The invention provides crosslinked rubber moldings for golf balls obtained by spherically molding and crosslinking a rubber composition containing a base rubber, a co-crosslinking agent and a crosslinking agent, then impregnating the crosslinked rubber molding with a rubber compounding chemical and inducing a chemical reaction. The rubber compounding chemical-impregnated crosslinked molding has a higher surface hardness than the crosslinked molding prior to impregnation. The invention also provides a method for manufacturing such crosslinked rubber moldings for golf balls. The invention enables a sufficient rise in the surface hardness of the core to be achieved, thus increasing the degree of freedom in the design of the golf ball.

Golf balls are known to include solid golf balls composed of a solid core obtained by molding and crosslinking a rubber composition and a one-layer or multilayer cover which encloses the solid core, and one-piece golf balls obtained by molding and crosslinking a rubber composition and using the entire resulting spherical object as the ball. In these golf balls, a rubber composition composed chiefly of a base rubber is vulcanized to produce a spherical crosslinked molding as the core. By adjusting the hardness difference between the center portion and surface portion, it is possible to increase the degree of freedom in the ball hardness profile. To this end, JP-A 10-43330 discloses a golf ball having a core in which silica particles are included at the core surface as a means for increasing the surface hardness of the ball.
However, in such golf balls, because the silica particles are merely an inorganic filler, the interfacial loss of material arises, worsening the rebound.

Crosslinked rubber moldings for golf balls and method of manufacture


The present invention concerns a method and a device for absolute measurement of a print repeat length and/or at least one package length of a moving packaging web (1) in line with a printing machine. Normally the print repeat length and one package length are measured and analysed simultaneously. The measurements are made by means of a number of CCD-cameras (2, 3, 4) connected to a computer (6) by means of a frame grabber (7).

If the package length of a packaging web is not correct there may be trouble at the filling machine. Thus, it is important to check the packaging web concerning the package length and possibly the print repeat length. The package length (PL) is defined as the length of each package in the packaging web. The print repeat length (PRL) is defined as the length of each turn of the printing roller on the packaging web.
It is previously known to use photocells often combined with a pulse counter to measure package lengths or the like on packaging web. As photocells measure only in one point the position of the photocells has to be amended for measurement of different package webs. Furthermore, when using a pulse counter the package length is only measured indirectly and the measurement may be inaccurate due to slip between the web and the rollers or the like.

Method and device for length measurement of packaging webs


A rubber composition suitable for reinforcing beads of tires, having high hardness, high durability and high aging resistance, which comprises a rubber component containing 30 to 70% by weight of a butadiene rubber containing syndiotactic crystals, 60 to 75 parts by weight of a carbon black having a specified iodine adsorption number and a specified oil absorption, 1 to 2 parts by weight of sulfur and 2 to 4 parts by weight of a sulfenamide accelerator, respectively, per 100 parts by weight of the rubber component, wherein the total amount of sulfur and the sulfenamide accelerator is from 3 to 5 parts by weight.

The present invention relates to a rubber composition suitable for reinforcing bead portion of pneumatic tires, and more particularly to a rubber composition suitable for use in a chafer in the bead portion of heavy duty tires for an auto truck, auto bus and other large vehicles.
Tires used for trucks, buses and so on are required to have high speed performance because of the spread of a superhighway, and in addition so that they can bear a larger load with the increase of size and loadage of the vehicles. Consequently, rubber compositions used in the chafer disposed in bead of tires are required more and more to have high hardness, high durability and high aging resistance.
Since these tires are recapped and reused by re-covering their tread rubber after the completion of the first life, they are also required to be free from fault. One of faults which prevents the recapping of used tires is deformation of the bead in tube tires. Bead deformation is a phenomenon that occurs in tube tires with the rubber in the bead caves in at a spacing between the wheel rim and a ring, thus resulting in deformation after use for a long term. Rubber compositions used in the chafer and bead of tube tires are required to have high hardness, high durability and high aging resistance also in order to prevent occurrence of this phenomenon.
In order to obtain rubber compositions satisfying these properties, it has been practiced (1) to select the kind of carbon black or to increase the amount of carbon black, (2) to increase the amount of sulfur, or (3) to use ultraaccelerator TT (tetramethylthiuramdisulfide). However, the use of a large amount of carbon black causes problems in processing that it becomes difficult to conduct milling with good dispersion, and burning takes place due to heat generation resulting from high loading, and a problem that the crack growth resistance of the rubber is deteriorated. When a large amount of sulfur is incorporated in a rubber, there arise problems that change in physical properties owing to heat, change in physical properties with the lapse of time and a permanent set (deformation owing to heat) become large, and the aging resistance and a resistance to breaking such as cracking are deteriorated. Since the thiuram ultraaccelerator TT produces nitrosoamine which is a cancer causing substance and was found as a mutagen, its use is being prohibited. It is also proposed in Japanese Patent Publication Kokoku No. 57-20164 to incorporate a syndiotactic-1,2-polybutadiene short fiber into a rubber. However, the short fiber cannot be uniformly dispersed by application of a mechanical force and, therefore, desired physical properties are not obtained by incorporation of only such a short fiber.
It is an object of the present invention to provide a rubber composition suitable for reinforcing the bead of tires and having high hardness, high durability and high aging resistance.
A further object of the present invention is to provide a rubber composition suitable for use in the chafer in the bead of tube tires, which is excellent in processability such that it does not cause roll bagging and burning, and which is also excellent in hardness, durability and aging resistance and provides tires which avoid deformation in the bead, rim-chafing and cracking.
These and other objects of the present invention will become apparent from the description hereinafter.

Rubber composition for reinforcing bead of tires which contains butadiene rubber with syndiotactic crystals, carbon black, sulfur and sulfenamide accelerator


A stable signal is output in which when there is no movement, unstable output change does not occur, and an output change exceeding a predetermined limit does not occur. The variation xcex94PH in the output angle signal PH to be output is subjected to hysteresis and through rate limitations with respect to the variation APF in the input angle signal input thereto. When the variation APF in the input signal is in a hysteresis range of xe2x88x92Hys less than xcex94PF less than +Hys, the variation in the output angle signal is output as 0. When the variation xcex94PF in the input signal is in a hysteresis range of xcex94PF less than xe2x88x92(Hys+SR) or xcex94PF greater than (Hys+SR), a through rate limitation is effected to thereby clip the variation in the output angle signal to SR. When the variation xcex94PF is in other regions, the output follows the input linearly with the output delayed by the hysteresis quantity.

1. Field of the Invention
The present invention relates to a position detection apparatus for detecting a position of movement of two members which move relative to each other.
2. Description of the Related Art
Heretofore, a position detection apparatus for detecting a position of movement of two members which move relative to each other is well known. This position detection apparatus comprises a scale on which a periodic signal whose signal level varies in a certain wavelength is recorded along a certain direction, a head section for detecting the periodic signal recorded on the scale, and an arithmetic processing section for performing signal processing of the periodic signal detected by the head section to output position information. The scale and the head section are fitted to a moving element and a base element of two members moving relative to each other. The position detection apparatus detects with the scale the periodic signal whose signal level changes, and supplies the detected periodic signal to the arithmetic processing section. The arithmetic processing section outputs position information showing a position of relative movement of the two members, based on the periodic signal detected by the head section.
The position detection apparatus generally outputs a two-phase increase and decrease pulse, a so-called A/B phase signal, as position information. The two-phase increase and decrease pulse is composed of two signals, A phase signal and B phase signal, which have the same period to each other and whose phases are shifted by xc2xc period. The two-phase increase and decrease pulse is a signal showing a Gray coded two-bit count value, with the A phase signal being designated as a lower bit, and the B phase signal being designated as an upper bit. This count value shows a quantity of relative movement. In this manner, if the two-phase increase and decrease pulse is transmitted as position information, the quantity of information to be transmitted can be reduced. Moreover, since the displacement is shown using the Gray code, the direction of movement can also be transmitted clearly. Then, a control unit or the like which obtains the two-phase increase and decrease pulse from the position detection apparatus 1 as position information cumulatively adds (subtracts when two members move in the negative direction) the number of count of the two-phase increase and decrease pulse, to thereby determine the quantity of relative movement of two members, thereby controls a position of movement of two members.
With a conventional position detection apparatus, there is a case where the count speed of the two-phase increase and decrease pulse to be output may abruptly increase due to noise, quantize error, impact, vibration or the like, and may exceed the allowable speed temporarily. In such a case, the two-phase increase and decrease pulse is not counted for each count, and, for example, there is a possibility that a pulse is omitted for more than one count and the order of the count value is last. Thus, if the order of the count value is last, the control unit which has obtained the two-phase increase and decrease pulse cannot cumulatively add the count number, and cannot detect the displacement of a machine tool.
Moreover, with a conventional position detection apparatus, there is a case where though the two members to be measured are stationary, the count output of the two-phase increase and decrease pulse is not stable due to noise, quantize error or the like. In such a case, the output two-phase increase and decrease pulse fluctuate to the positive and negative sides, and the control unit is informed that the two members are in a slightly moving condition, though stationary.
It is an object of the present invention to provide a position detection apparatus capable of producing a stable output signal.
The position detection apparatus according to the present invention comprises: a recording medium on which a position signal comprising a periodic signal is recorded; a detection section comprising a first detection head which moves relative to the recording medium along the recording direction of the position signal for detecting the position signal, and a second detection head which is disposed apart from the first detection head by a predetermined distance in the recording direction of the position signal, and moves relative to the recording medium, operating together with the first detection head for detecting the position signal; a polar conversion section for converting the position signal detected by the first detection head and the second detection head into an angle signal showing a relative position of the recording medium and the detection section in one period as an angle; a response limiting section for limiting response of the angle signal; and an output section for outputting relative position information of the recording medium and the detection section, based on the angle information in which response is limited by the response limiting section, characterized in that the response limiting section limits response such that when an absolute value of a variation in the angle signal exceeds a predetermined threshold value, the absolute value of the variation in the angle signal is the predetermined threshold value.
With the position detection apparatus, response is limited by means of a through rate limitation such that when the absolute value of the variation in the angle signal exceeds a predetermined threshold value, the absolute value of the variation in the angle signal is the predetermined threshold value.
Moreover, with the position detection apparatus according to the present invention, the response limiting section limits response such that when the absolute value of the variation in the angle signal is a first threshold value or smaller, the angle signal does not change, when the absolute value of the variation in the angle signal is or exceeds a second threshold value which is larger than the first threshold value, the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the second threshold value, and when the absolute value of the variation in the angle signal is larger than the first threshold value and smaller than the second threshold value, the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the absolute value of the variation.
With this position detection apparatus, the response limiting section limits the response such that when the absolute value of the variation in the angle signal is the first threshold value or smaller, a hysteresis range is provided so that the angle signal does not change, and when the absolute value of the variation in the angle signal is or exceeds the second threshold value, the response limitation by means of a through rate limitation is performed so that the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the second threshold value, and when the absolute value of the variation in the angle signal is larger than the first threshold value and smaller than the second threshold value, the response limitation is performed so as to follow linearly, delayed by the hysteresis, so that the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the absolute value of the variation.
With the position detection apparatus according to the present invention, when the absolute value of the variation in the angle signal is or exceeds a predetermined threshold value, the position detection apparatus limits the response by means of a through rate limitation so that the absolute value of the variation in the angle signal is the predetermined threshold value.
As a result, with the position detection apparatus, since the through rate limitation is carried out, the change speed of the output signal does not exceed the allowable speed, and a stable output signal can be obtained.
Moreover, according to the position detection apparatus of the present invention, the response limiting section limits the response such that when the absolute value of the variation in the angle signal is the first threshold value or smaller, a hysteresis range is provided so that the angle signal does not change, and when the absolute value of the variation in the angle signal is or exceeds the second threshold value, the response limitation by means of a through rate limitation is performed so that the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the second threshold value, and when the absolute value of the variation in the angle signal is larger than the first threshold value and smaller than the second threshold value, the response limitation is performed so as to follow linearly, delayed by the hysteresis, so that the absolute value of the variation in the angle signal is a value obtained by subtracting the first threshold value from the absolute value of the variation.
As a result, with this position detection apparatus, since a hysteresis range is provided so that the angle signal does not change, the output does not vary when there is no movement such as in a stationary condition or in a condition close to the stationary condition, and hence a stable output can be performed. In addition, with this position detection apparatus, since the through rate limitation is carried out, the change speed of the output signal does not exceed the allowable speed, and a stable output signal can be obtained.


An automatic tensioner apparatus comprising an idler pulley engaging a transmission belt of a wrapping connector type transmission mechanism, an arm for swingably supporting the idler pulley with respect to a predetermined supporting surface, and a resilient member for exhibiting a resilient force for swinging the arm and the idler pulley in a direction to engage the transmission belt in order to apply a predetermined tension to the transmission belt. A casing for accommodating the resilient member is secured to the supporting surface and an arm pivot-supporting portion for swingably supporting a base portion of the arm is integrally provided on the casing in such a manner that the arm pivot-supporting portion is offset relative to the resilient member in a direction along the supporting surface and relative to the resilient member in a direction away from the supporting surface. The automatic tensioner apparatus need not be separated especially forwardly from the supporting surface to locate the so-called belt line at a front, distanced position from the supporting surface for ensuring a relatively wide space to place another functional part around the automatic tensioner apparatus between the base portion of the arm and the supporting surface. The space is obtained without difficulty.

1. Field of the Invention
The present invention relates to an automatic tensioner apparatus for applying a tensioning force to a transmission belt or the like of a wrapping connector type transmission mechanism, such as commonly used on automotive engines.
2. Description of the Prior Art
There is a conventionally known automatic tensioner apparatus comprising an idler pulley engaging a transmission belt of the wrapping connector type transmission mechanism, an arm for swingably supporting the pulley on a supporting surface, and a resilient member for exhibiting a resilient force for swinging the arm and idler pulley in a direction to engage the transmission belt.
Such an automatic tensioner apparatus can be used for various applications and, for example, is utilized on an internal combustion engine of an automobile. FIG. 6 is a sectional elevation that illustrates one example of such a conventional automatic tensioner apparatus for use on an internal combustion engine, in which a support shaft 100 is fixed onto a base plate 015 that is fixed to a supporting surface f of an engine block E of the internal combustion engine, and the base portion of an arm 011 is swingably carried on the support shaft 100. An idler pulley 010 is rotatably carried on a tip end of the arm 011 to engage a transmission belt Bs. A resilient member 012 in the form of a coiled spring is disposed between the base portion of the arm 011 and the base plate 015 for biasing the idler pulley 010 at the tip end of the arm 011 in a direction to engage the transmission tension belt Bs. However, behind the base portion of the arm 011, there is not sufficient space to place other functional parts around the automatic tensioner apparatus. Therefore, if the other functional parts, e.g., a transmission belt Bt of another wrapping connector type transmission mechanism is intended to be placed behind the base portion of the arm 011, it is necessary to provide special components to separate the entire automatic tensioner apparatus, including the base plate 015, from the supporting surface f, and to extend the so-called belt line of the transmission belt Bs forwardly, resulting in a problem of increasing the size of the entire apparatus and perhaps the overall length of the engine.


A method and device of link aggregation in computer networking, wherein data originally scheduled for forwarding by a scheduled data port are diverted for forwarding by a backup data port assigned to the scheduled data port upon detection that the scheduled data port is connected to a data link which is not capable of data traffic even though the data port is still a selected port.

Link aggregation is a term encompassing various methods of combining multiple network connections in parallel to increase the rate of data throughput beyond what a single connection could support, and to provide redundancy in case one of the data links forming the link aggregation fails. The term link aggregation does not only encompass vendor independent standards such as LACP ("Link Aggregation Control Protocol'), IEEE 802.3ad-2000 for Ethernet, and the technology independent IEEE 802.1ax-2008; but also other proprietary network solutions. Link aggregation technique is widely used in computer networking to increase bandwidth and enhance link reliability, and can be implemented at any of the lowest three layers of the OSI model, namely, physical, data link, or network layers. Common examples of aggregation at layers 1, 2 and 3 are, respectively, power line (IEEE 1901) and wireless (IEEE 802.11); data link layer such as Ethernet frame in local area networks (LANs) or multiple-link point-to-point protocol (PPP) in WANs; and at the network layer (e.g. IP or IPX).

This patent is subject to a terminal disclaimer.

Computer network method and device using link aggregation

HEWLETT PACKARD ENTERPRISE DEVELOPMENT LP


Billing identification numbers supplied to law enforcement agencies for monitored cellular calls are used to retrieve toll tickets generated by the cellular network. By processing the toll tickets, an identification may be made by the agency of the A-party to and routing of the monitored cellular call. Calling line identification (CLI) information is supplied to the monitoring law enforcement agency for each monitored call. The CLI information identifies the directory number of the A-party to the monitored cellular call when the A-party comprises another cellular subscriber. In those situations where the A-party comprises a wireline subscriber in a public switched telephone network (PSTN), the CLI information delivered to the monitoring law enforcement agency comprises either the calling line identification (CLI) information obtained over an integrated services user part (ISUP) trunk connection (identifying the wireline A-party), or converted A-number identification (ANI) information obtained over a non-ISUP trunk connection (identifying routing and switching information useful in tracing the call).

1. Technical Field of the Invention
The present invention relates to cellular telephone networks and, in particular, to the monitoring of cellular telephone calls by law enforcement agencies.
2. Description of Related Art
When law enforcement agencies are authorized to monitor telephone calls to obtain evidence for use in criminal investigations, perhaps the most important piece of information they obtain other than the recorded voice conversation itself is the identification of the parties participating in the call. In a conventional wireline telephone network, this information is readily accessible because a physical connection exists between the A-party (calling party) and the B-party (called party) to the call allowing the call to be traced, and because the communications protocols within the network support the transmission of party identification information like telephone numbers. Because of the lack of a physical connection and the limitations present in some communications protocols and switch operations, such party identification information is not so readily available during law enforcement agency monitoring of a cellular telephone call. The party identification problem is most prevalent with respect to being able to determine the identity of the A-party to the call.
The signaling protocols used between some telecommunications exchanges provide for the transmission of only two numbers in connection with the set-up of a cellular call. The first number comprises the actual telephone number of the B-party. The second number comprises a roamer number used to route the call within the cellular network. With space provided for only two numbers, there is no room within those signaling protocols for conveying the telephone number of the A-party to the cellular call. If the B-party is the party to be monitored, A-party information is then not typically made available to the monitoring law enforcement agency at the point where the telephone tap is made.
There is a need then during law enforcement agency monitoring of a cellular call for complete party identification information to be provided. In particular, there is a need to obtain information on the A-party to the monitored cellular call.

Method and apparatus for facilitating law enforcement agency monitoring of cellular telephone calls


Method for the fabrication of a supported liquid membrane having a dense layer in contact with a porous layer, and a membrane liquid layer within the interconnected pores of the porous layer. The dense layer is comprised of a solidified material having an average pore size less than or equal to about 0.1 nanometer, while the porous layer is comprised of a plurality of interconnected pores and has an average pore size greater than 10 nanometers. The supported liquid membrane is fabricated through the preparation of a casting solution of a membrane liquid and a volatile solvent. A pressure difference is established across the dense layer and porous layer, the casting solution is applied to the porous layer, and the low viscosity casting solution is drawn toward the dense layer. The volatile solvent is evaporated and the membrane liquid precipitates, generating a membrane liquid layer in close proximity to the dense layer.

Supported liquid membranes have been widely studied for the separation and concentration of a variety of compounds and present many potential advantages over other separation techniques. In a supported liquid membrane, the pores of a supporting membrane are impregnated with a particular liquid, and transport of the permeating species occurs by a solution diffusion mass transfer mechanism. The diffusion of species in liquids is generally faster than diffusion in solids, and the permeability across supported liquid membranes is typically greater than that achieved using solid membranes.
Supported liquid membranes are typically fabricated by either direct immersion, or various pressure and vacuum methods. In direct immersion, immobilization of the membrane liquid takes places by contacting or immersing the supporting membrane and allowing the supporting membrane to soak up the membrane liquid. In pressure methods, immobilization is achieved by contacting a porous membrane and a membrane liquid, and applying typically nitrogen pressure to force the membrane liquid to flow into the pores of the membrane. The vacuum method operates by submerging the porous membrane in a volume of membrane liquid and applying a vacuum to the membrane in order to evacuate the membrane pore and draw in the membrane liquid. The pressure and vacuum methods are typically utilized on supporting membranes generally classified as macroporous with a pore sizes of at least greater than 50 nanometers, and typically in the hundreds of nanometers, and success is gauged either by the visual presence of membrane liquid in all pores of the supporting membrane or by the presence of membrane liquid being forced through the lower pressure membrane surface. Pressure and vacuum methods have also been particularly applied to membrane liquids of relatively high viscosity, such as ionic liquids. See e.g., Hernandez-Fernandez et al., "Preparation of supported ionic liquid membranes: Influence of the ionic liquid immobilization method on their operational stability," Journal of Membrane Science 341 (2009); see also Neves et al., "Gas permeation studies in supported ionic liquid membranes," Journal of Membrane Science 357 (2010).
The current methods of supported liquid membrane fabrication suffer from a number of shortcomings, such as the unsustainable loss of membrane liquid in macroporous supporting membranes under applicable operating conditions. This membrane liquid loss in-situ is typically attributed to a differential pressure across the macroporous membrane in excess of a capillary force maintaining the membrane liquid immobilized, and places limits on the differential pressure that the supported liquid membrane can sustain. This maximum differential pressure is related to the maximum pore size of the membrane, the pore structure, the interfacial tension of membrane liquids, and the contact angle, among other factors. See e.g., Zhao et al., "Membrane liquid loss mechanism of supported ionic liquid membrane for gas separation," Journal of Membrane Science 411-412 (2012).
On the other hand, gas separation membranes which operate in the absence of a supported liquid typically consist of a dense film, through which permeates are transported by diffusion under the driving force of a pressure or concentration. These dense film membranes may be significantly more tolerant of differential pressures, however they suffer from a permeability-selectivity tradeoff, where generally as permeability improves the selectivity declines, and vice versa. It would be advantageous to provide a method whereby a membrane liquid could be placed within the pores of a supporting membrane having a dense, skin surface, so that a highly permeable dense layer could be coupled with a highly selective membrane liquid, the permeability-selectivity tradeoff could be greatly reduced, and a differential pressure across the supported liquid membrane could be applied with mitigated concern toward its relation to a capillary force. A limitation of polymeric membranes for gas and vapour transport is the so-called permeability-selectivity trade-off, first reported by Robeson et al. in 1991 and then further updated. This trade-off basically allows that if one is looking for a new material with a higher permeability, the price to pay is a lower selectivity, and vice versa.
Additionally, the membrane liquid layer thickness is of significant concern in supported liquid membranes. Typically, the immersion, pressure and vacuum methods applied to porous supporting membranes offers little control over the resulting liquid layer thickness, and during fabrication the liquid typically extends throughout all pores of the supporting membrane. As a second step, the supported liquid is usually allowed to drain under the influence of gravity or some other force from those pores exerting an insufficient capillary force, so that the final layer thickness and location becomes largely a function of local pore size, pore configuration, the viscosity of the membrane liquid, and the surface tension of the liquid. This liquid layer thickness generally has an inversely proportional influence on permeability, and correspondingly the permeance of the supported liquid membrane suffers, or at a minimum is poorly controlled during fabrication. It would be advantageous to provide a method whereby the membrane liquid could be distributed within the pores of a supporting membrane in a relatively thin, continuous fluid layer, as opposed to a layer which generally extends throughout the interconnected pores of the supporting membrane.
Additionally, significant work is underway to mitigate the relative instability and short lifetimes of supported liquid membranes by utilizing ionic liquids as the membrane liquid. Careful selection of the cation and anion makes possible minimal vaporization losses, and their generally high chemical and thermal stability, high ion conductivity, and high solvent power provide additional advantages. The large diversity of ionic liquids is a result of the nearly unlimited combination of cations and anions which can permit very precise tuning of the ionic liquid solvation properties, density, viscosity, melting point, and even conductivity, enabling the rational design for specific applications. See e.g., Ilconich, et al., "Experimental investigation of the permeance and selectivity of supported ionic liquid membranes for CO2/He separation at temperatures up to 125° C.," Journal of Membrane Science, 41-47, (2007); see also Pennline, et al., Progress in carbon dioxide capture and separation research for gasification-based power generation point sources, Fuel Process. Technol. 897-907, (2012). However, ionic liquids possess relatively high viscosities, and the preparation of supported ionic liquid membranes using either immersion, pressure, or vacuum applied to a supporting membrane having a dense layer is difficult. It would be particularly advantageous to provide a method where a relatively high viscosity ionic liquid could be placed within the pores of a supporting membrane having a dense, skin surface, so that the ionic liquid could be distributed within the pores of the supporting membrane in a relatively thin, continuous fluid layer, and so that a highly selective ionic liquid could be coupled with a permeable dense layer, greatly mitigating the permeability-selectivity tradeoff of gas separation membranes, and greatly reducing concerns stemming from the relationship between a differential pressure and the capillary forces within the pores in an operating environment.
These and other objects, aspects, and advantages of the present disclosure will become better understood with reference to the accompanying description and claims.

Method of fabrication of supported liquid membranes


A class of tryptamine analogues bearing an optionally substituted phenyl nucleus at the 2-position are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse neurological conditions, including psychotic disorders such as schizophrenia.

The present invention relates to the use of a class of indole derivatives which act on serotonin receptors (also known as 5-hydroxytryptamine or 5-HT receptors). More particularly, the invention concerns analogues of tryptamine bearing an optionally substituted phenyl substituent at the 2-position. These compounds are selective antagonists of the human 5-HT2A receptor and are therefore useful as pharmaceutical agents, especially in the treatment and/or prevention of adverse conditions of the central nervous system, including psychotic disorders such as schizophrenia.
Schizophrenia is a disorder which is conventionally treated with drugs known as neuroleptics. In many cases, the symptoms of schizophrenia can be treated successfully with so-called xe2x80x9cclassicalxe2x80x9d neuroleptic agents such as haloperidol. Classical neuroleptics generally are antagonists at dopamine D2 receptors.
Notwithstanding their beneficial antipsychotic effects, classical neuroleptic agents such as haloperidol are frequently responsible for eliciting acute extrapyramidal symptoms (movement disorders) and neuroendocrine (hormonal) disturbances. These side-effects, which plainly detract from the clinical desirability of classical neuroleptics, are believed to be attributable to D2 receptor blockade in the striatal region of the brain.
The compound (+)-xcex1-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidinemethanol (also known as MDL-100,907) is described in WO 91/18602. In preclinical studies, MDL-100,907 failed to induce catalepsy and failed to block apomorphine-induced stereotyped behaviour in animal models, strongly suggesting that this compound would be free from any liability to cause extrapyramidal side-effects. MDL-100,907 is currently undergoing clinical trials in schizophrenic patients and has demonstrated efficacy in a multicentre, placebo-controlled study for antipsychotic potential, with no neurological adverse effects. Pharmacologically, MDL-100,907 has been shown to be a potent antagonist of human 5-HT2A receptors, whilst being essentially devoid of activity at the human dopamine D2 receptor. It is accordingly believed that compounds which can interact selectively with the 5-HT2A receptor relative to the dopamine D2 receptor will display the beneficial level of antipsychotic activity associated with 5-HT2A receptor antagonism, whilst minimizing or even avoiding the extrapyramidal and other side-effects arising from an interaction with dopamine D2 receptors.
The compounds of use in the present invention are potent antagonists of the human 5-HT2A receptor, and are accordingly of benefit in the treatment and/or prevention of psychotic disorders such as schizophrenia. The compounds of use in the invention may display more effective binding to the human 5-HT2A receptor than to the human dopamine D2 receptor, and they can therefore be expected to manifest fewer side-effects than compounds which do not discriminate in their binding affinity as between 5-HT2A and D2 receptors.
By virtue of their potent human 5-HT2A receptor antagonist activity, the compounds of use in the present invention are also effective in the treatment of neurological conditions including depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, sleep disorders such as insomnia, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA; and cardiovascular conditions including variant angina, Raynaud""s phenomenon, intermittent claudication, coronary and peripheral vasospasms, fibromyalgia, cardiac arrhythmias and thrombotic illness. They may also be generally of benefit in the inhibition of platelet aggregation, as well as in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They may further be effective in the lowering of intraocular pressure and may therefore be beneficial in treating glaucoma (cf. T. Mano et al. and H. Takaneka et al., Investigative Ophthalmology and Visual Science, 1995, vol. 36, pages 719 and 734 respectively).
Being 5-HT2A receptor antagonists, the compounds of use in the present invention may also be beneficial in preventing or reducing the toxic symptoms associated with the intake of ergovaline in animals consuming Acremonium coenophialum infected tall fescue (cf. D. C. Dyer, Life Sciences, 1993, 53, 223-228).
The preparation of a series of indole derivatives, including 3-aminoalkyl-2-phenylindoles, for pharmacological study is described in Ames et al., J. Chem. Soc., 1959, 3388-3399. No actual pharmaceutical utility is, however, ascribed to the compounds disclosed therein.
Julia et al. in Annales de l""Institut Pasteur, 1965, 343-362, describe the preparation of a number of 2-aryltryptamine derivatives, which are stated to have weak antiserotonin (rat uterus) activity.
Agarwal et al. in Indian Drugs, 1979, 209-212, and in J. Indian Chem. Soc., 1980, 57, 742-743, describe the synthesis of inter alia the compound 3- [2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole. However, no pharmacological activity is ascribed in either publication to this specific compound.
In JP-A-55-151505 is described a class of indoles, including 3-aminoalkyl-2-phenylindole derivatives which are optionally substituted on the 2-phenyl moiety and on the benzo moiety of the indole nucleus. These compounds are stated therein to be fungicides.
Hiriyakkanavar and Siddappa in Indian J. Chem., 1966, 4, 188-190, describe the synthesis of various 5,7-dimethyl-substituted 2-phenyltryptamine derivatives, which are stated to exhibit antiserotonin activity.
Joshi et al. in Agric. Biol. Chem., 1978, 42, 1723-1726, and in Monatsh. Chem., 1980:, 111, 1343-1350, describe various fluorinated analogues of 2-phenyltryptamine. Certain of these compounds are stated to act as mild stimulants.
In none of the prior art publications referred to above, in which 2-phenyl analogues of tryptamine are described, is there any disclosure or suggestion that such compounds might be potent and selective antagonists of the human 5-HT2A receptor, nor indeed that they might be of particular benefit in the treatment in particular of neurological conditions, including psychotic disorders such as schizophrenia.
FR-A-2102282 and FR-A-2181559 describe separate series of inter alia 2-phenyltryptamine analogues, both of which are stated to possess a variety of actions on the nervous system.
The compounds of use in the present invention are potent and selective 5-HT2A receptor antagonists having a human 5-HT2A receptor binding affinity (Ki) of 100 nM or less, typically of 50 nM or less and preferably of 10 nM or less. The compounds of use in the invention may possess at least a 10-fold selective affinity, suitably at least a 20-fold selective affinity and preferably at least a 50-fold selective affinity, for the human 5-HT2A receptor relative to the human dopamine D2 receptor.
The present invention provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein
A and B independently represent hydrogen, halogen, cyano, nitro, trifluoromethyl, trifluoromethoxy, C1-6 alkyl or C1-6 alkoxy;
X and Y independently represent hydrogen, halogen, C1-6 alkyl, C1-6 alkoxy or phenyl;
R1 represents hydrogen or C1-6 alkyl;
R2 represents hydrogen, methyl, ethyl, 2-methoxyethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl or n-pentyl; and
R3 represents C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l) or (m):
in which the broken line represents an optional chemical bond;
Z represents oxygen, sulphur, Nxe2x80x94R6 or CR7R8;
R4 represents hydrogen, C1-6 alkyl, C1-6 alkoxy(C1-6)alkyl, C3-7 heterocycloalkyl(C1-6)alkyl or aryloxy;
R5 represents hydrogen, C1-6 alkyl or C1-6 alkoxy(C1-6)alkyl;
R6 represents hydrogen, xe2x80x94COR9 or xe2x80x94CO2R9; or C1-6 alkyl, C2-6 alkenyl, C3-9 cycloalkyl, aryl(C1-6)alkyl, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
R7 represents hydrogen, hydrocarbon, a heterocyclic group, xe2x80x94COR9 or xe2x80x94CO2R9;
R8 represents hydrogen, phenyl or acetoxy; and
R9 represents C1-6 alkyl;
for the manufacture of a medicament for the treatment and/or prevention of clinical conditions for which a selective antagonist of 5-HT2A receptors is indicated, especially psychotic disorders including schizophrenia.
The present invention also provides a method for the treatment and/or prevention of clinical conditions for which a selective antagonist of 5-HT2A receptors is indicated, especially psychotic disorders including schizophrenia, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.
A particular subset of compounds of use in the present invention comprises the compounds of formula I as depicted above, and pharmaceutically acceptable salts thereof, wherein
A, B, X, Y and R1 are as defined above;
R2 represents hydrogen, methyl or ethyl; and
R3 represents C1-6 alkyl, C3-9 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl or heteroaryl(C1-6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
R2 and R3 taken together with the intervening nitrogen atom represent a group of formula (a) to (k) as defined above, in which
R4 represents hydrogen or C1-6 alkyl; and
Z, R5, R6, R7, R8 and R9 are as defined above.
For use in medicine, the salts of the compounds of formula I will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid. Furthermore, where the compounds of use in the invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The term xe2x80x9chydrocarbonxe2x80x9d as used herein includes straight-chained, branched and cyclic groups containing up to 18 carbon atoms, suitably up to 15 carbon atoms, and conveniently up to 12 carbon atoms. Suitable hydrocarbon groups include C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-9 cycloalkyl, C3-9 cycloalkyl(C1-6)alkyl, indanyl, aryl, aryl(C1-6)alkyl and aryl(C2-6)alkenyl.
The expression xe2x80x9ca heterocyclic groupxe2x80x9d as used herein includes cyclic groups containing up to 18 carbon atoms and at least one heteroatom preferably selected from oxygen, nitrogen and sulphur. The heterocyclic group suitably contains up to 15 carbon atoms and conveniently up to 12 carbon atoms, and is preferably linked through carbon. Examples of suitable heterocyclic groups include C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(C1-6)alkyl, heteroaryl and heteroaryl(C1-6)alkyl groups.
Suitable alkyl groups include straight-chained and branched alkyl groups containing from 1 to 6 carbon atoms. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and 2,2-dimethylpropyl.
Suitable alkenyl groups include straight-chained and branched alkenyl groups containing from 2 to 6 carbon atoms. Typical examples include vinyl, allyl, 2-methylpropenyl and dimethylallyl groups.
Suitable alkynyl groups include straight-chained and branched alkynyl groups containing from 2 to 2 carbon atoms. Typical examples include ethynyl and propargyl groups.
Suitable cycloalkyl groups include groups containing from 3 to 9 carbon atoms. Particular cycloalkyl groups are cyclopropyl, cyclopentyl, cyclohexyl and cyclooctyl.
Typical examples of C3-9 cycloalkyl(C1-6)alkyl groups include cyclopropylmethyl, cyclohexylmethyl and cyclohexylethyl.
Particular indanyl groups include indan-1-yl and indan-2-yl.
Particular aryl groups include phenyl and naphthyl.
Particular aryl(C1-6)alkyl groups include benzyl, phenylethyl, phenylpropyl, phenylbutyl and naphthylmethyl.
Typical aryl(C2-6)alkenyl groups include phenylethenyl and phenylpropenyl.
Suitable heterocycloalkyl groups include tetrahydrofuryl, tetrahydrothienyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl groups.
Typical C3-7 heterocycloalkyl(C1-6)alkyl groups include tetrahydrofurylmethyl, morpholinylethyl and pyrrolidinylpropyl.
Suitable heteroaryl groups include pyridinyl, quinolinyl, isoquinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzthienyl, pyrrolyl, indolyl, pyrazolyl, indazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, benzimidazolonyl, oxadiazolyl, thiadiazolyl, triazolyl and tetrazolyl groups.
The expression xe2x80x9cheteroaryl(C1-6)alkylxe2x80x9d as used herein includes furylmethyl, furylethyl, thienylmethyl, thienylethyl, oxazolylmethyl, oxazolylethyl, thiazolylmethyl, thiazolylethyl, imidazolylmethyl, imidazolylethyl, oxadiazolylmethyl, oxadiazolylethyl, thiadiazolylmethyl, thiadiazolylethyl, triazolylmethyl, triazolylethyl, tetrazolylmethyl, tetrazolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrazinylmethyl, quinolinylmethyl and isoquinolinylmethyl.
The hydrocarbon and heterocyclic groups, as well as the substituents R3 and R6, may in turn be optionally substituted by one or more groups, preferably by one or two optional groups, selected from C1-6 alkyl, adamantyl, phenyl or halophenyl (except when R3 is C1-3 alkyl), benzyl, thiadiazolyl, halogen, C1-6 haloalkyl, C1-6 aminoalkyl, difluoromethyl, trifluoromethyl, hydroxy, C1-6 alkoxy, difluoromethoxy, trifluoromethoxy, aryloxy, benzyloxy, OXO, C1-3 alkylenedioxy, 1,3-dioxabutylene, nitro, cyano, carboxy, C2-6 alkoxycarbonyl, C2-6 alkoxycarbonyl(C1-6)alkyl, C2-6 alkylcarbonyloxy, arylcarbonyloxy, aminocarbonyloxy, C2-6 alkylcarbonyl, arylcarbonyl, C1-6 alkylthio, C1-6 alkylsulphinyl, C1-6 alkylsulphonyl, arylsulphonyl, xe2x80x94NRvRw, xe2x80x94NRvCORw, xe2x80x94NRvCO2Rw, xe2x80x94NRvSO2Rw, xe2x80x94CH2NRvSO2Rw, xe2x80x94NHCONRvRw, xe2x80x94CONRvRw, xe2x80x94SO2NRvRw and xe2x80x94CH2SO2NRvRw, in which Rv and Rw independently represent hydrogen, C1-6 alkyl, aryl or aryl(C1-6)alkyl, or Rv and Rw together represent a C2-6 alkylene group.
When Rv and Rw together represent a C2-6 alkylene group, this group may be an ethylene, propylene, butylene, pentamethylene or hexamethylene group, preferably butylene or pentamethylene.
The term xe2x80x9chalogenxe2x80x9d as used herein includes fluorine, chlorine, bromine and iodine, especially fluorine or chlorine.
Where the compounds of use in the invention have at least one asymmetric centre, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereoisomers. It is to be understood that the use of all such isomers and mixtures thereof in any proportion is encompassed within the scope of the present invention.
Particular values for the substituent A in the compounds of formula I above include hydrogen, fluoro, trifluoromethyl and methyl, especially hydrogen.
Suitably, B represents hydrogen, fluoro, chloro, cyano, nitro, trifluoromethyl, trifluoromethoxy, methyl or methoxy.
Particular values for the substituent X include hydrogen and fluoro, especially hydrogen.
Suitably, Y represents hydrogen, fluoro, chloro, bromo, methyl, methoxy or phenyl.
Suitably, R1 represents hydrogen or methyl, especially hydrogen.
Suitably, R2 represents hydrogen, methyl or ethyl, typically hydrogen or methyl.
In one embodiment, R2 represents hydrogen. In another embodiment, R2 is methyl.
Illustrative values of R3 include methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, n-pentyl, 2-methylpropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, tetrahydrothienyl, piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl, morpholinylpropyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R3 include methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclooctyl, phenyl, tetrahydrothienyl, piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl and furylmethyl, any of which groups may be optionally substituted by one or more substituents.
The moiety R3 may be unsubstituted, or substituted by one or more substituents. Preferably, R3 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R3 include benzyl, fluoro, chloro, bromo, trifluoromethyl, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, oxo, 1,3-dioxabutylene and diisopropylamino.
Specific values of R3 include methyl, ethyl, fluoroethyl, trifluoroethyl, methoxyethyl, diisopropylamino-ethyl, n-propyl, fluoropropyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, n-pentyl, 2-methylpropenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, isopropoxyphenyl, difluoromethoxy-phenyl, trifluoromethoxy-phenyl, 1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl, tetrahydrofurylmethyl, morpholinethyl, pyrrolidinylpropyl, morpholinylpropyl and furylmethyl.
Particular values of R3 include methyl, ethyl, diisopropylaminoethyl, n-propyl, isopropyl, cyclopropyl, cyclopentyl, cyclooctyl, phenyl, fluorophenyl, chlorophenyl, dichlorophenyl, methoxyphenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, isopropoxyphenyl, difluoromethoxy-phenyl, trifluoromethoxy-phenyl, 1,3-dioxabutylenephenyl, tetrahydrothienyl dioxide, benzyl-piperidinyl, tetrahydrofurylmethyl, morpholinylethyl, pyrrolidinylpropyl and furylmethyl.
In one embodiment, Z represents oxygen or sulphur. In another embodiment, Z represents CR7R8.
In a further embodiment, Z represents oxygen, sulphur or Nxe2x80x94R6. In a still further embodiment, Z represents Nxe2x80x94R6 or CR7R8. In a yet further embodiment, Z represents oxygen, sulphur or CR7R8.
Suitably, R4 represents hydrogen, methyl, methoxymethyl, pyrrolidinylmethyl or phenoxy, especially hydrogen or methoxymethyl, and more especially hydrogen. More particularly, R4 may represent hydrogen or methyl, especially hydrogen.
Suitably, R5 represents hydrogen, methyl, ethyl, n-propyl or methoxymethyl, especially hydrogen.
Illustrative values of R6 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, n-propyl, isopropyl, allyl, cyclopentyl, cyclohexyl, benzyl, phenylethyl, phenylethenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl and benzofuryl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R6 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl, benzyl, phenylethyl, phenylethenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl and benzofuryl, any of which groups may be optionally substituted by one or more substituents.
The moiety R6 may be unsubstituted, or substituted by one or more substituents. Preferably, R6 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R6 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, dipropylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl. More specific examples of typical substituents on the moiety R6 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl.
Specific values for the moiety R6 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, dimethylamino-ethyl, diethylamino-ethyl, dipropylamino-ethyl, dimethylamino-propyl, isopropyl, allyl, cyclopentyl, cyclohexyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, 1-phenylethyl, 2-phenylethyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl and benzofuryl.
Particular values of R6 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, diethylamino-ethyl, dimethylamino-propyl, allyl, cyclohexyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, phenylethyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl and benzofuryl.
Suitable values of R7 include hydrogen, C2-6 alkylcarbonyl and C2-6 alkoxycarbonyl; and C1-6 alkyl, C2-6 alkenyl, C3-7 cycloalkyl, aryl, aryl(C1-6)alkyl1, aryl(C2-6)alkenyl, C3-7 heterocycloalkyl(C1-6)alkyl and heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Representative values of R7 include hydrogen, acetyl and tert-butoxycarbonyl; and methyl, ethyl, propyl, allyl, cyclohexyl, phenyl, benzyl, phenylethyl, phenylpropyl, phenylbutyl, phenylethenyl, phenylpropenyl, morpholinylethyl, pyridinyl, quinolinyl, isoquinolinyl, pyrimidinyl, benzofuryl and benzimidazolonyl, any of which groups may be optionally substituted by one or more substituents.
The moiety R7 may be unsubstituted, or substituted by one or more substituents. Preferably, R7 is unsubstituted, or substituted by one or two substituents. Examples of typical substituents on the moiety R7 include methyl, ethyl, tert-butyl, phenyl, fluorophenyl, chlorophenyl, fluoro, chloro, trifluoromethyl, methoxy, ethoxy, benzyloxy, methylenedioxy, nitro, cyano, acetoxy, methylthio, dimethylamino, diethylamino, N-methyl-N-phenylaminocarbonyl and pyrrolidinylcarbonyl.
Specific values for the moiety R7 include hydrogen, acetyl, tert-butoxycarbonyl, methyl, benzyloxymethyl, N-methyl-N-phenylaminocarbonyl-methyl, pyrrolidinylcarbonyl-methyl, ethyl, methoxyethyl, acetoxyethyl, diethylamino-ethyl, dimethylamino-propyl, allyl, cyclohexyl, phenyl, methylphenyl, dimethylphenyl, ethylphenyl, fluorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl-phenyl, (chloro)(trifluoromethyl)phenyl, bis(trifluoromethyl)phenyl, methoxyphenyl, (dichloro)(methoxy)phenyl, dimethoxyphenyl, trimethoxyphenyl, ethoxyphenyl, methylenedioxy-phenyl, nitrophenyl, (dinitro)(trifluoromethyl)phenyl, cyanophenyl, dicyanophenyl, methylthiophenyl, benzyl, tert-butylbenzyl, diphenylmethyl, (chlorophenyl)(phenyl)methyl, di(fluorophenyl)methyl, di(chlorophenyl)methyl, chlorobenzyl, methylenedioxy-benzyl, phenylethyl, 3,3-diphenylpropyl, 4-phenylbut-2-yl, chlorophenyl-ethenyl, cyanophenyl-ethenyl, phenylpropenyl, morpholinylethyl, pyridinyl, trifluoromethyl-pyridinyl, (chloro)(trifluoromethyl)pyridinyl, trifluoromethyl-quinolinyl, isoquinolinyl, pyrimidinyl, trifluoromethyl-pyridimidinyl, benzofuryl and benzimidazolonyl.
In relation to formula (c) above in which Z represents CR7R8, the moiety R7 suitably represents hydrogen, methyl, benzyloxymethyl, phenyl, methoxyphenyl, benzyl, phenylethyl or benzimidazolonyl. More particularly, R7 in this context may suitably represent hydrogen, benzyloxymethyl, benzyl, phenylethyl or benzimidazolonyl.
In relation to formula (e) above, the moiety R7 suitably represents methylenedioxy-phenyl, chlorophenyl-ethenyl, cyanophenyl-ethenyl or benzofuryl.
In relation to formula (f) above, the moiety R7 suitably represents benzyl.
Suitably, R8 represents hydrogen.
Suitably, R9 represents methyl or tert-butyl.
Specific compounds of use in the present invention include:
3-[2-(N,N-dimethylamino)ethyl]-2-phenyl-1H-indole;
3-[2-(N,N-diethylamino)ethyl]-2-phenyl-1H-indole;
2-phenyl-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole;
2-phenyl-3-[2-(piperidin-1-yl)ethyl]-1H-indole;
3-[2-(2-methylpiperidin-1-yl)ethyl]-2-phenyl-1H-indole;
3-[2-homopiperidin-1-yl)ethyl]-2-phenyl-1H-indole;
3-[2-(morpholin-4-yl)ethyl]-2-phenyl-1H-indole ;
2-(4-fluorophenyl)-3-[2-(piperidin-1-yl)ethyl]-1H-indole;
and pharmaceutically acceptable salts thereof.
Certain compounds falling within the definition of formula I above are novel. Accordingly, in a further aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, wherein B represents trifluoromethyl or trifluoromethoxy.
In another aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, wherein Y represents phenyl.
In another aspect, the present invention provides a compound of formula I as defined above, or a salt thereof, provided that:
(i) when A and B independently represent hydrogen, halogen, cyano, nitro, alkyl or alkoxy, and X and Y independently represent hydrogen, halogen, alkyl or alkoxy, then either R3 does not represent alkyl, or R2 and R3 taken together with the intervening nitrogen atom do not represent piperidin-1-yl or morpholin-4-yl; and
(ii) when A, B, X, Y and R1 each represents hydrogen, then R2 and R3 taken together with the intervening nitrogen atom do not represent pyrrolidin-1-yl, 2-methylpiperidin-1-yl or homopiperidin-1-yl.
Particular sub-classes of novel compounds in accordance with the present invention are represented by the compounds of formula IA and IB, and salts thereof:
wherein R2 and R3 are as defined above.
Specific compounds in accordance with the present invention include those compounds disclosed in the accompanying Examples, with the exception of Example Nos. 1, 9, 22, 34, 36, 38, 49 and 55.
The invention also provides pharmaceutical compositions comprising one or more of the novel compounds according to the invention in association with a pharmaceutically acceptable carrier. Preferably these compositions are in unit dosage forms such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, auto-injector devices or suppositories; for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation. Alternatively, the compositions may be presented in a form suitable for once-weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection. An erodible polymer containing the active ingredient may be envisaged. For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention, or a pharmaceutically acceptable salt thereof. When referring to these preformulation compositions as homogeneous, it is meant that the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention. Favoured unit dosage forms contain from 1 to 100 mg, for example 1, 2, 5, 10, 25, 50 or 100 mg, of the active ingredient. The tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
The liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavoured syrups, aqueous or oil suspensions, and flavoured emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
In the treatment of schizophrenia, a suitable dosage level is about 0.01 to 250 mg/kg per day, preferably about 0.05 to 100 mg/kg per day, and especially about 0.05 to 5 mg/kg per day. The compounds may be administered on a regimen of 1 to 4 times per day.
If desired, the compounds of use in this invention may be co-administered with another anti-schizophrenic medicament, for example one producing its effects via dopamine D2 and/or D4 receptor subtype blockade. In such circumstances, an enhanced anti-schizophrenic effect may be envisaged without a corresponding increase in side-effects such as those caused by, for example, D2 receptor subtype blockade; or a comparable anti-schizophrenic effect with reduced side-effects may alternatively be envisaged. Such co-administration may be desirable where a patient is already established on an anti-schizophrenic treatment regime involving conventional anti-schizophrenic medicaments. Suitable anti-schizophrenic medicaments of use in combination with the compounds according to the present invention include haloperidol, chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine, trifluoperazine, chloroprothixene, thiothixene, clozapine, olanzapine, pimozide, molindone, loxapine, sulpiride, risperidone, xanomeline, fananserin and ziprasidone, and pharmaceutically acceptable salts thereof.
The compounds of formula I above, including the novel compounds according to the present invention, may be prepared by a process which comprises reacting a compound of formula II with a compound of formula III:
wherein A, B, X, Y, R1, R2 and R3 are as defined above, L1 represents a suitable leaving group and Rp represents a hydrogen atom, an amino-protecting group or an attached resin moiety; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
The leaving group L1 is suitably an alkylsulphonyloxy or arylsulphonyloxy moiety such as trifluoromethanesulphonyloxy (triflyloxy) or p-toluenesulphonyloxy (tosyloxy), preferably triflyloxy.
Where Rp represents an amino-protecting group, this is suitably a carbamoyl moiety, e.g. tert-butoxycarbonyl (BOC), which can readily be removed as required by treatment with acid, typically trifluoroacetic acid, or with base, e.g. sodium methoxide in methanol.
Where Rp represents an attached resin moiety, this is suitably a polymeric moiety such as the commercially available WANG resin, whereby the substituent Rp represents (4-benzyloxycarbonyl) phenoxymethylcopoly(styrene-1% divinylbenzene). The WANG resin can be conveniently removed at the appropriate stage by treatment with pyrrolidine at an elevated temperature, typically in a solvent such as N,N-dimethylformamide.
The reaction between compounds II and III is conveniently effected by stirring in an appropriate solvent, e.g. dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide, optionally under basic conditions, for example in the presence of potassium carbonate.
In an alternative procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula IV with a compound of formula V:
wherein A, B, X, Y, R1, R2, R3 and Rp are as defined above; one of M1 and M2 represents a suitable leaving group, and the other represents a boronic acid moiety xe2x80x94B(OH)2 or a 1-4 alkyl ester or anhydride thereof; in the presence of a transition metal catalyst; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
The leaving group M1 or M2 is suitably a halogen atom, e.g. bromine.
The transition metal catalyst of use in the reaction between compounds IV and V is suitably tetrakis(triphenylphosphine)palladium (0);. The reaction is conveniently carried out in an inert solvent such as ethanolic toluene, aqueous tetrahydrofuran or aqueous 1,2-dimethoxyethane, advantageously in the presence of a base such as sodium acetate or sodium carbonate, optionally in the presence of lithium chloride, and typically at an elevated temperature.
Where L1 represents triflyloxy or tosyloxy, the intermediates of formula II above may be prepared by triflylation or tosylation of the corresponding 3-(2-hydroxyethyl)indole derivative using standard techniques, e.g. by treatment with triflic anhydride (Tf2O), typically in a solvent such as dichloromethane or 1,2-dichloroethane and optionally in the presence of a base such as 2,6-di-tert-butyl-4-methylpyridine. The hydroxy compound may in turn be prepared by reaction of a compound of formula V as defined above with a compound of formula VI:
wherein X, Y, R1, Rp and M1 are as defined above, and Rq represents hydrogen or a hydroxy-protecting group; under conditions analogous to those defined above for the reaction between compounds IV and V; followed, where necessary, by removal of the hydroxy-protecting group Rq.
Where Rq represents a hydroxy-protecting group, this is ideally a tetrahydro-2H-pyran-2-yl moiety, which can conveniently be removed as necessary under acidic conditions, for example by treatment with pyridinium p-toluenesulphonate (PPTS) in a suitable solvent, e.g. ethanol or a mixture of ethanol and 1,2-dichloroethane.
The intermediates of formula IV may be prepared by reacting a compound of formula III as defined above with a compound of formula VII:
wherein X, Y, R1, Rp, L1 and M1 are as defined above; under conditions analogous to those described above for the reaction between compounds II and III.
Where L1 represents triflyloxy or tosyloxy, the intermediates of formula VII may be prepared by triflylation or tosylation of the appropriate compound of formula VI wherein Rq represents hydrogen, using standard techniques.
In another procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula III as defined above with a compound of formula VIII:
wherein A, B, X, Y, R1 and Rp are as defined above; in the presence of a reducing agent; followed, where necessary, by removal of the amino-protecting group or attached resin moiety Rp.
A suitable reducing agent for use in the reaction between compounds III and VIII is sodium triacetoxyborohydride. The reaction is conveniently effected in the presence of acetic acid, typically in an inert solvent such as 1,2-dichloroethane.
In a further procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula IX or an acid addition salt thereof, typically the hydrochloride salt, with a compound of formula X:
wherein A, B, X, Y, R1, R2 and R3 are as defined above.
The reaction between compounds IX and X, which is an example of the well-known Fischer indole synthesis, is suitably effected by stirring in ethanol at 25xc2x0 C., followed by heating in trifluoroacetic acid at 70xc2x0 C.
In a still further procedure, the compounds of formula I above, including the novel compounds according to the invention, may be prepared by a process which comprises reacting a compound of formula XI with a compound of formula XII (cf Larock and Yum, J. Am. Chem. Soc., 1991, 113, 6689):
wherein A, B, X, Y, R1, R2 and R3 are as defined above; in the presence of a transition metal catalyst.
Similarly, the intermediates of formula II, or their hydroxy precursors, and the intermediates of formula VIII may be prepared by reacting a compound of formula XI as defined above with the appropriate compound of formula XIII or XIV:
wherein A, B and R1 are as defined above, and L11 corresponds to the moiety L1 or represents hydroxy; in the presence of a transition metal catalyst.
The transition metal catalyst employed in the reaction between compound XI and compound XII, XIII or XIV is suitably a palladium-containing catalyst. Typical catalysts include palladium(II) acetate, optionally in the presence of triphenylphosphine, and dichlorobis(triphenylphosphine)palladium(II). A preferred catalyst is dichlorobis(triphenylphosphine)palladium(II).
The transition metal catalysed indole formation reaction between compound XI and compound XII, XIII or XIV is advantageously carried out under basic conditions. Typical basic reagents of use in the reaction include sodium carbonate, potassium carbonate, sodium acetate or potassium acetate, optionally in the presence of lithium chloride or tetra-n-butylammonium chloride; and tetramethylguanidine. A preferred base is tetramethylguanidine. The reaction is conveniently effected in a polar aprotic organic solvent such as N,N-dimethylformamide, typically at an elevated temperature, e.g. a temperature in the region of 80-110xc2x0 C.
Where they are not commercially available, the starting materials of formula III, V, VI, IX, X, XI, XII, XIII and XIV may be prepared by procedures analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be appreciated that any compound of formula I initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further desired compound of formula I using techniques known from the art.
Where the above-described processes for the preparation of the compounds of use in the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers by standard techniques such as preparative HPLC, or the formation of diastereomeric pairs by salt formation with an optically active acid, such as (xe2x88x92)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.
The following Examples illustrate the preparation of compounds of use in the invention.
The compounds useful in this invention potently inhibit [3H]-ketanserin binding to the human 5-HT2A receptor expressed in clonal cell lines. Moreover, those compounds of use in the invention which have been tested display a selective affinity for the 5-HT2A receptor relative to the dopamine D2 receptor.
The compounds of the accompanying Examples were all found to possess a Ki value for displacement of [3H]-ketanserin from the human 5-HT2A receptor, when expressed in Chinese hamster ovary (CHO) clonal cell lines, of 100 nM or less.

Phenylindole derivatives as 5-HT2A receptor ligands


A transducer comprises a conductive pin and a waveguide for directing electromagnetic radiation onto the pin, wherein the pin is configured to create a rectangular flat top field distribution at a surface of a storage medium positioned adjacent to an end of the pin, leading to a flat top thermal profile within the storage medium. A second pin can be included in the transducer. Recording heads that include the transducer, disc drives that include the recording head, and a method of heating a portion of a storage medium that is performed by the recording head, are also included.

Magnetic recording heads have utility in magnetic disc drive storage systems. Magnetic recording in its conventional form has been projected to suffer from superparamagnetic instabilities at high bit densities.
Superparamagnetic instabilities become an issue as the grain volume is reduced in order to control media noise for high areal density recording. The superparamagnetic effect is most evident when the grain volume V is sufficiently small that the inequality KuV/kBT>70 can no longer be maintained. Ku is the material's magnetic crystalline anisotropy energy density, kB is Boltzmann's constant, and T is absolute temperature. When this inequality is not satisfied, thermal energy demagnetizes the stored bits. Therefore, as the grain size is decreased in order to increase the areal density, a threshold is reached for a given material Ku and temperature T such that stable data storage is no longer feasible.
The thermal stability can be improved by employing a recording medium formed of a material with a very high Ku. However, with the available materials conventional "longitudinal" recording heads are not able to provide a sufficient or high enough magnetic writing field to write on such a medium. An alternative to longitudinal recording that overcomes at least some of the problems associated with the superparamagnetic effect is "perpendicular" magnetic recording. Perpendicular magnetic recording is believed to have the capability of extending recording densities well beyond the limits of longitudinal magnetic recording. Perpendicular magnetic recording heads for use with a perpendicular magnetic storage medium may include a pair of magnetically coupled poles, including a main write pole having a relatively small bottom surface area and a flux return pole having a larger bottom surface area. A coil having a plurality of turns is located adjacent to the main write pole for inducing a magnetic field between the pole and a soft underlayer of the storage media. The soft underlayer is located below the hard magnetic recording layer of the storage media and enhances the amplitude of the field produced by the main pole. This, in turn, allows the use of storage media with higher coercive force, consequently, more stable bits can be stored in the media. In the recording process, an electrical current in the coil energizes the main pole, which produces a magnetic field. The image of this field is produced in the soft underlayer to enhance the field strength produced in the magnetic media. The flux density that diverges from the tip into the soft underlayer returns through the return flux pole. The return pole is located sufficiently far apart from the main write pole such that the material of the return pole does not affect the magnetic flux of the main write pole, which is directed vertically into the hard layer and the soft underlayer of the storage media.
Another development that is expected to overcome most of the problems associated with the superparamagnetic effect is "heat assisted magnetic recording", sometimes referred to as optical or thermal assisted recording. Heat assisted magnetic recording generally refers to the concept of locally heating a recording medium to reduce the coercivity of the recording medium so that the applied magnetic writing field can more easily direct the magnetization of the recording medium during the temporary magnetic softening of the recording medium caused by the heat source. Once the medium cools to ambient temperature, the medium has a sufficiently high value of coercivity to assure thermal stability of the recorded information. Heat assisted magnetic recording allows for the use of small grain media, which is desirable for recording at increased areal densities, with a larger magnetic anisotropy at room temperature to assure sufficient thermal stability. Heat assisted magnetic recording can be applied to any type of magnetic storage media, including tilted media, longitudinal media, perpendicular media and patterned media.
When applying a heat or light source to the medium, it is desirable to confine the heat or light to the track where writing is taking place and to generate the write field in close proximity to where the medium is heated to accomplish high areal density recording. In addition, for heat assisted magnetic recording (HAMR) one of the technological hurdles to overcome is to provide an efficient technique for delivering large amounts of light power to the recording medium confined to spots of, for example, 50 nm or less. A variety of transducer designs have been proposed and some have been experimentally tested. Among these are metal coated glass fibers and hollow pyramidal structures with metal walls. For all these approaches, confinement of the light depends on an aperture which is to be fabricated into the end of the structure and gives this kind of transducer the name "aperture probes." Generally these devices suffer from very low light transmission rendering the devices useless for HAMR recording. For example, tapered and metallized optical fibers have demonstrated light confinement down to approximately 50 nm with a throughput efficiency of 10−6. Pyramidal probes made from anisotropic etching of Si wafers have been designed with throughput efficiencies of 10−4 for similar spot sizes. Although this is the state of the art, it is still about two orders of magnitude too small for HAMR.
Solid immersion lenses (SILs) and solid immersion mirrors (SIMs) have also been proposed for concentrating far field optical energy into small spots. The optical intensity is very high at the focus but the spot size is still determined by the diffraction limit which in turn depends on the refractive index of the material from which the SIL or SIM is made. The smallest spot size which can be achieved with all currently known transparent materials is ˜60 nm, which is too large for HAMR.
A metal pin can be used as a transducer to concentrate optical energy into arbitrarily small areal dimensions. The metal pin supports a surface plasmon mode which propagates along the pin, and the width of the external electric field generated by the surface plasmon mode is proportional to the diameter of the pin.
There is a need for transducers that can provide an electromagnetic field distribution that is suitable for heat assisted magnetic recording.

Heat assisted magnetic recording with heat profile shaping