A substrate processing system (100) includes a main transfer line (20) configured to transfer wafers (W) over the entire system, and an auxiliary transfer line (30) configured to transfer wafers (W) inside a photolithography process section (1a). The photolithography process section (1a) is arranged such that a resist coating process apparatus (2) and a developing process apparatus (5) are disposed separately from each other, a first light exposure process apparatus (3a) and a first PEB process apparatus (4a) are disposed adjacent to each other, and a second light exposure process apparatus (3b) and a second PEB process apparatus (4b) are disposed adjacent to each other.

In the process of manufacturing semiconductor devices, a photolithography sequence is repeatedly performed to form patterns on a semiconductor wafer (which may be simply referred to as "wafer" hereinafter). The photolithography sequence comprises a resist coating process for forming a resist film on the surface of a semiconductor wafer, a light exposure process for performing light exposure by use of a light exposure mask on the wafer with the resist film formed thereon, and a developing process for performing development on the wafer after the light exposure. Further, a pre-light-exposure baking (PAB) process is performed before the light exposure process, and a post-light-exposure baking (post-exposure baking; PEB) process is performed after the light exposure process.
In semiconductor manufacturing processes, photolithography sequences are respectively performed by photolithography process sections connected to an AMHS (Automated Material Handling Systems) in the factory. Conventionally, due to process restrictions, each photolithography process section is arranged such that a resist coating/developing process apparatus and light exposure process apparatus are disposed in series as one unit, so that wafers W are transferred between this unit and the AMHS described above (for example, Jpn. Pat. Appln. KOKAI Publication No. 2000-124124 (paragraph 0027 and FIG. 2)). In a conventional apparatus having such layout, a plurality of wafers are transferred from the AMHS by use of cassettes, and are supplied onto the resist coating/developing process apparatus of each photolithography process section in units of a cassette. Then, the wafers W are taken out one by one from the cassette by a transfer mechanism of the resist coating/developing process apparatus, and are subjected to a series of processes, such as resist coating, light exposure, and development.
In recent years, along with improvements of technical nodes in semiconductor devices, i.e., progress of the miniaturization level of semiconductor devices, new techniques, such as double light exposure, have been developed. The double light exposure is arranged to process a wafer with a resist film formed thereon such that, for example, a light exposure process is first performed in accordance with a predetermined line width, and a second light exposure process is then performed with a different mask position in accordance with a smaller line width, so as to improve the resolution. However, the double light exposure technique literally comprises two light exposure processes, and thus doubles the time period necessary for the photolithography sequence by simple arithmetic. Accordingly, there is concern that the double light exposure technique significantly lowers the throughput in manufacturing semiconductor devices.

Substrate processing system and substrate transfer method


Distortion amounts .delta.1, .delta.2, .delta.12 of workpieces are measured. Based on these distortion amounts, those correction amounts A1, A2, A3 for correcting the workpieces which are required to eliminate the distortions after the workpieces have been combined are computed. Clamp units are moved to thereby deflect the workpieces by the correction amounts. In this state, the workpieces are combined.

1. Field of the Invention
The present invention relates to a method of combining or joining workpieces in which two or more workpieces are set in position on a jig having mounted thereon clamp units and then these workpieces are combined while they are clamped by the clamp units.
2. Description of the Related Art
In Japanese Published Unexamined Patent Application No. 153387/1989, the following method is conventionally known. Namely, clamp units are arranged to be movable. In the first place, workpieces are combined by clamping them together in a condition or state in which the clamp units are positioned in predetermined reference positions to be determined by design data. Then, the accuracy of a product thus assembled by this combining work is optically measured. Based on the result of this measurement, the positions of the clamp units are corrected and the combining work and its accuracy measurement are performed with the next workpieces. These steps are repeated until a product having a desired accuracy can be obtained.
An example is now considered in which a product having a closed cross section is assembled by combining two workpieces Wa, Wb as shown in FIG. 1. For example, if the workpiece Wa has a distortion .delta. as shown in FIG. 2A, the workpiece Wa will be forcibly deflected by the amount of the distortion .delta. as shown in FIG. 2B at the time of clamping. If the product W is assembled by combining the workpieces in this state, the product W will give rise to a distortion .delta.' by springing back when it is unclamped as shown in FIG. 2C.
In the above-described conventional art, this kind of distortion .delta.' in the product is measured, and the positions of the clamp units are corrected in a direction to decrease the distortion, followed by the combining work of the next workpieces. In this kind of feedback system of correction, however, it is impossible to obtain a product of higher accuracy from the very beginning, with the result that much waste occurs. Further, workpieces have an inherent dispersion of their own within the same lot in addition to a dispersion from lot to lot. In case the distortion of the workpieces of this time is different from the distortion of the workpieces of the last time, the correction based on the measured data of the product obtained by the combining the workpieces of the last time does not apply to the workpieces of this time any more. It follows that the conventional feedback system of correction cannot deal with the dispersions of the respective workpieces.


A system and method of demodulating antenna data containing multiple signals in multiple protocols for multiple users is disclosed. The method comprises buffering the antenna data with an input buffer of the demodulation system. Next, the protocol to be demodulated is determined and a dynamically reconfigurable datapath for the system is configured for that protocol. The antenna data containing multiple signals is read from the input buffer, demodulated by the datapath, and stored in an output buffer. The next protocol to be demodulated is determined and the datapath is configured appropriately. Again, the signal for each of the users is demodulated by the datapath and the output data is stored in the output buffer. This process continues until all of the signals for all of the users have been demodulated for all of the prescribed protocols.

1. Field of Invention
The present invention generally relates to a method and system for demodulating data and more particularly to a method and system utilizing the capabilities of a reconfigurable datapath for the demodulation of antenna data containing information in multiple protocols.
2. Status of the Prior Art
Currently, wireless communication systems, such as CDMA, are based upon multiple users sharing a common spectrum. The data for the different users may be coded according to different standards (different protocols). The base stations for the wireless communication system receive the data for all of the users through a common input. Each base station demodulates the data with decoding techniques corresponding to the coding defining the standard that separates the multiple users.
In order to properly demodulate the data, the wireless communication base station uses specialized hardware for each algorithm and protocol in the demodulation process. Multiple users and multiple protocols are accommodated by running specialized hardware in parallel. Dedicated hardware for each protocol runs a respective algorithm to demodulate the data. The hardware for each protocol are run in parallel to demodulate the data from the common input.
The use of specialized hardware for the demodulation of each protocol adds considerable expense to the system. The dedicated hardware must be designed, tested and fabricated for each protocol. Additionally, the size of the system will increase as each piece of hardware is added for each protocol to be demodulated. The adaptability of the system is also compromised due to the fact that new hardware must be designed and installed in order to implement new protocols.
The present invention addresses the above-mentioned deficiencies in prior art systems by providing a method and system of demodulating data from multiple users using multiple protocols defined in multiple standards with a dynamically reconfigurable datapath. The present invention provides a method and system whereby data for multiple users using multiple protocols (standards) is demodulated by using dynamically reconfigurable hardware with repeatedly read-buffered data antenna input data.

Demodulation of multi-user, multi-protocol data in a reconfigurable datapath


A system and method for using asynchronous changes to memory to detect malware is disclosed. The technology initially receives a memory buffer location to be evaluated, the memory buffer location possibly having at least a portion of malware therein. The technology then performs a plurality of double fetches to the memory buffer location. The technology additionally compares a plurality of responses to the plurality of double fetches, wherein a plurality of similar responses to the plurality of double fetches indicates the portion of malware is not present and wherein at least two distinct responses to the plurality of double fetches indicates the portion of malware is present.

Malware is software designed to infiltrate or damage a computer system, without the owner's consent. The term is probably a combination of "malicious" and "software", and describes the intent of the creator, rather than any particular features. The term malware normally encompasses computer viruses, Trojan horses, spyware and adware.
Many early infectious programs, including the Internet Worm and a number of viruses, were written as experiments or pranks. That is, they were intended to be annoying rather than to cause serious damage. For example, programmers might write an infectious program just to prove that they can do it, or to see how far the infectious program could spread.
A slightly more hostile intent can be found in programs designed to vandalize or cause data loss. For example, some viruses are designed to destroy files or corrupt a file system by writing junk data. Other viruses include network-borne worms designed to vandalize Web pages. In other cases, revenge is the motivator for writing malicious software. For example, a programmer about to be fired from a job will generate a virus to damage the former employer's systems or destroy the programmer's own earlier work.
Moreover, a large portion of malicious software is focused strictly on a profit motive. For example, a majority of viruses and worms have been designed to take control of users' computers. Infected computers are "hijacked" and are remotely used to send email spam, host contraband data or engage in distributed denial-of-service attacks as a form of extortion.
Another strictly for-profit category of malware has emerged in spyware. That is, programs designed to monitor users' Internet browsing. In some cases, the spyware displays unsolicited advertisements which provide marketing revenues to the spyware creator.
Presently, stealth malware will try to hide itself on the computing system such that user's cannot see it. Thus, the user will not recognize the malware infection and as such, will not know that the computing system is infected until it is too late. That is, after the malware has performed its malicious purpose. In one case, the malware will hook the application programming interface (API) to present a view of the filesystem, registry, and the like that doesn't show or contain the resources of the malware.
Current methods for detecting stealth malware include checking or detecting patching of either data-structures or code. However, the malware can easily change the patch points to bypass these checks. Moreover, the checking and detecting techniques likely requires loading kernel mode drivers which is difficult and time consuming.
Therefore, what is needed is a method for using asynchronous changes to memory to detect malware.

Using asynchronous changes to memory to detect malware


Clusters are described which may be utilized to organize electronically-stored items. A variety of techniques may be employed using the clusters to organize the items. For instance, the clusters may be automatically generated and then modified by a user to classify the items as desired such that a modification made to a single item is propagated to other similar items. Therefore, the single item and the other similar items may be clustered automatically through interaction with the single item.

Users are continually exposed to ever increasing numbers of electronically stored items. For example, users may store documents, spreadsheets, photos, music, and messages electronically. However, as the number of electronically-stored items has continued to increase, so to has the difficulty in locating a particular item of interest.
Message communication, for example, has become and continues to be one of the most prevalent uses of computing devices, such as personal computers, wireless phones, and so on. For instance, users may communicate, one to another, through the use of email (i.e., electronic mail), instant messages, and so on. The amount of messages that is received by the user is ever increasing, however, and may consequently hinder the user's efficiency in dealing with each message. For example, the user may not be able to readily differentiate between these different uses of messages (e.g., work and personal), and therefore not readily navigate to particular messages of interest. Other types of electronically-stored items suffer from similar difficulties. The user, for instance, may stores thousands of songs and photos on a portable digital device and may therefore encounter difficulty in locating a particular photo or song.

Cluster organization of electronically-stored items


A mold-releasable curable organopolysiloxane composition suitable for use as a material of a matrix mold having excellent durability of mold releasability in the preparation of replicas by resin casting is disclosed. The composition comprises, in addition to the conventional ingredients including a vinyl-containing diorganopolysiloxane, an organohydrogenpolysiloxane as a crosslinking agent of the diorganopolysiloxane, a reinforcing silica filler and a platinum compound as a catalyst, a strongly alkaline compound of an alkali metal such as potassium hydroxide, potassium siliconate, lithium siliconate and the like in a limited amount.

The present invention relates to a mold-releasable curable organopolysiloxane composition or, more particularly, to a curable organopolysiloxane composition suitable as a material of a matrix mold having good mold-releasability for the preparation of replicas from an epoxy resin, urethane resin, plaster of paris and the like by casting into the matrix.
It is a well established technology to prepare replicas by using a matrix mold made from a cured silicon rubber into which a curable liquid resin such as epoxy resins, urethane resins and the like is cast and cured therein into a replica body. A great variety of parts in automobiles, electric appliances and others are fabricated by this technique and are under practical use. As a trend in recent years, these casting-prepared resin parts are required to be more and more upgraded in respect of performance as well as in appearance. In this regard, improvements are now under way in the properties of the casting resin while the improvements in the properties of the casting resin per se are sometimes accompanied by an adverse influence on the surface of the silicone rubber-made matrix mold greatly decreasing the durability of the mold or the number of replica pieces prepared by using a single matrix mold to cause an economical disadvantage.
With an object to improve the durability of a silicone rubber-made matrix mold used in resin casting, it is practiced that the finely divided reinforcing silica filler before compounding in the silicone rubber composition is rendered hydrophobic by the surface treatment with an organosilazane compound such as hexamethyl disilazane, octamethyl trisilazane, 1,5-di(3,3,3-trifluoropropyl)-1,1,3,3,5,5-hexamethyl trisilazane and the like. It is also known that silicone rubber-made matrix molds can be imparted with an improved tear strength when the hydrophobic treatment of the reinforcing silica filler is performed with a mixture of the above mentioned organosilazane compound and a vinyl-containing organosilazane compound such as 1,3-divinyl-1,1,3,3-tetramethyl disilazane, 3-vinyl-1,1,1,3,5,5,5-heptamethyl trisilazane, tris(trimethylsilylamino) vinyl silane, vinyl-containing poly(dimethylsilazane) and the like or the hydrophobic reinforcing silica filler is further treated with these vinyl-containing organosilazane compound.
The above mentioned method by the surface treatment of the reinforcing silica filler is indeed effective at least to some extent for increasing the durability in the mold releasability of silicone rubber-made matrix molds but is still not quite satisfactory in respect of the mold releasability with durability when the casting resin is a high-performance urethane resin or epoxy resin as in the major current of the modern resin casting technology.

Mold-releasable curable organopolysiloxane composition


An image-transfer medium for ink-jet printing, comprising a releasing layer and a transfer layer containing fine particles of a thermoplastic resin and a polymeric binder, provided on a base material, wherein the polymeric binder is a thermoplastic resin.

1. Field of the Invention
The present invention relates to a transfer medium suitable for use in forming an image on a printing medium by transfer printing, a transfer printing process using this image-transfer medium and a transfer printing cloth, and more particularly to an image-transfer medium for ink-jet printing in which an ink-jet printing system is used upon forming an ink image on a transfer layer thereof, a transfer printing process in which such an image-transfer medium is used to transfer the image formed on a transfer layer to a portion of a cloth, thereby forming an image on the cloth, and a cloth having the transferred image formed by the transfer printing process.
2. Related Background Art
An ink-jet printing method is a printing method in which printing is conducted by generating and ejecting droplets of an ink by one of various ink ejection systems, for example, an electrostatic attraction system, a system in which a piezoelectric element is used to give an ink mechanical vibration or change, or a system in which an ink is heated to form bubbles in the ink, thereby using the pressure thus produced, and applying the droplets in whole or in part to a printing medium. The ink-jet printing method attracts attention as a printing system which scarcely produces noise and can conduct high-speed printing and color printing.
In recent years, ink-jet printers, by which color printing can be simply conducted as described above, have been spread, and there has thus been an increasing demand for conducting color printing on various media, particularly, cloth, using these printers. In particular, a printing method using an image-transfer medium is very effective in that printing can be conducted irrespective of the forms of printing media, namely, the formation of an image can be performed on any medium which cannot be directly printed by a printer, so that it is possible to conduct printing on a cloth after subjecting to sewing or a large-sized cloth.
As processes in which an image-transfer medium making good use of an ink-jet technique is used, Japanese Patent Application Laid-Open Nos. 58-215392 and 58-222878 have proposed processes for printing an image on a transparent film. The former process is a heat transfer printing process in which an image is formed on a colorless transparent base paper sheet coated with a coating agent, and a transparent film is then laminated on the paper sheet to heat-transfer the image to the film. Accordingly, this process is a process of transferring the image by heat-fusing the film which is a transfer-printing medium. Therefore, this process cannot be applied to transfer-printing media having no heat fusibility. Japanese Patent Application Laid-Open No. 2-295787 has proposed a process in which a swelling layer is provided on a base material, an image is formed on this swelling layer, and the image is transferred to a cloth by heating it from the side of the base material, and a transfer-printing medium used in this process. However, dyes usable in the formation of the image in this proposal are sublimate dyes, so that it cannot be applied if an image-transfer medium is formed of natural fiber such as cotton. Japanese Patent Application Laid-Open No. 62-140879 discloses an image forming process in which an image is formed on a transfer-printing medium having a surface layer having high liquid permeability and fusibility and an ink-retaining layer, and the surface layer of the transfer medium is brought into contact with a medium to be transferred, thereby fuse-bonding the surface layer, and a printing medium. According to this process, it is possible to transfer the image to cloth, but the process involves a problem that since the image is formed on the ink-retaining layer composed mainly of a water-soluble polymer, the transferred image transferred to the cloth is poor in resistance to water and the like.
Japanese Patent Application Laid-Open No. 62-170383 has proposed a printing medium of constitution similar to the present invention though its object is different from that of the present invention. This printing medium comprises a base material and an ink-absorbing layer composed of fine particles of a thermoplastic resin and a polymeric binder provided on the base material. The thermoplastic fine particles are heated into a transparent film after printing, thereby providing a print having high weather resistance. However, if this printing medium is used as an intermediate transfer medium for cloth, it is difficult to transfer the ink-absorbing layer to the cloth even if heated because adhesion between the ink-absorbing layer and the base material is high, whereby a good image cannot be provided.
With respect to the transfer-printing media making good use of an ink-jet technique for forming an image on cloth, there are various problems to be solved as described above. In particular, the following requirements may be mentioned.
(1) Quality of Image Printed by an Ink-jet System:
First, in order to provide a clear transfer image having high color depth on a printing medium such as cloth, it is necessary to keep an image on an image-transfer medium high quality. Accordingly, image-transfer media for ink-jet printing are required to have such performance characteristics that they can receive inks quickly, that they have high ink absorbing capacity, that the diameters of ink dots formed thereon do not more increase than they need, that they can provide ink dots high in optical density and clear in periphery, and that they can provide ink dots having a substantially round shape and a smooth periphery.
(2) Transferability to Cloth:
In order to provide an image having high color depth after transfer, it is necessary for an image formed on a transfer medium to be efficiently transferred to cloth. Accordingly, image-transfer media for ink-jet printing are required to have good transferability to the cloth and further to permit the formation of an image-forming layer (transfer layer) adapted to cloth because the cloth generally has considerably high stretch properties.
(3) Fastness Properties after Transferred to Cloth:
Performance characteristics required of an image formed on cloth after transfer include fastness properties such as fastness to laundering and fastness to perspiration. In particular, when an image is formed by means of a general-purpose ink-jet printer, it is impossible to select optimum coloring materials for individual fibers among various kinds of fibers. Accordingly, in order to permit a wide variety of formation of images for various kinds of fibers, the image-transfer media for ink-jet printing are required to cause coloring materials to strongly fix to cloth so as to prevent the coloring materials from bleed when a transferred image is wetted with water or perspiration even when the coloring materials have no dyeing property to fiber of the cloth in themselves.
It is therefore an object of the present invention to provide an image-transfer medium making good use of an ink-jet printing technique, which permits the formation of a satisfactory image on cloth, a transfer printing process using this medium and a transfer-printing cloth having an image formed by the transfer printing process, and particularly to provide an image-transfer medium for ink-jet printing, which satisfies the following requirements:
(1) having a transfer layer high in ink absorbency;
(2) permitting the formation of a clear transferred image having high color depth on cloth;
(3) having a transfer layer high in adhesion to cloth and providing a transferred image having good transferability; and
(4) having a transfer layer which exhibits high fastness properties after transferred to cloth.
Another object of the present invention is to provide an image-transfer medium for ink-jet printing, which satisfies the above-described requirements (1) to (4) and permits the simple formation of images on cloth even in homes by means of a general-purpose ink-jet printer, and a transfer-printing process using this medium.
The above objects can be achieved by the present invention described below.
According to the present invention, there is thus provided an image-transfer medium for ink-jet printing, comprising a releasing layer and a transfer layer containing fine particles of a thermoplastic resins and a polymeric binder, provided on a base material, wherein the polymeric binder is a thermoplastic resin.
According to the present invention, there is also provided a transfer printing process comprising ejecting inks on a transfer layer of an image-transfer medium for ink-jet printing, which has the transfer layer provided on a base material, in accordance with an ink-jet printing method to form an image, placing cloth on the image-transfer medium from the side of the transfer layer on which the image has been formed, and heating and pressing the transfer layer from the side of the cloth or the base material to transfer the transfer layer to the cloth, thereby forming an image on the cloth, wherein the image-transfer medium for ink-jet printing is the image-transfer medium for ink-jet printing described above.
According to the present invention, there is further provided a transfer-printing cloth having a transfer image formed by the transfer printing process described above.

Image-transfer medium for ink-jet printing, transfer printing process using the same, and transfer printing cloth


The present invention permits translation of SM addresses (*, G1) and (*, G2) to configurable SSM addresses (S0, G0). IGMPv2 group membership queries from the receiver subnet are translated to IGMPv3 membership queries for processing in a SSM network. In the preferred embodiment, packets travel via a connection to the multicast router (mrouter). The mrouter queries an IGMPv2 receiver. The IGMPv2 receiver generates a membership report and sends it back to the mrouter. The mrouter translates the membership report into a (S0, G0) as specified in a multicast address translation table and stores the translation in the Multicast Forward Information Base (MFIB) located in the mrouter. Multicast payload addressed (S0, G0) flowing towards the IGMPv2 receiver can be translated to (S0, G0). When media data is addressed to (S0, G0), the mrouter consults the MFIB for forwarding and can also translate the destination address to (S1, G1).

The internet is a collection of networks that are interconnected logically as a single, large, virtual network. Messages between computers are exchanged by using packet switching. Networks can communicate with one another because they all use a protocol. Protocols are formal descriptions of messages to be exchanged and of rules to be followed in order for two or more systems to exchange information in a manner that all parties will understand.
Internet Protocol (IP) specifies the format of IP packet headers as they travel through the network, performs routing functions and selects the transmission path on which data will be sent. Routers utilize ports and addresses in routing tables to send data packets or cells through the network from node to node. IP handles packet forwarding and transporting of datagrams across a network.
With packet forwarding, computers can send a packet on to the next appropriate network component, based on the address in the packet's header. IP defines the basic unit of data transfer, the datagram or the packet, and it also defines the format of IP packet headers as they travel across the internet.
Every computer on the internet has a unique address. The entire datagram or packet has four entities—the payload field, the next protocol field, the IP field and the layer 2 field. Datagram or packet refers to the combination of the payload, the next protocol field and the IP address.
IP specifies the requirements to route, store and forward data among hosts on the network. IP functions at Layer 3, the network layer, and it provides several services, including host addressing, error notification, fragmentation and reassembly, routing, and packet timeout. The Layer 4 protocol, usually TCP or UDP, presents the data to IP in order to provide basic host-to-host communication. IP then attaches to the packet, in a protocol header, the address from which the data comes and the address of the system to which it is going.
Internet Group Management Protocol (IGMP) is a Layer 3, network layer, protocol whose primary purpose is to allow internet hosts to participate in multicasting. The IGMP standard describes the basics of multicasting IP traffic, including the format of multicast IP addresses, multicast Ethernet encapsulation, and the concept of a host group (a set of hosts interested in traffic for a particular multicast address). IGMP enables a router to determine which host groups have members on a given network segment, but IGMP does not address the exchange of multicast packets between routers.
IGMPv1 was the first widely-deployed version of IGMP. IGMPv2 is an upgrade from the first version of IGMP. IGMPv2 allows group membership termination to be quickly reported to the routing protocol. IGMPv3 is a further upgrade from IGMPv2. IGMPv3 has the ability for a system to report interest in receiving packets only from specific source addresses, or from all but specific source addresses, sent to a particular multicast address. That information may be used by multicast routing protocols to avoid delivering multicast packets from specific sources to networks where there are no interested receivers.
IGMPv3 hosts and routers interoperate with hosts and routers that have not yet been upgraded to IGMPv3. This compatibility is maintained by hosts and routers taking appropriate actions depending on the versions of IGMP operating on hosts and routers within a network. If any older versions of IGMP are present on a Local Area Network (LAN) segment (router interface), the IGMP querier on the router must use the lowest version of IGMP present on the LAN segment.
Multicasting involves sending information from one transmitter to multiple receivers. With multicast, an individual only needs one IP connection to do a videoconferencing session between one city and another city having, for example, four remote offices rather than needing four separate IP connections. A multicast router located in the first city enfolds IP packets in special multicast packets and forwards those packets to a multicast router in the second city which removes the IP packets, replicates them, and then distributes them to the four locations in the second city. In IP networks, the IP multicast protocol involves the use of a special group of addresses known as multicast addresses. Each destination address identifies a group of receivers to which all information is replicated.
The current generation of IP is called IP version 4 (IPv4). IPv4 addresses have two parts: the network ID and the host ID. Under IPv4, there are five classes that support different numbers of networks and hosts. The fourth class belongs to the multicast backbone.
The multicast backbone conserves bandwidth over a distance, relieves congestion on transit links, and makes it possible to address a large population in a single multicast. The first octet of the multicast addresses starts at 224 and runs through 239.
The present invention is directed to the problem of limited IP multicast addresses. IPv4 provides limited addressing space for multicast (220.127.116.11<G<184.108.40.206) for a total of 268 million multicast group addresses.
Source Specific Multicast (SSM) removes the limited address space restriction by allowing each source with IP address (S) to use the entire SSM space, such that each combination of (S, G) represents a different multicast group. However, the problem of limited address space persists in the majority of cases where IGMPv2 is used with SSM and SSM translation from (*, G0) to (S0, G0).
There is no prior art directly targeted towards solving the same problem. SSM translations allow the use of IGMPv2 receivers with a SSM IP network by having the receiver IGMP querier translate (*, G0), IGMPv2 queries, into (S0, G0), IGMPv3 queries, before processing. However, the group address is never translated with SSM translations.
If two channels (*, G1) and (*, G2) are joined by an IGMPv2 receiver, the SSM translations at the querier translates these groups into two SSM groups with (S1, G1) and (S2, G2). There is no flexibility in translating the group address of the (S, G) multicast channel. The rapid rollout of IPTV service by network operators is accelerating the exhaustion of IP multicast address space, in the majority of cases where IGMPv2 receivers are used.
Hence, there is a need in the art for a convenient to implement, reliable, inexpensive and efficient method and device for translating SM addresses (*, G1) and (*, G2) to configurable SSM addresses (S0, G0).

Method and tool for IP multicast network address translation (MNAT)


The present application relates to carboxylic acid amides of general formula

The last decade of oncological research has made it possible for the first time to achieve a molecular understanding of the regulatory mechanisms involved in the formation of tumours. These include, for example, the function of oncogenes, tumour suppressor genes, growth factors, receptors, signal transduction cascades, pro- and anti-apoptotic genes in controlling cell growth, differentiation, migration and cell death. These new findings have also shown, however, that cancer is a multifactorial disease at the molecular level, during the onset of which tissues may undergo malignant degeneration as a result of different mechanisms. This heterogeneity of the malignant cells in turn explains the clinical problems of tumour therapy.
As long ago as 1965 Hayflick postulated (Hayflick, Exp. Cell Res. 37, 614-636 (1965)) that the limited proliferative lifespan of normal somatic cells, replicative senescence, may act as a tumour suppressor mechanism. This hypothesis was supported by experimental work which showed that overcoming replicative senescence is a prerequisite for the malignant transformation of cells (Newbold et al. in Nature, 299, 633-636 (1989); Newbold and Overell in Nature, 304, 648-651 (1983)).
However, only in the last few years has there been any understanding of the molecular mechanisms by which somatic cells achieve the state of replicative senescence.
The ends of eukaryotic chromosomes, the telomers, consist of simple repetitive sequences the integrity of which is essential for the function and structure of the chromosomes. However, linear chromosomes lose a certain length of their telomers in each round of DNA replication, a phenomenon which was recognised by Watson back in 1972 (Watson in Nature New Biol. 239, 197-201 (1972)). The cumulative loss of telomeric DNA over numerous cell divisions constitutes the reason for the limited replicative potential of somatic cells, whereas more than 85% of all tumours in humans reactivate an enzyme, telomerase, to compensate for the loss of telomers and thus become immortal (see Shay and Bacchetti in European Journal of Cancer, 33, 787-791 (1997)).
Telomerase in humans is a ribonucleoprotein (RNP) which is made up of at least one catalytic subunit (hTERT), and one RNA (hTR). Both components have been molecularly cloned and characterised. Biochemically, telomerase is a reverse transcriptase which uses a sequence fragment in hTR as a matrix in order to synthesise a strand of telomeric DNA (Morin in Cell 59, 521-529 (1989)). Methods of identifying telomerase activity as well as methods of diagnosing and treating replicative senescence and immortality by modifying telomers and telomerase have already been described (Morin in Cell 59, 521-529 (1989); Kim et al. in Science 266, 2011-2014 (1994)).
Inhibitors of telomerase may be used for tumour therapy, as somatic cells, unlike tumour cells, are not dependent on telomerase.
Moreover, U.S. Pat. No. 3,940,422 inter alia describes the compound trans-3,4-dimethoxy-cinnamic acid-N-anthranilic acid-amide, which has antiallergenic properties, in particular.
It has now been found that the carboxylic acid amides of general formula
the isomers thereof, particularly the trans-isomers thereof, and the salts thereof, particularly the physiologically acceptable salts thereof, surprisingly have an inhibiting effect on telomerase.
The present invention relates to the new carboxylic acid amides of the above general formula I and the salts thereof, particularly the physiologically acceptable salts thereof, which have an inhibiting effect on telomerase, processes for preparing them, pharmaceutical compositions containing these compounds and the use thereof.
The invention further relates to the use of the above carboxylic acid amides of general formula I in inhibiting telomerase and the preparation of a suitable pharmaceutical preparation.
In the new carboxylic acid amides of the above general formula I
R1 denotes a hydrogen atom, a C1-3-alkyl or trifluoromethyl group,
R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C1-3-alkyl group,
R3 denotes a hydrogen atom or a C1-5-alkyl group,
A denotes a phenyl or naphthyl group substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-6-alkyl, C3-7-cycloalkyl, phenyl, C1-3-alkoxy, cyano, trifluoromethyl or nitro group, whilst the abovementioned monosubstituted phenyl and naphthyl groups may additionally be substituted by a fluorine, chlorine or bromine atom, by a C1-3-alkyl or C1-3-alkoxy group and the abovementioned disubstituted phenyl groups may additionally be substituted by a C1-3-alkyl or C1-3-alkoxy group,
a naphthyl group,
a chromane or chromene group wherein a methylene group may be replaced by a carbonyl group,
or a 5- or 6-membered heteroaryl group optionally substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a C1-3-alkyl or C1-3-alkoxy group, while the 6-membered heteroaryl groups contain one, two or three nitrogen atoms and the 5-membered heteroaryl groups contain an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom, or one or two nitrogen atoms and additionally a phenyl ring may be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms and may also be substituted in the carbon skeleton by a fluorine, chlorine or bromine atom or by a C1-3-alkyl or C1-3-alkoxy group, and
B denotes a phenyl or naphthyl group which is substituted in each case by a carboxy group, by a group which may be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions and may optionally additionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, trifluoromethyl or methoxy group, whilst the abovementioned phenyl groups are additionally substituted
by a C1-3-alkyl group which is substituted by an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C3-7-cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group,
while the amino and imino groups mentioned in the definition of the abovementioned groups may additionally be substituted by a group which can be cleaved in vivo.
By a group which can be converted in vivo into a carboxy group is meant, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, wherein the alcoholic moiety preferably denotes a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, whilst a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-cycloalkanol wherein a methylene group in the 3 or 4 position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol, with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol, a bicycloalkanol having a total of 8 to 10 carbon atoms which may additionally be substituted by one or two C1-3-alkyl groups in the bicycloalkyl moiety, a 1,3-dihydro-3-oxo-1-isobenzfuranol or an alcohol of formula
Raxe2x80x94COxe2x80x94Oxe2x80x94(RbCRc)xe2x80x94OH,
wherein
Ra denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl- C1-3-alkyl group,
Rb denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or a phenyl group and
Rc denotes a hydrogen atom or a C1-3-alkyl group,
by a group which is negatively charged under physiological conditions is meant a carboxy, hydroxysulphonyl, phosphono, tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, C1-6-alkylsulphonylamino, phenylsulphonylamino, benzylsulphonylamino, trifluoromethylsulphonylamino, C1-6-alkylsulphonylaminocarbonyl, phenylsulphonylaminocarbonyl, benzylsulphonylaminocarbonyl or perfluoro-C1-6-alkylsulphonylaminocarbonyl group,
and by a group which can be cleaved in vivo from an imino or amino group is meant, for example, a hydroxy group, an acyl group such as the benzoyl or pyridinoyl group or a C1-6-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, an allyloxycarbonyl group, a C1-16-alkoxycarbonyl group such as the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert. butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, a phenyl-C1-6-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a C1-3-alkylsulphonyl- C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or Raxe2x80x94COxe2x80x94Oxe2x80x94(RbCRc)xe2x80x94Oxe2x80x94COxe2x80x94 group wherein Ra to Rc are as hereinbefore defined.
Moreover, the saturated alkyl and alkoxy moieties containing more than 2 carbon atoms mentioned in the definitions given above and hereinafter also include the branched isomers thereof, such as the isopropyl, tert.butyl, isobutyl group, etc.
Preferred compounds of the above general formula I are those wherein
R1 denotes a hydrogen atom or a C1-3-alkyl group,
R2 denotes a hydrogen, fluorine, chlorine or bromine atom or a C1-3-alkyl group,
R3 denotes a hydrogen atom or a methyl group,
A denotes a phenyl or naphthyl group substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-6-alkyl or C1-3-alkoxy group which may additionally be substituted in each case by a fluorine, chlorine or bromine atom, by a C1-3-alkyl or
C1-3-alkoxy group,
a naphthyl group,
a chromane or chromene group wherein a methylene group may be replaced by a carbonyl group,
or a 5 or 6-membered heteroaryl group, while the 6-membered heteroaryl groups contain one, two or three nitrogen atoms and the 5-membered heteroaryl groups contain an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom, or an imino group optionally substituted by a C1-3-alkyl group and an oxygen or sulphur atom or one or two nitrogen atoms and additionally a phenyl ring may be fused to the abovementioned monocyclic heteroaryl groups via two adjacent carbon atoms, and
B denotes a phenyl or naphthyl group which may be substituted in each case by a carboxy group, by a group which may be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions and optionally additionally substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, trifluoromethyl or methoxy group, whilst the abovementioned phenyl groups are additionally substituted
by a C1-3-alkyl group, which is substituted by an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C3-7-cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group,
the isomers thereof and the salts thereof.
Particularly preferred compounds of the above general formula I are those wherein
R1 denotes a hydrogen atom or a C1-3-alkyl group,
R2 denotes a hydrogen atom or a methyl group,
R3 denotes a hydrogen atom,
A denotes a phenyl group mono- or disubstituted by fluorine, chlorine, bromine or iodine atoms, by C1-5-alkyl or methoxy groups, while the substituents may be identical or different, or
a naphthyl group optionally substituted by a fluorine, chlorine or bromine atom, by a methyl or methoxy group,
a chromene group wherein a methylene group is replaced by a carbonyl group, or
a benzofuryl, benzothienyl, quinolyl or isoquinolyl group optionally substituted by a methyl group and
B denotes a naphthyl group substituted by a carboxy group or
a phenyl group substituted by a carboxy, methoxycarbonyl, ethoxycarbonyl or tetrazolyl group which may optionally be substituted by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl, a trifluoromethyl or a methoxy group and is additionally substituted
by a C1-3-alkyl group, which is substituted by an amino, C1-4-alkylamino, di-(C1-4-alkyl)-amino, C3-7-cycloalkylamino, pyrrolidino, piperidino, morpholino, piperazino or N-(C1-3-alkyl)-piperazino group,
the isomers thereof and the salts thereof.
Most particularly preferred new compounds of the above general formula I are those wherein
R1, R2, R3 and A are as hereinbefore defined,
and B has the meanings given hereinbefore, while the carboxy, methoxycarbonyl, ethoxycarbonyl or tetrazolyl substituent is in the 2 position and the alkyl group which is substituted as described above is in the 5 position of the phenyl ring,
the isomers thereof and the salts thereof,
but particularly those compounds of general formula I wherein
R1 denotes a methyl group,
R2 denotes a hydrogen atom,
R3 denotes a hydrogen atom,
A denotes a naphthyl group
and B denotes a 2-carboxy-phenyl group, while the abovementioned 2-carboxy-phenyl group is additionally substituted in the phenyl nucleus
in the 5 position by a methyl group which is substituted by an amino, C1-4-alkylamino, di-(C1-3-alkyl)-amino, cyclopentylamino or pyrrolidino group,
the isomers thereof and the salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(1) trans-3-(naphth-2-yl)-but-2-enoic acid-N-(2-carboxy-5-dimethylaminomethyl-phenyl)-amide,
(2) trans-3-(naphth-2-yl)-but-2-enoic acid-N-[2-carboxy-5-(pyrrolidin-1-yl)methyl-phenyl]-amide,
(3) trans-3-(naphth-2-yl)-but-2-enoic acid-N-(2-carboxy-5-ethylaminomethyl-phenyl)-amide,
(4) trans-3-(naphth-2-yl)-but-2-enoic acid-N-(2-carboxy-5-isopropylaminomethyl-phenyl)-amide,
(5) trans-3-(naphth-2-yl)-but-2-enoic acid-N-(2-carboxy-5-cyclopentylaminomethyl-phenyl)-amide,
and the salts thereof.
The carboxylic acid amides of the above general formula I are obtained, for example by the following methods known per se:
a. Acylating an amine of general formula
wherein
R3 is as hereinbefore defined and
Bxe2x80x2 denotes B or a group which may be converted into B by transforming a hydroxyalkyl into an optionally substituted aminoalkyl group,
with a carboxylic acid of general formula
wherein
R1, R2 and A are as hereinbefore defined, or the reactive derivatives thereof.
The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide or sulpholane, optionally in the presence of an inorganic or organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
However, the acylation may also be carried out with the free acid, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
If B contains a substituted or unsubstituted aminoalkyl group, the optionally protected hydroxyalkyl derivative may be used as the educt for acylation. Protective groups which may be used include, for example, the trimethylsilyl or tert. butyl-diphenylsilyl group, which may be introduced or cleaved by a method described in the literature or hereinafter. Following the acylation the protecting group is cleaved and the hydroxy group is converted by methods known per se into a good leaving group, such as a methylsulphonyl, triflate or benzylsulphonyl group or a halogen atom, and reacted with the corresponding amine and any protecting groups present are cleaved, to obtain the desired final compound.
b. In order to prepare a carboxylic acid amide of general formula I which contains a carboxy group:
converting a compound of general formula
wherein
R1 to R3, A and B are as hereinbefore defined, with the proviso that A or B or A and B contain a group which can be converted into a carboxy group, into a compound of general formula I which contains a carboxy group.
Examples of a group which can be converted into a carboxy group include carboxyl groups protected by protecting groups, such as the functional derivatives thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters thereof, which are conveniently converted into a carboxyl group by hydrolysis,
the esters thereof with tertiary alcohols, e.g. the tert. butyl ester, which are conveniently converted into a carboxyl group by treating with an acid or by thermolysis, and
the esters thereof with aralkanols, e.g. the benzyl ester, which are conveniently converted into a carboxyl group by hydrolysis.
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The conversion of a tert. butyl or tert. butyloxycarbonyl group into a carboxy group can also be carried out by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between 0 and 60xc2x0 C., or thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120xc2x0 C.
The conversion of a benzyloxy or benzyloxycarbonyl group into a carboxy group may also be carried out hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50xc2x0 C., e.g. at ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
If according to the invention a compound of general formula I is obtained which contains a hydroxy group, this may be converted into a corresponding sulphonyl-oxy compound by means of a sulphonyl halide, or
if a compound of general formula I is obtained which contains a cyano group, this can be converted by means of hydrazoic acid into a corresponding tetrazolyl compound, or
if a compound of general formula I is obtained which contains an amino or imino group with a basic hydrogen atom, this can be converted by acylation or sulphonylation into a correspondingly acylated compound or into a corresponding prodrug compound, or
if a compound of general formula I is obtained which contains a carboxy group, this can be converted into a compound which contains a group which may be converted into a carboxy group in vivo, or
if a compound of general formula I is obtained which contains one or two carboxy groups, this can be converted by reduction with a complex metal hydride into a compound which contains one or two hydroxymethyl groups.
The subsequent sulphonylation is conveniently carried out with a corresponding halide in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane, optionally in the presence of an inorganic or organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
The subsequent preparation of a compound of general formula I which contains a tetrazole group is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150xc2x0 C., preferably between 120 and 130xc2x0 C. The hydrazoic acid required is conveniently liberated during the reaction from an alkali metal azide, e.g. from sodium azide, in the presence of a weak acid such as ammonium chloride. The reaction may also be carried out with another salt or derivative of hydrazoic acid, preferably with aluminum azide or tributyl tin azide, and the tetrazole compound optionally obtained in this way is then liberated from the salt contained in the reaction mixture by acidification with a dilute acid such as 2N hydrochloric acid or 2N sulphuric acid.
The subsequent acylation or sulphonylation or the subsequent conversion into a corresponding prodrug compound is preferably carried out with a corresponding acid halide in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulpholane, optionally in the presence of an inorganic or organic base such as tri-ethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine at temperatures between xe2x88x9220 and 200xc2x0 C., but preferably at temperatures between xe2x88x9210 and 160xc2x0 C.
The subsequent conversion of a carboxy group into a group which may be converted into a carboxy group in vivo is preferably carried out by esterification with a corresponding alcohol or by alkylation of the carboxy group. The esterification is conveniently carried out in a solvent or mixture of solvents such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used in the presence of a dehydrating agent, e.g. in the presence of hydrochloric acid, sulphuric acid, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-carbonyldiimidazole or N,Nxe2x80x2-thionyldiimidazole, triphenylphosphine/carbon tetrachloride or triphenylphosphine/diethyl azodicarboxylate, optionally in the presence of a base such as potassium carbonate, N-ethyl-diisopropylamine or N,N-dimethylamino-pyridine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C., and the alkylation is conveniently carried out with a corresponding halide in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine, which may simultaneously serve as solvent, or optionally in the presence of silver carbonate or silver oxide at temperatures between xe2x88x9230 and 100xc2x0 C., but preferably at temperatures between xe2x88x9210 and 80xc2x0 C.
The subsequent reduction is preferably carried out in the presence of a complex metal hydride such as lithium aluminum hydride or lithium triethyl borohydride in a solvent such as tetrahydrofuran, conveniently at the boiling temperature of the solvent used.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, benzyl or tetrahydropyranyl group and
protecting groups for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120xc2x0 C., preferably at temperatures between 10 and 100xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100xc2x0 C., but preferably at temperatures between 20 and 60xc2x0 C., and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar. A 2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.
A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid or by treating with iodotrimethylsilane optionally using a solvent such as methylene chloride, dioxane, methanol or diethylether.
A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at temperatures between 50 and 120xc2x0 C. or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50xc2x0 C.
A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50xc2x0 C.
The compounds of general formulae II to IV used as starting materials are known from the literature in some cases but may also be prepared by methods known from the literature.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, as mentioned hereinbefore. Thus, for example, compounds with at least one optically active carbon atom may be separated into their enantiomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical enantiomers and compounds of general formula I with at least 2 stereogenic centres may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain an acidic group such as a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, arginine, lysine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
As already mentioned hereinbefore, the carboxylic acid amides of general formula I and the salts thereof, particularly the physiologically acceptable salts thereof, have an inhibiting effect on telomerase.
The inhibiting effect of the carboxylic acid amides of general formula I on telomerase was investigated as follows:
Materials and Methods
1. Preparation of nuclear extracts from HeLa cells: Nuclear extracts were prepared according to Dignam (Dignam et al. in Nucleic Acids Res. 11, 1475-1489 (1983)). All the steps were carried out at 4xc2x0 C., all the equipment and solutions were pre-cooled to 4xc2x0 C. At least 1xc3x97109 HeLa-S3 cells growing in suspension culture (ATCC catalogue number CCL-2.2) were harvested by centrifuging for 5 minutes at 1000xc3x97g and washed once with PBS buffer (140 mM KCl; 2.7 mM KCl; 8.1 mM Na2HPO4; 1.5 mM KH2PO4). After the cell volume had been determined, the cells were suspended in 5 times the volume of hypotonic buffer (10 mM HEPES/KOH, pH 7.8; 10 mM KCl; 1.5 mM MgCl2) and then left for 10 minutes at 4xc2x0 C. After centrifuging for 5 minutes at 1000xc3x97g the cell pellet was suspended in twice the volume of hypotonic buffer in the presence of 1 mM DTE and 1 mM PMSF and broken up with a Dounce homogeniser. The homogenised material was made isotonic with 0.1 volume of 10-fold saline buffer (300 mM HEPES/KOH, pH 7.8; 1.4 M KCl; 30 mM MgCl2). The cell nuclei were separated from the cytoplasmic components by centrifuging and then suspended in twice the volume of nuclear extraction buffer (20 mM HEPES/KOH, pH 7.9; 420 mM KCl; 1.5 mM MgCl2; 0.2 mM EDTA; 0.5 mM DTE; 25% glycerol). The nuclei were broken up using a Dounce homogeniser and incubated for 30 minutes at 4xc2x0 C. with gentle stirring. Any insoluble ingredients were removed by centrifuging for 30 minutes at 10,000 rpm (SS-34 Rotor). Then the nuclear extract was dialysed for 4-5 hours against AM-100 buffer (20 mM Tris/HCl, pH 7.9; 100 mM KCl; 0.1 mM EDTA; 0.5 mM DTE; 20% glycerol). The nuclear extracts obtained were frozen in liquid nitrogen and stored at xe2x88x9280xc2x0 C.
2. Telomerase test: The activity of telomerase in nuclear extracts from HeLa cells was determined using the method described by Morin (Morin in Cell 59 521-529 (1989)). The nuclear extract (up to 20 xcexcl per reaction) was incubated for 120 minutes at 30xc2x0 C. in a volume of 40 xcexcl in the presence of 25 mM Tris/HCl pH 8.2, 1.25 mM dATP, 1.25 mM TTP, 6.35 xcexcM dGTP; 15 xcexcCi xcex1-32P-dGTP (3000 Ci/mmol), 1 mM MgCl2, 1 mM EGTA, 1.25 mM spermidine, 0.25 U RNasin, and 2.5 xcexcM of an oligonucleotide primer (for example TEA-fw [CAT ACT GGC GAG CAG AGT T], or TTA GGG TTA GGG TTA GGG) (=telomerase reaction). If the inhibition constant of potential telomerase inhibitors was to be determined, these were also added to the telomerase reaction in a concentration range of from 1 nM to 100 xcexcM. The reaction was then stopped by the addition of 50 xcexcl of RNase stop buffer (10 mM Tris/HCL, pH 8.0; 20 mM EDTA; 0.1 mg/ml of RNase A 100 U/ml of RNase T1; 1000 cpm of an xcex1-32P-dGTP labelled, 430 bp DNA fragment) and incubation was continued for a further 15 minutes at 37xc2x0 C. Proteins present in the reaction mixture were cleaved by the addition of 50 xcexcl of proteinase K buffer (10 mM tris/HCL, pH 8.0; 0.5% SDS; 0.3 mg/ml of proteinase K) and subsequent incubation for 15 min at 37xc2x0 C. The DNA was purified by extracting twice with phenol-chloroform and precipitated by adding 2.4 M ammonium acetate; 3 xcexcg tRNA and 750 xcexcl ethanol. Then the precipitated DNA was washed with 500 xcexcl of 70% ethanol, dried at ambient temperature, taken up in 4 xcexcl of formamide probe buffer (80% (v/v) formamide; 50 mM of tris-borate, pH 8.3; 1 mM EDTA; 0.1 (w/v) of xylene cyanol; 0.1% (w/v) bromophenol blue) and separated by electrophoresis on a sequence gel (8% polyacrylamide, 7 M urea, 1xc3x97TBE buffer). The DNA synthesised by telomerase in the presence or absence of potential inhibitors was identified and quantified by Phospho-Imager Analysis (Molecular Dynamics) and in this way the concentration of inhibitor which inhibits the telomerase activity by 50% (IC50) was determined. The radiolabelled DNA fragment to which the RNase stop buffer had been added was used as an internal control for the yield.
The inhibitors of Examples 1 to 5 inhibited the telomerase activity by more than 50% at a concentration of 5 xcexcM.
The following abbreviations were used in the foregoing description:
In view of their biological properties, the carboxylic acid amides of general formula I are suitable for treating pathophysiological processes which are characterised by an increased telomerase activity. These are e.g. tumour diseases such as carcinomas, sarcomas and leukaemias including skin cancer (e.g. plate epithelial carcinoma, basalioma, melanoma), small-cell bronchial carcinoma, non-small-cell bronchial carcinoma, salivary gland carcinoma, oesophageal carcinoma, laryngeal carcinoma, pharyngeal carcinoma, thyroid carcinoma, gastric carcinoma, colorectal carcinoma, pancreatic carcinoma, carcinoma of the liver, carcinoma of the breast, uterine carcinoma, vaginal carcinoma, ovarian carcinoma, prostate carcinoma, testicular carcinoma, bladder carcinoma, renal carcinoma, Wilms"" tumour, retinoblastoma, astrocytoma, oligodendroglioma, meningioma, neuro-blastoma, myeloma, medulloblastoma, neurofibrosarcoma, thymoma, osteosarcoma, chondrosarcoma, Ewing""s sarcoma, fibrosarcoma, histiocytoma, dermatofibrosarcoma, synovialoma, leiomyosarcoma, rhabdomyosarcoma, liposarcoma, Hodgkin""s lymphoma, non-Hodgkin""s lymphoma, chronic myeloid leukaemia, chronic lymphatic leukaemia, acute promyelocytic leukaemia, acute lymphoblastoid leukaemia and acute myeloid leukaemia.
In addition, the compounds may also be used to treat other diseases which have an increased rate of cell division or increased telomerase activity, such as e.g. epidermal hyperproliferation (psoriasis), inflammatory processes (rheumatoid arthritis), diseases of the immune system, etc.
The compounds are also useful for treating parasitic diseases in man and animals, such as e.g. worm or fungal diseases as well as diseases caused by protozoan pathogens, such as e.g. Zooflagellata (Trypanosoma, Leishmania, Giardia), Rhizopoda (Entamoeba spp.), Sporozoa (Plasmodium spp., Toxoplasma spp.), Ciliata, etc.
For this purpose the carboxylic acid amides of general formula I may optionally be used in conjunction with other pharmacologically active compounds and therapeutic preparations which will reduce tumour size, and incorporated in conventional galenic preparations. These may be used, for example, in tumour therapy, in monotherapy or in conjunction with irradiation, surgical interventions or other anti-tumour therapeutics, e.g. in conjunction with topoisomerase inhibitors (e.g. etoposide), mitosis inhibitors (e.g. paclitaxel, vinblastine), cell cycle inhibitors (e.g. flavopyridol), inhibitors of signal transduction (e.g. farnesyltransferase inhibitors), compounds which interact with nucleic acid (e.g. cis-platin, cyclophosphamide, adriamycin), hormone antagonists (e.g. tamoxifen), inhibitors of metabolic processes (e.g. 5-FU etc.), cytokines (e.g. interferons), tumour vaccines, antibodies, etc. These combinations may be given either simultaneously or sequentially.
The daily dose is 0.1 to 3 g by oral or intravenous route, divided up into one to four doses a day. For this purpose the compounds of general formula I, optionally in conjunction with the other active substances mentioned above, may be formulated together with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
The following Examples are intended to illustrate the invention in more detail:

Carboxylic acid amides, pharmaceutical compositions containing these compounds, their use and the preparation thereof

Abstract: wherein

Abstract: A, B and R1 to R3 are defined as in claim 1, processes for preparing them, pharmaceutical compositions containing these compounds and the use thereof and their preparation.


An AFC magnetic recording medium having a three-layered ferromagnetic structure capable of reducing noises without deteriorating thermal stability is provided in order to achieve ultra-high recording density. In one embodiment, the AFC magnetic recording medium has a magnetic recording layer formed on a substrate via an underlayer, the magnetic recording medium consisting of a first ferromagnetic layer formed on the underlayer, a second ferromagnetic layer formed on the first ferromagnetic layer via a nonmagnetic layer inducing the antiferromagnetic interaction, and a third ferromagnetic layer formed on the second ferromagnetic layer, wherein the center of gravity G of the magnetic recording medium is defined using the distance tg from the upper surface of the third ferromagnetic layer as:                tg=(Mst)eff/(2MS3); when the center of gravity G is at the third ferromagnetic layer,        tg=((Mst)eff/2−MS3t3)/MS2+t3; when the center of gravity G is at the second ferromagnetic layer,and when the total film thickness of the magnetic recording layer is ttotal, the value tg/ttotal is lower than about 0.33.

The present invention relates to a magnetic recording medium based on the longitudinal recording system, appropriate for ultra-high density recording, capable of obtaining thermally stable recording information with low noise.
It is desired that a magnetic disc device has a large capacity as an external magnetic recording device for a computer. For increasing the capacity, or achieving a higher recording density, the challenge for a magnetic recording medium is to lower noises. A magnetic recording medium has, for example a structure formed by providing a Co-alloy recording magnetic layer such as CoCrTa, CoCrPt and an overcoat film on a substrate via a Cr underlayer controlling the crystalline magnetic anisotropy of the magnetic layer (JP-A No. 257618/1987, JP-A No. 197018/1988), and in the past, the grain size was made finer, the film thickness was made thinner and the coercivity was made higher for lowering of noises. Thereby, the magnetization disorder in the magnetization transition region between recording bits, which might cause noises, can be smaller and the magnetization transition region can be narrower. However, finer magnetic grains and thinner recording layer might cause thermal fluctuation in the recorded magnetization and accordingly, the magnetization might be decayed. In general, the value Ku·V/(k·T) calculated by dividing the product of a magnetic anisotropy coefficient Ku and a grain volume V by the product of a Boltzmann's constant and a temperature T is known as thermal stability factor (IEEE Trans. Magn. 30 (1994) p. 4230). Ku·V/(k·T) indicates that a medium is thermally more unstable as this value gets smaller. From the thermal stability factor, even when the grain size is finer and the film thickness is thinner, thermal stability can be achieved by using a large Ku material. However, a medium with large Ku cannot be recorded by a magnetic head because large Ku is equivalent to a large anisotropic magnetic field. With the similar reason, the coercivity cannot easily be made larger.
As a means for achieving high recording density without increasing Ku, a magnetic recording medium having at least two ferromagnetic layers antiferromagnetically coupled with each other via a nonmagnetic layer was proposed (JP-A No. 148110/2001). At the Intermag international conference (Digest (Intermag 2000 conf.) IEEE, HT-01) held in April 2000, and in Appl. Phys. Lett. 77(2000) 3806, a medium formed by antiferromagnetically coupling two-layered and three-layered ferromagnetic layers (antiferromagnetically-coupled medium ('AFC medium' for short)) was reported to have excellent thermal stability and read-write characteristics. Then, these AFC media have been energetically investigated at various companies and institutions and have been used for today's magnetic disc devices.
FIG. 2 shows a simple schematic diagram illustrating a sectional structure and magnetic moments of a conventional magnetic recording medium when the AFC medium has two ferromagnetic layers. As shown in the drawing, the magnetic moment of the lower ferromagnetic layer 3 is in the opposite direction to the magnetic moment of the upper ferromagnetic layer 5. This is because the nonmagnetic layer 4 containing a material made of Ru, Cr, Rh, Ir, Cu or their alloys is used for antiferromagnetically coupling ferromagnetic layers 3, 5 placing the nonmagnetic layer therebetween. Where the saturation magnetization of the lower ferromagnetic layer 3 is MS1, the film thickness is t1, the saturation magnetization of the upper ferromagnetic layer 5 is Msu, and the film thickness is tu, the effective product (Mst)eff of the saturation magnetization and the film thickness of the entire recording layer is shown below.(Mst)eff=Msutu−Mslt1
Accordingly, (Mst)eff of the recording medium is smaller than that of a single-layered medium made solely of a second ferromagnetic layer, and the noises would be reduced. In addition, since both the upper and lower ferromagnetic layers contribute to achieving thermal stability, the thermal stability would be improved compared to the single-layered ferromagnetic layer medium.
However, as the capacity gets larger, even with using the AFC medium, it would be difficult to achieve higher recording density. This is because finer magnetic grains and thinner films are increasingly required for obtaining required SNR (signal-to-noise ratio), and at the same time, the structure of the AFC medium for securing thermal stability has come to the limit. That is, for securing finer magnetic grains and thinner films and thermal stability at the same time, it is required to increase the thickness of lower ferromagnetic layers while increasing the thickness of upper ferromagnetic layers. However, the antiferromagnetic boundary coupling energy density Jex induced by the nonmagnetic layer is limited, and the magnetic coupling field Hex generated by Jex, which applies to the lower magnetic layer would be reduced in inverse proportion to the film thickness t1 of the lower ferromagnetic layer, as shown in the following formula.Hex=Jex/(Mslt1)
Accordingly, as the film thickness is larger, the antiferromagnetic coupling of the upper ferromagnetic layer and the lower ferromagnetic layer would be weaker and the effective film thickness would be increased instead of reducing the thickness. This means that differently from the initial intention, (Mst)eff would be larger, and the noises would be increased. Additionally, the thermal stability would be deteriorated.
In JP-T No. 515028/2004, it is disclosed that lower noises and improved thermal stability can be achieved by providing two upper ferromagnetic layers in an AFC medium and by increasing the saturation magnetization of the ferromagnetic layer further to a substrate than that of the other ferromagnetic layer. However, according to the inventors' investigation, it was found that good SNR can never be obtained even by increasing the saturation magnetization. Additionally, since increasing of (Mst)eff should be avoided, the ratio of saturation magnetization of the two layers is limited. That is, higher recording density is also limited.
In JP-A No. 85729/2003, it is disclosed that the layer to a substrate side can have a function for preventing turbulence in crystalline magnetic anisotropy at the layer to the substrate side, and good thermal activation and read-write characteristics (medium noise, etc.) can be achieved by providing a plurality of upper ferromagnetic layers in an AFC medium and in a case of providing, for example two layers, by providing one of the layers to the substrate side with thinner film thickness than that of the other layer. This means that the layer to the substrate side has works less as a recording layer.

Magnetic recording media with ultra-high recording density

Hitachi Global Storage Technologies Netherlands B.V.


A communication system is provided in which a transmitter performs modulation upon a number sequence to be transmitted. The modulation scheme includes embedding a sequence of numbers into a waveform such that the sequence is present in the waveform on multiple time scales. The transmitted waveform has a selected number of different frequency bands of successively doubling bandwidths. Each of the frequency bands includes the sequence of numbers, repeated therein at a certain rate. The rate is directly proportional to the bandwidth of the frequency band. The communication system further includes a receiver designed to average the value of the repeated sequence as received by the receiver. This scheme allows for accurate communication over noisy, uncertain, and/or hostile channels in both point to point and broadcast communication applications.

In the field of communications, it is desirable to send a message from a transmission point, through a channel, and to receive such message at one or more destination points. The message may consist of certain information in the form of discrete numbers, continuous analog waveforms, or the like. Consequently, the message may be as diverse as a digital data transmission between computers or a television broadcast. The channel includes the medium through which the message is sent. A typical channel is the atmosphere, such as in a radio broadcast communication scenario, for example. It has become general practice in the communication field to modulate the information to be sent into a continuous waveform which will be transmitted over the channel. The channel, due to natural phenomena, will alter the continuous waveform in some respects such as adding noise and/or fading in certain frequency ranges and time intervals. In addition, in hostile environments, the waveform may be intercepted or subjected to man-made interference in certain frequency ranges and/or time intervals. As such, recovery of the information transmitted becomes problematic. Moreover, many current communication schemes employ compression techniques for compressing the information to be transmitted, in an effort to save time or reduce bandwidth requirements, which, in turn, increases the possibility of error in recovery.
As illustrated in FIG. 1, the classical configuration for such a communication system involves a modulator 10 at the transmitter, for embedding the data sequence q[n] into a signal x(t) which is transmitted over the channel 12. The data sequence q[n] is the information to be communicated. The channel 12 alters the transmitted signal x(t), producing the distorted signal r(t). At the receiver, a demodulator 14 processes the distorted signal r(t)to extract an optimal estimate q[n] of the data sequence q[n].
Typically, the channel 12 would be open for some time interval T during which it has a particular bandwidth W and signal-to-noise ratio (hereinafter "SNR"). This rather generic model of the channel 12, as illustrated in FIG. 2, can be used to describe both characteristics of the transmission medium, and constraints inherent in one or more receivers, for a multiple receiver application. As illustrated in FIG. 2, z(t) represents the noise which is added by the channel to the transmitted signal x(t). In short, the transmitted signal x(t) is affected by channel bandwidth constraints (indicated by the filter B(w)) and duration constraints (indicated by switch 15), noise characteristics, and receiver processing limitations (which may typically be lumped into the function B(w) and switch 15) in certain applications.
When either the bandwidth or duration parameters or properties of a channel are known before transmission, many well-established approaches for transmitting and receiving information (q[n]) reliably, exist. In a wide range of applications, however, both the bandwidth and duration parameters are either unknown or at least inaccessible to the transmitter. As such, with present communication systems, in such applications, communication may become unreliable at times and accurate communication unattainable.
Such applications, in which both the bandwidth and duration parameters are either unknown or at least inaccessible to the transmitter, encompass both point-to point and broadcast communication scenarios, and include the following:
1. Broadcast communication involving multiple receivers of unknown or differing processing capabilities;
2. Communication involving channels subject to hostile jamming and other interception attempts;
3. Communication involving multiple access channels;
4. Communication involving fading channels; and
5. Covert communication involving desired low probability of intercept.
In a broadcast communication application, involving multiple receivers, the various receivers may have different and diverse processing capabilities which may be described in terms of different bandwidth and/or duration constraints. Additionally, there may exist uncertainty in the bandwidth and duration characteristics of the channel.
In a communication system utilizing a channel subject to hostile jamming, attempted interception and/or transmission blocking occurs within certain unknown frequency ranges and time intervals. Thus, similarly, unknown bandwidth and time-varying constraints are encountered.
In a communication system involving multiple access channels, such as that used in telephone and satellite communication systems, for examples, multiple communication users share each channel. In such applications, there exist only a few known fairly burdensome ways to differentiate among the multiple users. These few known ways include sharing in the time domain, sharing in the frequency domain, coding among users and combinations thereof. As such, the effective time and bandwidth channel restraints to a potential user are similar. Additionally, in communication systems involving packet switching schemes, such as those used in telephone and computer communication systems, packets of information are sent asynchronously. As such, routing problems exist such as potential collisions of such packets. These scenarios can present similar time and bandwidth constraints.
In a communication system involving fading channels, such as meteor burst channels, ocean acoustic channels, or mobile radio channels, strong attenuation exists in certain time intervals and/or frequency ranges. In the meteor burst application, an optimum situation arises when a meteor burst occurs, for transmission of information. This optimum situation, however, is unpredictable and unreliable. In both the ocean acoustic and mobile radio channel scenarios, transmitted signals are subject to reflection and possible refraction and, therefore, both constructive and destructive interference occurs. This constructive and destructive interference is, for the most part, uncontrollable and unreliable. Therefore, these fading channel scenarios can present a situation analogous to that of a channel with unknown bandwidth and duration parameters.
Accordingly, a general purpose of the present invention is to provide a communication system capable of accurate transmission and reception of information.

Communication system utilizing self-similar signals


A storage medium for gas molecules has a nanowire core and a number of organic molecules attached to the exterior surface of the nanowire. The organic molecules attached to the exterior of the nanowire are adapted to releasably hold gas molecules. Methods for making and using the invention, including the use of a silicon nanowire, are disclosed.

Several recent developments related to energy production and utilization have created increased need for storage of gases, especially efficient means of storing neutral hydrogen with high storage density. Such high storage density of hydrogen is required for effective functioning of fuel cells and is also important for other increasing uses of hydrogen gas in the national economy and in the world economy.
There are several ways to store neutral hydrogen at relatively high densities: tanks of compressed gas, dewars of liquid hydrogen, chambers containing metal hydrides, and others. Metal hydrides, while useful, have a problem of undesirable weight. The liquid form of hydrogen requires maintenance of very low temperatures. Storage of compressed gas uses high pressures. Thus, no ideal method is available at present, and development of alternative methods is desirable.
Physisorption of gas molecules on a solid surface is another phenomenon that may be exploited for gas storage. For that purpose, materials and media with large surface-to-volume ratios are required. Various media have been tried, including glass spheres and carbon nanotubes. While such media have performed the desired function, there is an ongoing need for gas storage media which have increased surface-to-volume ratios and gas storage capacity for neutral hydrogen and for other gas molecules.

Hewlett-Packard Development Company, L.P.


An image processing apparatus for deinterlacing and vertical scaling a plurality of initial scan lines includes a control unit, a deinterlacer, a vertical scaler and a buffer. The control unit controls the deinterlacer and the vertical scaler to store parts of the processed scan lines thereof into the buffer according to a scaling ratio factor and a vertical scaling algorithm.

1. Field of the Invention
This invention generally relates to an image processing apparatus and method, and more particularly, to an image processing apparatus and method in a video output system.
2. Description of the Related Art
A conventional image processing apparatus usually performs deinterlacing and vertical scaling on images. However, in order to perform deinterlacing and vertical scaling, the scan lines of the images have to be accessed frequently so as to execute interpolation operation. Therefore, the accessing method of the scan lines will influence the performances of the deinterlacing and vertical scaling.
Since conventional methods of accessing scan lines are unsatisfactory, a same scan line may be accessed and executed repeatedly during deinterlacing and vertical scaling thereby causing redundant using of the bandwidth.


Techniques are provided for monitoring thoracic fluid levels based on thoracic impedance (ZT) and cardiogenic impedance (ZC). In one example, the implantable device tracks the maximum time rate of change in cardiogenic impedance (i.e. max(dZC/dt)) to detect trends toward hypervolemic or hypovolemic states within the patient based on changes in heart contractility. The detection of these trends in combination with trends in thoracic impedance allows for a determination of whether the thoracic cavity of the patient is generally “too wet” or “too dry,” and thus allows for the titration of diuretics to avoid such extremes. In particular, a decrease in thoracic impedance (ZT) in combination with a decrease in max (dZC/dt) is indicative of the thorax being “too wet” (i.e. a fluid overload). Conversely, an increase in thoracic impedance (ZT) in combination with a decrease in max (dZC/dt) is indicative of the thorax being “too dry” (i.e. a fluid underload).

Heart failure is a debilitating disease in which abnormal function of the heart leads in the direction of inadequate blood flow to fulfill the needs of the tissues and organs of the body. Typically, the heart loses propulsive power because the cardiac muscle loses capacity to stretch and contract. Often, the ventricles do not adequately eject or fill with blood between heartbeats and the valves regulating blood flow become leaky, allowing regurgitation or back-flow of blood. The impairment of arterial circulation deprives vital organs of oxygen and nutrients. Fatigue, weakness and the inability to carry out daily tasks may result. Not all heart failure patients suffer debilitating symptoms immediately. Some may live actively for years. Yet, with few exceptions, the disease is relentlessly progressive. As heart failure progresses, it tends to become increasingly difficult to manage. Even the compensatory responses it triggers in the body may themselves eventually complicate the clinical prognosis. For example, when the heart attempts to compensate for reduced cardiac output, it adds muscle causing the ventricles (particularly the left ventricle) to grow in volume in an attempt to pump more blood with each heartbeat. This places a still higher demand on the heart's oxygen supply. If the oxygen supply falls short of the growing demand, as it often does, further injury to the heart may result. The additional muscle mass may also stiffen the heart walls to hamper rather than assist in providing cardiac output. A particularly severe form of heart failure is congestive heart failure (CHF) wherein the weak pumping of the heart leads to build-up of fluids in the lungs and other organs and tissues.
The current standard treatment for heart failure is typically centered on medical treatment using angiotensin converting enzyme (ACE) inhibitors, diuretics, beta-blockade, and digitalis. Cardiac resynchronization therapy (CRT) may also be employed, if a biventricular pacing device is implanted. Briefly, CRT seeks to normalize asynchronous cardiac electrical activation and resultant asynchronous contractions associated with CHF by delivering synchronized pacing stimulus to both ventricles. The stimulus is synchronized so as to improve overall cardiac function. This may have the additional beneficial effect of reducing the susceptibility to life-threatening tachyarrhythmias. CRT and related therapies are discussed in, for example, U.S. Pat. No. 6,643,546 to Mathis, et al. entitled "Multi-Electrode Apparatus and Method for Treatment of Congestive Heart Failure"; U.S. Pat. No. 6,628,988 to Kramer, et al., entitled "Apparatus and Method for Reversal of Myocardial Remodeling with Electrical Stimulation"; and U.S. Pat. No. 6,512,952 to Stahmann, et al., entitled "Method and Apparatus for Maintaining Synchronized Pacing".
In view of the potential severity of heart failure, it is highly desirable to track the progression of the condition so that appropriate therapy can be provided. Many patients suffering heart failure already have pacemakers or ICDs implanted therein or are candidates for such devices. Accordingly, it is desirable to provide such devices with the capability to automatically track progression of heart failure. Some aspects of the present invention are directed to this end.
Pulmonary edema is a swelling and/or fluid accumulation in the lungs often caused by heart failure (i.e. the edema represents one of the "congestives" of CHF.) Briefly, the poor cardiac function resulting from heart failure can cause blood to back up in the lungs, thereby increasing blood pressure in the lungs, particularly pulmonary venous pressure. The increased pressure pushes fluid—but not blood cells—out of the blood vessels and into lung tissue and air sacs (i.e. the alveoli). This can cause severe respiratory problems and, left untreated, can be fatal. Pulmonary edema can also arise due to other factors besides heart failure, such as infections.
One therapy delivered to address pulmonary edema is to administer diuretics to the patient in an effort to reduce the amount of fluids within the thorax of the patient. One technique uses thoracic electrical impedance measurements to detect a "fluid overload," i.e. a significant increase in thoracic fluids. A drop in thoracic impedance is deemed to be indicative of such a fluid overload. In response, diuretics such as furosemide or bumetanide are administered to the patient to reduce the fluid overload. (Diuretics are drugs that increase the flow of urine, thus eliminating water from the body, ultimately reducing thoracic fluid levels.)
The use of electrical impedance is promising since thoracic impedance can be readily measured in situ using pacemaker or ICDs. However, a significant concern with thoracic impedance-based techniques is that the thoracic impedance measurement provides only a relative measurement of thoracic fluid levels, i.e. the technique merely detects a drop in impedance indicative of a possible increase in thoracic fluid levels. It does not necessarily establish that thoracic fluid levels have increased beyond an acceptable range. Moreover, impedance drops can occur frequently within some patients without any clinical consequences and are often merely "false positive" events. When titrating a patient with diuretics based on such drops in thoracic impedance, it is thus possible to overcorrect the fluid overload by dispensing too much diuretic. The patient may then become hypovolemic (a condition wherein there is too little blood).
Accordingly, it would also be desirable to provide improved techniques for monitoring thoracic fluid levels, which avoid the aforementioned problems, and it is to this end that aspects of the invention are primarily directed. It is particularly desirable to provide techniques for titrating diuretics within patients to keep thoracic fluid levels within an optimal range and such techniques are described herein.

System and method for monitoring thoracic fluid levels based on impedance using an implantable medical device