that the built-in light plate thereof cannot cover the whole range of camera's shooting angle because the covering angle of the built-in light plate is too small. Additionally, the light plate is fixed inside the machine so that it cannot be rotated or be tilted. Instead, the light plate can only be used in a fixed angle, or be amended by an adjusting mechanism. As a result, in certain viewing angles, the effective light projection length may be insufficient, or light around the edge of the video may be too dark.


A vortex flow meter includes a vortex responsive assembly having a diaphragm. The diaphragm seals a base end of the assembly to form an isolation chamber. The assembly is adapted to seal an opening in a sidewall of a flow passage. Support struts preferably protrude from the assembly into the flow passage. In one configuration, a vortex oscillation sensor plate has a proximate edge supported on the diaphragm and an opposite distal edge that is unsupported. The vortex oscillation sensor plate has upstream and downstream edges preferably supported by the support struts. A pivoting strut extends along a central region of the vortex oscillation sensor plate. The pivoting strut extends through the diaphragm. The pivoting strut transfers vortex oscillations to a sensor. An electronic transmitter circuit receives a sensor output and provides an output related to flow of the fluid.

This invention relates to flow meters, and in particular to flow meters which operate on the principle of measuring the frequency or period of vortices in a Karman vortex street set up in a moving fluid.
Flow meters are used in industrial processes to measure flow of process fluid. One type of flow meter, known as a vortex flow meter, measures flow by sensing vortexes in the flow. These vortexes can be sensed by using a vortex oscillation plate. The accuracy of the measurements is affected by the ability of the oscillation late to respond to the vortexes. A thin plate can provide more accurate measurements, however, it is also more prone to failure than a thicker plate.

Vortex flow meter with vortex oscillation sensor plate


Prosthesis, tools and surgical methods treat joint instability by avoiding loosening over time. A shoulder prosthesis includes a humeral member with a humeral joint surface and a humeral fixation member and a glenoid member comprising a glenoid body with a glenoid joint surface, and a glenoid fixation member attaching the glenoid body to a scapula. The glenoid fixation member may be attached orthogonally to the scapula. A dampener may be included to absorb loads that may loosen one or more components of the prosthesis.

Many joints of the human body naturally articulate relative to one another. Generally, the articulation surfaces of these joints are substantially smooth and without abrasion. However, joints, such as shoulder joints, undergo degenerative changes due to a variety of causes, such as, disease, injury, exercise and other strenuous activities, and various other issues. When these degenerative changes become advanced, to the point of becoming irreversible, such joints or portions thereof may need to be replaced with one or more prosthetics.
In light of the degenerative changes found in shoulder joints, various shoulder prosthetics of conventional design have been proposed. However, conventional shoulder prosthetics and their associated surgical components suffer from many disadvantages. For example, glenoid components of conventional design are subject to various types of load forces, such as, shear forces, anterior/posterior forces, lateral/medial forces, and rotational forces, which may cause notching and chipping of bone and/or loosening of the implanted components, thereby reducing the lifespan of the prosthetic. In addition, such load forces may create a rocking moment causing glenoid components to cantilever, which can further result in notching and chipping of bone and/or separation of the glenoid component from the scapula. Furthermore, the loosening of conventional shoulder prosthetics may pulverize, grind, crush and deform portions of a scapula, for example, a glenoid cavity of a scapula, which as a result, can prohibit the replacement of a worn, damaged or non-functional shoulder prosthetic. For these and other reasons, there is a need for improved shoulder prosthetics.


By one or more processors of a computing device, receive a player game election of a player, the player game election comprising a skill based video game and one or more player characteristics of the player, determine a first player eligibility of the player to participate in the skill based video game comprising verify the one or more player characteristics, send the first player eligibility to an operator of the skill based video game, receive a list of one or more players that fulfilled a win condition for the skill based video game, determine a second player eligibility to receive a payout based on the list of one or more players that fulfilled the win condition, the first player eligibility, and a player preference for a payout type, and distribute the payout to the one or more players that fulfill the win condition.

An online game is a video game played over some form of computer network, typically on the internet. Online games may range from simple text based environments to games incorporating complex graphics and virtual worlds populated by many players simultaneously. A multiplayer online game may be played via a game server over the internet, with other players around the world. Many online games have associated online communities, making online games a form of social activity beyond single player games. A wide variety of online games are available for all type of game players.

This patent is subject to a terminal disclaimer.

Promoting competitive balance in multiplayer gaming


A machine tool has a tool retainer for retaining a tool, a motor and a drivetrain which couples the motor with the tool retainer for transmitting a torque. A system pushbutton is coupled with a motor control. When the system pushbutton is activated by a user, the motor control controls the motor in such a way that the motor turns in a first sense of rotation for a duration and then in a sense of rotation opposed to the first sense of rotation. The duration is shorter than 100 ms.

The present invention relates to a machine tool, in particular a portable drilling machine tool such as a portable drill, hammer drill, etc. More specifically, the present invention relates to a control procedure for the machine tool, in particular a control procedure for turning on or activating the machine tool.


An apparatus for driving a rod antenna element for expansion or contraction according to the invention is characterized in that its rotary drum for winding or unwinding a base portion of a rope for expanding or contracting the antenna element is provided with a means for frictionally transmitting rotary force comprising a plurality of minute ridges and recess formed on the inner peripheral surface of the shaft bearing section in order to frictionally and directly or indirectly transmit in part the rotary force of an electric motor to the rotary drum and that the inner rope-sliding peripheral surface of a rope storage area of the rotary drum is flared from the remotest point thereof toward the rope inlet/outlet port to form a peripheral surface of a frustum of cone.

1. Field of the Invention
This invention relates to an apparatus for driving for expansion or contraction a rod antenna element of an expansion antenna to be suitably used on an automobile or the like and, more particularly, it relates to an improvement made on the rotary drum of an expansion antenna for reeling or unreeling a rope for expansion or contraction of the antenna.
2. Description of the Related Art
The rotary drum of an apparatus for driving a rod antenna element of an expansion antenna for expansion or contraction of the above described type is normally located coaxially with and adjacent to a rope feeding wheel (or a pinion when a rope provided with a rack is used) so that a base portion of the rope for expanding or contracting the antenna device may be wound onto or unwound from a rope storing area inside the outer peripheral wall of the drum. Such a conventional drum is normally freely rotatable relative to its shaft so that it may rotate to follow the movement of the rope base portion (which is freely movable) independent of the rotary motion of the rope feeding wheel which is normally driven by an electric motor.
The structural design of a conventional rotary drum as described above is based on the fact that, if the rotary drum is also driven by a motor so that it may rotate in synchronism with the rotation of the rope feeding wheel, there arises a difference between the peripheral speed of the rope storing area of the rotary drum and the rope feeding rate of the rotary drum to give rise to undesirable friction there. The rotary drum is inevitably made to freely rotate in order to get rid of this undesirable friction.
A conventional rotary drum of the above identified type is accompanied by certain problems as described below. As the inner surface of the rotary drum loses its original smoothness with a prolonged use, the load of winding a rope to be borne by the drum is increased. The inner surface of such a rotary drum is normally coated with a layer of grease and, therefore, well lubricated. So, the rope will move smoothly sideways in a direction parallel to the axis of the drum to ensure an even and smooth winding or unwinding operation. If the rotary drum is used for a long period of time, however, the grease is moved away from the inner surface by silt and/or sand carried in on the peripheral surface of the rope which is frequently wound and unwound so that the inner surface of the rotary drum gradually loses its original smoothness and becomes coarse. Under this condition, the operation of unwinding a rope will put a heavy load on the drum, although the load of winding a rope will not be so heavy. More specifically, the rope would not move smoothly particularly sideways in a direction parallel to the axis of the drum in the rope storage area and the force F2 required for the rope to slidingly move in that direction eventually exceeds the force (winding force) F1 applied to the rope to move it longitudinally. As a result, the rotation of the rotary drum comes to be often disrupted, emitting shaky rattling noises along with large banging noises that would be generated when the portion of the rope being wound up by the drum abruptly slides sideways in a direction parallel to the axis of the drum. Particularly in the case where the operation of the apparatus for driving a rod antenna element for expansion/contraction is controlled electronically as a function of the intensity of the electric current running through the motor circuit, any excess current running through the motor circuit is detected by the current sensor of the control system to disconnect the power supply of the motor even when the antenna element is on the way of being contracted if the increase in the load of winding the rope is too large.

Apparatus for driving rod antenna element for expansion/contraction


The present invention relates to an apparatus and a method for neuromuscular stimulation which is useful for stimulation of weak muscles in general, in sports clinical mode for muscle growth and endurance and in clinical mode for muscular rehabilitation. EMG signals are received from the subject adjacent a muscle whose contraction is to be stimulated. A succession of stimulation (STIM) pulses are supplied to the muscle to be stimulated. The EMG-receiving module is operated during quiescent periods between successive pulses, and the amplitude of stimulation pulses supplied to the subject in the succession is modulated proportionately depending on the a detected voluntary component of the received EMG signals. Modulation is in real time during supply of stimulation pulses whereby the subject is given a sensation of natural muscle control and/or the possibility for greater precision of neuromuscular control.

Electrical pulses have been used for many years for muscle stimulation. For example, U.S. Pat. No. 5,092,329 (Graupe et al.) explains in its background section that work on functional electrical stimulation of paraplegics is based on the discovery of the Italian physiologist Luigi Galvani in the late 18th century that a muscle will contract when in contact with an electrical charge. This was said to have been first applied systematically to paralyzed patients by W. Liberson et al., Arch. Phys. Med. Rehab., Vol. 42, p. 101, (1961). Application of trains of pulses of adequate amplitude, pulse-width and pulse-repetition-frequency at appropriate locations above the region of certain key muscles enabled paraplegic patients with complete or near-complete upper-motor-neuron lesions to stand up and to take steps with the support of parallel bars or a walker. Stimulation parameters for successful functional electrical stimulation (FES) have been said to be of frequency: 20-50 Hz, pulse width: 30-500 μs and amplitude ≤100 mA, see Quandt et al., Exp Transl Stroke Med. 2014; 6: 9. This is an involuntary muscular response out of the control of the patient. Such electrical stimulation has been shown to produce muscle response even in dead bodies for several hours after death.
Electromyography (EMG) is an electro-diagnostic medical technique for evaluating and recording the electrical activity produced by skeletal muscles. EMG is performed using an electromyograph to produce a record called an electromyogram. An electromyograph detects the electrical potential generated by muscle cells when these cells are electrically or neurologically activated. Evoked (involuntary) EMG signals comprise a combination that can include M, H, F and E waves each one with a different characteristic and latency, and the signals can be analysed to detect medical abnormalities, activation level, or recruitment order or to analyse the biomechanics of human or animal movement. As the amplitude of an individual pulse increases from zero to the point where the muscle just starts to engage with mechanical force (perhaps about 10 mA) an evoked EMG (m wave etc.) will appear and its amplitude start to increase from a low level up to perhaps as much or even more than 10 millivolts as the FES pulse amplitude is increased to the point where the muscle is exhibiting maximal contraction. A single pulse of FES will cause a single pulse of muscular contraction to occur with its peak a few milliseconds after the pulse. However, if a train of pulses are applied to the muscle with small enough delay between one pulse and the next (for example 40 mS) then what appears to be a sustained mechanical contraction of the muscle will result.
The evoked EMG between each pulse and the next has been measured and used to control and regulate the electrical stimulator for improved results. In EMG biofeedback, surface electrodes or vaginal/anal probe are used to record the electrical activity in a muscle or muscle group at rest and during contraction. EMG biofeedback is used both for diagnosis and as a therapy to provide the patient and the therapist with information about the electrical activity in the muscles. This method provides extra feedback when the natural feedback signals of the patient are insufficient to achieve the contraction. In other words, it supplements the physiological feedback. This method is especially useful in the case of muscular activity that produces a contraction or movement that is invisible to the patient. An example is to be found in the muscles of the pelvic floor and anus. Myofeedback provides extra information for the motor learning process. The electromyographic signal (EM signal=the electrical resultant of the neuromuscular activity) is detected both in a contraction and in the exclusively electrical activity of a muscle when there is no discernible muscle activity. Therefore, it allows the patient to realize that he or she has control over the activity of their muscles, even if it is very small, or in the case of complete paralysis provides a view on how much it increases during therapy. In addition, the EMG biofeedback allows learning control of muscle contraction, using specialized equipment amplifying the signal received from the muscles. Together with appropriate software and configuration this allows visualization of muscle activity on a computer or other screen in real time. A patient on a regular basis can correct muscle contractile activity, seeing on an electronic display what he or she is not able to feel.
FES such as, for example, that used for "foot drop", can be triggered by a button press. Alternatively, voluntary EMG arising from a typically inadequate voluntary contraction can be used to trigger the onset of a period of useful electrically driven muscular contraction such as that needed, in this example, just long enough to keep the front of the foot up for a sufficient time to complete the step. In both cases the time period of the electrical stimulation and its intensity is predetermined and pre-set to achieve the desired functional result.
EMG-triggered FES links voluntary movement attempts to electrical stimulation, see Quandt et al., supra. An assessment was reported of the efficacy of electromyogram (EMG)-triggered neuromuscular stimulation (EMG-stim) in enhancing upper extremity motor and functional recovery of acute stroke survivors, see Francisco G et al., Electromyogram-triggered neuromuscular stimulation for improving the arm function of acute stroke survivors: a randomised pilot study, Arch Phys Med Rehabil, 79:5 570-5, (1998). EMG signal from the paretic muscle was rectified and integrated. If the processed signal exceeded the pre-set threshold (a minimum of 5 μV), an Automove stimulator (Krauth & Timmerman, GmbH) generated a 0.2 msec width, 0 to 60 mA, biphasic square wave pulse at 20 to 100 Hz. The duty cycle was set for 5 seconds on and 5 seconds off. The EMG detector sensitivity ranged between 5 and 80 μV. The "all or none" stimulus was set for maximum range of motion, not torque. Frequency was adjusted to subject comfort. The skin was examined before and after each session for burns and skin breakdown. Stimulus threshold was gradually increased with each session as voluntary recruitment increased. It was concluded that EMG-triggered stim enhanced the arm function of acute stroke survivors. An EMG-controlled (i.e. triggered) grasping system for tetraplegics is described by Saxena, Nikolic and Popovic, J Rehabil Res & Develop, 32:17-24, 1995. The control signal that turned the stimulation of forearm finger and thumb flexors on and off was based on the detection of the threshold of the amplified, rectified, and integrated electromyographic recordings using surface electrodes positioned over the wrist extensors. The voluntary contraction of wrist extensors was suitable for triggering the stimulation, and it was reproducible enough for daily home use. It was possible to use very similar parameters of stimulation in all subjects: T=200 μs, f=20 Hz, I=35 mA, monophasic charged compensated pulses. The patient selected the level of stimulation using video or audio feedback during stimulation while performing routine activities. The designed device worked using an on-off controller, and there was no gradation in the force.


A height adjustment mechanism for electronic equipment is disclosed. The height adjustment mechanism includes a first sliding component that includes a first set of mechanical structures for engaging a second set of mechanical structures, a first mechanical sub-component coupled to the first sliding component and coupled to a second mechanical sub-component that includes the second set of mechanical structures and a second sliding component coupled to the first sliding component. The first set of mechanical structures and the second set of mechanical structures are configured to mesh. A movement of the first sliding component causes either an expansion or a retraction of the first mechanical sub-component.

Consumer demand for smaller, lighter and more compact products that can be easily managed fuels the desire of manufacturers to deliver such products to market. Responding to the demand of consumers, manufacturers produce products such as desktop, laptop and hand-held computing devices that use components that require a minimal amount of space. As a result, consumer products that are increasingly convenient to manage in terms of their weight and the amount of space that they occupy continually arrive on the market. However, there exists a continued need for innovation in this area.
Vertical height adjustment is a basic feature of many electronic device assemblies, e.g., desktop computers, other devices that use flat panel displays etc. Moreover, flat panel display assemblies that feature vertical height adjustment provide consumers with a capacity to adjust the vertical height of a display to suit an individual consumers needs. However, many of the conventional approaches to vertical height adjustment include parts that are heavy and that consume a significant amount of space.
Several approaches to height adjustment have been employed in the past. In one approach, an assembly that includes a heavy column that uses a constant force spring and racks with gears is employed. The assembly is very heavy which adds cost for shipping and work for setup.
In another approach, an assembly that includes a double pivoted arm is employed. The assembly includes plates and springs and pivot washers at the upper and lower pivots of the double pivoted arm. Because of the friction washers that are used to keep the double pivoted arm in position, users have to overcome the friction that is provided by the friction washers during adjustment of the double pivoted arm. To overcome this problem, either more force is required from the user to adjust the double pivoted arm, or additional springs are needed in the pivot shafts to assist the users' adjustment of the double pivoted arm. In addition, the assembly of the double pivoted arm must be made sufficiently stiff to provide stability (e.g., resist wobbling), which adds parts, weight, size, and cost.

Height adjustment mechanism for electronic equipment

Hewlett-Packard Development Company, L.P.


Diamond electrodes with improved adhesion of the diamond layer to the electrode are produced by sandblasting a surface of the electrode body, and then non-oxidatively etching the roughened (sandblasted) surface so as to remove at least 5 μm of material from under the roughened surface. By removing at least 5 μm of material, the sand particulates in the surface of the electrode body are eliminated, and damage in the form of cracks in the electrode body which result from sandblasting is reduced or eliminated, and further, a surface metal oxide coating is not created. All of these contribute to preparing a surface where spalling of the diamond layer is less likely to occur. Concentrated phosphoric acid is an exemplary non-oxidative etchant used in the process.

Diamond electrodes of this type are produced in a known manner by a diamond layer being built up on a metallic electrode body under defined ambient conditions. The problem with this process is that a stable connection has to be ensured between the diamond layer and the electrode body. In order to improve this connection, it is known to bombard the surface of the electrode body with particles of a size of from 20 to 100 μm by means of a sand blasting process in order to thereby produce a topographically nonuniform surface—and therefore an enlarged contact surface with the diamond layer. The particles used in this process may be formed from any sufficiently hard material that does not react with the material of the electrode body. A preferred material is sic.
In some applications, nevertheless, the adhesion of the built-up diamond layer to the electrode body having a surface roughened in this way does not have the desired stability. In particular, spalling of the diamond layer from the electrode body may occur.
Investigations have revealed that one cause of the spalling is that a not inconsiderable quantity of sand blasting particles are mechanically anchored in the surface of the electrode body during the sand blasting process, and therefore there are between 103 and 104 blasting particles in each square centimeter of the electrode surface after the sand blasting. In this process, the blasting particles are more or less firmly anchored in the surface, in which case the loosely anchored blasting particles could represent a cause of the spalling of the diamond layer which has been built up.
It has therefore been proposed to etch the surface using a conventional oxidative etchant, such as hydrofluoric acid (HF) or nitric acid (HNO3), after the sand blasting. In fact, etching with hydrofluoric acid has succeeded in reducing the number of blasting particles per square centimeter of electrode surface to below 5. Nevertheless, this measure has not resulted in improved diamond electrodes. Firstly, a metal oxide is formed during etching, i.e. niobium oxide in the case of a preferably used electrode body composed of niobium, and this permits only impaired adhesion of the diamond layer. Furthermore, the electrode surface which is embrittled during etching results in delamination of the diamond layer.
A problem present in the prior art is therefore that many of the diamond electrodes produced become unusable owing to spalling of the diamond layer, and therefore thorough testing has to be carried out. This makes the diamond electrodes considerably more expensive. In addition, the diamond electrodes have to be handled very carefully since they also tend toward spalling of the diamond layer when in use.

Diamond electrode and process for producing it


Apparatus for measuring the articulation angle between a tractor and trailer connected by a kingpin and fifth wheel include a transfer assembly associated with the kingpin and interacting with the fifth wheel such that the transfer assembly is rotationally moved relative to the kingpin by relative rotational movement between the kingpin and the fifth wheel. This rotational movement is read by an articulation sensing mechanism having one of a reader element and output element mounted to the transfer assembly and the other of the reader element and the output element operatively mounted to the trailer such that the reader element and the output element interact to provide a signal corresponding to the articulation angle between the tractor and trailer. This signal can be analyzed by a processor for any beneficial use, for example, outputting to a counter steering mechanism.

Articulated vehicles are well-known, and generally include a tractor and a trailer, the trailer being secured to the tractor such that the two may pivot relative to one another about the point of connection. The tractor provides the means for driving the tractor and trailer combination, and is typically the steering means for the combination. In a 'double combination' vehicle, a second trailer is typically towed by a dolly attached to the back of the first trailer and is the steering means for the second trailer such that the two may pivot relative to one another about the point of connection. However, the prior art does provide for trailers that provide a counter-steering function.
For example, in U.S. Pat. No. 7,793,965, apparatus and methods are provided for measuring the angle of articulation between a tractor and trailer so that the wheels of the trailer can be counter-steered to better track the movement of the tractor. The counter-steering of the trailer wheels is dependent upon an articulation angle measurement, and the present invention serves to provide improvements in apparatus designed to measure such an angle of articulation.

Apparatus for measuring articulation angle between a tractor and trailer in an articulated vehicle


There is provided a compound of formula I,

This invention relates to pharmaceutically useful compounds, in particular compounds that bind to opiate receptors (e.g. mu, kappa and delta opioid receptors).
Compounds that bind to such receptors are likely to be useful in the treatment of diseases mediated by opiate receptors, for example irritable bowel syndrome; constipation; nausea; vomiting; and pruritic dermatoses, such as allergic dermatitis and atopy in animals and humans. Compounds that bind to opiate receptors have also been indicated in the treatment of eating disorders, opiate overdoses, depression, smoking and alcohol addiction, sexual dysfunction, shock, stroke, spinal damage and head trauma.
There is a particular need for an improved treatment of itching. Itching, or pruritus, is a common dermatological symptom that can give rise to considerable distress in both humans and animals. Pruritus is often associated with inflammatory skin diseases which may be caused by hypersensitivity reactions, including reactions to insect bites, such as flea bites, and to environmental allergens, such as house dust mite or pollen; by bacterial and fungal infections of the skin; or by ectoparasite infections.
Existing treatments that have been employed in the treatment of pruritus include the use of corticosteroids and antihistamines. However, both of these treatments are known to have undesirable side effects. Other therapies that have been employed include the use of essential fatty acid dietary supplements, though these have the disadvantages of being slow to act, and of offering only limited efficacy against allergic dermatitis. A variety of emollients such as soft paraffin, glycerine and lanolin are also employed, but with limited success.
Thus, there is a continuing need for alternative and/or improved treatments of pruritus.
Certain 4-arylpiperidine-based compounds are disclosed in inter alia European patent applications EP 287339, EP 506468, EP 506478 and J. Med. Chem. 1993, 36, 2833-2850 as opioid antagonists. In addition, International Patent Application WO 95/15327 discloses azabicycloalkane derivatives useful as neuroleptic agents.
According to the invention there is provided compounds of formula I:
wherein Het1 represents a 5- or 6-membered heterocyclic ring comprising at least one atom selected from nitrogen, oxygen and sulfur, which ring is optionally fused to a 5- or 6-membered ring, which latter ring optionally contains one or more heteroatoms selected from nitrogen, oxygen and/or sulfur, and which heterocyclic ring system (Het1) is optionally substituted by one or more substituents selected from halo, nitro, xe2x80x94OH, xe2x95x90O, Si(R4a)(R4b)(R4c), N(R5a)(R5b), SR6a, N(R6b)S(O)2R7a, N(R6c)C(O)OR7b, N(R6d)C(O)R7c, C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms); R4a to R4c independently represent C1-C6 alkyl or aryl;
R5a and R5b independently represent H, C1-C6 alkyl, C1-C4 alkylphenyl, aryl (which latter three groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C1-C4 alkyl or C1-C4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms)) or, together with the N-atom to which they are attached, form a 4- to 6-membered heterocyclic ring (which ring is optionally substituted by one or more substituents selected from C1-C4 alkyl, C1-C4 alkoxy, OH, xe2x95x90O, nitro, amino or halo);
R6a to R6d each independently represent H, C1-C6 alkyl, C1-C4 alkylphenyl or aryl (which latter three groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C1-C4 alkyl or C1-C4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms));
R7a to R7c independently represent C1-C6 alkyl, C1-C4 alkylphenyl or aryl, which four groups are all optionally substituted by one or more substituents selected from OH, nitro, amino, halo, C1-C4 alkyl or C1-C4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
R1 and R2 are each independently H or C1-C4 alkyl;
R3 represents aryl (optionally substituted by one or more substituents selected from OH, nitro, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy, C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms) and xe2x80x94N(R8a)(R8b)), C1-C10 alkyl, C3-C10 alkenyl or C3-C10 alkynyl wherein said alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR8c, S(O)pR8d, CN, halo, C2-C6 alkanoyl, C1-C6 alkoxy carbonyl, C2-C6 alkanoyloxy, C3-C8 cycloalkyl, C4-C9 cycloalkanoyl, N(R9a)S(O)2R10, Het2, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c);
p is 0, 1 or 2;
W represents a single bond, C(O) or S(O)q;
A1 represents a single bond or C1-C10 alkylene;
provided that when both W and A1 represent single bonds, then the group xe2x80x94N(R9b)(R9c) is not directly attached to an unsaturated carbon atom;
q is 0, 1 or 2;
R8a to R8d each independently represent H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C1-C4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)) or Het3;
provided that R8d does not represent H when p represents 1 or 2;
R9a to R9c each independently represent H, C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, C3-C8 cycloalkyl, C1-C4 alkylphenyl, aryl (which latter six groups are optionally substituted by or one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), Het4, or R9b and R9c together represent unbranched C2-C6 alkylene which alkylene group is optionally interrupted by O, S and/or an N(R11) group and is optionally substituted by one or more C1-C4 alkyl groups;
R10 represents C1-C6 alkyl, C3-C8 cycloalkyl, C1-C4 alkylphenyl or aryl, which four groups are optionally substituted by or one or more substituents selected from C1-C4 alkyl, C1-C4 alkoxy, OH, nitro, amino or halo;
R11 represents H, C1-C6 alkyl, C3-C8 cycloalkyl, A2xe2x80x94(C3-C8 cycloalkyl) or
A2-aryl;
A2 represents C1-C6 alkylene;
Het2, Het3 and Het4 independently represent 3-to 8-membered heterocyclic groups, which groups contain at least one heteroatom selected from oxygen, sulfur and/or nitrogen, which groups are optionally fused to a benzene ring, and which groups are optionally substituted in the heterocyclic and/or fused benzene ring part by one or more substituents selected from OH, xe2x95x90O, nitro, amino, halo, CN, aryl, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms);
X is H, halo, C1-C4 alkyl or C1-C4 alkoxy (which latter two groups are optionally substituted by one or more halo atoms);
n is 0, 1 or 2;
or pharmaceutically, or veterinarily, acceptable derivatives thereof;
which compounds are referred to together hereinafter as xe2x80x9cthe compounds of the invention.xe2x80x9d
In the definitions used herein, alkyl, alkylene, alkoxy, alkoxy carbonyl, alkanoyl, alkanoyloxy, alkenyl, alkynyl and the alkyl parts of alkylphenyl and aryl alkoxy groups may, when there is a sufficient number of carbon atoms, be straight or branched-chain and/or optionally interrupted by one or more oxygen and/or sulfur atom(s). The term halo includes fluoro, chloro, bromo or iodo. The term xe2x80x9carylxe2x80x9d includes optionally substituted phenyl, naphthyl and the like, and xe2x80x9caryloxyxe2x80x9d includes optionally substituted phenoxy and naphthyloxy and the like. Unless otherwise specified, aryl and aryloxy groups are optionally substituted by one or more (e.g. one to three) substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkoxy carbonyl and C1-C5 alkanoyl (which latter four groups are optionally substituted by one or more halo atoms).
The heterocyclic rings that Het1, Het2, Het3 and Het4 represent may be fully saturated, partially unsaturated and/or wholly or partially aromatic in character. Specific rings that may be mentioned include: for Het1, adenine, benzimidazole, benzoxadiazole, benzoxazole, benzthiazole, cinnoline, cytosine, furan, furoxan, guanine, hydroxypyridine, hypoxanthine, imidazole, 1H-imidazo[4,5-b]pyrazine, indole, isoquinoline, isothiazole, isoxazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, oxazole, phthalazine, purine, pyrazine, pyrazole, pyridazine, pyridine, pyridine N-oxide, pyrimidine, pyrrole, quinazoline, quinoline, quinoxaline, 4,5,6,7-tetrahydrobenzimidazole, 4,5,6,7-tetrahydrobenzoxazole, 4,5,6,7-tetrahydro-1H-imidazo[4,5-b]-pyrazine, 1,2,4,5-tetrazine, tetrazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, thiazole, thiophene, thymine, 1,2,3-triazine, 1,2,4-triazine, 1,3,5-triazine, 1,2,3-triazole, 1,2,4-triazole and uracil; for Het2, dioxane, dioxolane, morpholine, piperidine, perhydroazepine, tetrahydrofuran, tetrahydropyran or tetrazole. Substituents on Het1, Het2, Het3, and Het4 groups may be located at any point on the ring/fused ring system.
For the avoidance of doubt, when Het (Het1, Het2, Het3 and Het4) groups are at least part-saturated, possible points of substitution include the atom (e.g. the carbon atom) at the point of attachment of the Het group to the rest of the molecule. Het2, Het3 and Het4 groups may also be attached to the rest of the molecule via a heteroatom.
The piperidine moiety in compounds of formula I may be in N-oxidised form. Sulfur atoms that may interrupt (e.g. alkyl) substituents in compounds of formula I may be present in oxidised form (e.g. as sulfoxides or sulfones). All Het1, Het2, Het3 and Het4 groups may also be in N- or S-oxidized forms.
The term xe2x80x9cpharmaceutically, or veterinarily, acceptable derivativesxe2x80x9d includes non-toxic salts. Salts which may be mentioned include: acid addition salts, for example, salts formed with sulfuric, hydrochloric, hydrobromic, phosphoric, hydroiodic, sulfamic, organo-sulfonic, citric, carboxylic (e.g. acetic, benzoic, etc.), maleic, malic, succinic, tartaric, cinnamic, ascorbic and related acids; base addition salts; salts formed with bases, for example, the sodium, potassium and C1-C4 alkyl ammonium salts.
The compounds of the invention may also be in the form of quaternary ammonium salts, e.g. at the piperidine moiety, which salts may be formed by reaction with a variety of alkylating agents, such as an alkyl halide or an ester of sulfuric, or an aromatic sulfonic, acid.
The compounds of the invention may exhibit tautomerism. All tautomeric forms of the compounds of formula I are included within the scope of the invention.
The compounds of the invention contain one or more asymmetric centres and thus they can exist as enantiomers and diastereomers. Diastereoisomers may be separated using conventional techniques e.g. by fractional crystallisation or chromatography. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques e.g. fractional crystallisation or HPLC. The desired optical isomers may be prepared by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation. Alternatively, the desired optical isomers may be prepared by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base. The invention includes the use of both the separated individual isomers as well as mixtures of isomers.
Also included within the scope of the invention are radio-labelled derivatives of compounds of formula I which are suitable for biological studies.
Preferred compounds of the invention include those wherein:
Het1 is attached in the meta- position relative to the piperidine ring;
R1 represents C1-C2 alkyl;
R2 represents H or C1-C2 alkyl;
R3 represents saturated C1-C10 (e.g. C1-C8) alkyl, optionally interrupted by oxygen and/or optionally substituted and/or terminated by one or more substituents selected from CN, halo, C1-C6 alkoxy carbonyl, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C3-C8 cycloalkyl, C4-C9 cycloalkanoyl, OR8c, N(R9a)S(O)2R10, Het2, phenyl (which latter group is optionally substituted by one or more substituents selected from OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C5 alkanoyl, halo, nitro, amino, CN, CH2CN, CONH2 and CF3), and/or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c);
R8c represents H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C4 alkylphenyl or phenyl (which latter two groups are optionally substituted by one or more substituents selected from OH, C1-C4 alkyl, C1-C4 alkoxy, C2-C5 alkanoyl, halo, nitro, amino, CN, CH2CN, CONH2 and CF3);
R9a to R9c each independently represent H, C1-C4 alkyl, C1-C2 alkylphenyl or phenyl (which latter two groups are optionally substituted by or one or more substituents selected from C1-C2 alkyl, C1-C2 alkoxy, OH or halo);
R10 represents C1-C4 alkyl or aryl, which two groups are optionally substituted by or one or more substituents selected from C1-C2 alkyl, C1-C2 alkoxy, nitro or halo;
W represents C(O) or S(O)2;
A1 represents a single bond or C1-C4 alkylene.
More preferred compounds of the invention include those wherein:
Het1 represents one of the rings specifically identified hereinbefore in respect of Het1;
R1 represents methyl;
R2 represents H or methyl;
R3 represents linear, saturated C1-C7 alkyl, optionally substituted by one or more substituents selected from CN, halo, C1-C2 alkoxy carbonyl, OR8c, N(H)S(O)2R10, Het2, phenyl (which latter group is optionally substituted by one or more substituents selected from C1-C2 alkyl, C1-C2 alkoxy and halo), or C(O)N(R9b)(R9c);
R8c represents H, C1-C4 alkyl, phenyl or C1-C2 alkylphenyl (which latter three groups are optionally substituted by one or more substituents selected from C1-C2 alkyl, C1-C2 alkoxy and halo);
R9b and R9c independently represent H, C1-C4 alkyl or C1-C2 alkylphenyl;
R10 represents C1-C2 alkyl;
X represents halo, particularly fluoro;
n represents 1 or, preferably, 0.
Still further preferred compounds of the invention include those wherein:
Het1 represents a 5- or 6-membered heterocyclic ring comprising at least one nitrogen and/or at least one oxygen atom, which ring is optionally substituted by one or more substituents selected from Si(R4a)(R4b)(R4c), halo, thiobenzyl or C1-C6 alkyl;
R1and R2 both represent methyl groups in the mutually trans configuration;
R3 represents benzyl, 2-(benzyloxy)ethyl, N-benzyl-3-propanamido, 2-butoxyethyl, n-butyl, N,N-diethyl-3-propanamido, 3-(2,5-dimethoxy-phenoxy)propyl, 2-(1,3-dioxan-2-yl)ethyl, 4-(1,3-dioxolan-2-yl)butyl, 2-(1,3-dioxolan-2-yl)ethyl, 2-ethanesulfonamidoethyl, 1-ethoxycarbonyl-methyl, 3-ethoxypropyl, 2-(4-fluorophenyl)ethyl, 6-hexanenitrile, n-hexyl, 3-hydroxy-3-phenylpropyl, 4-methoxybutyl, 5-methoxycarbonylpentyl, 2-(2-methoxyethoxy)ethyl, 2-(3-methylphenyl)ethyl, 3-(4-morpholino)-propyl, 5-pentanenitrile, n-pentyl, 2-(1-perhydroazepinyl)ethyl, 2-phenoxyethyl, 3-phenoxypropyl, 2-phenylethyl, 3-phenylpropyl, 2-(1-piperidino)ethyl, 3-(1-piperidino)propyl, N-propyl-3-propanamido, 2-propoxyethyl, 3-tetrahydro-3-furanylpropyl, 3-tetrahydro-2H-pyran-2-ylpropyl or 3-(tetrazol-1-yl)-propyl;
R4a to R4c independently represent C1-C6 alkyl.
Particularly preferred compounds of the invention include those wherein:
Het1 represents preferably unsubstituted 2- or 4-imidazole, tetrazole, 5-oxazole, 5-isoxazole, 4- or 5-pyrazole, 1,2,3- or 1,2,4-triazole.
Preferred compounds of the invention include the compounds of the Examples described hereinafter.
According to a further aspect of the invention there is provided processes for the preparation of compounds of the invention, as illustrated below.
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
1. Compounds of formula I may be prepared by transition-metal- (for example, palladium-) catalysed cross-coupling between a compound of formula II,
wherein L is a suitable leaving group such as halogen, preferably bromine or iodine, or a sulfonate such as trifluoromethanesulfonate, and R1, R2, R3, X and n are as hereinbefore defined, with a compound of formula III,
Het1xe2x80x94Mxe2x80x83xe2x80x83III
where M is a tin-containing moiety (e.g. tributylstannyl), a boron derivative (e.g. a boronic acid), or a zinc halide (which may be formed in situ from the corresponding halide) and Het1 is as hereinbefore defined, for example at between room temperature and boiling point in a reaction-inert solvent (e.g. dimethylformamide) in the presence of an appropriate coupling agent (e.g. palladium(II) chloride, tris(dibenzylideneacetone)-dipalladium(0) combined with triphenylarsine, or tetrakis(triphenyl-phosphine)palladium(0)).
2. Compounds of formula I in which Het1 represents 1H-1,2,3-triazol-4-yl, optionally substituted by Si(R4a)(R4b)(R4c), C1-C6 alkyl or C1-C6 haloalkyl, wherein R4a to R4c are as hereinbefore defined, may be prepared by reaction of a nitrile of formula IV,
wherein R1, R2, R3, X and n are as hereinbefore defined, with a compound of formula V,
R12CHN2xe2x80x83xe2x80x83V
wherein R12 represents H, Si(R4a)(R4b)(R4c) or C1-C6 alkyl, which latter group is optionally substituted by one or more halo atoms, and R4a to R4c are as hereinbefore defined, for example at between xe2x88x9210xc2x0 C. and room temperature in the presence of a suitable strong base (e.g. n-butyllithium) and a reaction-inert organic solvent (tetrahydrofuran).
Compounds of formula IV may be prepared by reaction of a compound of formula VI,
wherein R1, R2, R3, X and n are as hereinbefore defined with an alkali metal cyanide (e.g. potassium cyanide), for example at raised temperature in the presence of a reaction-inert solvent (e.g. N-methylpyrrolidine) and a suitable catalyst (e.g. palladium(II) acetate combined with 1,1xe2x80x2-bis(diphenylphosphino)ferrocene).
Compounds of formula VI may be prepared by reaction of a corresponding compound of formula VII,
wherein R1, R2, R3, X and n are as hereinbefore defined, with an appropriate triflating agent (e.g. N-phenyltrifluoromethanesulfonimide), for example at between 0xc2x0 C. and room temperature in the presence of a reaction-inert organic solvent (e.g. dichloromethane) and a suitable base (e.g. triethylamine).
Compounds of formula VII may be prepared by reaction of a corresponding compound of formula VIII,
with a compound of formula IX,
R3L1xe2x80x83xe2x80x83IX
wherein R3 is as hereinbefore defined, and L1 represents a leaving group (e.g. halo, alkanesulfonate, perfluoroalkanesulfonate or arenesulfonate), under conditions that are known to those skilled in the art, which include, for example, alkylation at between room temperature and reflux temperature in the presence of a reaction-inert organic solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. NaHCO3), and arylation at between room temperature and reflux temperature in the presence of a suitable catalyst system (e.g. tris(dibenzylideneacetone)palladium(0) combined with tri-o-tolylphosphine), an appropriate strong base (e.g. sodium tert-butoxide) and a reaction-inert solvent (e.g. toluene).
3. Compounds of formula I in which Het1 represents 1H-1,2,4-triazol-4-yl, optionally substituted by an R12 group, wherein R12 is as hereinbefore defined, may be prepared by reaction of an imidate of formula X,
wherein R13 represents C1-C6 alkyl, and R1, R2, R3, X and n are as hereinbefore defined, with a compound of formula XI,
H2NNHCOR12xe2x80x83xe2x80x83XI
wherein R12 is as hereinbefore defined, for example at between room temperature and reflux temperature in the presence of a suitable organic solvent (e.g. an alcohol), followed by, if necessary, continued heating of the reaction until completion in the absence of solvent.
Compounds of formula X may be prepared by methods well known to those skilled in the art. For example, compounds of formula X may be prepared by saturating a solution of a corresponding nitrile of formula IV, as hereinbefore defined, in an alcohol of formula R13OH, wherein R13 is as hereinbefore defined, with gaseous HCl, for example at 0 to 50xc2x0 C.
4. Compounds of formula I in which Het1 represents 1H-1,3-imidazol-2-yl, optionally substituted by up to two R12 groups, wherein R12 is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula X, as hereinbefore defined, with a compound of formula XII,
H2NCH(R12b)C(OMe)2R12axe2x80x83xe2x80x83XII
wherein independent substituents R12a and R12b represent R12, and R12 is as hereinbefore defined, for example at between room temperature and reflux temperature in the presence of a suitable organic solvent (e.g. an alcohol), followed by, if necessary, continued heating of the reaction until completion in the absence of solvent.
5. Compounds of formula I in which Het1 represents 1H-benzimidazol-2-yl, 1H-benzoxazol-2-yl, 1H-benzthiazol-2-yl (all of which are optionally substituted in the benzene ring part) may be prepared by reaction of a corresponding compound of formula X, as hereinbefore defined, with a compound of formula XIII,
wherein D represents one to four substituents as defined hereinbefore in respect of Het1 and E represents O, S or NH, under conditions known to those skilled in the art, for example at between room temperature and reflux temperature in the presence of a suitable organic solvent (e.g. an alcohol), followed by, if necessary, continued heating of the reaction until completion in the absence of solvent.
6. Compounds of formula I in which Het1 represents 5-chloro-1,2,4-thiadiazol-3-yl may be prepared by reaction of a corresponding compound of formula XIV,
or a suitable (e.g. hydrogen halide) adduct thereof, wherein R1, R2, R3, X and n are as hereinbefore defined, with trichloromethanesulfenyl chloride, for example at between xe2x88x9210 and +10xc2x0 C. in the presence of a reaction-inert solvent (e.g. dichloromethane) and optionally in the presence of a suitable base (e.g. aqueous sodium hydroxide).
Compounds of formula XIV may be prepared by reaction of a compound of formula IV, as hereinbefore defined, with ammonia and/or or a suitable adduct thereof (e.g. a hydrohalide), for example at between room temperature and 100xc2x0 C., optionally at elevated pressure and optionally in the presence of a suitable solvent (e.g. water, a lower alkyl alcohol such as methanol or ethanol, or an appropriate mixture thereof).
7. Compounds of formula I in which Het1 represents 1H-1,3-imidazol-4-yl may be prepared by desulfurisation of a corresponding compound of formula I in which Het1 represents 2-thiobenzylated 1H-1,3-imidazol-4-yl, for example using Raney(copyright) nickel in the presence of a suitable organic solvent (e.g. ethanol) and an appropriate base (e.g. sodium hydroxide).
8. Compounds of formula I in which Het1 represents 2-thiobenzylated 1H-1,3-imidazol-4-yl may be prepared by reaction of a corresponding xcex1-halocarbonyl compound of formula XV,
wherein R1, R2, R3, X and n are as hereinbefore defined with 2-benzyl-2-thiopseudourea, for example at between room temperature and reflux temperature in the presence of a reaction-inert organic solvent (e.g. N,N-dimethylformamide) and a suitable base (e.g. potassium carbonate).
Compounds of formula XV may be prepared by reaction of a corresponding methylketone of formula XVI,
wherein R1, R2, R3, X and n are as hereinbefore defined, with trimethylsilylchloride, for example at between xe2x88x9278 and xe2x88x9210xc2x0 C. in the presence of a strong base (e.g. lithium bis(trimethylsilyl)amide) and a reaction-inert organic solvent (e.g. tetrahydrofuran), followed by reaction with bromine.
Compounds of formula XVI may be prepared by reaction of a corresponding triflate of formula VI, as hereinbefore defined, with a compound that provides a suitable source of an acyl anion equivalent (e.g. vinyl butyl ether), for example at between room temperature and reflux temperature in the presence of an appropriate catalyst (e.g. palladium(II) acetate combined with 1,1xe2x80x2-bis(diphenylphosphino)ferrocene), an organic base (e.g. triethylamine) and a suitable solvent (e.g. N,N-dimethyl-formamide), followed by hydrolysis of the resulting enol ether under conditions known to those skilled in the art (for example, by reaction at room temperature with aqueous hydrochloric acid).
Alternatively, compounds of formula XVI may be prepared by reaction of a compound corresponding to a nitrile of formula IV with a methyl-delivering organometallic compound (e.g. methyl lithium), for example at between xe2x88x9280 and 10xc2x0 C. in the presence of a reaction-inert organic solvent (e.g. tetrahydrofuran).
9. Compounds of formula I in which Het1 represents 1H-tetrazol-5-yl may be prepared by reaction of a corresponding compound of formula IV, as hereinbefore defined, with a suitable source of the azide ion (e.g. trimethylsilyl azide), for example at between room temperature and reflux temperature in the presence of a reaction-inert solvent (e.g. toluene) and an appropriate Lewis-acidic catalyst (e.g. dibutyltin oxide).
10. Compounds of formula I wherein R3 represents C1 alkyl optionally substituted by C3-C8 cycloalkyl, Het2, aryl, adamantyl, (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or R3 represents C2-C10 alkyl, C3-C10 alkenyl or C3-C10 alkynyl (which three groups are all optionally substituted by one or more of the relevant substituents identified hereinbefore in respect to R3), which alkyl, alkenyl or alkynyl groups are attached to the piperidine nitrogen atom via a CH2 group, wherein Het2 is as hereinbefore defined, may be prepared by reduction of a corresponding compound of formula XVII,
wherein R31 represents H, C3-C8 cycloalkyl, Het2, aryl, adamantyl, (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), C1-C9 alkyl, C2-C9 alkenyl or C2-C9 alkynyl, which alkyl, alkenyl or alkynyl groups are optionally substituted and/or terminated by one or more substituents selected from OR8c, S(O)pR8d, CN, halo, C1-C6 alkoxy carbonyl, C2-C6 alkanoyl, C2-C6 alkanoyloxy, C3-C8 cycloalkyl, C4-C9 cycloalkanoyl, N(R9a)S(O)2R10, Het2, aryl, adamantyl (which latter two groups are optionally substituted by one or more substituents selected from OH, nitro, amino, halo, CN, CH2CN, CONH2, C1-C4 alkyl, C1-C4 alkoxy and C1-C5 alkanoyl (which latter three groups are optionally substituted by one or more halo atoms)), or xe2x80x94Wxe2x80x94A1xe2x80x94N(R9b)(R9c), and R1, R2, R8c, R8d, R9a to R9c, R10, Het1, Het2, n, p, W, X and A1 are as hereinbefore defined, using a suitable reducing agent (e.g. lithium aluminium hydride or a borane derivative), for example as described hereinbefore.
Compounds of formula XVII may be prepared by reaction of a corresponding compound of formula XVIII,
wherein Het1, R1, R2, X and n are as hereinbefore defined with a compound of formula XIX,
R31CO2xe2x80x83xe2x80x83H XIX
or a suitable (e.g. carboxylic acid) derivative thereof (e.g. an acid halide or anhydride), wherein R31 is as hereinbefore defined, using coupling conditions known to those skilled in the art.
Compounds of formulae XVII and XVIII may be prepared from appropriate precursors by analogy with methods disclosed herein that describe to the introduction, or formation, of a Het1 group.
11. Compounds of formula I in which Het1 represents 1H-pyrazol-3-yl may be prepared by reaction of a corresponding xcex1,xcex2-unsaturated ketone of formula XX,
wherein R1, R2, R3, X and n are as hereinbefore defined, with hydrazine, for example at between room temperature and reflux temperature in the presence of a reaction-inert solvent (e.g. a methanol/water mixture).
Compounds of formula XX may be prepared by aldol condensation of a corresponding methyl ketone of formula XVI, as hereinbefore defined, with dimethylaminoacetaldehyde dimethylacetal, for example at between room temperature and reflux temperature in the presence of a reaction-inert organic solvent (e.g. N,N-dimethylformamide).
12. Compounds of formula I wherein Het1 represents 1H-pyrazol-4-yl may be prepared by reaction of a corresponding compound of formula VI, as hereinbefore defined, with a compound of formula XXI,
for example at between room temperature and reflux temperature in the presence of a reaction-inert solvent (e.g. N,N-dimethylformamide), an appropriate coupling agent (e.g. tris(dibenzylideneacetone)dipalladium(0) combined with triphenylarsine) and a suitable source of a halide ion (e.g. lithium chloride).
13. Compounds of formula I wherein Het1 represents oxazol-5-yl, thiazol-5-yl or imidazol-5-yl (which three groups are all optionally substituted in the 4-position by R12, wherein R12 is as hereinbefore defined, and which imidazol-5-yl group is substituted at the 1-position by C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms)) may be prepared by reaction of a corresponding compound of formula XXII,
wherein G represents NR14, O or S, R14 represents C1-C6 alkyl, C1-C6 alkoxy or C3-C6 cycloalkyl (which latter three groups are optionally substituted by one or more halo atoms), and R1, R2, R3, X and n are as hereinbefore defined, with a compound of formula XXIII,
CNCH(R12)L2xe2x80x83xe2x80x83XXIII
wherein L2 represents a group capable, when attached to a C2 alkylene unit, of undergoing 1,2-elimination (relative to the L2 group, e.g. an alkyl or aryl sulfoxide or sulfone), and R12 is as hereinbefore defined, for example at between room and reflux temperature in the presence of an appropriate base (e.g. potassium carbonate) and a reaction-inert solvent (e.g. a lower alkyl alcohol, such as methanol).
Compounds of formula XXII in which G represents O may be prepared from a corresponding vinyl derivative of formula XXIV,
wherein R1, R2, R3, X and n are as hereinbefore defined, by reaction with a suitable dihydroxylating reagent (e.g. sub-stoichiometric OSO4 combined with morpholine N-oxide), for example at between 0xc2x0 C. and refluxtemperature in the presence of a reaction-inert solvent (e.g. a water/acetone mixture) and an appropriate reagent to effect 1,2-diol oxidative cleavage (e.g. sodium periodate).
Compounds of formula XXII in which G represents NR14, wherein R14 is as hereinbefore defined, may be prepared by reaction of a corresponding compound in which G represents 0 with a compound of formula XXV,
R14xe2x80x94NH2xe2x80x83xe2x80x83XXV
wherein R14 is as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. a lower alkyl alcohol such as methanol or ethanol), and optionally in the presence of a suitable Lewis-acidic catalyst.
Compounds of formula XXII in which G represents S may be prepared by reaction of a corresponding compound in which G represents O with a reagent that effects oxygen-sulfur exchange (e.g. Lawesson""s Reagent), for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. toluene).
Compounds of formula XXIV can be prepared from a corresponding compound of formula VI, as hereinbefore defined, by reaction with a suitable source of vinyl anion equivalent (e.g. vinyltributyltin), for example at between room temperature and reflux temperature in the presence of a reaction-inert solvent (e.g. THF), an appropriate coupling agent (e.g. tetrakis(triphenylphosphine)palladium(0)) and a suitable source of halide ion (e.g. lithium chloride).
14. Compounds of formula I wherein Het1 represents isoxazol-5-yl may be prepared by reaction of a corresponding compound of formula XX, as hereinbefore defined, with a suitable form of hydroxylamine, for example at between room temperature and reflux temperature in the presence of a reaction-inert solvent (e.g. a methanol/water mixture).
15. Compounds of formula I in which Het1 represents 1H-1,2,3-triazol-4-yl, optionally substituted by Si(R4a)(R4b)(R4c), C1-C6 alkyl or C1-C6 haloalkyl or halo, wherein R4a to R4c are as hereinbefore defined, may alternatively be prepared by reaction of a corresponding compound of formula XXVI,
wherein R15 represents H, Si(R4a)(R4b)(R4c), halo or C1-C6 alkyl, which latter group is optionally substituted by one or more halo atoms, and R1, R2, R3, R4a to R4c, L2, X and n are as hereinbefore defined, with a suitable source of the azide ion (e.g. sodium azide), for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. N,N-dimethylformamide).
Compounds of formula XXVI may be prepared by reaction of a compound of formula XXII, as hereinbefore defined, in which G represents O, with a compound of formula XXVII,
L2xe2x80x94CH2xe2x80x94R15xe2x80x83xe2x80x83XXVII
wherein L2 and R15 are as hereinbefore defined, for example at between xe2x88x9280xc2x0 C. and room temperature in the presence of a strong base (e.g. n-butyl lithium) and a reaction-inert solvent (e.g. THF), followed by dehydration of the resultant hydroxy compound under conditions well known to those skilled in the art (e.g. by reaction with methanesulfonyl chloride in the presence of triethylamine).
16. Compounds of formula I may be prepared by reaction of a corresponding compound of formula XVIII, as hereinbefore defined, with a compound of formula IX, as hereinbefore defined, under conditions that are well known to those skilled in the art, for example as described hereinbefore in respect of the production of compounds of formula VII.
17. Compounds of formula I wherein R3 represents C1 alkyl, which, in place of being optionally substituted by the substituents as defined hereinbefore, is instead optionally substituted by R31, wherein R31 is as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula XVIII, as hereinbefore defined, with a compound of formula XXVIII,
R31CHOxe2x80x83xe2x80x83XXVIII
wherein R31 is as hereinbefore defined, for example in the presence of a suitable reducing agent (e.g. sodium borohydride, sodium cyano-borohydride or sodium triacetoxyborohydride) and an appropriate solvent (e.g. methanol).
18. Compounds of formula I wherein R3 is a C1-C10 alkyl, C4-C10 alkenyl or C4-C10 alkynyl group that is fully saturated from 1- to 3-C (relative to the piperidine N-atom), and which R3 group is substituted at 2-C (relative to the piperidine N-atom) by S(O)R8d, S(O)2R8d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), xe2x80x94S(O)xe2x80x94Alxe2x80x94N(R9b)(R9c), or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R9b)(R9c), wherein R8d, R9b, R9c and A1 are as hereinbefore defined, may be prepared by reaction of a corresponding compound of formula XVIII, as hereinbefore defined, with a compound of formula XXIX,
R3axe2x80x94Zxe2x80x83xe2x80x83XXIX
wherein R3a represents R3 as hereinbefore defined except that it does not represent aryl, and that the R3a chain contains an additional carbon-carbon double bond xcex1,xcex2 to the Z-substituent, and Z represents S(O)R8d, S(O)2R8d, alkanoyl, cycloalkanoyl, alkoxy carbonyl, CN, xe2x80x94C(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), xe2x80x94S(O)xe2x80x94A1xe2x80x94N(R9b)(R9c), or xe2x80x94S(O)2xe2x80x94A1xe2x80x94N(R9b)(R9c), wherein R8d, R9b, R9c and A1 are as hereinbefore defined, for example at between room and reflux temperature in the presence of a reaction-inert solvent (e.g. THF).
Compounds of formulae II, III, V, VIII, IX, XI, R13OH, XII, XIII, XIX, XXI, XXIII, XXIV, XXVII, XXVIII, XXIX, and derivatives thereof, when not commercially available or not subsequently described, may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from readily available starting materials using appropriate reagents and reaction conditions. For example, Het1 or Het1-M groups in compounds of formulae I, III, XVII, XVIII and XXI may also be prepared by, or by analogy with, the methods disclosed in European patent application EP 590 971, Houben-Weyl Methods of Organic Chemistry, Additional and Supplementary Volumes to the 4th Edition (Volumes E6a, E6b, E6b2, E7a, E7b, E8a, E8b, E8c, E8d, E9, E9a), edited by E Schaumann and R Kreher, Thieme (Stuttgart) or Comprehensive Heterocyclic Chemistry II, edited by A R Katritsky, C W Rees and EFV Scriven, 1st Edition, Elsevier Science Ltd., Volumes 1-11 (1996). Conventional synthetic procedures, and standard techniques also include, for example, those relating to process 1 described hereinbefore, examples of which may be found in: xe2x80x9cPalladium Reagents in Organic Synthesisxe2x80x9d RF Heck, Academic Press (1985); xe2x80x9cComprehensive Organometallic Chemistryxe2x80x9d, edited by AG Davies, 2nd Edition, Volume 12, Chapter 3, Section D, Pergamon Press (1995); J K Stille, Angew. Chem. Intl. Ed. Eng., 1986, 25, 508; A Suzuki, N Niyaura, Chem. Rev. 1995, 95, 2457; xe2x80x9cOrganometallics in Synthesis A Manualxe2x80x9d, M. Schlosser, John Wiley and Sons (1994); xe2x80x9cMetal-catalysed Cross-coupling Reactionsxe2x80x9d, F Diedrich and P J Stang, Wiley-Vch (1998); and xe2x80x9cPalladium Reagents and Catalysts Innovations in Organic Synthesisxe2x80x9d, J Tsuji, John Wiley and Sons (1995), the disclosures in which documents are hereby incorporated by reference.
Substituents on alkyl, heterocyclic and aryl groups in the above-mentioned compounds may also be introduced, removed and interconverted, using techniques which are well known to those skilled in the art (including those specifically disclosed hereinbefore). For example, nitro may be reduced to amino, OH may be alkylated to give alkoxy, alkoxy and alkanoyloxy may be hydrolysed to OH, alkenes may be hydrogenated to alkanes, halo may be hydrogenated to H, etc.
In some cases it is possible to introduce further substituents into the compounds of formula I directly. For example, chlorination of the phenyl group of compounds of formula I, may be performed by reaction with a solution of chlorine in acetic acid.
It will be appreciated by those skilled in the art that heterocycles prepared by the processes described hereinbefore may, if desired, be further substituted by, for example, halogen, nitro and xe2x80x94SR, by treatment with electrophilic reagents such as halosuccinimides, nitric acid and sulfenyl halides. It will further be understood that these substituents may be subjected to further transformations, for example reduction of nitro groups and subsequent acylation or alkylation of the resultant amino groups, to provide further examples within the scope of the invention. These methodologies and their applicability will be known and understood by the skilled person.
Thus, the skilled person will appreciate that various standard substituent or functional group interconversions and transformations within certain compounds of formula I will provide other compounds of formula I.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
It will be appreciated by those skilled in the art that, in the course of carrying out the processes described above, the functional groups of intermediate compounds may need to be protected by protecting groups.
Functional groups which it is desirable to protect include oxo, hydroxy, amino and carboxylic acid. Suitable protective groups for oxo include acetals, ketals (e.g. ethylene ketals) and dithianes. Suitable protective groups for hydroxy include trialkylsilyl and diarylalkylsilyl groups (e.g. tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) and tetrahydropyranyl. Suitable protective groups for amino include benzyl, tert-butyloxycarbonyl, 9-fluorenylmethoxycarbonyl or benzyloxycarbonyl. Suitable protective groups for carboxylic acid include C1-C6 alkyl or benzyl esters.
The protection and deprotection of functional groups may take place before or after any of the reaction steps described hereinbefore.
Protective groups may be removed in accordance with techniques which are well known to those skilled in the art.
The use of protecting groups is fully described in xe2x80x9cProtective Groups in Organic Chemistryxe2x80x9d, edited by JWF McOmie, Plenum Press (1973), and xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d, 2nd edition, TW Greene and PGM Wutz, Wiley-Interscience (1991).
Persons skilled in the art will also appreciate that, in order to obtain compounds of formula I in an alternative, and, on some occasions, more convenient, manner, the individual process steps mentioned hereinbefore may be performed in a different order, and/or the individual reactions may be performed at a different stage in the overall route (i.e. substituents may be added to and/or chemical transformations performed upon, different intermediates to those mentioned hereinbefore in conjunction with a particular reaction). This will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, the type of chemistry involved will influence the choice of reagent that is used in the said synthetic steps, the need, and type, of protecting groups that are employed, and the sequence for accomplishing the synthesis. The procedures may be adapted as appropriate to the reactants, reagents and other reaction parameters in a manner that will be evident to the skilled person by reference to standard textbooks and to the examples provided hereinafter.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula I, which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as xe2x80x9cprodrugsxe2x80x9d. Further, certain compounds of formula I may act as prodrugs of other compounds of formula I.
It will be further appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as xe2x80x9cpro-moietiesxe2x80x9d, for example as described in xe2x80x98Design of Prodrugsxe2x80x99 by H. Bundgaard, Elsevier, 1985 (the disclosure in which document is hereby incorporated by reference), may be placed on appropriate functionalities, when such functionalities are present within compounds of formula I.
All protected derivatives, and prodrugs, of compounds of formula I are included within the scope of the invention.
Pharmaceutically acceptable acid addition salts of the compounds of formula I which contain a basic centre may be prepared in a conventional manner. For example, a solution of the free base may be treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt may then be isolated either by filtration of by evaporation under vacuum of the reaction solvent. Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula I with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The above procedures may be adapted as appropriate to the particular reactants and groups involved and other variants will be evident to the skilled chemist by reference to standard textbooks and to the examples provided hereafter to enable all of the compounds of formula I to be prepared.
The compounds of the invention are useful because they possess pharmacological activity in animals, especially mammals including humans. They are therefore indicated as pharmaceuticals and, in particular, for use as animal medicaments.
According to a further aspect of the invention there is provided the compounds of the invention for use as medicaments, such as pharmaceuticals and animal medicaments.
By the term xe2x80x9ctreatmentxe2x80x9d, we include both therapeutic (curative) or prophylactic treatment.
In particular, the compounds of the invention have been found to be useful in the treatment of diseases mediated via opiate receptors, which diseases include irritable bowel syndrome; constipation; nausea; vomiting; pruritus; and conditions characterised by pruritus as a symptom.
Thus, according to a further aspect of the invention there is provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of a disease mediated via an opiate receptor. There is further provided the use of the compounds of the invention in the manufacture of a medicament for the treatment of irritable bowel syndrome; constipation; nausea; vomiting; pruritus or a medical condition characterised by pruritus as a symptom.
The compounds of the invention are thus expected to be useful for the curative or prophylactic treatment of pruritic dermatoses including allergic dermatitis and atopy in animals and humans. Other diseases and conditions which may be mentioned include contact dermatitis, psoriasis, eczema and insect bites.
Thus, the invention provides a method of treating or preventing a disease mediated via an opiate receptor. There is further provided a method of treating irritable bowel syndrome; constipation; nausea; vomiting; pruritus or a medical condition characterised by pruritus as a symptom in an animal (e.g. a mammal), which comprises administering a therapeutically effective amount of a compound of the invention to an animal in need of such treatment.
The compounds of the invention will normally be administered orally or by any parenteral route, in the form of pharmaceutical preparations comprising the active ingredient, optionally in the form of a non-toxic organic, or inorganic, acid, or base, addition salt, in a pharmaceutically acceptable dosage form. Depending upon the disorder and patient to be treated, as well as the route of administration, the compositions may be administered at varying doses (see below).
While it is possible to administer a compound of the invention directly without any formulation, the compounds are preferably employed in the form of a pharmaceutical, or veterinary, formulation comprising a pharmaceutically, or veterinarily, acceptable carrier, diluent or excipient and a compound of the invention. The carrier, diluent or excipient may be selected with due regard to the intended route of administration and standard pharmaceutical, and/or veterinary, practice. Pharmaceutical compositions comprising the compounds of the invention may contain from 0.1 percent by weight to 90.0 percent by weight of the active ingredient.
The methods by which the compounds may be administered for veterinary use include oral administration by capsule, bolus, tablet or drench, topical administration as an ointment, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation or, alternatively, they can be administered by injection (e.g. subcutaneously, intramuscularly or intravenously), or as an implant. Such formulations may be prepared in a conventional manner in accordance with standard veterinary practice.
The formulations will vary with regard to the weight of active compound contained therein, depending on the species of animal to be treated, the severity and type of infection and the body weight of the animal. For parenteral, topical and oral administration, typical dose ranges of the active ingredient are 0.01 to 100 mg per kg of body weight of the animal. Preferably the range is 0.1 to 10 mg per kg.
The compositions are preferably formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg, more usually about 5 to about 300 mg, of the active ingredient. The term xe2x80x9cunit dosage formxe2x80x9d refers to physically discreet units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier.
In any event, the veterinary practitioner, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which may vary with the species, age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
For veterinary use, the compounds of the invention are of particular value for treating pruritus in domestic animals such as cats and dogs and in horses.
As an alternative for treating animals, the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
For human use, the compounds are administered as a pharmaceutical formulation containing the active ingredient together with a pharmaceutically acceptable diluent or carrier. Such compositions include conventional tablet, capsule and ointment preparations which are formulated in accordance with standard pharmaceutical practice.
Compounds of the invention may be administered either alone or in combination with one or more agents used in the treatment or prophylaxis of disease or in the reduction or suppression of symptoms. Examples of such agents (which are provided by way of illustration and should not be construed as limiting) include antiparasitics, e.g. fipronil, lufenuron, imidacloprid, avermectins (e.g. abamectin, ivermectin, doramectin), milbemycins, organophosphates, pyrethroids; antihistamines, e.g. chlorpheniramine, trimeprazine, diphenhydramine, doxylamine; antifungals, e.g. fluconazole, ketoconazole, itraconazole, griseofulvin, amphotericin B; antibacterials, e.g. enroflaxacin, marbofloxacin, ampicillin, amoxycillin; anti-inflammatories e.g. prednisolone, betamethasone, dexamethasone, carprofen, ketoprofen; dietary supplements, e.g. gamma-linoleic acid; and emollients. Therefore, the invention further provides a product containing a compound of the invention and a compound from the above list as a combined preparation for simultaneous, separate or sequential use in the treatment of diseases mediated via opiate receptors.
The skilled person will also appreciate that compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Thus, according to a further aspect of the invention there is provided a pharmaceutical, or veterinary, formulation including a compound of the invention in admixture with a pharmaceutically, or veterinarily, acceptable adjuvant, diluent or carrier.
Compounds of the invention may also have the advantage that, in the treatment of human and/or animal patients, they may be more efficacious than, be less toxic than, have a broader range of activity than, be more potent than, produce fewer side effects than, be more easily absorbed than, or they may have other useful pharmacological properties over, compounds known in the prior art.
The biological activities of the compounds of the present invention were determined by the following test method.
Biological Test
Compounds of the present invention have been found to display activity in binding assays selective for the mu opioid receptor in dog brain. The assays were conducted by the following procedure.
Laboratory bred beagles were used as a source of dog brain tissue. Animals were euthanised, their brains removed and the cerebellum discarded. The remaining brain tissue was sectioned into small pieces approximately 3 g in weight and homogenised in 50 mM Tris pH 7.4 buffer at 4xc2x0 C. using a Kinematica Polytron3 tissue homogeniser. The resulting homogenate was centrifuged at 48,400xc3x97 g for 10 minutes and the supernatant discarded. The pellet was resuspended in Tris buffer and incubated at 37xc2x0 C. for 10 minutes. Centrifugation, resuspension and incubation steps were repeated twice more, and the final pellet was resuspended in Tris buffer and stored at xe2x88x9280xc2x0 C. Membrane material prepared in this manner could be stored for up to four weeks prior to use.
For mu assays, increasing concentrations of experimental compound, (5xc3x9710xe2x88x9212 to 10xe2x88x925 M), Tris buffer and 3H ligand, ([D-Ala2, N-Me-Phe4,Gly-ol5]-Enkephalin, DAMGO), were combined in polystyrene tubes. The reaction was initiated by the addition of tissue, and the mixture was incubated at room temperature for 90 minutes. The reaction was terminated by rapid filtration using a Brandel Cell Harvester3 through Betaplate3 GF/A glass fibre filters pre-soaked in 50 mM Tris pH 7.4, 0.1% polyethylenimine buffer. The filters were then washed three times with 0.5 mL ice-cold Tris pH 7.4 buffer. Washed filters were placed in bags and Starscint3 scintillant added. Bags containing the filters and scintillant were heat sealed and counted by a Betaplate3 1204 beta counter.
Duplicate samples were run for each experimental compound and the data generated was analysed using IC50 analysis software in Graphpad Prism. Ki values were calculated using Graphpad Prism according to the following formula:
Ki=IC50/1+[3H ligand]/KD
where IC50 is the concentration at which 50% of the 3H ligand is displaced by the test compound and KD is the dissociation constant for the 3H ligand at the receptor site.
The invention is illustrated by the following Preparations and Examples in which the following abbreviations may be used:
APCI =atmospheric pressure chemical ionisation
br (in relation to NMR)=broad
DMF=N,N-dimethylformamide
DMSO=dimethylsulfoxide
d (in relation to time)=day
d (in relation to NMR)=doublet
dd (in relation to NMR)=doublet of doublets
dt (in relation to NMR)=doublet of triplets
EtOAc=ethyl acetate
EtOH=ethanol
ESI=electrospray ionisation
h=hour(s)
m (in relation to NMR)=multiplet
MeOH =methanol
min(s)=minute(s)
q (in relation to NMR)=quartet
s (in relation to NMR)=singlet
t (in relation to NMR)=triplet
THF=tetrahydrofuran
When reverse phase HPLC is mentioned in the text the following 2 sets of conditions were employed.
Condition 1: A Phenomenex Magellen3 column, 150xc3x9721 mm, packed with 5xcexc C18 silica, eluting with a gradient of acetonitrile: 0.1 M aqueous ammonium acetate (30:70 to 95:5 over 10 mins, flow rate 20 mL per min).
Condition 2: A Dynamax3 column, 42xc3x97250 mm, packed with 8xcexc C18 silica, eluting with acetonitrile: 0.1 M aqueous ammonium acetate (30:70) at 45 mL per minute.
In both cases, combination and evaporation of appropriate fractions, determined by analytical HPLC, provided the desired compounds as acetate salts.
Analytical HPLC conditions used to highlight appropriate fractions were Phenomenex Magellan3 column, 4.6xc3x97150 mm, packed with 5xcexc C18 silica, eluting with a gradient of acetonitrile: 0.1 M aqueous heptanesulfonic acid (10:90 to 90:10 over 30 min, followed by a further 10 min at 90:10) at 1 mL per minute. Column oven temperature was 40xc2x0 C., and ultraviolet detection of components was made at 220 nM.
When column chromatography is referred to this usually refers to a glass column packed with silica gel (40-63 xcexcm). Pressure of xcx9c165 kPa is generally applied and the ratio of crude product:silica gel required for purification is typically 50:1. Alternatively, an Isolute SPE (solid phase extraction) column or Waters Sep-Pak3 cartridge packed with silica gel may be used under atmospheric pressure. The ratio of crude product to silica gel required for purification is typically 100:1.
The hydrochloride salt may be made by methods commonly known to those skilled in the art of synthetic chemistry. Typically, to a solution of free base in dichloromethane (1 g: 100 mL) was added ethereal hydrochloric acid (1.0 M, 1.2 equivalent), the excess solvent was decanted off and the remaining precipitate was washed three times with ether and then dried in vacuo.
Nuclear magnetic resonance (NMR) spectral data were obtained using a Varian Inova 300 or Varian Inova 400 spectrometer, the observed chemical shifts (xcex4) being consistent with the proposed structures. Mass spectral (MS) data were obtained on a Finnigan Masslab Navigator or a Fisons Instruments Trio 1000 spectrometer. The calculated and observed ions quoted refer to the isotopic composition of lowest mass. HPLC means high performance liquid chromatography. Room temperature means 20 to 25xc2x0 C.

4-arylpiperidine derivatives for the treatment of pruritus

Abstract: wherein Het1, R1, R2, R3, X and n have meanings given in the description, which are useful in the prophylaxis and in the treatment of diseases mediated by opiate receptors, such as pruritus.


An apparatus includes a first encoder for receiving a plurality of symbol streams for respective ones of a plurality of mobile stations and encoding each of the symbol streams with one of a plurality of covering sequences to form a plurality of covered sequences. The apparatus further includes a summer for summing the plurality of covered sequences to form a first Code Division Multiplexed (CDM) signal. In addition, the apparatus includes a second encoder for covering the first CDM signal with a covering sequence to form a first covered CDM signal. A system and method for multiplexing plurality of symbol streams are also provided.

Wireless communication systems are widely deployed to provide various types of communication such as voice and data. These systems may be based on code division multiple access (CDMA), time division multiple access (TDMA), or some other multiple access techniques. A CDMA system provides certain advantages over other types of systems, including increased system capacity.
A CDMA system may be designed to support one or more CDMA standards such as (1) the "TIA/EIA-95-B Mobile Station-Base Station Compatibility Standard for Dual-Mode Wideband Spread Spectrum Cellular System" (the IS-95 standard), (2) the standard offered by a consortium named "3rd Generation Partnership Project" (3GPP) and embodied in a set of documents including Document Nos. 3G TS 25.211, 3G TS 25.212, 3G TS 25.213, and 3G TS 25.214 (the W-CDMA standard), (3) the standard offered by a consortium named "3rd Generation Partnership Project 2" (3GPP2) and embodied in "TR-45.5 Physical Layer Standard for cdma2000 Spread Spectrum Systems" (the IS-2000 standard), and (4) some other standards.
In the above named standards, the available spectrum is shared simultaneously among a number of users, and techniques such as power control and soft handoff are employed to maintain sufficient quality to support delay-sensitive services, such as voice. Data services are also available. More recently, systems have been proposed that enhance the capacity for data services by using higher order modulation, very fast feedback of Carrier to Interference ratio (C/I) from the mobile station, very fast scheduling, and scheduling for services that have more relaxed delay requirements. An example of such a data-only communication system using these techniques is the high data rate (HDR) system that conforms to the TIA/EIA/IS-856 standard (the IS-856 standard).
In contrast to the other above named standards, an IS-856 system uses the entire spectrum available in each cell to transmit data to a single user at one time, selected based on link quality. In so doing, the system spends a greater percentage of time sending data at higher rates when the channel is good, and thereby avoids committing resources to support transmission at inefficient rates. The net effect is higher data capacity, higher peak data rates, and higher average throughput.
Systems can incorporate support for delay-sensitive data, such as voice channels or data channels supported in the IS-2000 standard, along with support for packet data services such as those described in the IS-856 standard. One such system is described in a proposal submitted by LG Electronics, LSI Logic, Lucent Technologies, Nortel Networks, QUALCOMM Incorporated, and Samsung to the 3rd Generation Partnership Project 2 (3GPP2). The proposal is detailed in documents entitled "Updated Joint Physical Layer Proposal for 1xEV-DV", submitted to 3GPP2 as document number C50-20010611-009, Jun. 11, 2001; "Results of L3NQS Simulation Study", submitted to 3GPP2 as document number C50-20010820-011, Aug. 20, 2001; and "System Simulation Results for the L3NQS Framework Proposal for cdma2000 1xEV-DV", submitted to 3GPP2 as document number C50-20010820-012, Aug. 20, 2001. These, and related documents generated subsequently, such as Revision C of the IS-2000 standard, including C.S0001.C through C.S0006.C, are hereinafter referred to as the 1xEV-DV proposal.
In order to coordinate usage of the forward and reverse link in an efficient manner, a system, the 1xEV-DV proposal, for example, may need to direct feedback from a base station to a number of supported mobile stations. It is common for such feedback to be transmitted on one or more control channels. In a CDMA system, such control channels may be multiplexed with other control and/or data channels using Code Division Multiplexing (CDM). Traditionally, to reach a plurality of mobile stations, a control channel is time-shared to transmit to each of the mobile stations. Thus, a control channel may be multiplexed using Time Division Multiplexing (TDM) to incorporate signals or commands for multiple mobile stations. The resultant TDM control channel may then be transmitted along with other channels, whether control, voice, or data, using CDM. One example of such a TDM on CDM channel is the power control channel in cdma2000.
As is well known in wireless system design, when a channel can be transmitted using less power for the same reliability, the capacity of the system may be improved. Thus, there is a need in the art for more efficient control channels. Furthermore, TDM on CDM channels may have peak power requirements that are inefficient, or even unattainable given system design parameters. There is therefore a need in the art for control channels that can reach a plurality of mobile stations, thus allowing for efficient use of the shared communication resource, while meeting peak power design constraints as well as reducing the amount of system capacity allocated to such control.

Code division multiplexing commands on a code division multiplexed channel


A driver assembly (50) for an introducer assembly (10) for the deployment of an implantable medical device (16) includes a sprung element (52) coupled to a yoke (56). The yoke (56) is coupled to a gripper element (58). The yoke (56) is coupled to a first handle unit (30) of the introducer (10). The sprung element (52) is coupled to a proximal handle unit (32). A brake element (66) acts to prevent operation of the sprung element (52) when no manual force is being applied to attract a sheath (24) and the assembly (10). When manual retraction force is applied to the assembly (50) the gripper element (58) the brake element (66) releases a sprung element (52) so that the lighter can apply a force assistance to assist in the retraction of the sheath (24) and thereby to assist in the deployment of a medical device.

Implantable medical devices, such as stents, stent grafts, vena cava filters, occlusion devices, embolisation coils and so on, are often deployed endoluminally through a suitable percutaneous entry point of a patient. For instance, a medical device to be fitted within the aorta may be passed via the femoral artery, thus from an entry point a substantial distance from the treatment site.
The introducers used for the deployment of such devices tend to be elongate catheter assemblies in which the medical device is held at a distal end of the introducer in a radially compressed state until it is ready to be deployed. Typically, such introducer assemblies are formed from a plurality of components including one or more catheters, device restraining elements, guide wires and so on. The introducer also includes a covering sheath which covers the components of the introducer as well as the medical device.
Once the introducer has been inserted into a patient and the distal end thereof carrying the medical device located at the site of a patient's vasculature at which the device is to be positioned, the deployment mechanism is operated. The first stage of this is to pull back the outer sheath so as to expose the medical device, whereupon the constraining mechanism holding the medical device to the carrier catheter is then activated, normally in stages, to release the device. In some cases the device is releasable by self-expansion while in other cases a separate expansion mechanism, such as a balloon, is used.
In order to maintain the integrity of the components carried in the introducer, as well as to keep the outer diameter of the introducer, particularly at its distal end, as small as possible, the components of the assembly tend to be a relatively tight fit with one another. This relatively tight fit results in friction between the various slidable components of the assembly. To add to this, the proximal end of the device, that is the end which remains outside the patient during the procedure and which includes the various manual controls used by the clinician, is provided with at least one haemostatic valve or seal, often several, to prevent undesired loss of bodily fluids during the operation. There is necessarily provided a seal or valve between the covering sheath and the inner catheter or catheters to prevent fluid leakage from the space between these components. Such seals tend to contribute to friction between the various sliding components of the device and thus to an increased required operation force.
Moreover, introducer devices of this nature tend to be very long, an introducer for a medical device to be implanted in the aorta or heart typically having a length of at least 1.5 metres. Furthermore, the path such introducers have to follow through a patient's vasculature is normally tortuous, such that they have to curve and often twist along their length. Such curvature and twisting also adds to the friction between the slidable components of the assembly.
The above-mentioned factors lead to it being necessary for the clinician to apply a substantial force to the assembly in order, in particular, to pull the outer sheath back so as to expose the medical device. Having to use a large force to operate the assembly can cause practical difficulties, not only in the effort which the clinician must expend in operating the device, but also in augmenting the risk of the introducer assembly, particularly its distal end, moving unintentionally out of position. Any such movement can lead to incorrect positioning of the medical device. Furthermore, in the case of a device which is rotationally dependant, such as a fenestrated or branched stent graft, for example, any shifting of the introducer can cause rotational misalignment. In order to seek to mitigate these problems, the clinician may need to carry out positional adjustments to the assembly at the same time as effecting the various steps required to deploy the device, which is a complex and time consuming task. At worst, the device cannot be properly deployed and the procedure must be aborted.
There are devices which effect the deployment of the medical device, in particular retraction of the outer sheath, automatically, for instance by means of a sprung loaded and trigger actuated handle assembly. Some rotary handles are known which use a screw mechanism to overcome the longitudinal pulling force; as well as ratchet type handles. These devices can overcome the difficulties indicated above, by providing what could be described as motorised assistance, allowing the clinician to maintain accurate control of the positioning of the introducer while the device exerts the effort required to retract the sheath.
However, in many instances clinicians do not wish to lose the manual control of the operation of the introducer assembly as this can lead to a loss of the fine adjustments clinicians often desire during deployment of the medical device. For instance, a clinician may wish to slow or even temporarily stop the withdrawal of the sheath part way in order to carry out a fine adjustment of the position or orientation of the medical prosthesis. An automatic deployment device may not provide for this. Furthermore, a manually operated introducer gives the clinician tactile feedback as to how the deployment is progressing, whereas an automatic deployment mechanism will generally fail to provide such feedback, causing the clinician to have to rely upon imaging only.
As a result, it in some circumstances it is preferred to retain manual operation of the introducer, despite the problems associated with this.

Drive assembly for facilitating deployment of an implantable medical device