First, an MVNO 230A that has obtained one or more SIM cards logs in to a management screen provided by an MVNE 210 in association with a user ID of the MVNO 230A. From the standpoint of the MVNE 210, it is determined whether a user ID of a user who has accessed a management screen of a management server of the MVNE 210 is under MVNO contract (S301). When the user ID is under MVNO contract, an identification number given to each SIM card and a passcode for authentication given as needed are received as registration information (S302). If the management server of the MVNE 210 can receive necessary registration information, each SIM card of which an identification number is specified by the registration information is associated with the user ID as an SIM card used by the MVNO 230A (S303).

Recently, with the advent of a mobile virtual network operator (MVNO), retailing of a wireless communication line is becoming popular. Conventionally, a mobile network operator (MNO) having a wireless communication infrastructure provided a wireless communication service to an end user directly. However, MVNOs provide original wireless communication services to the end user using the wireless communication infrastructure of an MNO.
MVNOs can be roughly classified into a form where a company does not have an in-house communication infrastructure and a form where a company itself has an in-house communication infrastructure and the communication infrastructure is connected to the communication infrastructure of an MNO to provide a wireless communication service (see FIG. 1). As compared with the case of the former, in the case of the latter, because the company has the in-house communication infrastructure and price setting according to communication quality such as communication speed and communication capacity is enabled, attempts to meet various needs are made. For example, SIM cards for a wireless communication service of which the price is suppressed by setting maximum communication capacity that allows high-speed data communication are sold in mass merchandisers.
Specifically, such an MVNO receives SIM cards from an MNO and provides the SIM cards to the end users. The MVNO manages communication quality such as speed limit and capacity limit set to each SIM card together with the identification number of each SIM card by a database and provides a wireless communication service according to the contract details for a portable terminal such as a smart phone and a tablet requesting an access to the Internet.
Also, there is a case in which a mobile virtual network enabler (MVNE) providing a support service to enable MVNOs to run a business smoothly intervenes between an MNO and an MVNO and the MVNE receives SIM cards from the MNO and provides the SIM cards to the MVNO.
When the MVNO or the MVNE holds a gateway (GGSN in 3G and P-GW in LTE) as an end point of a core network as an in-house communication infrastructure, L2 connection (full MVNO connection (S5/S8 interface in LTE and Gn interface in 3G)) with a communication infrastructure (SGSN in 3G and S-GW in LTE) of an MNO is enabled and an L2 tunnel is formed between a wireless terminal on which a SIM card of an end user is mounted and the gateway. Because the L2 connection has higher freedom in designing of a wireless communication service than L3 connection (light MVNO connection), the L2 connection is attracting attention.
A movement of IoT to connect all things to the Internet by adding wireless communication functions is the example of recent remarkable increase in the needs for wireless communication service. Hereinafter, a wireless apparatus that can be connected to a computer network including the Internet is called an "IoT apparatus".
The IoT apparatus also includes a portable terminal such as a smart phone and a tablet held by a person. However, the IoT apparatus is expanding to apparatuses requiring communication of a form different from a communication form for a person, like a transportation means such as an automobile moving faster than a person and a sensor rarely moving from a specific position. For this reason, the required communication speed or communication frequency is various. It may be said that optimal communication quality is changing. For example, in the case in which it is considered that SIM cards are incorporated into 10 or 100 industrial machines to realize IoT and the industrial machines are remotely caused to perform communication with other apparatuses, installation of a large number of SIM cards is required even if each IoT apparatus performs communication of low capacity at a low frequency.
With the spread of IoT apparatuses, the number of users such as providers managing a plurality of IoT apparatuses increases, but on the other hand it is difficult under the present conditions for each user to make a contract with an MNO as an MVNO and collectively manage the plurality of IoT apparatuses, that is, a plurality of SIM cards mounted on the plurality of IoT apparatuses. First, the needs diversify together with the spread of IoT apparatuses and a situation where a small number of SIM cards such as several to several tens of SIM cards are used, like the case of making apparatuses IoT apparatuses on a trial basis, can be envisioned. When the user desires to manage the SIM cards collectively, instead of using the SIM cards through individual contracts, an MVNO contract with an MNO is necessary. However, there are many cases in that the small-scale MVNO cannot make a contract with the MNO to begin with. Then, even if the user can make a contract with an MNO as a small-scale MVNO, to increase SIM cards by several to several tens of pieces, the MVNO needs to make a request to the MNO to associate the additional SIM cards with the ID of the MVNO (hereinafter, referred to as an "user ID"). After completion of the association, the MVNO receives the additional SIM cards and these become available for use. Specifically, as an association, a name of the MVNO, an identification number of each SIM card such as IMSI and ICCID, status such as in-use and inactive, etc. are input to each SIM card manually by a dedicated device and are registered in a database of the MNO. A series of procedures accompanying the circulation of SIM cards to an MVNO are complicated and requires several weeks. In addition, initial investment is necessary from economic point of view and it is not possible to meet the needs of a user who desires to use necessary number of SIM cards necessary for IoT apparatuses as needed.
An environment where a large number of users can become MVNOs easily is strongly required while it is anticipated that the number of small-scale and medium-scale MVNOs increases rapidly.

Management method and management server for using SIM cards


A method for performing a rendering process of a rendering system includes generating a primary ray to render an image, determining whether the primary ray is capable of generating at least one secondary ray, storing information on the primary ray in a reference memory in response to determining that the primary ray is capable of generating the at least one secondary ray; and generating the at least one secondary ray based on the stored information on the primary ray.

1. Field
Apparatuses and methods consistent with exemplary embodiments relate to generating and rendering a ray, and more particularly, managing a memory for generating and rendering a ray.
2. Description of the Related Art
A ray tracing method refers to a method of reverse-tracing a route of light along a ray to each pixel in a virtual screen and generating an image in a point of view of a camera.
The ray tracing method generally includes operations of ray generation, acceleration structure traversal, intersection test, and shading. A final color of a ray which is generated in a ray generator is determined through the shading operation after obtaining information on an intersection through the acceleration structure traversal operation and the intersection test operation. According to a medium of the intersection, secondary rays, such as reflection, refraction, or a shadow ray, are derived from a primary ray generated from the ray generator. The ray generator stores the secondary rays in order to perform the acceleration structure traversal operation and following operations with respect to the secondary rays.
However, in case of a plurality of light sources and objects, a space for storing rays may be insufficient at times. In this case, performance of a rendering system may be deteriorated due to memory stalls with respect to the entire rendering system.
Accordingly, there is a need for a method of reducing a load of a memory to enhance performance of the rendering system.

Rendering system and method for generating ray


A modified sol-gel method to create metal-rich siliceous material, such as colloidal silica or aluminosilicate particles is disclosed. Initially, the metal salt of choice is added to a silicic acid solution or a silicic acid solution containing aluminum salt. The aluminum is added to vary the metal-support interaction as it forms Al—O—Si linkages within the silica matrix. Besides aluminum, other metals can be added that form M—O—Si (M=Ti, B, etc.) linkages, which do not become reduced when treated with a reducing agent. Once the metal, silicic acid and/or aluminum salt is generated, it is subjected to colloidal growth by addition to a basic heel. Upon colloidal synthesis, the metal salt containing colloidal particle is left as is to maximize colloidal stability or is reduced with hydrazine to produce the zero valence metal-containing colloidal particle. Keeping a particle colloidal before use may be an effective method of forming a catalyst material as it can be easily spray-dried or mixed with other materials for extruded catalyst particles.

The preparation and use of colloidal materials, such as colloidal silica, are generally knownused. Typically, the silica colloid is first synthesized. The colloid is then coated with a metal oxide. This coating procedure produces both negatively and positively charged surfaces, depending upon the properties of the metallic starting material and the coating method used. Metal-containing silica colloids are useful in various areas, such as chemical mechanical polishing agents in the electronics industry, coating applications, and as support materials in catalytic processes. Despite this versatility, conventional-type silica colloids have several disadvantages.
Liquid suspended metal nanoparticles have several drawbacks in catalysis including difficulties in recycling the nanoparticle catalyst. Immobilization of the catalyst on a solid support makes it possible to recycle the catalyst via simple filtration. Synthesis of the immobilized catalyst (which involves infusing the solid support with metal nanoparticles), however, can be highly time consuming. For example, palladium-catalyzed reaction for carbon-carbon bond formation (Heck Reaction) is a versatile industrial synthesis tool. It includes impregnating a solid support, such as precipitated silica, with Palladium (II) acetate, drying, and reducing with hydrogen gas or other suitable reducing agent.
Two well-known methods of incorporating metals onto porous supports are impregnation (sometimes referred to as the "incipient wetness" technique) and direct synthesis via the sol-gel technique. Impregnation involves taking a solid porous support and adding metal salt solutions to the support. The metal salt solutions intercalate through the structure of the porous support and form surface deposits upon drying. During reduction of the deposited metal salts, the metal particles have a tendency to migrate over the surface of the porous support and must make their way through the porous structure to disperse. This migration leads to sintering and an overall decrease in catalytic activity due to smaller active surface areas (See Hermans & Geus, Interaction of Nickel Ions With Silica Supports During Deposition-Precipitation, Stud. Surf. Sci. Catal., 1979, pp. 113 to 130).
The sol-gel technique (See Lopez et al., Pt/SiO2 Sol-Gel Catalysts: Effects of pH and Platinum Precursor, J. Phys. Chem., 1993, pp. 1671 to 1677) involves mixing metal salts with a silane precursor, such as tetraethyl orthosilicate ("TEOS"). Over time, the TEOS hydrolyzes and its SiOH groups interact with the metal salts. Once the SiOH groups begin to condense and form a precipitate, the metals are dispersed within the SiO2 matrix via terminating SiO− or SiOH groups. The metal salts in the sol-gel technique tend to become occluded within the structure during synthesis.
A need therefore exists for improved methods of incorporating metals into siliceous colloidal compositions. In particular, synthesis methods for creating silica-based colloids or particles having more homogenously dispersed metal loads and enhanced stability over a greater pH range and/or other suitable characteristics are desirable. Furthermore, it is desirable to form such colloids with a narrow particle size distribution.

Metal-rich siliceous compositions and methods of producing same


Tetrapolyimide films derived from oxydiphthalic dianhydride, pyromellitic acid dianhydride, p-phenylene diamine and 4,4'-diaminodiphenyl ether, and their preparation are described. The tetrapolymer films have low water absorption, low coefficients of thermal and hygroscopic expansion, high modulus and are caustic etchable and can be used in flexible printed circuit and tape automated bonding applications.

This invention relates to a tetrapolyimide film having low water absorption, low coefficients of hygroscopic and thermal expansion, high modulus, and which is caustic etchable, for use as a tape automated bonding (TAB) substrate.
TAB is an electronic chip packaging technology which uses an etched, fine-line conductor pattern in a flexible carrier tape form.
The common construction of the tape carrier/interconnect product is virtually identical to flexible circuitry, except for two special features. An opening, appropriately called a window, is formed near the center of the conductor array in the dielectric base film. The window permits the etched conductor leads to extend over the opening, creating the essential beam type interconnect array.
The other characteristic of TAB is the precision sprocket holes located on the edge of the tape. TAB tape is provided in reel form, looking much like movie film and is available in widths from 8 to 70 mm.
The integrated circuit (IC) connection to TAB is accomplished by placing the chip in the window area beneath the unsupported connectors, or "fingers", aligning the leads with the metal-coated bonding pads on the chip, and then gang bonding the entire array by thermal compression. A raised metal area, called a "bump", must be incorporated into the IC pads or into the TAB leads to make the bonding process workable. This gang bonding technique, called inner lead bonding (ILB), provides two important features, viz. assembly speed and connection to higher density chips. The bonded IC is usually protected by applying organic potting compound onto the chip for protection in a process called "globbing" or "encapsulation". The loaded tape is then assembled to the printed circuit.
The subsequent TAB-to-circuit bonding step, called outer lead bonding (OLB) requires that the TAB interconnect area be etched from the tape. The etched TAB component is bonded to the surface of the printed circuit by aligning the TAB outer lead frame to corresponding bond sites on the circuit and then applying bonding energy by thermal compression or reflow soldering. The resulting assembly occupies a smaller space, has a very low profile and has superior electrical characteristics compared to its popular wire-bonded counterpart.
Three-layer TAB tapes are the most widely used today. This type of tape consists of copper foil which is often 1.4 mils thick and is bonded to a polyimide film with a layer of polyester, acrylic, or epoxy based adhesive. Normally, the polyimide film is coated on one side with adhesive and slit to the correct width. The windows and sprocket holes are punched or chemically etched out and the tape is then laminated to the copper foil. The foil is then selectively etched into the radiating patterns that form the IC interconnects.
Two-layer TAB tapes are becoming more functionally useful and consist of copper bonded directly to polyimide, without a layer of polyester, acrylic, or epoxy based adhesive. Most often, the copper is applied to the polyimide by sputtering or electroless plating and built to a thick, 1.4 mil layer of copper by electroplating. Sprocket holes can be punched, but windows are etched in the polyimide.
The polyimide used as the base film in TAB tapes must have a relatively small thermal expansion coefficient which is close to the thermal expansion coefficient of the metallic film, otherwise curling of the composite tape occurs during exposure to high temperatures during processing. The film must have good flexibility to avoid cracking on TAB equipment and high modulus so that sprocket holes do not distort during movement of the tape.
The film must also have a low coefficient of hygroscopic expansion so that dimensions stay more constant with humidity changes, thereby making humidity control less important in processing and causing less stress to build up in humidity cycling to prevent cracking. Finally, film etchability allows chemical etching of holes in the dielectric rather than punching them or using laser cutting.
U.S. Pat. No. 4,778,872, issued to Sasaki et al. on Oct. 18, 1988, discloses a copolyimide film containing from 15 to 85 mole % of a biphenyltetracarboxylic acid dianhydride, 15 to 85 mole % of pyromellitic acid dianhydride, 30 to 100 mole % of p-phenylene diamine and 0 to 70 mole % of a diaminodiphenyl ether. Up to 5 mole % of the tetracarboxylic acid dianhydrides can be substituted by other dianhydrides such as oxydiphthalic dianhydride to provide pentapolyimide films. The invention film compositions are tetrapolyimides not pentapolyimides and do not contain biphenyltetracarboxylic acid dianhydride.
U.S. Pat. No. 4,535,105, issued to Inaike et al. on Aug. 13, 1985, discloses a copolyamic acid solution for preparing a copolyimide insulating varnish containing at least 80 mole % of a tetracarboxylic acid component consisting of a 30:70 to 75:25 mole ratio of biphenyltetracarboxylic acid dianhydride and pyromellitic acid dianhydride and less than 20 mole % of a diamine component consisting of at least 70 mole % of 4,4'-diaminodiphenyl ether and 30 mole % or less of p-phenylene diamine. The tetracarboxylic acid component can additionally contain 20 mole % or less of an acid ingredient such as oxydiphthalic dianhydride. The invention compositions are tetrapolyimides not pentapolyimides and do not contain biphenyltetracarboxylic acid dianhydride.
U.S. Pat. No. 4,855,391, issued to Berdahl et al. on Aug. 8, 1989, discloses a high temperature stable copolyetherimide film derived from oxydiphthalic dianhydride, p-phenylene diamine and 4,4'-diaminodiphenyl ether. The prior art patent does not disclose a tetrapolyimide film containing pyromellitic acid dianhydride.
Coassigned U.S. patent application Ser. No. 07/516,887, filed on Apr. 30, 1990, discloses a tetrapolyimide film comprising a tetracarboxylic acid component containing from 10 to 90 mole % of biphenyltetracarboxylic acid dianhydride, 90 to 10 mole % of pyromellitic acid dianhydride and a diamine component containing from 10 to 90 mole % of p-phenylene diamine and 90 to 10 mole % of a diaminodiphenyl ether. The invention tetrapolyimide films contain oxydiphthalic dianhydride as a component not biphenyltetracarboxylic acid dianhydride.
The present invention provides a tetrapolyimide film, and a process for its preparation, comprising oxydiphthalic dianhydride, pyromellitic acid dianhydride, p-phenylene diamine and diaminodiphenyl ether having the unique property advantages of high modulus, low coefficients of thermal and hygroscopic expansion, low water absorption and caustic etchability for use in flexible printed circuits and tape automated bonding applications.

Tetrapolyimide film containing oxydipthalic dianhydride


A near infrared analyzer has, arranged on a base, a halogen tungsten lamp as light source, an optical stop for light from the source, an optical system for converging a flux of light for measuring and directing it to a measuring section and a system including an integrating sphere at which a sample is set. A spectrometer part has its entrance slit placed on the bottom surface of the integrating sphere, and includes a diffraction grating for diffraction and dispersion of incident light flux from the entrance slit, an arrayed detector and a reflective mirror for reflecting the diffracted light from the diffraction grating so as to be dispersed and focused on the surface of the detector. Signals from the detector can be sequentially retrieved for electronically scanning wavelengths without mechanically oscillating or rotating the grating. This makes it possible to maintain high accuracy in wavelengths over a long period of time. As the speed of measurement is increased, measurements can be repeated and obtained data integrated for reducing noise and improving accuracy of measurement.

This invention relates to a near infrared analyzer for quantitative and/or qualitative analysis of a sample by measuring the optical characteristics of its transmitted and/or reflected light in a near infrared region. Analyzers of this kind have been in use for measuring spectroscopic characteristics, for example, of agricultural products, processed foods, chemical substances and medicines against light.
Near infrared analyzers were developed initially as an apparatus for analyzing the protein and water content of wheat and have since come to be used extensively for the analysis of processed foods, liquors, products of chemical industries and medicines. When a near infrared analyzer is used for analysis, the sample is generally not pretreated chemically, that is, the sample is usually used in the apparatus in a non-destructed condition. According to an exemplary method of quantitative analysis, an absorption or reflection spectrum of an unknown sample is measured over a certain range of wavelength principally in the near infrared region or at a plurality of near infrared wavelengths, and the content of a desired component is obtained by using the spectral data with a preliminarily prepared predictive formula. For a simultaneous quantitative analysis of a plurality of components, predictive formulas are individually prepared for the desired components and individually applied to the spectral data. Such predictive formulas are prepared by a statistical method from the spectral data of a plurality of samples with a variety of known contents. Where a quantitative analysis is the objective, such formulas may be prepared, say, by a multiple regression analysis. These predictive formulas are similar to what is commonly known as the detection line in ordinary instrumental analyses but involve much more complicated calculations.
Since such analyzers are used principally for sorting agricultural products and quality control of processed foods, they mostly perform analyses of similar kinds many times day in and day out. Since the results of these measurements are very important in the quality control and determination of the prices of the measured samples, the analyzers must be able to perform the measurements speedily, their accuracy must be at least as good as by prior art methods of chemical analyses, and stability must be high both on a long-term basis and on a short-term basis.
From the point of view of the structure of spectroscopic elements to be used, prior art analyzers which have been used to satisfy these requirements can be classified into the kind which scans a wavelength band of the detection light and the kind which performs measurements at a fixed wavelength. The latter is characterized by the a plurality of band pass filters within a narrow band which are sequentially inserted into an optical path such that absorptivity can be measured at a plurality of wavelengths. Analyzers of the latter (fixed wavelength) kind are advantageous in that the structure is simple and they can be inexpensive. They are disadvantageous, however, in that the wavelength cannot be freely selected for measurements and hence that the kind of samples which can be measured becomes limited, depending on the analyzer to be used.
Analyzers of the former (wavelength-scanning) kind may be characterized as having a diffraction grating and scanning a wavelength band of light emitted through an exit slit by rotating or oscillating the grating. The wavelength of the light to be used for analysis can be freely selected with an analyzer of this kind, and such an analyzer can be used for a larger variety of samples and for broader research purposes. In order to satisfy the requirements mentioned above with an analyzer of this kind with a diffraction grating, that is, to achieve high-speed measurements with high accuracy with high short-term and long-term stability, however, many improvements must be effected. For example, the optical system inclusive of a spectrometer must be designed for low optical losses, both the speed and accuracy of the scanning of the diffraction grating must be improved, and the temperature variations and vibrations of each component of the device must be reduced or compensated for. In view of the above, U.S. Pat. No. 4,283,596 disclosed an optical system using a unique cam drive structure to oscillate a diffraction grating. U.S. Pat. No. 4,540,282 disclosed a combination of a return force spring, a detector of back electromagnetic flux and a DC motor for providing a harmonic oscillation to a diffraction grating. European Patent Application Publication No. 378,108 disclosed a combination of a DC motor and an optical encoder to control the speed of the motor to oscillate a diffraction grating. In addition, it has been known, as has been used in visible-light, ultraviolet and infrared spectrophotometers, to convert the rotary motion of a motor into a linear motion by means of a feed screw and to convert it again for the rotation of a diffraction grating by means of a sine bar.
There have been problems with prior art near infrared analyzers, and in particular with those which use a diffraction grating spectrometer to scan a wavelength band by rotating or oscillating the diffraction grating. If the grating is mechanically scanned, as with all of the devices described above, a complicated power-transmitting mechanism such as a cam is necessary and, since the speed of its rotation must be increased in order to reduce the time of measurement, long-term maintenance of mechanical reliability and accuracy becomes a serious problem. In the case of devices with a combination of a DC motor and an encoder, it must be remembered that components like the encoder requiring high accuracy are extremely vulnerable to vibrations and shocks. In the case of measurements of agricultural products outdoors where there are noises and severe temperature changes, for example, there arise short-term problems of reliability. Moreover, both the motor and the encoder are rotary machine components, but bearings have a limited mechanical lifetime. One cannot forget the additional problems of deterioration in accuracy of measurements due to wears and tears of parts over a long time of use.
It is therefore an object of the present invention to provide a near infrared analyzer capable of high-speed measurements with high accuracy which is stable both on long-term and short-term bases.


An image processing device includes an image generation mechanism configured to generate computer graphics images based on computer graphics description data, an image mapping mechanism configured to designate an object or a part of the object of computer graphics drawn by the image generation mechanism as a texture map target, and to texture map texture map images to a surface of the texture map target, and a superimposition mechanism configured to superimpose superimposition images at a position corresponding to the texture map target of the computer graphics images where the texture map has been performed in the image mapping mechanism, based on position information for the texture map target of the computer graphic image.

1. Field of the Invention
The present invention relates to an image processing device and an image processing method, and more particularly, to an image processing device or the like which performs an image synthesis by texture mapping an image by image data to computer graphics images.
2. Description of the Related Art
In a three-dimensional graphics system, an image's entirety is drawn by decomposing three-dimensional coordinates into polygons such as triangles and drawing the polygons. Therefore, in this case, the three-dimensional image can be said to be defined by the combination of the polygons. Meanwhile, surfaces of ambient things have many repetitive patterns of complicated shapes, and the shapes or the patterns are complicated and detailed, and thus it is difficult to model each shape or pattern as a triangle or the like. Therefore, as a means for solving this, a texture map can be used.
The texture map realizes an image with high realism with a small number of vertices by adding image data received from a scanner or the like to an object surface, defines a mapping from the object coordinate system to the texture coordinate system, finds out a mapping from the window coordinate system to the texture coordinate system, and finds out texels (texture cell elements) which are elements of texture corresponding to the respective pixels (picture cell elements) at the window coordinate system.
Image data used for the texture is stored in a memory area called a texture memory. Accordingly, the texture memory is update process is performed at any time using moving image data, and thereby the texture map process related to the moving image can be performed.
For example, a telop generation device is disclosed in Japanese Unexamined Patent Application Publication No. 2006-325165 which is an example of related art, in which a stereopsis object desired to be given a telop is recognized in a stereoscopic vision image, and parallax corresponding to this stereopsis object is provided to the telop so as not to harm the entire stereoscopic vision. Also, for example, a three-dimensional picture edition display device, disclosed in Japanese Unexamined Patent Application Publication No. 2002-015339 which is an example of related art, enables character edition and/or display temporally synchronized with a three-dimensional object.

Image processing device and image processing method


The invention encompasses the novel class of compounds represented by formula I, which are caspase-3 inhibitors.

Apoptotic cell suicide is a fundamentally important biological process that is required to maintain the integrity and homeostasis of multicellular organisms. Inappropriate apoptosis, however, underlies the etiology of many of the most intractable of human diseases. In only the last few years, many of the molecules that participate in a conserved biochemical pathway that mediates the highly ordered process of apoptotic cell suicide have been identified. At the heart of this pathway are a family of cysteine proteases, the xe2x80x98caspasesxe2x80x99, that are related to mammalian interleukin-1xcex2 converting enzyme (ICE/caspase-1) and to CED-3, the product of a gene that is necessary for apoptotic suicide in the nematode C. elegans (Nicholson et al., 1997, Trends Biochem Sci 22:299-306). The role of these proteases in cell suicide is to disable critical homeostatic and repair processes as well as to cleave key structural components, resulting in the systematic and orderly disassembly of the dying cell.
The central importance of caspases in these processes has been demonstrated with both macromolecular and peptide-based inhibitors (which prevent apoptosis from occurring in vitro and in vivo) as well as by genetic approaches. Inhibition of apoptosis via attenuation of caspase activity should therefore be useful in the treatment of human diseases where inappropriate apoptosis is prominent or contributes to disease pathogenesis. Caspase inhibitors would thus be useful for the treatment of human diseases including, but not limited to, acute disorders such as cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, as well as chronic disorders such as neurodegenerative diseases (e.g. Alzheimer""s, polyglutamine-repeat disorders, Down""s, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HIV), diabetes, alopecia and aging.
Ten caspases have so far been identified in human cells. Each is synthesized as a catalytically dormant proenzyme containing an amino-terminal prodomain followed by the large and small subunits of the heterodimeric active enzyme. The subunits are excised from the proenzyme by cleavage at Asp-X junctions (Nicholson et al., 1997, Trends Biochem Sci 22:299-306). The strict requirement by caspases for Asp in the P1 position of substrates is consistent with a mechanism whereby proenzyme maturation can be either autocatalytic or performed by other caspases. The three dimensional crystal structures of mature caspase-1 and -3 show that the large subunit contains the principle components of the catalytic machinery, including the active site Cys residue which is harbored within the conserved pentapeptide motif, QACxG,1 and residues that stabilize the oxyanion of the tetrahedral transition state (Wilson et al., 1994, Nature 370:270-75; Walker et al., 1994, Cell 78:342-52; Rotonda et al., 1996, Nat Struct Biol 3:619-25). Both subunits contribute residues which stabilize the P1 Asp of substrates while the small subunit appears to contain most of the determinants that dictate substrate specificity and, in particular, those which form the specificity-determining S4 subsite. One distinctive feature of these proteases is the absolute requirement for an aspartic acid residue in the substrate P1 position. The carboxylate side chain of the substrate P1 Asp is tethered by four residues in caspase-1 (Arg179, Gln238 from p20 and Arg341, Ser347 from p10) that are absolutely conserved in all caspase family members. Catalysis involves a typical cysteine protease mechanism involving a catalytic dyad, composed of His237 and Cys285 (contained within an absolutely conserved QACxG pentapeptide) and an xe2x80x98oxyanion holexe2x80x99 involving Gly238 and Cys285. Inhibitors bind, however, in an unexpected non-transition state configuration (which raises important considerations for inhibitor design) with the oxyanion of the thiohemiacetal being stabilized by the active site His237.
Members of the caspase family can be divided into three functional subgroups based on their substrate specificities which have been defined by a positional-scanning combinatorial substrate approach. The principle effectors of apoptosis (group II caspases, which include caspases-2, -3 and -7 as well as C. elegans CED-3) have specificity for [P4]DExD[P1], a motif found at the cleavage site of most proteins known to be cleaved during apoptosis. On the other hand, the specificity of group III caspases (caspases-6, -8, -9 and -10, as well as CTL-derived granzyme B) is [P4](I,V,L)ExD[P1] which corresponds to the activation site at the junction between the large and small subunits of other caspase proenzymes including group II (effector) family members. This and other evidence indicates that group III caspases function as upstream activators of group II caspases in a proteolytic cascade that amplifies the death signal. The role of group I caspases (caspases-1, -4 and -5) appears to be to mediate cytokine maturation and their role in apoptosis, if any, has not been substantiated.
A tetrapeptide corresponding to the substrate P4-P1 residues is sufficient for specific recognition by caspases and as a consequence has formed the basis for inhibitor design. In addition to the requirement for a P1 Asp, the P4 residue in particular appears to be most important for substrate recognition and specificity. Caspase-1, for example, prefers a hydrophobic residue such as Tyr in P4 (which corresponds to its YVHD cleavage site within proIL-1xcex2) whereas caspase-3 (and other group II enzymes) has a preference for an anionic Asp residue (which corresponds to the DXXD cleavage sites within most polypeptides that are cleaved by these enzymes during apoptosis). Peptide aldehydes, nitriles and ketones are potent reversible inhibitors of these proteases while compounds that form thiomethylketone adducts with the active site cysteine (e.g. peptide (acyloxy)methylketones) are potent irreversible inhibitors. For example, the tetrapeptide aldehyde Ac-YVAD-CHO (SEQ ID NO: 24) (which was designed to mimic the YVHD caspase-1 recognition sequence within proIL-1xcex2) is a potent inhibitor of caspase-1 (Ki less than 1 nM) but a poor inhibitor of caspase-3 (Ki=12 xcexcM) (Thornberry et al., 1992, Nature 356:768-74). In contrast, the Ac-DEVD-CHO (SEQ ID NO: 25) tetrapeptide aldehyde (which was designed to mimic the caspase-3 recognition site) is a very potent inhibitor of caspase-3 (Ki less than 1 nM) although it is also a weaker but reasonable inhibitor of caspase-1, presumably owing to promiscuity in the S4 subsite of this enzyme (Nicholson et al., 1995, Nature 376:37-43).
Several features plague these peptide-derived inhibitors as a platform for drug design. In addition to their metabolic instability and membrane impermeability, the slow-binding time-dependent inhibition of activity (e.g. kon caspase-1:Ac-YVAD-CHO (SEQ ID NO: 24)=3.8xc3x97105 Mxe2x88x921sxe2x88x921; kon caspase-3:Ac-DEVD-CHO (SEQ ID NO: 25)=1.3xc3x97105 Mxe2x88x921sxe2x88x921) precludes them from the rapid inhibition characteristics that may be necessary to abolish enzymatic activity in vivo. The present patent application describes the resolution of this issue with the discovery of several novel ketones that make highly suitable caspase inhibitors.
The invention encompasses the novel class of compounds represented by formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CO2C1-4alkyl,
(s) CH2SC1-4alkyl,
(t) CH2S(O)2C1-4alkyl,
or R2 and X2 together form a saturated monocyclic ring having the following structure:
R3 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CH2CO2C1-4alkyl,
(s) CH2CH2S(O)2C1-4alkyl,
or R3 and X3 together form a saturated monocyclic ring having the following structure:
R4 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
or R4 and X4 together form a saturated monocyclic ring having the following structure:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl and
(c) aryl as defined above in items (1) to (21) of (b), wherein the aryl portions may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or Nxe2x80x94R8 substituted piperazine wherein R8 is H or C1-3alkyl; and
X2, X3 and X4 are independently H or X2 and R2, X3 and R3, or X4 and R4 may together form a saturated monocyclic ring having the following structure:
The invention also encompasses a pharmaceutical composition comprising a compound of formula I in combination with a pharmacuetically acceptable carrier.
The invention also encompasses a method of treating cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), type I diabetes, immune deficiency syndrome (including AIDS), cerebral and spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson""s disease, Alzheimer""s disease, Down""s syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound of formula I.
The invention encompasses the novel class of compounds represented by formula I, which are caspase-3 inhibitors.
or a pharmaceutically acceptable salt thereof, are disclosed, wherein:
R is selected from the group consisting of:
(a) H and
(b) C(O)R1;
R1 is selected from the group consisting of:
(a) hydrogen,
(b) C1-6alkoxy,
(c) NR6R7,
(d) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
(e) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenyl C1-3alkoxy,
(6) phenyl C1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(f) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl and
(20) oxazolyl, and
(g) mono and di-substituted aryl as defined above in items (1) to (20) of (f), wherein the substituents are independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio,
(15) C1-6alkylsulfonyl and
(16) deuterio;
R2 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CO2C1-4alkyl,
(s) CH2SC1-4alkyl,
(t) CH2S(O)2C1-4alkyl,
or R2 and X2 together form a saturated monocyclic ring having the following structure:
R3 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
(r) CH2CH2CO2C1-4alkyl,
(s) CH2CH2S(O)2C1-4alkyl,
or R3 and X3 together form a saturated monocyclic ring having the following structure:
R4 is selected from the group consisting of:
(a) H,
(b) CH3,
(c) CH(CH3)2,
(d) CH2CH(CH3)2,
(e) CH2Ph,
(f) CH2PhOH,
(g) CH2OH,
(h) CH2SH,
(i) CH2CH2SCH3,
(j) CH(CH3)CH2CH3,
(k) CH(CH3)OH,
(l) CH2COOH,
(m) CH2CH2COOH,
(n) CH2CH2CH2NHCNH(NH2),
(o) CH2CH2CH2CH2NH2,
(p) CH2C(O)NH2,
(q) CH2CH2C(O)NH2,
or R4 and X4 together form a saturated monocyclic ring having the following structure:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl,
(4) furyl,
(5) thienyl,
(6) thiazolyl,
(7) isothiazolyl,
(8) imidazolyl,
(9) benzimidazolyl,
(10) pyrazinyl,
(11) pyrimidyl,
(12) quinolyl,
(13) isoquinolyl,
(14) benzofuryl,
(15) benzothienyl,
(16) pyrazolyl,
(17) indolyl,
(18) purinyl,
(19) isoxazolyl,
(20) oxazolyl and
(21) coumarinyl, and
(c) aryl as defined above in items (1) to (21) of (b), wherein the aryl portions may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-6alkyl,
(10) C1-6fluoroalkyl,
(11) C1-6alkylcarbonyl,
(12) C1-6alkoxycarbonyl,
(13) C1-6alkoxy,
(14) C1-6alkylthio and
(15) C1-6alkylsulfonyl;
R6 and R7 are independently selected from the group consisting of:
(a) C1-4alkyl,
(b) C1-4fluoroalkyl and
(c) benzyl or mono- or disubstituted benzyl wherein the substituent is selected from the group consisting of:
(1) methyl,
(2) halogen,
(3) methoxy and
(4) cyano,
or R6 and R7 may be joined to form a pyrrolidine, piperidine, morpholine, thiamorpholine or Nxe2x80x94R8 substituted piperazine wherein R8 is H or C1-3alkyl; and
X2, X3 and X4 are independently H or X2 and R2, X3 and R3, or X4 and R4 may together form a saturated monocyclic ring having the following structure:
In a preferred embodiment, the compounds are represented by formula Ia
or a pharmaceutically acceptable salt thereof, wherein the amino acids from which the structure is constructed, represented in formula Ia as AA1, AA2 and AA3, are selected from a group consisting of the L- and D-forms of the amino acids including alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine and valine. The structures of the L-amino acids are shown below.
A preferred embodiment of the invention is that wherein R1 is C1-6alkyl or phenyl.
Another preferred embodiment of the invention is that wherein R5 is arylC1-8alkyl, wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, and mono-, or di-substituted derivatives thereof, wherein the substituents are individually selected from the group consisting of:
(1) halo,
(2) amino,
(3) nitro,
(4) hydroxy,
(5) cyano,
(6) carboxy,
(7) formyl,
(8) amino carbonyl,
(9) C1-3alkyl,
(10) C1-3fluoroalkyl,
(11) C1-3alkylcarbonyl,
(12) C1-3alkoxycarbonyl,
(13) C1-3alkoxy,
(14) C1-3alkylthio and
(15) C1-3alkylsulfonyl;
Another preferred embodiment of the present invention is that wherein:
R1 is selected from the group consisting of:
(a) C1-6alkoxy,
(b) benzyloxy or mono- or disubstituted benzyloxy, wherein the substituent is selected from methyl, halogen, methoxy and cyano,
(c) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenylC1-3alkoxy,
(6) phenylC1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(d) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyland
(2) naphthyl, and
(e) mono and di-substituted aryl as defined above in items (1) to (2) wherein the substituents are independently selected from:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio,
(12) C1-3alkylsulfonyl and
(13) deuterio; and
R5 is arylC1-8alkyl wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, and mono-, or di-substituted derivatives thereof, wherein the substituents are individually selected from the group consisting of:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio and
(12) C1-3alkylsulfonyl.
Another preferred embodiment of the invention is that wherein R1 is selected from the group consisting of:
(a) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenylC1-3alkoxy,
(6) phenylC1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(b) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl and
(2) naphthyl, and
(c) mono and di-substituted aryl as defined above in items (1) to (2) wherein the substituents are independently selected from:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio,
(12) C1-3alkylsulfonyl and
(13) deuterio.
Another preferred embodiment of the present invention is that wherein R2 is selected from the group consisting of:
(a) CH2CO2H,
(b) CH2CO2C1-4alkyl,
(c) CH2SC1-4alkyl and
(d) CH2S(O)2C1-4alkyl.
Another preferred embodiment of the invention is that wherein R3 is selected from the group consisting of:
(a) CH3,
(b) CH2CH2CO2H,
(c) CH2CH2CO2C1-4alkyl,
(d) CH2CH2S(O)2C1-4alkyl.
A preferred embodiment of the present invention is that wherein R4 is isopropyl.
Another preferred embodiment of the invention is that wherein R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl and
(4) coumarinyl, and
(c) aryl as defined above in items (1) to (4) of (b), wherein the aryl portions may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio and
(12) C1-3alkylsulfonyl.
In one subset that is of particular interest, the compounds are represented by formula II:
including pharmaceutically acceptable salts thereof, wherein:
R5 is selected from the group consisting of:
(a) C1-6alkyl,
(b) arylC1-8alkyl wherein the aryl is selected from the group consisting of:
(1) phenyl,
(2) naphthyl,
(3) pyridyl and
(4) coumarinyl and
(c) aryl as defined above in items (1) to (4) of (b), wherein the aryl portions may be optionally mono- or di-substituted with a substituent independently selected from:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio and
(12) C1-3alkylsulfonyl.
(13)
Another subset of compounds that is of particular interest relates to compounds of formula II wherein:
R5 is selected from the group consisting of:
(a) methyl,
(b) propyl,
(c) phenyl,
(d) phenylC1-5alkyl,
(e) 4-methoxyphenylpropyl,
(f) napthylpropyl and
(g) 4-methylcoumarinyl.
(h)
Representative compounds that are of particular interest are the following:
In another embodiment that is of particular interest, the compounds are represented by formula III:
including pharmaceutically acceptable salts thereof, wherein:
R1 is selected from the group consisting of:
(a) C1-6alkyl or substituted C1-6alkyl, wherein the substituent is selected from the group consisting of:
(1) hydroxy,
(2) halo,
(3) C1-3alkoxy,
(4) C1-3alkylthio,
(5) phenylC1-3alkoxy,
(6) phenylC1-3alkylthio,
(7) phenylcarboxy and
(8) carboxy,
(b) aryl or arylC1-6alkyl wherein the aryl group is selected from the group consisting of:
(1) phenyl and
(2) naphthyl, and
(c) mono and di-substituted aryl as defined above in items (1) to (2) wherein the substituents are independently selected from:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio,
(12) C1-3alkylsulfonyl and
(13) deuterio; and
R5 is arylC1-8alkyl wherein aryl is selected from the group consisting of phenyl, naphthyl, pyridyl, and mono-, or di-substituted derivatives thereof, wherein the substituents are individually selected from the group consisting of:
(1) halo,
(2) hydroxy,
(3) cyano,
(4) carboxy,
(5) amino carbonyl,
(6) C1-3alkyl,
(7) C1-3fluoroalkyl,
(8) C1-3alkylcarbonyl,
(9) C1-3alkoxycarbonyl,
(10) C1-3alkoxy,
(11) C1-3alkylthio and
(12) C1-3alkylsulfonyl.
A subset of compounds that are of particular interest are defined in accordance with formula III wherein:
R1 is selected from the group consisting of:
(a) methyl,
(b) phenyl and
(c) mono- or disubstituted phenyl, wherein the substituents are selected from the group consisting of:
(1) halo and
(2) deuterio; and
R5 is arylC3-5alkyl wherein aryl is selected from the group consisting of phenyl and naphthyl.
Representative compounds that are of particular interest are the following:
Yet another embodiment that is of particular interest is represented by formula IV:
including pharmaceutically acceptable salts thereof, wherein:
R9 is selected from the group consisting of:
(a) CO2H,
(b) CO2C1-4alkyl,
(c) SC1-4alkyl and
(d) S(O)2C1-4alkyl;
R10 is selected from the group consisting of:
(a) H,
(b) CH2CO2H,
(c) CH2CO2C1-4alkyl,
(d) CH2S(O)2C1-4alkyl; and
Ar is selected from the group consisting of:
(a) phenyl and
(b) napthyl.
A subset of compounds that are of particular interest are defined in accordance with formula IV wherein:
R9 is selected from the group consisting of:
(a) CO2H,
(b) SCH3 and
(c) S(O)2CH3;
R10 is selected from the group consisting of:
(a) H and
(d) CH2S(O)2CH3; and
Ar is phenyl or napthyl.
Representative compounds that are of particular interest are the following:
In a preferred embodiment, the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said caspase-3 mediated disease.
In another embodiment, the invention encompasses a method of treating cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), type I diabetes, immune deficiency syndrome (including AIDS), cerebral and spinal cord trauma injury, organ damage during transplantation, alopecia, aging, Parkinson""s disease, Alzheimer""s disease, Down""s syndrome, spinal muscular atrophy, multiple sclerosis and neurodegenerative disorders, comprising administering to a mammalian patient in need of such treatment an effective amount of a compound of formula I.
In another embodiment, the invention encompasses a method of treating acute disorders, including cardiac and cerebral ischemia/reperfusion injury (e.g. stroke), spinal cord injury and organ damage during transplantation, in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said acute disorder.
In another embodiment, the invention encompasses a method of treating chronic disorders, including neurodegenerative diseases (e.g. Alzheimer""s, polyglutamine-repeat disorders, Down""s, spinal muscular atrophy, multiple sclerosis), immunodeficiency (e.g. HIV), diabetes, alopecia and aging, in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula I in an amount effective to treat said chronic disorder.
In another embodiment, the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula II in an amount effective to treat said caspase-3 mediated disease.
In another embodiment, the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula III in an amount effective to treat said caspase-3 mediated disease.
In another embodiment, the invention encompasses a method of treating a caspase-3 mediated disease in a mammalian patient in need of such treatment, comprising administering to said patient a compound of formula IV in an amount effective to treat said caspase-3 mediated disease.
For purposes of this specification, the following abbreviations have the indicated meanings:
For purposes of this specification alkyl means linear, branched or cyclic structures and combinations thereof, containing one to twenty carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclopropyl, cyclopentyl, cycloheptyl, adamantyl, cyclododecylmethyl, 2-ethyl-1-bicyclo[4.4.0]decyl and the like.
Alkylcarbonyl signifies groups having the formula xe2x80x94C(O)xe2x80x94 alkyl, wherein alkyl is defined as above.
Alkylsulfonyl signifies groups having the formula xe2x80x94S(O)2xe2x80x94 alkyl, wherein alkyl is defined as above.
For purposes of this specification fluoroalkyl means linear, branched or cyclic alkyl groups and combinations thereof, of one to ten carbon atoms, in which one or more hydrogen but no more than six is replaced by fluorine. Examples are xe2x80x94CF3, xe2x80x94CH2CH2F, and xe2x80x94CH2CF3, and the like.
Alkoxy means alkoxy groups of one to ten carbon atoms of a straight, branched or cyclic configuration. Examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, and the like.
Alkoxycarbonyl signifies groups having the formula xe2x80x94C(O)xe2x80x94 alkoxy, wherein alkoxy is defined as above.
Alkylthio means alkylthio groups of one to ten carbon atoms of a straight, branched or cyclic configuration. Examples of alkylthio groups include methylthio, propylthio, isopropylthio, etc. By way of illustration, the propylthio group signifies xe2x80x94SCH2CH2CH3.
Aryl is, for example, phenyl, naphthyl, pyridyl, furyl, thienyl, thiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, pyrazinyl, pyrimidyl, quinolyl, isoquinolyl, benzofuryl, benzothienyl, pyrazolyl, indolyl, purinyl, isoxazolyl, oxazolyl and coumarinyl.
Halo includes F, Cl, Br and I.
The compounds described typically contain asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
The pharmaceutical compositions of the present invention comprise a compound of formula I as an active ingredient or a pharmaceutically acceptable salt thereof in combination with a pharmaceutically acceptable carrier, and optionally other therapeutic ingredients. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable bases including inorganic bases and organic bases. Representative salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, ammonium, potassium, sodium, zinc and the like. Particularly preferred are the calcium, magnesium, potassium, and sodium salts. Representative salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nxe2x80x2-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Examples of such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids.
In the discussion of methods of treatment which follows, reference to the compounds of formula I are meant to also include the pharmaceutically acceptable salts.
The ability of the compounds of formula I to inhibit caspase-3 make them useful research tools in the field of apoptosis. These compounds are also useful to treat, prevent or ameliorate in mammals and especially in humans, diseases including but not limited to:
1. cardiac and cerebral ischemia/reperfusion injury (e.g. stroke)
2. type I diabetes
3. immune deficiency syndrome (including AIDS)
4. cerebral and spinal cord trauma injury
5. organ damage during transplantation
6. alopecia
7. aging
8. Parkinson""s disease
9. Alzheimer""s disease
10. Down""s syndrome
11. spinal muscular atrophy
12. multiple sclerosis
13. neurodegenerative disorders
The magnitude of therapeutic dose of a compound of formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of formula I and its route of administration and vary upon the clinician""s judgement. It will also vary according to the age, weight and response of the individual patient. An effective dosage amount of the active component can thus be determined by the clinician after a consideration of all the criteria and using is best judgement on the patient""s behalf. A representative dose will range from 0.001 mpk/d to about 100 mpk/d.
An ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of formula I in an acceptable ophthalmic formulation may be used.
Any suitable route of administration may be employed for providing an effective dosage of a compound of the present invention. For example, oral, parenteral and topical may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The compositions include compositions suitable for oral, parenteral and ocular (ophthalmic). They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
In practical use, the compounds of formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, alcohols, oils, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case or oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amound of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformLy and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. For example, each dosage unit may contain from about 0.01 mg to about 1.0 g of the active ingredient.
Method of Synthesis
Compounds of the instant invention are conveniently prepared using the procedures described generally below and more explicitly described in the Example section thereafter.
A mixed anhydride of N-protected-L-aspartic acid xcex2-tert-butyl ester (protected-L-Asp (OtBu)-OH)(V) and isobutylchloroformate (IBCF) is formed in the presence of N-methylmorpholine (NMM). This anhydride is reduced to the corresponding alcohol VI using sodium borohydride at xe2x88x9278xc2x0 C. The alcohol VI is then oxidized using dimethyl sulfoxide (DMSO), oxalyl chloride, and N,N-diisopropylethylamine to the corresponding aldehyde. The aldehyde (VII) is not isolated but reacted immediately with an organometallic reagent to afford the secondary alcohol (VIII) which can be oxidized to the corresponding ketone (IX).
The ketones IX are loaded onto a solid support using the technology described by Webb et al. (J. Am. Chem. Soc. 114, 3156 (1992)). This method uses the solution synthesis of the complete semicarbazone carboxylic acid linker XI by first reacting ketone IX with semicarbazidyl-trans-4-methyl cyclohexanecarboxylic acid trifluoroacetate salt (X) to give XI. Coupling of XI to the commercially available Merrifield resin gives the insoluble support XII. This material has all the physical and chemical properties for the automated synthesis of peptides.
Toward this end the 9050 Plus PepSynthesizer from PerSeptive Biosystems is used (Millipore Corporation, 34 Maple Street, Milford, Mass. 01757, User""s Guide 9050 Plus OM 1.0). The synthesis procedure given in the user""s guide is followed for the preparation of the tetrapeptide XIII on solid support.
O-(7-Azabenzotriazol-l-yl)N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU) and N,N-diisoproylethylamine (DIEA) are used as coupling reagents instead of of TBTU and HOBt as described in the user""s guide.
The uncapped tetrapeptide XIII is acylated and peptide I can be obtained by simultaneous deesterification and cleavage from solid support via exposure to a 9:1 mixture of TFA:H2O.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) all operations were carried out at room or ambient temperature, that is, at a temperature in the range 18-25xc2x0 C.,
(ii) evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 pascals: 4.5-30 mm. Hg) with a bath temperature of up to 60xc2x0 C.,
(iii) the course of reactions was followed by thin layer chromatography (TLC) and reaction times are given for illustration only;
(iv) melting points are uncorrected and xe2x80x98dxe2x80x99 indicates decomposition; the melting points given are those obtained for the materials prepared as described; polymorphism may result in isolation of materials with different melting points in some preparations;
(v) the structure and purity of all final products were assured by at least one of the following techniques: TLC, mass spectrometry, nuclear magnetic resonance (NMR) spectrometry or microanalytical data;
(vi) yields are given for illustration only;
(vii) when given, NMR data is in the form of delta (xcex4) values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as internal standard, determined at 300 MHz or 400 MHz using the indicated solvent; conventional abbreviations used for signal shape are: s. singlet; d. doublet; t. triplet; m. multiplet; br. broad; etc.: in addition xe2x80x9cArxe2x80x9d signifies an aromatic signal;
(viii) chemical symbols have their usual meanings; the following abbreviations have also been used v (volume), w (weight), b.p. (boiling point), m.p. (melting point), L (litre(s)), mL (millilitres), g (gram(s)), mg (milligrams(s)), mol (moles), mmol (millimoles), eq (equivalent(s)).

Gamma-ketoacid tetrapeptides as inhibitors of caspase-3

Abstract: The invention also encompasses certain pharmaceutical compositions for treatment of caspase-3 mediated diseases comprising compounds of formula I.


The present invention regards method and apparatus relating to wireless office system. The present invention addresses the problem of enabling it to be determined in the wireless office system (5) when voice mail messages for users of mobile stations having subscriptions in the wireless office system (5) are received at the voice mail system (15), the voice mail system (15) being associated with but not included in the wireless office system (5). The duration(s) of greeting message(s) associated with the voice mail system (15) and the or each mobile station having an associated voice mailbox (16b1-16bM) in the voice mail system (15) is/are measured. The connection times to the voice mail system (15) are measured when calls for the mobile stations are forwarded to the voice mail system (15) from the wireless office system (5). By comparing the duration(s) of the greeting message(s) with the measured connection times, it is determined whether voice mail messages have been received.

The present invention belongs to the field of methods and apparatuses relating to a wireless office system, and in particular to a wireless office system which is associated with a voice mail system providing voice mail services to one or more mobile stations having subscriptions in the wireless office system.
A PBX (Private Branch Exchange) is a local telephony switching system which interconnects a number of fixed phones, typically in an office or similar. The PBX enables the introduction of a local numbering plan which makes it possible to perform calls between the fixed phones connected to the PBX using local short (4-5 digit) numbers. The marginal costs associated with setting up calls between the fixed phones connected to the PBX is also very low, since connections are set up in the PBX without using an outside telephone network such as a PSTN (Public Switched Telephone Network), i.e. a conventional fixed telephone network.
Furthermore, the PBX is capable of performing various telephone management functions, such as integrating a voice mail system having voice mailboxes associated with the fixed phones connected to the PBX (see for example U.S. Pat. No. 5,561,703; or U.S. Pat. No. 5,388,151). If a call is made to one of the fixed phones connected to the PBX and a subscriber associated with the fixed phone does not answer, then the call is forwarded to the voice mail system, which plays a recorded so called greeting message to a calling party. The greeting message requests the calling party to leave a voice mail message, which will be recorded in a voice mailbox associated with the called fixed phone. When a message has been recorded in the voice mailbox, a small packet of informationxe2x80x94a message waiting indicator MWI (also known as a voice mail notification)xe2x80x94is sent from the voice mail system, via the PBX, to the called fixed phone. The MWI normally contains information about the number of the calling party, a voice mail index and, if known, the name of the calling party. The fixed phone is arranged for indicating the receipt of the MWI, for example by flashing a light or by presenting information relating to the MWI on a display. The gain of receiving a MWI is clear, since users of the fixed phones must not continuously check whether they have new voice mail messages in the voice mail system.
Today there is an increasing interest in wireless communications, for example mobile (cellular) telephony or mobile data transfer. So called wireless office systems (WOS) have therefore been developed in order to incorporate mobile stations, e.g. mobile telephones, mobile communicators or mobile computers having radio communication capabilities, into the local numbering plan. The WOS comprises a number of radio nodes, commonly known as radio heads. The radio heads are arranged for performing functions that are similar to the functions performed by radio base stations in a PLMN (Public Land Mobile Network). The radio heads are thus arranged for providing radio communication coverage in different parts of the office (or other location) where the local numbering plan is to be implemented. Mobile stations, when being present in the coverage area of the radio heads, are able to communicate with the radio heads over a radio interface. The WOS further comprises a radio control system, which controls the radio traffic between the mobile stations and the radio heads, and a switching system, which provide the necessary switching functions of the WOS. The WOS is normally connected to the PBX by means of a PRI (primary rate interface). With the WOS, it is therefore possible, using a local short number, to make a call to a mobile station, having a subscription in the WOS, from a fixed phone connected to the PBX or from a mobile station being in the coverage area of the radio heads. It is also possible, using a local short number, to make a call from a mobile station being in the coverage area of the radio heads to one of the fixed phones connected to the PBX. The marginal costs for making these calls are also very low, since the connections are set up in the WOS and, when appropriate, in the PBX. The WOS can also be used on it own without being connected to a PBX.
When a voice mail system is integrated with the PBX, it is not unusual that the voice mail system is also shared with the WOS that is connected with the PBX. One or more mobile stations, having subscriptions in the WOS, will then have associated voice mailboxes in the voice mail system. However, a drawback with having a shared voice mail system is that not all PRIs are able to transfer MWIs, and therefore it is not always possible to send MWIs from the voice mail system to the mobile stations having subscriptions in the WOS.
The present invention relates to a wireless office system providing wireless communication services to a predetermined number of mobile stations having subscriptions in the wireless office system. One or more of the mobile stations also have associated voice mailboxes in a voice mail system which is associated with but not included in the wireless office system.
The present invention addresses the problem of enabling determination in the wireless office system of when voice mail messages for users of the mobile stations are received at the voice mail system.
In short, the above stated problem is solved according to the following. The duration(s) of greeting message(s) associated with the voice mail system and the or each mobile station having an associated voice mailbox in the voice mail system is/are measured. The connection times to the voice mail system are measured when calls for the mobile stations are forwarded to the voice mail system from the wireless office system. By comparing the duration(s) of the greeting message(s) with the measured connection times, it is determined whether voice mail messages have been received.
The main object of the present invention is thus to enable determination in a wireless office system of when voice mail messages for users of the mobile stations are received at the voice mail system. The present invention includes methods, devices and systems relating to the above stated object.
The above stated problem can be solved more specifically according exemplifying embodiments of the invention. For example, in one exemplifying embodiment, the wireless office system is connected to a private branch exchange, and the voice mail system is shared between the wireless office system and the private branch exchange.
A main advantage of the present invention, in addition to solving the above stated problem, is that the invention provides the possibility to send message waiting indicators to the mobile stations, even if it is not possible to send message waiting indicators from the voice mail system to the wireless office system.

Method and apparatus relating to wireless office system


An electric cable and in particular a coaxial cable, said cable having at least one conductor surrounded by electrical insulation and at least one longitudinal strength member formed by a cord of aromatic polyamide fibres, disposed parallel to the conductor or twisted in a helix therearound. Various kinds of cords are described: twisted; non-twisted; in one or in several layers; embedded in insulation or constituting the insulation.

Electric cables used at present include strength members so that they can be suspended between posts or vertically. These strength members are constituted by steel wires which carry the mechanical stresses. These wires are sometimes inserted in the cores of cables (coaxial sub-marine cables) or between conductors. In most cases they are wound round cables and constitute their outer reinforcement.
The disadvantage of metal strength members is that they modify the dielectric characteristics of the insulation. Further, they increase the volume of the cable when they constitute its outer reinforcement and in any case, they increase its weight very appreciably.
It has already been proposed to provide electric cables with longitudinal strength members made of a synthetic resin, for example an aliphatic polyamide such as Nylon, or ethylene-glycol polyterephthalate or polyesters, or polyolefines, or polycarbonates, etc. (French Pat. No. 2 039 355, U.S. Pat. Nos. 3,265,809 and 3,980,808). Such strength members have the disadvantage of allowing the cable to elongate appreciably and of not being very resistant to moisture, so that metal strength members have continued to be used despite their disadvantages.

Electric cable with a longitudinal strength member

Societe Anonyme dite: Les Cables de Lyon


A heat exchanger comprising tubes (4) for configuring a first heat exchanger (A) and tubes (5) for configuring a second heat exchanger (B), the tubes (4) and (5) being disposed upstream and down stream of a direction that air is flown, fins (6) disposed between the tubes (4), (5), and ends of the respective tubes (4), (5) connected into the respective tanks (2), (3), wherein the fins (6) have louvers (7A), (7B), which are formed into a group of louvers (7A), (7A) formed on the fins disposed in the first heat exchanger (A) and a group of louvers (7B), (7B) formed on the fins disposed in the second heat exchanger (B), these two groups having a different shape of louvers.

Conventionally, there is known a heat exchanger, which is made of two heat exchangers, which are used differently. Such a heat exchanger is proposed to have a first heat exchanger, which is configured to have tubes and fins between a pair of tanks, and a second heat exchanger, which is also configured in the same way as the first heat exchanger, both disposed in parallel to each other and integrally connected to each other as described in, for example, Japanese Utility Model Publication No. Hei 6-45155 and Japanese Patent Application Laid-Open Publication No. Hei 7-332890.
Japanese Utility Model Application Laid-Open Publication No. Hei 2-54076 proposes a heat exchanger having a first heat exchanger and a second heat exchanger which are formed into one body, which is configured by stacking flat plate fins, connecting to communicate a plurality of tubes with the plate fins, connecting ends of the tubes to an end plate configuring a tank, and assembling a tank plate to the end plate, wherein the end plate and the tank plate are separately formed or the tank plate is separately formed.
There is also known another heat exchanger, which is produced with two different heat exchangers assembled in series vertically or horizontally. As described in, for example, Japanese Utility Model Publication No. Sho 59-16692 and Japanese Utility Model Application Laid-Open Publication No. Hei 2-36772, there is proposed a heat exchanger which is in a single form structurally but actually has two heat exchangers by disposing tubes and fins between a pair of tanks and a partition plate at the midpoint of the pair of tanks.
Such a heat exchanger has the tanks and tubes to form a heat exchange medium passage and the fins to form an air passage. And, a heat exchange medium supplied from the tank is flown through the plurality of tubes to make heat exchange with the exterior by means of the fins.
The fin is formed to have a corrugated side view with the same pitch by passing a flat fin material through gear-shaped rolls, which are vertically disposed in several sets to shrink the fin material in a longitudinal direction or to compress it. And, in view of improvement of the heat exchange rate and an airflow resistance, the fins are generally formed with louvers on surfaces thereof, and the louvers are formed by the rolls when the fins are formed into the corrugated shape.
In the conventional heat exchanger formed by combining two heat exchangers, the fins disposed between the tubes are often integrally formed and disposed in the first and second heat exchangers. But, the individual heat exchanger has different use, performance and requirements of different heat radiation degrees and airflow resistances. Therefore, where the fins are formed to conform to the performance of one of the heat exchangers, the heat exchange rate of the other heat exchanger is lowered.
Accordingly, the fins connected to the first heat exchanger are separately formed from those connected to the second heat exchanger. But, it is not desirable to form the fins separately for the first and second heat exchangers because the number of parts increases and workability becomes complicated.
In view of the above, the present invention aims to provide a heat exchanger which can have an improved heat exchange performance with the above-described disadvantages remedied without forming the fins separately for the first and second heat exchangers.