An electric power generating system comprises a low reactance, large airgap permanent magnet generator driven by a hydraulic motor to generate a poly-phase AC output voltage. Because the permanent magnet generator is a low reluctance, large airgap machine, the output voltage regulation is low over the desired loading range of the system. The output voltage is controlled within acceptable limits by trimming the output speed of the hydraulic motor through the use of a servovalve. The control for the servovalve senses a parameter of output power and generates a speed control signal to compensate for deviations in the generator output. The system includes protection circuitry which monitors at least one parameter of the output power. This protection circuitry generates an output protection signal in response to a deviation in the monitored parameter which exceeds predetermined limits. In response to this signal, an on/off solenoid, which is coupled between the hydraulic motor and the external source of hydraulic power, terminates the flow of hydraulic power to the hydraulic motor. This results in a termination of the power generation by the permanent magnet generator. In one embodiment of the instant invention, the permanent magnet generator includes a second stator winding which is used to generate a second output voltage. A rectification circuit is coupled to this second output to transform the voltage produced thereon to a dc voltage to power dc loads.

In an aircraft electrical generating system the output voltage of a main channel generator must be regulated within a narrow band of output voltage so as to not damage any of the utilization equipment to which it supplies electric power. In conventional systems, a synchronous wound field generator is used to generate the electric power needed by the utilization equipment. This type of generator is typically used because the output voltage can be regulated by controlling the generator field excitation using a generator control unit (GCU). As more electrical loads are connected to the system, the amount of excitation provided to the wound field is increased, thereby preventing an unacceptable droop in output voltage. Such a generator is constructed with a fixed exciter field winding which is driven by the GCU. The excitation provided to this fixed winding induces a voltage in a three phase rotating exciter winding located on the rotor. The output of these rotating windings are rectified by a rotating rectifier assembly to produce a dc output used to drive the rotating main field winding. This main field winding, in turn, excites the main output stator windings which supply the electric power to the utilization equipment.
A problem associated with the use of such a generator is that there are undesirable losses in the rotor resulting from the "inside-out" nature of the exciter field. These losses occur at various points between the fixed winding which inductively couples a rotating three phase winding assembly whose output is rectified by a rotating diode assembly to drive a rotating main field winding which inductively couples the main stator windings. In addition to the lower efficiency resulting from these losses, the overall machine is less robust due to stresses placed on the rotating diode assembly. The use of suppression resistors are required for the rotating rectifier assembly to protect the diodes from large voltage spikes resulting from switching and large load transients.
A more robust and efficient machine is the permanent magnet generator (PMG). This type of generator uses strong permanent magnets constructed from materials such as samarium-cobalt or Nd-Fe-B (where the rotor temperature remains under 100.degree. C.) to generate the excitation flux needed to generate electricity. These permanent magnets are placed on the rotor of the PMG and provide a fixed excitation at a given speed. The absence of the rotating windings and diode assemblies in these PMGs makes them inherently rugged, efficient, and reliable machines. The output voltage of the PMG is a function of load and operating speed of the machine. A problem inherent with such a machine, however, is that the output voltage droops rather severely at a given speed as load is connected to its output as illustrated by the graph of output voltage versus load current 100 in FIG. 1. This is because the fixed excitation from the permanent magnets does not change. One way to counteract this severe voltage droop problem is to change the speed at which the rotor of the PMG is driven. As the speed of the PMG is increased, the PMG output voltage is increased to counteract the drooping voltage. As electrical load is removed from the PMG, the speed may be decreased to suppress the rising voltage.
While this input speed/output voltage control scheme would appear to solve the problem associated with changing electrical loads, such a system to date is unable to meet the power quality specifications which govern aircraft electric power generating systems. These specifications, such as MIL-G-21480, DO-160, and MIL-STD-704, require that narrow band voltage regulation be maintained as loads are switched on and off from no load to twice the normal per unit loading as may be seen from the limits 102.sub.U and 102.sub.L for DO-160 and 104.sub.U and 104.sub.L for MIL-STD-704 of FIG. 2. These specifications also require that this voltage regulation be maintained under normal conditions with allowance for very short transient variations as may be seen from limits 106.sub.U and 106.sub.L for generator loading up to rated load, limits 108.sub.U and 108.sub.L for generator overloading up to 150% rated capacity, and limits 110.sub.U and 110.sub.L for generator loading up to 200% rated capacity. Under such loading conditions it becomes difficult to overcome the rotational inertia of the PMG's rotor to force a speed change quick enough to meet the power quality specifications for the output voltage, not to mention the possibility of shearing the shaft from the torque required to effect such a speed change.
This problem is compounded even further if the electrical system is required to utilize a hydraulic motor to drive the PMG. For this type of system, in addition to the PMG rotor inertia delaying the output voltage response to a speed change command, delays caused by valve openings and closings and the change in hydraulic fluid flow rate further delay the electrical response of the system. These delays may result in the system being tripped off-line by the system's over voltage protection during normal off load transients because the PMG's output voltage increases beyond the trip level for longer than allowed by specification. This type of situation is unacceptable, and his severely limited the application of PMGs for hydraulically driven, highly regulated systems.
It is, therefore, an objective of the instant invention to overcome these and other problems known in the art. Specifically, it is an objective of the instant invention to provide an electric power generating system which is capable of utilizing the rugged and efficient permanent magnet generator. It is further an objective of the instant invention to provide a system which controls the output of the PMG in such a manner as to allow its use in accordance with industry power quality standards. A further objective of the instant invention is to provide a PMG based electrical power generating system which is driven by hydraulic power. Additionally, it is an objective of the instant invention to provide a system which will protect against faults which could damage the utilization equipment or the PMG itself. It is a further objective of the instant invention to provide such a system using a simple and economical control scheme.

Hydraulically driven low reactance, large air gap permanent magnet generator and voltage regulation system for use therewith


A method of fabricating a die containing an integrated circuit, including active components and passive components, includes producing a first substrate containing at least one active component of active components and a second substrate containing critical components of the passive components, such as perovskites or MEMS, and bonding the two substrates by a layer transfer. The method provides an improved monolithic integration of devices such as MEMS with transistors.

The present invention relates to the field of integrated circuits, and in particular to that of passive components integrated on die.
In the field of integrated circuits, there is an increasing requirement: to reduce the size taken up by the components, to reduce the fabrication costs, and to introduce new functions.
To achieve these objectives, it is necessary to integrate collectively onto the same analog or digital integrated circuit die an increasing number of components that were previously fabricated separately. There are essentially three categories of such components: circuits called "active" (transistors), components called "passive" (resistors, capacitors, inductors), and, finally, micro-electro-mechanical systems (MEMS) (acoustic filters, radio-frequency switches, variable capacitors).
Passive components and/or MEMS can be integrated independently of transistors, but their monolithic integration with transistors is the most beneficial in terms of compactness and cost. However, this monolithic integration causes a certain number of technological difficulties.
First, the nature of the layers and the treatments necessitated by the fabrication of the passive components are not always readily compatible with fabrication on the active circuits. For example, there exist situations in which the production of a second material after that of a first material in a stack on a silicon wafer necessitates the use of a temperature higher than that above which said first material is degraded unacceptably. This is the case in particular for integrating decoupling capacitors into integrated circuits. These capacitors must store a high electrical charge—the electrical charge is proportional to the capacitance and to the supply voltage, so increasing the capacitance improves the required performance (it will be remembered that the capacitance is proportional to the dielectric constant and to the electrode area and inversely proportional to the thickness of the dielectric of the capacitor).
Capacitors are conventionally produced on the same wafer as transistors. To reduce production costs, it is naturally desirable to use small capacitors. Obtaining the required capacitances using dielectric materials with a dielectric constant that is very high compared to the usual materials (SiO2, Si3N4, Ta2O5, ZrO2 or Al2O3) may then be envisaged.
There exist ferroelectric materials, belonging to the class of perovskites, which have very high dielectric constants (relative constant of several hundred units). Perovskites constitute almost all of the materials investigated for high-capacitance capacitor applications in the required range of dielectric constants (see for example the paper by T. Ayguavives et al. entitled "Physical Properties of (Ba,Sr)TiO3 Thin Films used for Integrated Capacitors in Microwave Applications", IEEE 2001). The perovskite crystalline phase is usually obtained at temperatures from 600° C. to 700° C. However, these temperatures are incompatible with the aluminum- or copper-based interconnection metal of the transistors. Although certain prior art low-temperature processes use a perovskite (see for example the paper by D. Liu et al. entitled "Integrated Thin Film Capacitor Arrays", International Conference on High Density Packaging and MCMs, 1999), they in fact relate to a phase in which the perovskite is not pure or is of mediocre structural or microstructural quality, which means that the dielectric constant is very much lower than that of the same material when annealed at a higher temperature.
The standard methods mentioned hereinabove therefore do not really exploit the advantages of perovskites, because the maximum authorized temperature decreases progressively as and when the process steps are carried out, and the main difficulty results from the fact that the placement of a "hot" process material (the dielectric) occurs after that of a "cold" process material (the interconnection metal).
There is nevertheless known in the art a method for heating the dielectric to a temperature higher than the interconnection metals can withstand. It consists in isolating the dielectric from the interconnection metal by means of a thermal protection layer and then annealing the dielectric using a pulsed laser with sufficiently brief pulses for the temperature of the metal to remain lower than the temperature of the dielectric and to remain acceptable, provided that thermal diffusion is relatively low (see for example the paper by P. P. Donohue et al. entitled "Pulse-Extended Excimer Laser Annealing of Lead Zirconate Titanate Thin Films", proceedings of the 12th International Symposium on Integrated Ferroelectrics, Aachen, Germany, March 2000, published in Integrated Ferroelectrics, vol. 31, pages 285 to 296, 2000). This method is difficult to control, however, because the protective layer remains on the wafer. The protective layer therefore cannot be very thick (it is usually less than 2 μm thick), and it may affect the electrical performance of the devices. The temperature difference between the interconnection metal and the dielectric is therefore limited; in other words, the temperature to which the dielectric may be subjected is limited. Moreover, the stack is subjected to a high thermal gradient during this operation, which can generate a surface temperature that is too high or cause non-homogeneous crystallization of the dielectric or deterioration of materials, such as microcracks, as a result of thermal expansion.
One prior art solution to this temperature problem consists in producing the passive devices incorporating the capacitors on a silicon wafer other than the substrate containing the active components and then connecting the two dies together by wires or by microballs (see for example the paper by R. Heistand et al. entitled "Advances in Passive Integration for C/RC Arrays & Networks with Novel Thin & Thick Film Materials", 36th Nordic IMAPS conference, Helsinki, 1999). These methods have certain drawbacks, however: wires cannot be used to make short connections between capacitor and transistors, and microball connections may be produced on top of a circuit only once; if the capacitors are made of this material, it is no longer possible to add other functions such as switches or surface wave filters, for example.
To avoid these problems, the production temperature is usually limited to about 450° C., which enables integration of the components in the usual metallizations, or above them, in integrated circuits based on aluminum or copper (see for example the paper by S. Jenei et al. entitled "High-Q Inductors and Capacitors on Si Substrate", IEEE 2001, or the paper by Bryan C. Hendrix et al. entitled "Low-Temperature Process for High-Density Thin-Film Integrated Capacitors", International Conference on High-Density Interconnect and Systems Packaging, 2000). Because of this temperature limit, these standard methods are greatly limited in terms of the type of material and the dielectric constants that can be achieved. The required capacitance values are therefore obtained by producing capacitors occupying a large area, which limits the integration possibilities and adds to the cost of the die because of the increased area that is occupied on the silicon wafer.
There is nevertheless known in the art a method for increasing the area of the electrodes without increasing the lateral dimensions of the die (see the paper by F. Roozeboom et al. entitled "High-Value MOS Capacitor Arrays in Ultradeep Trenches in Silicon", published in Microelectronic Engineering, vol. 53, pages 581 to 584, Elsevier Science 2000). This method consists in exploiting the depth of the substrate to integrate metal oxide semiconductor (MOS) decoupling capacitors by excavating an array of deep narrow trenches in the substrate: a dielectric layer and then an electrode layer are disposed around these trenches—the other electrode of the array of capacitors covers the surface of the substrate. However, apart from the difficulty of producing uniform dielectric layers in the trenches, the use of capacitor arrays in trenches makes planar integration of passive components with active components difficult.
More generally, a second difficulty arising from the monolithic integration of passive components or MEMS with transistors is that it is not possible to exploit the vertical dimension to improve the characteristics or the compactness of the passive components.
A third difficulty to which the monolithic integration of passive components or MEMS with transistors gives rise is that the type of substrate used for the active circuits disturbs the characteristics of the passive components.
For example, the substrates used for CMOS or BICMOS circuits have conductivities of the order of 10 Ω.cm at most. The currents induced in these substrates by the inductors or conductive lines cause high losses and thereby reduce the quality factors of these structures (high inductance, high resonant frequency, low stray capacitance).
A first prior art solution consists in eliminating a portion of the substrate under the areas that are to receive the inductors and conductive lines (see for example U.S. Pat. No. 5,539,241). A second prior art solution consists in making the substrate insulative under the areas that are to receive the inductors and conductive lines (see for example the paper by H.-S. Kim et al. entitled "A Porous-Si-based Novel Isolation Technology for Mixed-Signal Integrated Circuits", Symposium on VLSI Technology, 2000). A third solution is disclosed in U.S. Pat. No. 6,310,387—the underlying conductive layers are structured by producing a large number of small conductive areas in a checkerboard pattern that are separated from each other by an insulator and are not grounded. These areas serve as shielding because, in operation, low eddy currents are produced therein that prevent the magnetic field penetrating as far as the substrate; these areas are small enough to prevent these eddy currents inducing in the inductors a magnetic flux opposite to the required flux.
However, these various techniques are complex to use, may compromise the robustness of the integrated circuit and make the placement of active components difficult.
Finally, a difficulty raised specifically by the monolithic integration of MEMS with transistors is that it is necessary to add a cover to protect the mechanical components, without interfering with their operation. One prior art solution consists in bonding a silicon wafer of the same diameter as the wafer on which the circuits have been produced (see for example the paper by H. Tilmans et al. entitled "Zero-Level Packaging for MEMS or MST Devices: the IRS Method", mstnews 1/00). This technology is relatively costly because it is necessary to add to the cost of the supplementary substrate the cost of bonding, the cost of thinning and the cost of local etching to obtain access to the output electrical contacts on the surface of the circuit, and all of this is needed only to provide protection by means of a cover.

Integrated circuit on high performance chip


An image capturing apparatus in which the ratio between the brightness just before preliminary light emission and the brightness at preliminary light emission is calculated for each of a plurality of photometric areas. The highest ratio among the ratios in the areas is extracted as a reference value, the extracted reference value is compared with the ratio in each area, and a weighting coefficient in each area is calculated. By using the obtained weighting coefficient, the amount of light to be emitted for obtaining correct exposure is calculated.

1. Field of the Invention
The present invention relates to an image capturing apparatus, an image capturing method, and a computer program, particularly used for performing an exposure operation.
2. Description of the Related Art
Hitherto, various strobe camera systems for performing an exposure operation by adjusting the amount of light emitted to a subject in order to automatically obtain adequate exposure have been proposed. Among those systems, the following type of system is effectively used for responding to various situations of a picture frame. That is, in the system, preliminary light emission is performed prior to exposure, light reflected from a subject at the preliminary light emission is measured for each area in a picture frame, and the amount of light to be emitted at actual light emission is controlled based on the measurement result.
U.S. Pat. No. 5,309,193 discloses the following method. The light reflected from a subject at preliminary light emission is measured in each of a plurality of areas in a picture frame. Among those areas, areas where the measurement value is outside a predetermined range are eliminated from the target of calculation of the amount of light for actual light emission. Also, the amount of light to be emitted at the actual light emission is determined by adding a predetermined correcting value to the value of reflected light at the preliminary light emission.
On the other hand, U.S. Pat. No. 6,349,175 discloses the following method. That is, a weighting coefficient of each of a plurality of areas in a picture frame is determined based on the level of the reflected light at preliminary light emission, and weighting for the amount of light to be emitted at actual light emission is averaged by using the determined weighting coefficients, and the amount of light to be emitted is determined accordingly.
In these known techniques, however, when a reflective object, such as a window, faces a picture frame, the light emitted from a strobe device and reflected by a subject makes the photometric value high. Therefore, when the amount of light to be emitted from the strobe device is controlled, the amount of light may be smaller than necessary so as to cause underexposure.
In another case, if a main subject in a picture frame is too small, the light emitted from a strobe device and reflected by the subject makes the photometric value low. Therefore, when the amount of light to be emitted from the strobe device is controlled, the amount of light may be larger than necessary so as to cause overexposure.

Image capturing apparatus, image capturing method, and computer program


Compositions comprising one or more acid direct dyes and an organic solvent such as propylene carbonate are described. The compositions have an oil phase content of 5 percent by weight or less. The oil phase of the compositions can include a cyclopentasiloxane and dimethiconol. The compositions can be applied to hair that has been previously dyed with an oxidative hair dye composition to restore color to the hair. The compositions can also be applied to hair that has not been previously treated with an oxidative hair dye composition. Methods of applying these compositions to hair are also described. The methods involve applying the composition to wet hair, allowing the composition to remain on the hair, and subsequently rinsing the composition from the hair with water. The hair may be treated with a conditioner before applying the compositions to the hair.

1. Technical Field
This application relates generally to compositions for treating keratin and methods of use, and, in particular, to compositions comprising one or more acid direct dyes and to methods of applying these compositions to hair to impart color thereto.
2. Background of the Technology
It is well appreciated that individuals often wish to cosmetically alter the coloring of their hair by various known hair coloring treatments and that many individuals change their own hair color to their favorite hair color using currently available hair dye compositions. In particular, oxidative dye compositions are commonly used because such compositions simultaneously decolorize and dye hair, thus widening the degree of freedom of hair color. Thus, individuals having comparatively dark hair are able to use such products. Moreover, the products provide a greater number of color variations.
Use of oxidative dye compositions to treat hair is typically expensive and can be time consuming as well. In addition, the chemicals employed in these treatments can be caustic and somewhat damaging to the hair. Their frequent use is not preferred, and rather they are generally used at intervals of at least about one month. It is unavoidable that the color of hair dyed with oxidative dye compositions gradually fades during this one month owing to the influence of washing with shampoo, sweat, ultraviolet rays from sunshine and the like. The gradual fading of color results in a gradual reduction in the feeling of satisfaction generally felt immediately after dyeing.
Thus, individuals who have had their hair color-treated are often desirous of prolonging the effects of treatment for as long as possible and otherwise wish to keep their hair in as healthy a state as possible between visits to the colorist. One way of prolonging the freshness of a hair coloring treatment and to otherwise preserve the condition of the hair is to use hair color maintenance shampoos, conditioners, rinses, mousses, gels, sprays and the like. Examples of such hair color maintenance products include AVEDA™ shampoos and conditioners; TRICOL™ Color Plus™ products; ARTec Color Enhancing shampoos and conditioners; LOGICS™ Color Refresher™; and UTENA™ Cha Charl™. Such hair color maintenance products are typically formulated with a degree of coloring, so as to assist an individual in an attempt to prolong the duration of the coloring treatment. These products have a number of drawbacks, however. For example, such products require daily use in order to maintain hair color. Furthermore, such products are low in hair dyeing power, thus being insufficient for revitalizing fading color.
Methods for maintaining hair color are also disclosed in U.S. Pat. No. 5,643,341. In addition, a color refreshing rinse has been sold under the name ROUX® Fancifull®.
There still exists a need for improved color revitalizing products for hair that has been previously treated with an oxidative dye composition to supply color to the hair that has been lost by washing or shampooing. In addition, since untreated hair also fades when exposed to sunlight, shampooing and styling tools such as curling irons and dryers, there also exists a need for improved products which can be used on hair that has not been previously treated with an oxidative dye composition to impart color thereto.

Compositions for treating hair and methods of use


An electrical connector includes a male electrical plug, a female socket, a housing, and a control system. The male electrical plug, which is supplied with power, is electrically connected to the female socket. The housing contains the male electrical plug, the female socket, and a control system. The control system includes a temperature sensor and a transceiver with the temperature sensor sensing a temperature at a location within the housing and the transceiver transmitting a signal representative of the temperature to an alarm device remotely located from the electrical connector. The electrical connector can include one or more switches that are remotely controllable by the alarm device to interrupt the electrical connection between the male plug and the female socket.

Electrical connectors, such as electrical cords (e.g., pigtails), power strips, adapters, and in particular extension cords, are used extensively in many applications, both residential and commercial, because they provide a way to deliver electrical power from an electrical outlet to an electrical device (e.g., a device that needs power to perform a task) that is remotely positioned from the outlet. However, electricity, if not properly controlled, can result in serious danger to those who use it and to the structures in which it is used. Extensive usage of electrical connectors, such as extension cords, increases the likelihood of an electrical fault, cord degradation, cord overloading, or cord overheating, which can result in electrical fires, electrical shocks, and other hazards.
For example, the National Fire Protection Association (NFPA) reports, in a March 2019 publication, that electrical failures or malfunctions were the second leading cause of U.S. home fires in 2012-2016 accounting for 13% of residential structure fires. Further, home fires involving electrical failure or malfunction caused an estimated average of 440 civilian deaths and 1250 civilian injuries each year in 2012-2016, as well as an estimated $1.3 billion in direct property damage a year. The U.S. Fire Administration reports that during the years of 2014-2016, electrical failure or malfunction caused an estimated 8% of non-residential building fires. As such, the ability to monitor one or more parameters related to the delivery of electricity through an electrical connector may aid in reducing the dangers that delivery of electricity poses.

Wireless monitoring of electrical connector


An electronic device comprising a laminate constituted by pluralities of insulation layers on which conductor patterns are formed; ground electrodes being formed on an upper-surface-side insulation layer and a bottom-surface-side insulation layer in the laminate; the laminate being partitioned to first and second regions by a first shield constituted by a line of via-holes electrically connecting the upper-surface-side ground electrode to the bottom-surface-side ground electrode; conductor patterns constituting a first filter for a first frequency band and conductor patterns constituting a first balun for the first frequency band being arranged in the first and second regions, respectively; pluralities of terminal electrodes being formed on bottom or side surfaces of the laminate; one of terminal electrodes of the first filter, which acts as an unbalanced port, being adjacent to a terminal electrode of the first balun, which acts as an unbalanced port, with no other terminal electrode than a ground electrode existing therebetween; and the first filter and the first balun being not electrically connected.

The miniaturization of wireless communications apparatuses such as mobile phones, etc. has resulted in rapid miniaturization of electronic devices used therein. FIG. 25 shows a high-frequency circuit for wireless communications apparatuses for wireless LAN (local area network). This high-frequency circuit comprises a high-frequency switch SW connected to an antenna ANT for switching connection to a transmission circuit Tx and a receiving circuit Rx; a filter FIL2, an amplifier PA, a filter FIL1 and a balun BAL1 being connected in this order from the antenna ANT in a pass for transmission signals of a frequency f1, and a filter FIL4, a low-noise amplifier LNA, a filter FIL3 and a balun BAL2 being connected in this order from the antenna ANT in a pass for reception signals of a frequency f2. Used in the transmission circuit Tx and the receiving circuit Rx in such high-frequency circuit are semiconductor devices IC handling balanced signals highly resistant to noises. Also, because the input/output impedance of a semiconductor device IC may be different from those of other circuit devices, baluns are sometimes needed for conversion between balanced signals and unbalanced signals, and for impedance conversion.
JP 2003-018039 A discloses an RF module comprising a switch circuit disposed between a transmission circuit and a receiving circuit and an antenna for controlling connection between the transmission circuit and the antenna and connection between the receiving circuit and the antenna, and a first balanced-unbalanced circuit disposed between the switch circuit and the transmission circuit; the first balanced-unbalanced circuit being a balun transformer comprising a first transmission line, and second and third transmission lines electromagnetically coupled to the first transmission line; the first transmission line having one end connected to an unbalanced terminal, and the other end which is grounded or open; the second transmission line having one end grounded, and the other end connected to the first balanced terminal; the third transmission line having one end grounded, the other end connected to the second balanced terminal; and a balun transformer constituting the first balanced-unbalanced circuit having second and third transmission lines whose ends are connected and grounded via a capacitor. Transmission lines and capacitors constituting the filters, the balun transformer and the switch circuit are formed on dielectric layers constituting a laminate, and passive devices not contained in the laminate, and active devices such as diodes, GaAs FET, RFIC, etc. are mounted on an upper surface of the laminate.
JP 2003-258585 A discloses, as shown in FIG. 26, a laminate-type electronic device comprising a filter and a balun contained in a laminate of insulation layers 310A-310J having conductor patterns 330-390, the filter and the balun being laterally displaced to avoid overlapping, and connected between an unbalanced terminal and a pair of balanced terminals.
The production of a small electronic device having pluralities of circuit functions with a laminate suffers some problems. The first problem is that because electronic devices having various circuit functions cannot be used in common applications, high-frequency circuits for which they can be used are restricted. For example, when various circuit blocks described in JP 2003-018039 A are produced, electronic devices adapted to them are needed, making it difficult to provide commonly usable electronic devices. The costs of industrial products generally decrease as their numbers increase, but conventional electronic devices cannot be produced at low cost because they are not usable for common applications. Also, once circuit specifications are changed, electronic devices adapted to them should be redesigned from scratch.
The second problem is the deterioration of characteristics by electromagnetic interference between pluralities of circuits. In JP 2003-258585 A, conductor patterns constituting a bandpass filter and those constituting a balun are formed on insulation layers with lateral displacement, to avoid overlapping between the bandpass filter and the balun in a lamination direction. However, the size reduction of electronic devices makes a bandpass filter closer to a balun in the laminate, making it difficult to arrange them so separately as to avoid interference.

Laminate-type electronic device with filter and balun


The management computer 600 copies data in the volume 111 within the storage device 100A to the volume 115 within the storage device 100B. Upon completion of copy processing, the volume 115 is set to write protect. Then, the data in the volume 111 is read from the storage device 100A, and the data in the volume 115 is also read from the storage device 100B, to compare the two data items. Only when the data items agree with each other, setting of FC switch 400 is changed, and a target of the host computer 500 is switched from the storage device 100A to the storage device 100B.

It is related with a data migration technique, and more particularly, it relates to a data protection technique against illegal modification, in the course of data moving from a storage area in a source to a storage area in a destination.
These days, documentation by a computer, utilization of database, and widespread use of the Internet increase the amount of electronic information. Such electronic information may contain valuable information which is worth to preserve for a long term. In order to preserve this kind of valuable information in a form of electronic data for 10 or 30 years, or semi-permanently, following steps are necessary. That is, as shown in FIG. 14A, by use of computer 91, electronic data stored in storage device 92 as a source is copied to storage device 93 as a destination, before the life of the storage device 92 is expired, whereby preserving the data continues, with migrations from one storage device to another across several generations (see Kohyo (National Publication of Translated Version) No. H10-508967, hereinafter referred to as "Patent Document 1").
Furthermore, in order to preserve the valuable information in a form of electronic data without illegally modified, following measures are necessary. That is, a recording medium such as CD-R or DVD-R, which is available for write once only (Write-Once Media) may be utilized. Alternatively, as shown in FIG. 14B, computer 94 stores the electronic data in storage device 95 such as hard disk, and then, sets the storage area of the electronic data to write protect. Subsequently, the electronic data is made available for read only (For example, see Japanese Patent Laid-open Publication No. H3-3159, hereinafter referred to as "Patent Document 2").

Data migration method and a data migration apparatus

Abstract: Therefore, it is possible to detect or prevent an illegal data modification in the course of data copying from the source volume to the destination volume.


The invention concerns the use of stabilized oligonucleotides comprising at least an octamer motif of the type: 5′-purine-purine-CG-pyrimidine-pyrimidine-X1X2-3′ wherein the pair X1-X2- is AT, AA, CT or TT, for preparing a medicine with antitumor activity.

This application is a continuation-in-part of the national phase filing of U.S. Application Ser. No. 09/937,057 filed on Feb. 26, 2002 which claims priority from PCT/FR00/00676 filed on Mar. 17, 2000. Priority to each of these prior applications is expressly claimed, and the entire disclosure and claims of each of these prior applications is hereby incorporated by reference in its entirety. Priority is also claimed to FR 99/03433, filed Mar. 19, 1999.
This invention is in the field of immunostimulatory molecules that are administered to a patient to help the body's immune system respond to a disease, principally a solid, malignant tumor. Specifically, the present invention relates to compositions and methods of use of stabilized oligonucleotides with antitumor activity.
The effective treatment of cancers remains one of the major challenges of medicine today. The effectiveness of conventional surgical therapies or therapies aimed at cytolysis (chemotherapy and radiotherapy) remains very limited in many cancers. For astrocytomas for example, the treatment of which is based mainly on surgical exeresis, and local cerebral irradiation, the survival median is only 4 to 6 months after surgical exeresis and 8 to 10 months with the combination of surgery and radiotherapy. Supplementary chemotherapy prolongs survival in patients under the age of 60, but very modestly, usually by only about 3 months. Under this triple treatment, the survival median remains less than two years for histological grade III (anaplastic astrocytoma) and less than 1 year for grade IV (glioblastoma). The mortality for these two groups is near 100% (Daumas-Duport C. et al. (1988), Cancer 62(10) pp 2152–65).
Stimulation of the immune system in the treatment of cancers has been attempted through the administration of bacterial extracts (Jaeckle K. A. et al. (1990), J. Clin. Oncol. 8(8) pp 1408–18) or bacterial DNA, in particular that of Mycobacterium bovis (MY-1) (Tokunaga T. et al. (1984), JNCI72 pp 955–62). MY-1 is, however, ineffective in increasing survival in a model of glioma in mice (Nakaichi M. et al (1995), J. Vet. Med. Sci. 57(3) pp 583–5). IL-2 (Herrlinger U. et al. (1996), J. Neurooncol. 27(3) pp 193–203) and, more recently, IL-12 (Kishima H. et al. (1998), Br. J. Cancer 78(4) pp 446–53; Jean W. C. et al (1998), Neurosurgery 42(4) pp 850–6) have also been studied.
Unfortunately, previous attempts using bacterial DNA have had limited effectiveness or unacceptable toxicity and, to date, only the Mycobacterium bovis BCG has resulted in clinical applications, and then only in the limited indication of bladder cancer (Soloway M. S. et al. (1988), Urol. Clin. North Am. 15 pp 661–9).
Oligonucleotides are polymers formed by the combination of purine or pyrimidine bases and sugars, in particular ribonucleotides or deoxyribonucleotides. In the natural form, the linkages joining the individual nucleotides are phosphoesters which are sensitive to the nucleases of the human body. Thus, oligonucleotides have a very short in vivo half-life (of about one minute) when they are injected into humans, which limits their biological effects. To prolong the half-life oligonucleotides can be modified to be resistant to nucleases. Several types of stabilized oligonucleotide have thus been created, such as, phosphorothioates or methylphosphonates (Crooke R. M. (1991), Anti-Cancer Drug Design 6 pp 609–46). The most commonly used are phosphorothioate oligonucleotides.
In some applications, oligonucleotides are designed to be complementary to a known DNA sequence and are termed "anti-sense" due to the specific identity and sequence of the nucleotides relative to a native gene. Antisense application of oligonucleotide technology are very well known. Some oligodeoxynucleotides, and in particular some synthetic oligodeoxynucleotides, have biological effects per se due to the inherent nature of the sequences themselves, outside their conventional antisense properties. The injection of oligonucleotides as therapeutic compounds has been explored for many years, and the development of specific sequences and techniques continues to be an important area of research.
Some oligodeoxynucleotides, independently of any known antisense sequence, are known to stimulate, in vitro and in vivo, the proliferation of B lymphocytes and the activity of natural killer (NK) cells, and induce the secretion by the cells of cytokines such as α-IFN, β-IFN, γ-IFN, IL-6, IL-12 or TNF-α (Yamamoto S. et al (1992), J. Immunol. 148(12) pp 4072–6; Yamamoto T. et al. (1994), Microbiol. Immunol. 38(10), pp 831–6; Yi A. K. et al. (1996), J. Immunol. 157(12) pp 5394–402; Ballas Z. K. et al. (1996), J. Immunol. 157(5) pp 1840–5; Cowdery J. S. et al. (1996), J. Immunol. 156(12) pp 4570–5; Stacey K. J. et al. (1996), J. Immunol. 157(5) pp 2116–22). This set of cytokines directs toward a Th1-type immune response (Chu R. S. et al. (1997), J. Exp. Med. 186(10) pp 1623–31).
One specific group of oligonucleotides that have been the subject of extensive research are characterized by the presence of a "CpG" motif. This terminology indicates that the sequence of the oligonucleotide molecule contains the nucleotides cytosine (C) and guanine (G) with a phosphate backbone and exhibits a characteristic structure and function when administered therapeutically to a patient. The immunostimulatory properties of these oligodeoxynucleotides are in large part dependent on nonmethylated CG motifs (nonmethylated CpG dinucleotides) which are under-represented in mammalian DNA (Kuramoto E. et al. (1992), Jpn. J. Cancer Res., 83 pp 1128–31).
While the authors agree on the fact that the nonmethylated CG motif is essential to the immunostimulatory function, the identity of the other nucleotides in the complete oligonucleotide molecule are also crucial and the two nucleotides adjacent to the CG motif also dictate the immunostimulatory activity. Although numerous sequences have been studied, the data published on the function of the adjacent sequences are contradictory. It should be appreciated that small differences in the nucleotide sequence of the oligonucleotide, and any chemical modifications thereof, can yield dramatic differences in the therapeutic utility in vivo. Also, special injection techniques, formulations, and other therapeutic approaches can be used in combination with the specific sequence of the oligonucleotide to yield important differences in overall therapeutic utility.
Specifically, Krieg A. M. et al. ((1996), Antisense Nucleic Acid Drug Dev. 6(2) pp 133–9) describe a hexameric motif of the type 5′ pur-pur-C-G-pyrimidine-pyrimidine 3′, whereas application EP 468 520 claims a palindromic hexameric motif. International application WO 9855495 shows that not all the hexamers as defined by Krieg et al. 1996 are immunostimulatory, and that octamers, of sequence 5′-purine purine CG pyrimidine pyrimidine CC-3′ (pur-pur-CG-pyr-pyr-CC) or of sequence 5′-purine purine CG pyrimidine pyrimidine CG-3′ (pur-pur-CG-pyr-pyr-CG) should be defined to provide immunostimulatory activity.
Other immunostimulatory oligodeoxynucleotides, some which are and some which are not defined as oligonucleotides having a nonmethylated CG motif, have been described in application EP 855 184 and certain binding sequences for eukaryotic transcription factors such as NFκB or the AP-1 family.
Also, the use of immunostimulatory properties of oligodeoxynucleotides with nonmethylated CG-type motif has been applied to several medical fields:
(1) in the field of vaccination, in combination with the antigen, as an adjuvant for stimulating specifically a Th1-type immune response (Davis H. L. et al. (1998), The Journal of Immunology 160(2) pp 870–6, European Patent Application EP 855 184, PCT Application WO 98/18810, University of Iowa Research Foundation, and PCT Application WO 98/55495);
(2) in the field of allergy, for modulating the immune response (International Applications WO 98/18810 and WO 98/55495); and
(3) in the domain of cancer,                either in combination with a tumor antigen, as an adjuvant of an antitumor vaccine (application EP 855 184; Weiner G. J. et al. (1996), Proc. Natl. Acad. Sci. 94, pp 10833–7; Wooldridge J. E. et al. (1997) Blood 89(8) pp 2994–8),        or alone as antitumor agents (Connell et al. (1999), Proceedings of the American association for Cancer Research 40 pp 299; application EP 468 520; Carpentier A. F. et al. (1999), Cancer Research 59, pp 5429–5432.
In the latter case, the antitumor activity of only a few sequences, among those described, has been effectively demonstrated:                Weiner G. J. et al. and Wooldridge J. E. et al. (already cited) who use an oligonucleotide comprising a nonmethylated CG motif of sequence SEQ ID NO: 49 5′-TCTCCCAGCGTGCGCCAT-3′, show that this oligonucleotide has no antitumor effect when it is used alone;        Carpentier et al., Tokunaga et al. and Connell et al. (mentioned above), who use a phosphorothiate oligonucleotide of the octameric type (SEQ ID NO: 2 5 ′TGACTGTGAACGTTCGAGATGA3′), a nonstabilized palindromic hexameric oligonucleotide (SEQ ID NO: 50 5′ ACCGATGACGTCGCCGGTGACGGCACCACGACGACGGCCA CGTGCT 3′) and a hexameric phosphorothioate oligonucleotide of the type 5′ purine purine CG pyrimidine pyrimidine 3′, respectively, show antitumor activity.
Other than the nonmethylated CG motif, the exact nature of the active sequences of these immunostimulatory oligodeoxynucleotides, for producing antitumor activity, is not clearly defined; in particular, the data published on the nature of the sequences adjacent to the nonmethylated CG motif (2 bases in the 5′ direction and 2 bases in the 3′ direction (hexameric motifs) or 4 bases in the 3′ direction (octameric motif)) are contradictory as are the teachings of the significance of the identity of these sequences.
Recent studies reported by Hartmann G. et al. ((2000), The Journal of Immunology 164 pp 1617–24) explain the difficulty in defining the sequence of such oligonucleotides. These data indicate that not all immunostimulatory oligodeoxynucleotides are equivalent and effective for all the contemplated field defined above and that the stimulation of different compartments of the immune system to obtain the desired activity: adjuvant, antiallergic or antitumor activity highly depends on the specific nature and composition of the oligonucleotide sequence.
In addition, the immune mechanisms of tumor rejection are poorly understood and the data for stimulation of the compartments of the immune system, in vitro, as defined above do not make it possible to predict in advance the antitumor effectiveness of a given oligonucleotide, and it is therefore important to test their antitumor activity in vivo.
Furthermore, the toxicity of oligodeoxynucleotides containing a CG-type motif has been reported when used systemically (both intravenous IV) and (intraperitoneal IP) and also must be taken into account for therapeutic applications (See EP 855 184). Consequently, the immunostimulatory oligonucleotides comprising a CG motif of the prior art have varying and random antitumor activities and may be toxic. For this reason, a set of effective, non-toxic immunostimulatory sequences for antitumor use has not been defined.

Use of stabilized oligonucleotides for preparing a medicament with antitumor activity

Institut National de la Sante et de la Recherche Medicale


A plastics container of modular construction includes a first plastics segment and a second plastics segment. The first and second plastics segments are connected to one another by plastics welding. At least one of the first and second plastics segments has a paintable surface layer on an outer side thereof or is comprised of a paintable material.

The invention relates to a plastics container of modular construction, in particular a plastics container for a motor vehicle.
It is common for containers for motor vehicles which have at least one surface which is visible to the outside to be painted at least in the visible region. Such a container may for example be a fuel tank for a motorcycle.
To achieve a high-quality appearance, such containers are manufactured from a readily paintable material, for example from a metal. Such containers are however expensive and have a high weight.
It is therefore an object of the present invention to provide a container for a motor vehicle which has a low weight, can be produced inexpensively and at the same time has a readily paintable surface.
The object is achieved according to the invention by means of a plastics container of modular construction, comprising at least two plastics segments which are connected to one another by means of plastics welding, wherein at least one of the plastics segments has a paintable surface layer on its outer side or is composed of a paintable material.
Such a container has the advantage that, through the use of plastics segments, it is possible to achieve a low overall weight, and the overall production costs are low. It is possible for only those plastics segments which are situated in a visible region to be provided with a paintable surface layer or manufactured from a paintable material. Thus, a high-quality visual appearance is provided for a customer. In particular, it is possible to utilize specific advantages of the surface layer.
As a result of the division of the plastics container into individual plastics segments, it is furthermore possible to easily paint individual regions of the plastics container. For example, the individual plastics segments can be painted prior to the welding process. In this way, a masking of individual regions during the painting process can be omitted.
It is particularly advantageous if the plastics segments are formed such that, in an installed state of the plastics container, at least one plastics segment is situated virtually entirely in a visible region, whereas at least one further plastics segment is completely concealed. In this way, it is possible to provide the visible regions with a particularly high-quality surface, whereas the plastics segments in the concealed region remain free from paint or a surface layer and can thus be particularly inexpensive.
In one embodiment, the paintable surface layer may be a metal plate or a metal foil. Paints generally adhere particularly well to metallic materials. It is furthermore possible for metal plates to be provided with an individual design. For example, the metal plate may be provided with an individual engraving or paintwork. A customer can engrave their name or have a family crest or company logo painted onto the metal plate. Such individualization can be performed very easily by retroactive installation of the metal plate at a dealership. Furthermore, by means of a metal plate, the stability of a plastics segment can be improved. It is thus possible to combine the economic advantages of plastic with the visual and structural advantages of metal.
The metal plate preferably has a small wall thickness. This is possible because the metal faceplate itself does not have to perform any container function. For the same reason, during the production of the metal faceplate, a high degree of stretching can be realized in order to implement high-quality design forms.
For example, the paintable surface layer is composed of aluminum or titanium. These materials are perceived as being of particularly high quality and can also at least partially remain free from paintwork. In a particularly inexpensive embodiment, the paintable surface layer may be formed from sheet steel.
In a further embodiment, the paintable surface layer may have plastic or be composed of plastic. For example, the paintable surface layer is a plastics molded part or a plastics film. The plastics segment may in this case be composed of a main body and of a surface layer, wherein the main body has a first plastics component and the surface layer has a second plastics component which differs in terms of its composition from the first plastics component. A container with a surface layer composed of plastic can have a particularly low weight in relation to a container with metallic components. The paintable surface layer is preferably back-molded with plastic. Since stiffening means can be easily integrated into plastics molded parts, it is thus possible to realize a particularly high degree of stability of the individual plastics segments and consequently a high degree of stability of the container as a whole. During the back-molding process, the plastic can be connected directly to the surface layer without the need for additional connecting elements. In particular, the back-molded plastic can adhere to the surface layer.
In a further variant, the surface layer may be installed on a plastics segment with the aid of at least one connecting means. For example, the surface layer may be screwed, riveted or adhesively bonded to a plastics element. In this way, the connection of the surface layer to the plastics segment is particularly reliable. The use of a releasable connecting means, for example a screw, has the additional advantage that, in the event of damage to the surface layer, this can be easily and inexpensively exchanged.
In order to be able to install the surface layer on a plastics element particularly easily, the surface layer may have at least one installation element. For example, the installation element comprises a hook. The installation element may serve for the suspension or detent engagement of the surface layer on a plastics segment. The installation element serves in particular for pre-installing the surface layer, for example by virtue of the surface layer being suspended on a plastics segment by means of the installation element before the surface layer is fixedly connected to the plastics segment with the aid of a connecting means. By means of the at least one installation element, it is consequently possible for the installation of the surface layer to be simplified, and for the number of required connecting means to be reduced.
Each of the plastics segments may have at least one at least partially encircling welding flange. The welding flanges serve for the connection of the plastics segments by means of plastics welding.
The plastics container may have at least three plastics segments, wherein at least one plastics segment is formed as a central part which is open on two sides, and at least two further plastics segments are formed as covers which are open on one side, and the covers are arranged at both sides on the central part. This has the advantage that even complex geometries of the plastics container can be implemented without the need for complex tools.
The plastics container may for example be a fuel tank, in particular for a motorcycle. In motorcycles, the tank is commonly arranged in a region between a handlebar and a seat surface and has an outwardly visible painted surface. By means of the invention, the advantages of plastic can be combined with the visual characteristics of metallic or other materials.
The plastics container is preferably covered at least in certain regions by means of a faceplate. The faceplate may have a protective function. For example, the faceplate is manufactured from metal and is likewise painted. In the case of a fuel tank, for example a fuel tank for a motorcycle, the faceplate may protect the tank against damage in the event of an impact against the ground. In particular, there is the risk of the plastics container being damaged by stones or other sharp objects. Through the use of a faceplate, it is possible for the plastics container to have only a small wall thickness and to nevertheless be protected against damage. Furthermore, in the case of maintenance, the repair costs can be kept low, because only the faceplate and not the entire plastics container has to be exchanged.
Further features and advantages of the invention will emerge from the following description and from the following drawings, to which reference is made.

Bayerische Motoren Werke Aktiengesellschaft


An air passage that connects an inlet port that sucks air from a dehumidification target space and an outlet port that supplies air to the dehumidification target space; a heating device that heats the air; a first moisture adsorption/desorption device releasing moisture into air that has a relatively low humidity and absorbing moisture from air that has a relatively high humidity; a second moisture adsorption/desorption device disposed so as to be spaced apart from the first moisture adsorption/desorption device, a cooling device cooling air that has been humidified; and switching devices switching between an air path passing air through the first moisture adsorption/desorption device, the cooling device, and the second moisture adsorption/desorption device in this order, and an air path in which the air passes through the second moisture adsorption/desorption device, the cooling device, and the first moisture adsorption/desorption device in this order.

In the related art, a dehumidifying system has been proposed in which a rotating desiccant rotor supported by an adsorbent that carries out adsorption and desorption of moisture is used, and in which a heat exchanger of a heat pump is used as a regenerative heat source of a desorption portion of this desiccant rotor. This dehumidifying system is configured to carry out a continuous dehumidifying operation by disposing a desiccant rotor in an air passage through which air of a dehumidification target space circulates and by making the desiccant rotor rotate, and, further, by passing air through heating means serving as a regenerative heat source, the desorption portion of the desiccant rotor, cooling means, and an absorption portion of the desiccant rotor in this order (see Patent Literature 1, for example).


A trolley wire wear measuring device includes a processor configured to obtain a pair of line sensor images in which luminance signals of scanning lines are arranged; a differential processor configured to perform a differential process to create a line sensor image; a binary operation processor configured to perform a binary operation process on the line sensor image obtained by the differential process to create a binary operated image in which a worn portion of the trolley wire is emphasized; an edge detector configured to detect edges of both sides of the worn portion in the binary operated image; and a worn portion width calculator configured to calculate a point-to-point distance of the both side edges as a whole width of the worn portion of the trolley wire in the binary operated image and determine a worn portion width of the trolley wire using this whole width.

On the trolley wire that supplies a power to a car of an electric railroad or railway, contact with a pantograph current collector (a pantograph) occurs each time the car passes. Because of this, the trolley wire is gradually worn out during an operation of the electric railway car, and if a replacement is not made, a rupture or breaking finally occurs and causes an accident. A wear limit is then set for the trolley wire. By using the wear limit as an index of a change of the trolley wire, the trolley wire is changed and safety of the electric railway car is secured.
As a method of measuring the wear of the trolley wire, there are mainly two methods; one is a method that directly measures a thickness of the trolley wire, the other is a method that measures a width of a trolley wire worn portion and transforms this wear width into the thickness of the trolley wire.
As one method that directly measures the thickness of the trolley wire, there is a method that measures the thickness of the trolley wire using a ruler such as a vernier caliper. This is a method that measures the thickness of the trolley wire of a portion which an operator intends to measure, using the ruler such as the vernier caliper by hand. With this method, the thickness of the trolley wire to be measured can be surely determined. On the other hand, this measurement requires manpower and cannot be automated, thus it is difficult to measure the thickness of a long distance section.
As the other method that directly measures the thickness of the trolley wire, there is a method using an optical sensor. This is a method, in which a rotation roller is pressed against the trolley wire, and by a laser radiation device and a light receiving device which are installed so that the trolley wire is sandwiched on a roller mount, an amount of received light at a sandwiched portion of the trolley wire by the devices is measured, then the thickness of the trolley wire is transformed from the amount of the received light. With this method, it is possible to continuously measure the thickness of the trolley wire. However, because of contact with the trolley wire, a low speed operation is required. Furthermore, since a measurement structure in which the trolley wire is sandwiched between sensors is employed, usage in a place where a structure that is apt to collide with sensors such as a point, an air section and an anchor, exists, is impossible. Moreover, in such place where those existing structures exist, there is a need to move the devices apart from a measurement point so as not to collide.
As the method that measures the width of the trolley wire worn portion, there is a method that measures the trolley wire worn portion by applying sodium lamp or laser light (refer to a Patent Document 1). This is a method that uses the following relation; a lower portion of the trolley wire has a round gourd shape in cross section, and, as the trolley wire is shaved by the wear and becomes flatter, the width of the shaved portion becomes wider. Then, the thickness of the shaved portion of the trolley wire is transformed from the wear width.
As the width-measuring method of the trolley wire worn portion, positions of a light source and a line sensor of a light receiving part are precisely adjusted so that a reflected light from the trolley wire worn portion is received with regular reflection when applying the sodium lamp or laser light from the light source, and the trolley wire worn portion is changed into a whiteout state by way of imaging and capturing an intense light by the regular reflection, then the width of the trolley wire worn portion is measured from a width of the whiteout portion which receives the intense light.
This manner is a non-contact manner, thus a high speed operation is possible. However, this manner is susceptible to noises such as a clamp that pinches the trolley wire and a structure which appears on the background. Further, in a case where a wrong measurement result is obtained due to some noises, there is no way to verify the result. Then, with regard to the portion of the problem as the trolley wire wear measurement, it is verified using the method directly measuring the thickness of the trolley wire in the end. In addition, it is required that the regular reflection is received by precisely adjusting an application direction and a focus of the light source and a light-receiving direction of the light receiving device.
Patent Document 1: Japanese Patent Application Kokai Publication No. 10-194015

Trolley wire wear measuring device using binary operated images


The present invention relates to benzofuran derivatives having general Formula (I)

The present invention relates to novel benzofuran derivatives potently binding to the 5-HT1A receptor, pharmaceutical compositions containing these compounds and the use thereof for the treatment of certain psychiatric and neurological disorders. Many of the compounds of the invention are also potent serotonin reuptake inhibitors and are considered to be particularly useful for the treatment of depression.
Clinical studies of known 5-HT1A partial agonists such as e.g. buspirone, ipsapirone and gepirone have shown that 5-HT1A partial agonists are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Preclinical studies indicate that full agonists also are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharm., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of a beneficial effect of 5-HT1A partial agonists in the treatment of depression as well as impulse control disorders and alcohol abuse (van Hest, Psychopharm., 1992, 107, 474; Schipper et al, Human Psychopharm., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11; Grof et al., Int. Clin. Psychopharmacol. 1993, 8, 167-172; Ansseau et al., Human Psychopharmacol. 1993, 8, 279-283).
5-HT1A agonists and partial agonists inhibit isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchxc3xa9z et al, Psychopharmacology, 1993, 110, 53-59).
Furthermore, 5-HT1A agonists have been reported to show activity in animal models predictive for antipsychotic effects (Wadenberg and Ahlenius, J. Neural. Transm., 1991, 83,43; Ahlenius, Pharmacol. and Toxicol., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med Chem., 1989, 32, 1052) and may therefore be useful in the treatment of psychotic disorders such as schizophrenia. Recent studies also indicate that 5-HT1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609) suggesting that 5-HT1A agonists are useful in the treatment of the side effects induced by conventional antipsychotic agents such as e.g. haloperidol.
5-HT1A agonists have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn , Eur. J. Pharm. 1991, 203, 213).
Pharmacological studies have been presented which indicate that 5-HT1A antagonists are useful in the treatment of senile dementia (Bowen et al., Trends Neur. Sci. 1992, 15, 84).
An overview of 5-HT1A antagonists and proposed potential therapeutic targets for these antagonists based upon preclinical and clinical data are presented by Schechter et al., Serotonin, 1997, Vol.2, Issue 7. It is stated that 5-HT1A antagonists may be useful in the treatment of schizophrenia, dementia associated with Alzheimer""s disease, and in combination with SSRI antidepressants also to be useful in the treatment of depression.
Both in animal models and in clinical trials it has been shown that 5-HT1A agonists exert antihypertensive effects via a central mechanism (Saxena and Villalxc3x3n, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851). 5-HT1A ligands may, therefore, be beneficial in the treatment of cardiovascular disorders.
5-HT reuptake inhibitors are well known antidepressant drugs and useful for the treatment of panic disorders and social phobia
The effect of combined administration of a compound that inhibits serotonin reuptake and a 5HT1A receptor antagonist has been evaluated in several studies (Innis, R. B. et al., Eur. J. Pharmacol., 1987, 143, p 195-204 and Gartside, S. E., Br. J. Pharmacol. 1995, 115, p 1064-1070, Blier, P. et al, Trends Pharmacol. Sci. 1994, 15, 220). In these studies it was found that 5-HT1A receptor antagonists would abolish the initial brake on 5-HT neurotransmission induced by the serotonin reuptake inhibitors and thus produce an immediate boost of 5-HT transmission and a more rapid onset of therapeutic action.
Several patent applications have been filed which cover the use of a combination of a 5-HT1A antagonist and a serotonin reuptake inhibitor for the treatment of depression (see EP-A2-687 472 and EP-A-714 663).
Accordingly, agents acting on the 5-HT1A receptor, both agonists and antagonists, are believed to be of potential use in the therapy of psychiatric and neurological disorders and thus being highly desired. Furthermore, antagonists at the same time having potent serotonin reuptake inhibition activity may be useful for the treatment of depression.
It has now been found that compounds of a certain class of benzofuran derivatives bind to the 5-HT1A receptor with high affinities. Furthermore, it has been found that many of these compounds have potent serotonin reuptake inhibition activity.
Accordingly, the present invention relates to novel compounds of the general Formula I:
wherein
R1 is hydrogen, halogen, trifluoromethyl, trifluoromethylsulfonyloxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl, C1-6 alkoxy, hydroxy, formyl, acyl, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino, C1-6 alkoxycarbonylamino, aminocarbonylamino, C1-6 alkylaminocarbonylamino, C2-12 dialkylaminocarbonylamino, nitro, cyano, COOH, or COOxe2x80x94C1-6 alkyl;
R2 and R3 are each independently selected from hydrogen, tifluoromethyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-8 cycloalkyl and C1-6 alkoxy;
n is 1, 2, 3, 4 or 5;
m is 0 or 1;
A is selected from the following groups:
wherein
Z is O or S;
s is 0 or 1;
q is 0 or 1;
R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C2-6alkynyl, C1-6alkyl-Aryl, or C1-6-alkyl-O-Aryl,
D is a spacer group selected from branched or straight chain C1-6-alkylene, C2-6-alkenylene and C2-6-alkynylene;
B is a group selected from a group of formula (II), (III), and (IV)
wherein R5, R6, R7, R8, R9 and R10 are each independently selected among the R1 substituents;
or R8 and R9 together form a fused 5- or 6-membered ring optionally containing further heteroatoms;
or two of the groups of R5, R6 and R7 are linked together thereby forming a xe2x80x94oxe2x80x94(CH2)pxe2x80x94oxe2x80x94-bridge wherein p is 1 or 2;
Ar and Aryl are independently selected from the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-pyrimidyl, 1-indolyl, 2-indolyl, 3-indolyl, indol-2-on-1-yl, indol-2-on-3-yl, 2- or 3-benzofuranyl, 2- or 3-benzothiophenyl, 1-naphthyl or 2-naphthyl, each optionally substituted with halogen, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, hydroxy, C1-6 alkylsulfonyl, cyano, trifluoromethyl, trifluoromethylsulfonyloxy, C3-8 cycloalkyl, C3-8cycloalkyl-C1-6 alkyl, nitro, amino, C1-6 alkylamino, C2-12 dialkylamino, acylamino or alkylenedioxy;
its enantiomers, and pharmaceutically acceptable acid addition salt thereof.
In one embodiment of the invention A is a group of formula (1) and the other substituents are as defined above.
In another embodiment of the invention A is a group of formula (2) and the other substituents are as defined above.
In a third embodiment of the invention A is a group of formula (3) and the other substituents are as defined above.
In a fourth embodiment of the invention A is a group of formula (4) and the other substituents are as defined above.
Thus in a preferred embodiment of the invention A is a group of formula (1) and R4 is methyl, ethyl, propyl, prop-2-en-1-yl, 2-furylmethyl, or 2-phenoxyethyl; q=0; or A is a group of formula (1) and Z is O and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (II), preferably a alkoxysubstituted phenyl, a benzodioxan group or a 1,2-methylenedioxybenzene group and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (III), preferably a 3-indolyl group and the other substituents are as defined above.
In a further embodiment of the invention, B is a group of formula (HI), preferably a 3-indolyl group and the substituents R8 and R9 are preferably selected from hydrogen, methyl, fluoro, chloro, bromo, iodo, t-butyl or i-propyl in the 5-position; or fluoro, chloro or carboxy in the 7-position; or by 5,7-difluoro, 4-fluoro-7-methyl or 4-chloro-7-methyl; or the two substituents together form a pyridyl ring fused to the 3-indolyl.
In a further embodiment of the invention, B is a group of formula (IV) and the other substituents are as defined above.
Ar is preferably phenyl or phenyl substituted with halogen or CF3, most preferably substituted with F or Cl in the 4-position or Cl or CF3 in the 3-position.
R1 is preferably H, CN or F in the 5-position of the isobenzofuran group.
R2 and R3 are preferably selected from hydrogen or methyl.
n is preferably 2, 3 or 4.
m is preferably 0.
In a preferred embodiment of the invention n=2, 3 or 4; R2 and R3 are both hydrogen; R1 is H, CN or F in the 5-position of the isobenzofuran group; and Ar is phenyl which may be substituted with F or Cl in the 4-position or with Cl or CF3 in the 3-position and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (1); q=0; R4 is methyl; D is propylene; m=0; and B is a 1,4-benzodioxan group of Formula (II) attached in the 5-position and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (1); R4 is CH3 or prop-2-en-1-yl; n=3; D is ethylene or propylene; and B is a phenyl group wherein at least one substituent is OMe and the other substituents are as defined above.
In a further embodiment of the invention, A is a group of formula (1); q is 0; R4 is methyl, ethyl, propyl, 2-propen-1-yl, 2-furylmethyl or 2-phenoxyethyl; D is ethylene, propylene or butylene; m=0; and B is a 3-indolyl group of Formula (III) and the other substituents are as defined above.
In another preferred embodiment of the invention, A is a group of formula (2) or (3); n=3; m=0; and B is an 4- or 5-indolyl-group of Formula (IV) wherein R10 is hydrogen; R1 is CN in the 5-position of the isobenzofuran and Ar is 4-Fluorophenyl and the other substituents are as defined above.
The invention also relates to a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier or diluent.
In a further embodiment, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of a disorder or disease responsive to the effect of 5-HT1A receptors.
In particular, the invention relates to the use of a compound according to the invention or a pharmaceutically acceptable acid addition salt thereof for the preparation of a medicament for the treatment of depression, psychosis, anxiety disorders, panic disorder, obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischaemia, senile dementia, cardiovascular disorders or social phobia.
In still another embodiment, the present invention relates to a method for the treatment of a disorder or disease of living animal body, including a human, which is responsive to the effect of 5-HT1A receptors comprising administering to such a living animal body, including a human, a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable acid addition salt thereof.
The compounds of the invention have high affinity for the 5-HT1A receptor. Accordingly, the compounds of the invention are considered useful for the treatment of depression, psychosis, anxiety disorders, such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder, impulse control disorder, alcohol abuse, aggression, ischaemia, senile dementia, cardiovascular disorders and social phobia.
Due to their combined antagonism of 5-HT1A receptors and serotonin reuptake inhibiting effect, many of the compounds of the invention are considered particularly useful as fast onset of action medicaments for the treatment of depression. The compounds may also be useful for the treatment of depression in patients who are resistant to treatment with currently available antidepressants.
Some of the compounds of general Formula I may exist as optical isomers thereof and such optical isomers are also embraced by the invention.
The term C1-6 alkyl refers to a branched or unbranched alkyl group having from one to six carbon atoms inclusive, such as methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
Similarly, C2-6 alkenyl and C2-6 alkynyl, respectively, designate such groups having from two to six carbon atoms, inclusive.
Halogen means fluoro, chloro, bromo, or iodo.
The term C3-8 cycloalkyl designates a monocyclic or bicyclic carbocycle having three to eight C-atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The terms C1-6 alkoxy, C1-6 alkylthio, C1-6 alkylsulfonyl, designate such groups in which the alkyl group is C1-6 alkyl as defined above.
Acyl means xe2x80x94CO-alkyl wherein the alkyl group is C1-6 alkyl as defined above.
C1-6 alkylamino means xe2x80x94NH-alkyl, and C2-12 dialkylamino means xe2x80x94N-(alkyl)2 where the alkyl group is C1-6 alkyl as defined above.
Acylamino means xe2x80x94NH-acyl wherein acyl is as defined above.
C1-6 alkoxycarbonylamino means alkyl-Oxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
C1-6 alkylaminocarbonylamino means alkyl-NHxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
C2-12 dialkylaminocarbonylamino means (alkyl)2xe2x80x94Nxe2x80x94COxe2x80x94NHxe2x80x94 wherein the alkyl group is C1-6 alkyl as defined above.
Exemplary of organic acid addition salts according to the invention are those with maleic, fumaric, benzoic, ascorbic, succinic, oxalic, bis-methylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, and theophylline acetic acids, as well as the 8-halotheophyllines, for example 8-bromotheophylline. Exemplary of inorganic acid addition salts according to the invention are those with hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts of the invention are preferably pharmaceutically acceptable salts formed with non-toxic acids.
Furthermore, the compounds of this invention may exist in unsolvated as well as in solvated forms with pharmaceutically acceptable solvents such as water, ethanol and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of this invention.
Some of the compounds of the present invention contain chiral centres and such compounds exist in the form of isomers (e.g. enantiomers). The invention includes all such isomers and any mixtures thereof including racemic mixtures.
Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optically active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or l- (tartrates, mandelates, or camphorsulphonate) salts for example. The compounds of the present invention may also be resolved by the formation of diastereomeric derivatives.
Additional methods for the resolution of optical isomers, known to those skilled in the art, may be used. Such methods include those discussed by J. Jaques, A. Collet, and S. Wilen in xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, New York (1981).
Optically active compounds can also be prepared from optically active starting materials.
The compounds of the invention can be prepared by one of the following methods comprising:
a) alkylating an amine of formula
wherein R1, R2, R3, R4, n and Ar are as defined above with an alkylating agent of formula Gxe2x80x94(D)5xe2x80x94(Z)qxe2x80x94(CH2)mxe2x80x94B wherein D, Z, m, s, q and B are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
b) alkylating an amine of formula Hxe2x80x94Axe2x80x94(CH2)mxe2x80x94B wherein A, m and B are as defined above with an alkylating agent of formula
wherein R1, R2, R3, n and Ar are as defined above and G is a suitable leaving group such as halogen, mesylate, or tosylate;
c) reductive alkylation of an amine of formula
wherein R1, R2, R3, R4, n and Ar are as defined above with an aldehyde of formula
wherein Z, m, q and B are as defined above and t is 1-5;
d) reducing an amide of formula
wherein R1, R2, R3, R4, n, q, Ar, Z, m and B are as defined above and t is 1-5;
e) releasing final product by the means of Hofmann elimination from a resin of formula
wherein R1, R2, R3, R4, n, s, q, Ar, D, Z, m and B are as defined above, G is as defined above; and HORxe2x80x2 is a hydroxy substituted resin such as cross linked hydroxymethylpolystyrene or Wang resin.
f) reacting a compound of the formula
wherein R1, R2, R3, R4, Ar, D and N are as defined above; (OH)2Q is a diol such as substituted ethylene glycol or propylene glycol, or a polymer bound diol, with a hydrazine of formula
wherein R8 and R9 is as defined above, using Lewis acids as catalyst.
The alkylations according to Methods a and b are generally performed by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as acetone, methyl isobutyl ketone, tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone in the presence of a base such as triethylamine or potassium carbonate. Amines of formula V are prepared by means of demethylation according to the method described by Bigler et al, Eur. J. Med. Chem. Chim. Ther, 1977, 12, 289-295, or by the methods outlined in examples 14 and 15. The starting materials used in example 14 were prepared as described in example 9 or from readily available compounds by standard methods. The enantiomers of 1-[3-(dimethylamino)propyl]-1-(4-fluorophenyl)-1,3-dihydroisobenzofuran-5-carbonitrile used as starting material for the demethylation are prepared as described in EP patent No. 347066. The alkylating agents of formula Gxe2x80x94(D)sxe2x80x94(Zqxe2x80x94(CH2)mxe2x80x94B are commercially available, prepared by methods obvious to the chemist skilled in the art or prepared as exemplified in Examples 5-8. Ethyl 1,4-benzodioxan-5-carboxylate used as starting material in Example 5 is prepared by methods obvious to the chemist skilled in the art from the corresponding carboxylic acid prepared according to literature (Fuson et al., J. Org. Chem., 1948, 13, 489). Alkylating agents of formula VI are prepared from the corresponding dimethylamine (Formula VI: G=N(Me)2) as exemplified in example 9. The secondary amines of formula Hxe2x80x94Axe2x80x94(CH2)mxe2x80x94B are commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. 1-(2-methoxyphenyl)piperazine is prepared according to Pollard et al., J. Org. Chem., 1958, 23, 1333. [2-(2-Methoxyphenoxy)ethyl]methylamine and [2-(3-methoxyphenoxy)ethyl]-methylamine are prepared as exemplified in Examples 7 and 10 using commercially available 2-methoxyphenoxyacetic acid and 3-methoxyphenoxyacetic acid, respectively, as starting materials.
The reductive alkylations according to method c and d are performed according to standard literature methods using NaCNBH3, NaBH4 or NaBH(OAc)3 as reducing agent in a suitable solvent.
The reductions according to Methods e and f are generally performed by use of LiAlH4, AlH3 or diborane in an inert solvent such as tetrahydrofuran, dioxane, or diethyl ether at room temperature or at a slightly elevated temperature.
The release of final products by means of Hofmann elimination in Method g is generally performed by the use of an organic base such as triethylamine or diisopropylethylamine in an aprotic organic solvent such as dichloromethane, toluene or N,N-dimethylformamide. The polymer of formula XII is prepared in a synthesis sequence as exemplified in Example 4 and described in the following. The starting acryl ester resin (CH2CHC(O)ORxe2x80x2) is prepared according to literature procedures (Brown et al., J. Am. Chem. Soc., 1997, 119, 3288-95) by acylation of commercially available hydroxy substituted resins such as cross linked hydroxymethylpolystyrene or Wang resin with acryloyl chloride. Secondary amines of formula H2Nxe2x80x94Dxe2x80x94Zxe2x80x94(CH2)mxe2x80x94B are introduced by Michael addition in an organic solvent such as N,N-dimethylformamide at ambient temperature. The secondary amines used are either commercially available, prepared by methods obvious to the chemist skilled in the art or prepared according to literature procedures. 3-(2-Methoxyphenyl)propylamine is prepared according to Leeson et al., J. Med. Chem. 1988, 31, 37-54, 3-(3-methoxyphenyl)propylamine according to Meise et al. Liebigs Ann. Chem., 1987, 639-42, 3-(2-methoxyphenoxy)propylamine according to Augsein et al., J. Med. Chem., 1965, 8, 356-67, 3-(3-methoxyphenoxy)propylamine according to Brenner et al., Aust. J. Chem. 1984, 37, 129-41, 2-benzyloxyethylamine according to Harder et al. Chem. Ber. 1964, 97, 510-19, 2-(1H-indolyl-3-yl)ethylamine according to Nenitzescu et al., Chem. Ber., 1958, 91, 1141-45 and 3-(1H-indolyl-3-yl)propylamine according to Jackson et al., J. Am. Chem. Soc., 1930, 52, 5029. The second diversifying group is introduced by means of alkylation with an agent of formula VI by boiling the reactants under reflux or by heating them at a fixed temperature in a suitable solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone in the presence of a soluble base such as diisopropylethylamine or triethylamine, or by means of reductive alkylation with an aldehyde of formula IX using standard solid phase synthesis literature methods using NaCNBH3, NaBH4 or NaBH(OAc)3 as reducing agent in a suitable solvent. The third diversifying group was introduced by means of quarternisation using an alkylating agent of formula R4-G in an organic solvent such as tetrahydrofuran, dioxane, ethanol, 2-propanol, ethyl acetate, N,N-dimethylformamide, dimethyl sulfoxide or 1-methyl-2-pyrrolidinone at ambient temperature giving resins of formula XII.
The indole formation according to method h is performed by the reaction of acetals of formula XIII with aryl hydrazines of formula XIV resulting in the corresponding hydrazones, which subsequently are converted into indoles by means of the Fischer indole synthesis. The synthesis sequence is preferably performed as a one-pot procedure using a Lewis acid catalysts, preferably zinc chloride or boron fluoride, or protic acids, preferably sulfuric acid or phosphoric acid, in a suitable solvent such as acetic acid or ethanol at an elevated temperature. Acetals of formula XIII are prepared by alkylation of secondary amines of formula V with acetals of formula XV
using the conditions described above for methods a and b. Alternatively, the acetals of formula XIII are prepared by alkylation of acetals of formula XVI
with an alkylating agent of formula VI using the conditions described above for methods a and b. The acetals of formula XVI are prepared by reaction of acetals of formula XV with primary amines of formula NH2R4 using standard conditions.
Polymer bound acetals of formula XV is prepared by reaction of aldehydes of formula Gxe2x80x94Bxe2x80x94CH2CHO with commercially available 2,2-dimethyl-1,3dioxolan4-yl-methoxymethyl polystyrene in a suitable solvent such as toluene, using p-toluenesulfonic acid as catalyst at elevated temperature. 4-Chlorobutanal, 5-chloropentanal, and 6-chlorohexanal were prepared in analogy to the method described by Normant et al., Tetrahedron 1994, 50 (40), 11665.

Benzofuran derivatives, their preparation and use

Abstract: wherein A is selected from (1), (2), (3), (4)

Abstract: wherein

Abstract: Z is O or S; s is 0 or 1; q is 0 or 1; R4 is hydrogen, C1-6-alkyl, C2-6-alkenyl, C26-alkynyl, C1-6-alkyl-aryl, or C1-6-alkyl-O-aryl; D is a spacer group selected from branched or straight chain C1-6-alkylene, C2-6-alkenylene and C2-6-alkynylene; its enantiomers, and pharmaceutically acceptable acid addition salt thereof. The compounds are potently binding to the 5-HT1A receptor.