A novel protein which is useful as a diagnostic means for studies relating to the diagnosis and treatment of cancer (detection of cancer cells, estimation of the malignity, etc.) and for other medicinal and physiological purposes; a gene encoding the same; and an antibody, in particular, a monoclonal antibody specific to the protein. MT-MMP-3, which is a pro MMP-2 activator having the ability to activate pro MMP-2 which is under expression specifically on the surface layer of a human cancer cell and falling within the category of MMP but being different from MT-MMP-1; a DNA containing the base sequence encoding the same; host cells transformed by the DNA; a process for producing a matrix metalloproteinase protein by using the host cells; a monoclonal antibody binding specifically to the matrix metalloproteinase protein; and use of the protein and antibody.

1. Field of the Invention
The present invention relates to a novel protein useful as a diagnostic tool for studies and researches relating to diagnostic and therapeutic applications to tumors, including uses in detecting tumor cells, estimating cancer malignancies, etc., and/or useful in other medical and physiological uses; and to a novel gene encoding said protein. More specifically, the present invention relates to a new membrane-type protein which is one of the MMPs having the activation capability of pro-matrix metalloproteinase 2 (pro-MMP-2), i.e. an activator for pro MMP-2, provided that said protein is different from the first membrane-type matrix metalloproteinase (MT-MMP-1), and to a gene coding for said protein. The present invention also encompasses a novel matrix metalloproteinase being specifically expressed in a human tumor cell surface layer (the instant novel matrix metalloproteinase is named "membrane-type matrix metalloproteinase-3 (MT-MMP-3)"); DNA containing a nucleotide sequence coding the protein; a host cell transformed or transfected with the DNA, a process for producing the matrix metalloproteinase which comprises using said host cell, a monoclonal antibody capable of specifically binding with the matrix metalloproteinase protein, and applications of said protein and antibody.
2. Description of the Related Art
An extracellular matrix may block the transfer of tumor cells in the invasion and metastasis of tumor cells that are present in a primary nest tissue. In order for tumor cells to transfer and invade into tissues, they must deviate from the primary nest and destroy peripheral extracellular matrixes. The metastasis of tumor cells progresses via destruction of basement membranes, invasion into and effusion from blood vessels, successful implantation on secondary organs, further growth, etc. The extracellular matrix that blocks tumor metastasis is composed of various complex components, including type IV collagen, proteoglycans, elastin, fibronectin, laminin, heparan sulfate, etc. A family of enzymes, generally named "Matrix Metalloproteinase" (hereinafter briefly referred to as "MMP"), with distinct substrate specificities are responsible for the degradation of the extracellular matrix.
It has been reported that MMP includes fibroblast-type collagenase (MMP-1), 72 kDa gelatinase (referred to as type IV collagenase or gelatinase A; MMP-2), 92 kDa gelatinase (referred to as type IV collagenase or gelatinase B; MMP-9), stromelysin-1 (MMP-3), matrilysin (MMP-7), neutrophilic collagenase (MMP-8), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), etc. (Crit. Rev. Oral. Biol. Med., 4: 197 to 250, 1993). These MMPs form a family, and the primary structure of genes has been already reported. The reported amino-acid sequences deduced from cDNA data of these MMPs are recognized to be homologous, which are constituted of an N-terminal signal peptide basically removed during secretion and processing, followed by a propeptide domain, a Zn.sup.+ -binding catalytic domain, a proline-rich hinge domain composed of 5 to 50 amino acids, and a C-terminal hemopexin coagulation enzyme-like domain. There is no hemopexin-like domain in MMP-7. MMP-2 and MMP-9 include a gelatine-binding domain in addition to these.
Among these MMPs, it has been reported many times that type IV collagenase (MMP-2 and MMP-9) acting on, as a dominant substrate, type IV collagen that is a principal constituent for basement membranes is highly expressed in high metastatic tumor cells and there has been suggested that tumor cells are associated with tumor invasion into basement membrane invasion (Cell., 64: 327 to 336, 1991). The regulation of MMP activation is believed to be performed in steps including at least transcription level, a step for converting a proenzyme form wherein its enzymatic activity is latent into an active enzyme form, and controls by tissue inhibitor of metalloproteinase (TIMP) being a specific inhibitor against MMPs, etc. (Trends Genet., 6: 121 to 125, 1990).
All of the MMPs are secreted as inactive zymogens. In in vitro studies, activation of MMP-1 and MMP-9 is shown to be produced with serine proteinases such as plasmin, trypsin, cathepsin G. It has also been reported that activation of MMP-9 is caused by the action of active MMP-3 (J. Biol. Chem., 267: 3581 to 3584, 1992). However, since MMP-2 has no cleavage site sensitive to the above mentioned proteinase, activation of MMP-2 is believed not to be generated thereby (Curr. Opin. Cell Biol., 5: 891 to 897, 1993).
It has also been reported that these MMPs are produced by not only tumor cells but also circumferential fibroblasts and inflammatory cells which produce distinct MMPs, respectively (Breast Cancer Res. Treat., 24: 209 to 218, 1993; and Curr. Opin. Cell Biol., 5: 891 to 897, 1993).
It has previously been reported that, among them, MMP-2 is expressed in fibroblasts at a variety of sites accompanied with remodeling of tissue constructs and its activation is specifically generated in cancer tissues exemplified by lung cancer, in comparison with normal tissue and cancer tissue MMP-2s (Clin., Exp., Metastasis, 11: 183 to 189, 1993). In MMP-9, there is a low frequency that an active type is detected. In addition, there is proved in in vitro studies that active MMP-2 is localized at the apical site of tumor invasion (invadopodia) and it is suggested that the active MMP-2 has an important role on tumor invasion (Cancer Res., 53: 3159 to 3164, 1993; and Breast Cancer Res. Treat., 53: 3159 to 3164, 1994).
Under these backgrounds, attention has been focused on the activation mechanism of MMP-2. As described previously, however, activation of MMP-1 and MMP-9 is mediated by serine proteinases such as trypsin while the activation mechanism of MMP-2 is still undisclosed. In particular, an activating factor for MMP-2 remains unidentified. When HT1080 cells (MMP-2 producing cells) are treated with concanavalin A or 12-o-tetradecanoylphorbol 13-acetate (TPA), it is known that active MMP-2 appears in cultured medium, and it is believed that MMP-2 activating factors are induced in these cells (J. Natl. Cancer Inst., 85: 1758 to 1764, 1993; and Clin. Exp. Metastasis., 11: 183 to 189, 1993). Since this MMP-2 activation is induced by cellular membrane fractions and the activation is suppressed by chelating agents or TIMP, the MMP-2 activating factors have been presumed to be a membrane-type MMP (J. Biol. Chem., 268: 14033 to 14039, 1993).
The present inventors have previously cloned novel MMP genes using genetic engineering techniques, and obtained cloned genes coding for a new MMP having a typical transmembrane (TM) domain at the C-terminus thereof and being capable of activating MMP-2 (Nature, 370: 61 to 65, 1994). In fact, when this gene is expressed in cultured cells, the gene products are localized on the cell membrane without secretion. Thus, the present inventors have named such MMP as "membrane-type MMP (MT-MMP)".
Since, as described above, for MMPs, specifically MMP-2, the active form is found specifically in tumor cells, it is increasingly recognized that such should be targeted by anti-cancer or anti-metastatic drugs. Still, since MMP-2 exists relatively homeostatically as a zymogen in normal tissues, the regulation of MMP-2 activation resides in a process of activating it to active enzymes. Therefore, it is considered that the retrieval or identification of activating factors which are keys to this is extremely important in view of markers in the diagnosis of cancers and in the determination of malignancy and targets of anti-metastatic drugs against cancers.
In addition, it has been pointed out that MMP-2 may be involved in the cleavage of .beta.-amyloid protein which is associated with the crisis of Alzheimer's diseases. The .beta.-amyloid protein is a part of amyloid protein precursors, 1/4 of .beta.-amyloid protein area is included in the membrane-spanning (or transmembrane) area of the amyloid protein precursor, and the rest is outside the cells. It has been recently disclosed that several metabolic pathways of amyloid protein precursors exist, one of which is a process including a cleavage of inner sites of the .beta.-amyloid protein area with a protease called ".alpha.-secretase" and a discharge outside cells. It has been recently found that an amyloid protein-degrading activity is present in MMP-2, with the possibility that MMP-2 would function as .alpha.-secretase or an extracellular .beta.-amyloid protein-degrading enzyme (Nature, 362 : 839, 1993). The .beta.-amyloid protein is the main component of senile macula observed in the brains of patients with Alzheimer's diseases, and forms the core of senile macula by self-aggregation and deposition thereof. Since functional reduction of .beta.-amyloid protein-degrading enzymes may occur in the brain of the patient with Alzheimer's diseases, attention is focused on MMP-2. Here, the key is a process for activating MMP-2. The MT-MMP previously identified by the present inventors (newly named "MT-MMP-1" herein) is believed to be an activating factor for MMP-2, but the existence of unknown MMPs such as MT-MMP-1 can be anticipated from the fact that a variety of components exists in the extracellular matrix. The existence of activating factors for MMP-2, other than MT-MMP-1, is still undeniable.

Protein and monoclonal antibody specific thereto


Multi-ported memory systems (e.g., register files) employ self-timing for operational synchronization. Thus, rather than using a reference clock duty cycle for operational synchronization, as in conventional multi-ported register files, embodiments of the present disclosure employ self-timing for such operational synchronization. According to certain embodiments, self-timing is employed to synchronize all the internal events within the memory so that all the events are spaced in time for appropriate synchronization. For instance, the completion of one event leads to triggering another event, the completion of which leads to triggering another event, and so on. Thus, in one embodiment, the self-timing is achieved by referencing the operational events with the memory (or register file) to each other, rather than to a reference clock duty cycle.

Multi-ported register files are becoming increasingly prevalent in computing system designs. Multi-ported register files are particularly desirable for high performance computing, which may be implemented within a mobile application, like a cellular telephone, a personal digital assistant (PDA), etc., and/or as may be implemented in stationary applications, such as a mainframe computer, a personal computer (PC), etc. In general, memory systems conventionally have static random access memories (SRAMs), with single read and write ports, whereby a resource can perform either a write or a read at one time (i.e., the resource cannot perform both a read and write at the same time). Many integrated circuit (IC) based register files are implemented using such SRAMs having multiple ports. Such multi-ported SRAMs may have dedicated read and write ports, thus enabling read and write operations to be performed simultaneously via the respective ports.
It is often desirable to have a system where multiple agents (or applications) can access the same memory for performing reads and writes in parallel. As an example, such parallelism is often desirable in graphic processing to enable computations (e.g., pertaining to shades and colors, etc.) to be performed quickly so the user does not perceive a flicker or slowness in graphic transitions, but instead perceives a smooth transition of graphics. To achieve such efficient graphics computations, it becomes desirable to have a central memory with multiple agents being able to access the same, central memory. Accessing the same memory by multiple agents is often desirable because it reduces coherency issues. That is, by accessing the same memory, the multiple agents are assured to be accessing the latest data at that point in time without running into coherency issues, as are often encountered in many hierarchical cache systems.
Multi-ported memories are quite prevalent in current microprocessor architectures because they are used quite often as level zero (or "L0") cache. Conventional multi-ported memories in microprocessors operate based on sequence clocks. In particular, the system may have a clock generator based on phase lock loop (PLL), which generates a very high frequency, very accurate clock signal. The clock signal is supplied to the multi-ported memory, which uses the clock signal as a reference for synchronizing its operations. The clock signal has a periodically repeating high phase and low phase. In conventional multi-ported memories, a memory access operation (e.g., a read or write) may be performed in one phase (e.g., in the high phase) of the clock signal, and in the other phase (e.g., in the low phase) an operation is not performed. Thus, in conventional multi-ported memories, one memory access operation (e.g., a read or write) may be performed on each port per clock cycle.
Accordingly, register files are normally operated based on reference to a synchronization clock. A high-precision clock signal generator is thus required to ensure the proper synchronization of operations by the register files. Because the synchronization is dependent on the reference clock signal, such an implementation is undesirably prone to clock duty cycle, skew, and/or jitter issues. Additionally, because the conventional multi-ported register file implementation operates with reference to a clock signal running at high frequencies, power consumption tends to be very high in such an implementation.

Self-timing for a multi-ported memory system


A skin and/or fragrance mousse or foam is provided which is in the form of a light airy stable foam which does not readily break down, and which contains a unique combination of three moisturizers, an alkoxylated methyl glucose derivative such as polypropylene glycol-20 methyl glucose ether, an alkoxylated lanolin derivative such as polyethylene glycol-85 lanolin and acetylated lanolin alcohol.

Skin conditioners and moisturizers are usually available in the form of lotions and creams. Although many such lotions and creams are formulated to be non-greasy, in fact, practically all such skin products are inherently greasy to the touch.
Until now, hair mousses or hair foam products have been used to provide styling and body to hair. These products usually include a resinous material such as vinylmethacrylate/methacrylate copolymer to hold hair in place and to stabilize the foam. However, due to the presence of the resinous material, these hair products have a sticky consistency and therefore are messy to work with. Furthermore, use of such hair mousses often results in unsightly flaking.


An extractable cardiac probe comprising a catheter (4) and a sleeve (3) that is at least partially deformable and mountable to the catheter. The procedure for application of the extractable probe uses an extractor device (11) equipped to pass between the sleeve and catheter to deform the sleeve (3) elastically to permit removal and replacement of the catheter.

Cardiac probes are used for cardiac stimulation and to pick up electrical signals originating from the heart. A probe comprises two tips: one called proximal, which is, in the context of cardiac stimulation, intended to be connected to the signal generator; the other is called distal and is intended to be placed in contact with the cardiac muscle, e.g., the inner surface of the cardiac muscle.
The probe comprises an electrical conductor comprising a metal wire coiled in a spiral or helical manner and arranged inside a biocompatible flexible sheath made, for example, of silicone rubber. The conductor is connected to an electrode, e.g., a ring-shaped or cylindrical electrode, arranged at the distal tip of the probe.
Various incidents can occur on the occasion of use of cardiac probes. On the one hand, it is necessary to replace a probe which is not functioning correctly with a new probe. On the other hand, focuses of infection may break out at the tip or along the probe.
Extraction of the probe is imperative in the preceding cases. For this purpose, a known extraction procedure calls for pulling on the probe by applying a constant traction on the order of 1N to 5N until there is detachment of the probe from the surface of the cardiac muscle. This operation, which is long and arduous for the patient, often takes several days.
Documents DE 3,937,594, U.S. Pat. Nos. 4,574,800 and 4,988,347 describe three different devices for extraction of a cardiac probe, the common element of which is the following. These devices, expansible through enlargement of their outside diameter, are inserted inside the electrical conductor coiled in a spiral up to the vicinity of the distal tip of the probe. Then they are fastened to this distal tip by means of expansion of their outside diameter, so as to be able to exercise a traction on this distal tip. One drawback resulting from the use of these known devices is the risk of tearing of the fibrin surrounding the distal tip of the probe and, possibly, of a portion of the myocardium.

Extractable cardiac probe and its application procedure


An improved method of installing tensional anchor bolts or cable bolts into a geological or man made formation by preheating anchor bolts or cables prior to inserting them into a borehole, mixing the bonding material within the borehole by rotating the bolt and allowing curing of the bonding material prior to the cooling of the bolt, thereby placing the bolt under tension and the formation into compression, is provided.

The present invention relates to an improved method for installing a resin-grouted anchor bolt in a borehole, and, more particularly, to an improved method of quickly securing an anchor bolt or cable in a borehole using a settable bonding material. The improvement comprises heating the bolt to a temperature at least approximately 40.degree. above ambient temperature prior to contacting the bolt and bonding material during the installation procedure whereby curing is accelerated, and the bolt is placed under tension without mechanical torquing.
In the art of bolt anchoring systems, and especially in mine roof support, it is well known how to tension bolts by the use of a shell-type, plastic or metallic-sleeve mechanical expansion system with and without resin. Non-mechanical anchor bolts of the type which are installed with a settable bonding material are normally placed under tension after the bonding material has reached a predetermined initial cure strength by torquing a nut or a bolt on the exposed bolt end. Popular bonding materials; e.g., polyesters, epoxies, and other known commercially available synthetic resins, are typically provided in packages in which the resin and a catalyst for the resin are separated by a package film or reacted zone of the resin. During normal installation when the anchor bolt, or anchor bolt assembly, is forced into a drilled borehole which already contains the resin/catalyst package, the bolt breaks the package and then mixes the resin and catalyst as it is rotated from 30 to about 100 revolutions at a rate of 150 rpm to 1200 rpm. At ambient mine temperatures, which can range from 3.degree. to 35.degree. C., the elapsed time from insertion of the bolt until the resin reaches a satisfactory cure strength and can be torqued into tension can range from 14 seconds up to about 60 seconds.
Another method of securing a bolt or cable utilizes cementitious materials. Cementitious materials, packaged for water soaking or pumpable, are used in securing bolts and cables in various geological strata.
Packaged cementitious materials are soaked in water prior to inserting into the borehole. The bolt or cable is then installed through the cementitious material. Alternatively, the bolt or cable is installed first followed by pumping the cementitious material into the hole to grout the system.
U.S. Pat. No. 4,353,463, issued Oct. 12, 1982 to R. W. Seemann, discloses a cartridge assembly of a multicomponent curable system for use in anchoring bolts into solid structures wherein preheating the cartridge and/or the bolt can reduce reaction time. In such a system, the resin curing time is less than the bolt warming time and, therefore, the bolt goes into compression and the solid structure goes into tension. There is a need to achieve the opposite effect, that is, for the bolt to go into tension and the solid structure to go into compression. To achieve that, there is a need for a system where resin curing time is less than bolt cooling time.


In the HSM function, when supporting the file system snapshot function, a differential data volume is required for both a high-speed volume and a low-speed volume. Accordingly, when supporting the snapshot function by using a file system provided by the HSM function, a large amount of differential data volume is required. When the manager gives an instruction to acquire a snapshot, a snapshot management program executes snapshot acquisition processing to acquire a snapshot. In this processing, a snapshot reference relation building processing part copies a file storage location management table, and relates the file storage location management table to the acquired snapshot. Then, the snapshot reference relation building processing part checks a file that is migrated to a file system which does not have a differential data volume. Finally, the snapshot reference relation building processing part creates a link of the migrated file to the snapshot which is acquired previous time.

1. Field of the Invention
The present invention relates to a file management that uses one or more storage devices and optimally disposes files in accordance with the properties of a file system, in which file system snapshots are acquired.
2. Description of the Related Art
Currently, storage devices provided with various performances have been developed, and performances of volumes forming these storage devices are different from each other. Generally, a volume of high performance is expensive, and cannot have much capacity. On the other hand, a volume of low performance is inexpensive, and can have much capacity.
There is known a method for managing data referred to as the HSM function (Hierarchical Storage Management function) that optimally disposes files, in which a plurality of volumes of different properties are utilized to reduce the cost of storage. In the HSM function, the file system program migrates a frequently used file to a high-speed and expensive volume, and migrates an infrequently used file to a low-speed and inexpensive volume. In this way, the HSM function controls file-storing volumes, which can reduce the cost of storage.
The HSM function disclosed in a patent document 1 (US2004/0193760A1) creates a file system using a high-speed volume and a low-speed volume, in which a file system program sends an instruction to migrate an unutilized file to the low-speed volume. Then, when an application accesses the file, the file is migrated to the low-speed volume. In this processing, the file system rewrites file management information of the high-speed volume.
On the other hand, there is known the file system snapshot function (which may be simply referred to as snapshot function, hereinafter) which is disclosed in a patent document 2 (Japanese Laid-Open Patent Publication No. 2004-342050). The file system snapshot function can easily recover an original file when the user deletes the file or modifies the file by mistake. The file system snapshot function acquires a file system image of a specific time point like a "photograph (snapshot)". The user can recover a file, which is deleted by mistake, by acquiring the file from the snapshot. The snapshot function has a special volume referred to as a "differential data volume" to store data of a deleted file or a modified file.
In the HSM function disclosed in the patent document 1, when supporting the file system snapshot function, a differential data volume is required for both a high-speed volume (LU (Logical Unit) created with FC (Fibre Channel) Disk) and a low-speed volume (LU created with SATA (Serial Advanced Technology Attachment) Disk). Accordingly, when supporting the snapshot function using a file system provided by the HSM function, a differential data volume of large amount is required.

File sharing system, file server, and method for managing files


Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.

1. Field of the Invention
This invention relates to compounds, to processes of their preparation, to pharmaceutical compositions containing than and to their medical use as agonists at kappa opioid receptors.
2. Reported Developments
Opium and its derivatives are potent analgesics that also have other pharmacological effects, and exert their effects by interacting with high-affinity receptors.
It has been shown by investigators that there are at least three major opioid receptor types in the central nervous system (hereinafter CNS) and in the periphery. These receptors, known as mu (xcexc), delta (xcex4) and kappa (xcexa), have distinct pharmacological profiles, anatomical distributions and functions. [See, for example: Wood, P. L., Neuropharmacology, 21, 487-497,1982; Simon, E. J., Med. Res. Rev., 11, 357-374, 1991; Lutz et al, J. Recept. Res. 12, 267-286; and Mansour et al, Opioid I, ed. Herz,. A. (Springer, Berlin) pp. 79-106, 1993.] The xcex4 receptors are abundant in CNS and mediate analgesia, gastrointestinal motility and various hormonal functions. The xcexc receptors bind morphine-like drugs and mediate the opiate phenomena associated with morphine, including analgesia, opiate dependence, cardiovascular and respiratory functions, and several neuroendocrine effects.
The xcexa receptors have a wide distribution in CNS and mediate a spectrum of functions including the modulation of drinking water balance, food intake, gut motility, temperature control and various endocrine functions. They also produce analgesia [See, for example: Leander et al, J. Pharmacol. Exp. Ther. 234, 463-469, 1985; Morley et al, Peptides 4, 797-800, 1983; Manzanares et al, Neuroendocrinology 52, 200-205, 1990; and Iyengar et al, J. Pharmacol. Exp. Ther, 238, 429-436, 1986.]
Most clinically used opioid analgesics such as morphine and codeine act as xcexc receptor agonists. These opioids have well-known, undesirable and potentially dangerous dependence forming side effects. Compounds which are xcexa-receptor agonists act as analgesics through interaction with xcexa opioid receptors. The advantage of these agonists over the classical xcexc receptor agonists, such as morphine, lies in their ability to cause analgesia while being devoid of morphine-like behavioral effects and addiction liability.
A large number of classes of compounds which act as agonists at xcexa opioid receptors have been described in the art including the following illustrative classes of compounds.
U.S. Pat. No. 4,065,573 discloses 4-amino-4-phenylcyclohexane ketal compounds having analgesic activity.
U.S. Pat. No. 4,212,878 discloses phenylacetamide derivatives having analgesic properties and reduced physical dependence liability properties, relative to morphine and methadone.
U.S. Pat. No. 4,145,435 discloses N-(2-aminocycloaliphatic)-phenylacetamide compounds having analgesic activity and narcotic antagonist activity.
U.S. Pat. No. 4,098,904 discloses N-(2-aminocycloaliphatic)-benzoamides and naphthamides useful for pain.
U.S. Pat. No. 4,359,476 discloses substituted cycloalkane-amides useful as analgesic and having low abuse liability.
U.S. Pat. No. 4,438,130 discloses 1-oxa-, azo- and thiaspirocyclic compounds having analgesic activity, low physical dependence and abuse liability properties and little dysphoric inducing properties.
U.S. Pat. No. 4,663,343 discloses substituted nahthalenyloxy-1,2-diaminocylohexyl amides as analgesics.
U.S. Pat. No. 4,906,655 discloses 1,2-cyclohexylaminoaryl amides having high kappa-opioid affinity, selectivity and potency and useful as analgesics, diuretics, anti-inflammatory and psychotherapeutic agents.
Compounds having kappa opioid agonist activity, compositions containing them and method of using them as analgesics are provided.
In its compound aspect, the present invention provides a compound of the formulae I, II, III and IV, er a pharmaceutically acceptable salt thereof.
The compounds of formula (I) have the following structure:
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94(CH2)m; where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH) (CH2)2xe2x80x94;
CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH2)xe2x80x94; or
xe2x80x94(CH2)2CHCH2xe2x80x94;
Ar=unsubstituted er mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3, amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
Z is
xe2x80x94P(O)(OBn)2; xe2x80x94P(O)(OH)2; xe2x80x94(CH2)pC(O)NHOH; xe2x80x94(CH2)pCO2H; xe2x80x94SO2CH3; xe2x80x94SO2NH2; xe2x80x94CO (CH2)pCH(NH2)(CO2H); xe2x80x94COCH(NH2)(CH2)p CO2H; xe2x80x94CO2CH3; xe2x80x94CONH2; xe2x80x94(CH2)pO(CH2)p CO2H; xe2x80x94(CH2)pO(CH2)pCONHOH; xe2x80x94(CH2)p NHSO2CH3; xe2x80x94(CH2)pNHC(S)NHCH(CO2H) (CH2)p CO2H; xe2x80x94(CH2)pSO3H; or
or Z is
wherein
p=0-20;
R3=xe2x80x94H or -Ac;
X2=xe2x80x94CO2H; xe2x80x94NHSO2CH3; NHP(O)(OBn)2; NHP(O) (OH)2; xe2x80x94OP(O)(OBn)2; or OP(OH)2;
X and Y are independently
xe2x80x94CH2NHSO2CH3, xe2x80x94CH2NHP(O)(OBn)2, xe2x80x94CH2NHP(O)(OH)2, xe2x80x94CH2OP(O)(OBn)2,
xe2x80x94CH2OP(O)(OH)2, xe2x80x94(CH2)qO(CH2)qCO2H, xe2x80x94(CH2)qO(CH2)qSO3H,
xe2x80x94(CH2)qO(CH2)qCHNHOH,
xe2x80x94CH2NHC(S)NHCH(CO2H)(CH2)qH or
wherein
r=1-20
R4=xe2x80x94H or -Ac
X3=xe2x80x94CO2H; NHSO2CH3; NHP(O)(OBn)2; xe2x80x94NHP (O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2
The compounds of formula II have the following structure:
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH) (CH2)2xe2x80x94;
CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH)2xe2x80x94; or
xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X4 and X5 are independently
xe2x80x94OP(O)(OBn)2; xe2x80x94OP(O)(OH),; xe2x80x94CO2H; xe2x80x94SO3H; xe2x80x94SO3H; xe2x80x94O(CH2)CO2H;
NHSO2CH3; xe2x80x94CONH(CH2),CO2H; or xe2x80x94SO2NH (CH2),CO2H; wherein
s=1-5
or X4 and X5 are independently
wherein
t=1-20
R5=xe2x80x94H or -Ac
X6=xe2x80x94CO2H; NHSO2CH3; NHP(O)(OBn)2; xe2x80x94NHP (O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2
The compounds of formula III have the following structure:
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH) (CH2)2xe2x80x94;
CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH)2xe2x80x94; or
xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
Ar=unsubstituted or mono- or di-substituted phenyl wherein said substituents are selected from the group consisting of halogen, OCH3, SO2CH3, CF3amino, alkyl, and 3,4-dichloro; benzothiophenyl; benzofuranyl; naphthyl; diphenyl methyl; or 9-fluorene;
X7 is
NHSO2CH3; NHP(O)(OBn)2; NHP(O)(OH)2; xe2x80x94(CH2)uNHSO2CH3;
xe2x80x94(CH2)uNHC(S)NHCH(CO2H)(CH2)uCO2H; xe2x80x94CONHOH; or xe2x80x94CH2)uCONHOH;
wherein
u=1-5
or X7 is
R6=xe2x80x94H or -Ac;
X6=xe2x80x94CO2H; xe2x80x94NHSO2CH3; NHP(O)(OBn)2; xe2x80x94NHP(O)(OH)2; xe2x80x94OP(O)(OBn)2; or xe2x80x94OP(O)(OH)2;
R7=xe2x80x94NH(CH2)vCO2H; xe2x80x94NH(CH2)vCH(NH2)(CO2H); xe2x80x94NHCH(CO2H)(CH2)vNH2; xe2x80x94NH(CH2)vSO3H; xe2x80x94NH(CH2)vPO3H2; xe2x80x94NH(CH2)vNHC(NH)NH2; or xe2x80x94NHCH(CO2H)(CH2)CO2H; and
v=1-20.
The compounds of formula IV have the following structure:
wherein
n=1-3, where n=1 is preferred
R1 and R2 are independently xe2x95x90CH3; xe2x80x94CH2)m, where m=4-8, m=4 is most preferred; xe2x80x94CH2CH(OH) (CH2)2xe2x80x94;
CH2CH(F)(CH2)2xe2x80x94; xe2x80x94(CH2)2O(CH)2xe2x80x94; or
xe2x80x94(CH2)2CHxe2x95x90CHCH2xe2x80x94;
R3 and R4 are independently H; OCH3; alkyl; or c-O (CH2)2;
X9=1-4 substituents selected from the groups consists of
-halogen; xe2x80x94CF3; xe2x80x94OCH3; xe2x80x94SO2NH(CH2)qCO2H; xe2x80x94CONH(CH2)qCO2H;
xe2x80x94NH2; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; NHP(O) (OH)2; xe2x80x94SO2CH3;
xe2x80x94OP(O)(Obn)2; xe2x80x94OP(O)(OH)2; xe2x80x94CO2H; xe2x80x94O(CH2)qCO2H; xe2x80x94O(CH2)qSO3H,
xe2x80x94O(CH2)qOPO3H2; wherein
q=1=20.
or X9 is
wherein
t=1-20
R5=xe2x80x94H or -Ac
X6=xe2x80x94CO2H; xe2x80x94NHSO2CH3; xe2x80x94NHP(O)(OBn)2; NHP (O)(OH)2; xe2x80x94OP(O)(Obn)2; or xe2x80x94)P(OH)2.
Peripherally-acting xcexa agonists can be prepared by the attachment of polar groups to non-peptide xcexa opioid receptor selective agonists, such as the arylacetamides. In designing the peripherally-acting ligands, the introduction of the polar groups may result is either retention or enhancement of antinociceptive potency and selectivity and also may increase the polarity of the ligand sufficient to produce or eliminate CNS penetration across the blood-brain barrier (BBB). Thus the identity and the positioning of the polar group(s) are important.
Using the prototypic arylacetamide, U50,488, as an example, the arylacetamide pharmacophore can be divided into three regions: the aromatic region, the central region, and the amine region. All three regions represent potential positions for the attachment of polar groups.
Compounds of formula (I) of the present invention are made as follows.
A series of novel compounds were made based on the class of arylacetamides reported by Glaxo (J. Med. Chem 1993, 36, 2075). Specifically, compound 1 can be deprotected to yield intermediate 2, which can be derivatized by the attachment of a variety of polar groups (Scheme 1).
The 3xe2x80x2-substituted series can be prepared via Scheme 2. The reduction of the Schiff base intermediate ford during the cyclization to 6 is expected to be stereoselective due to the directing effect of the neighboring hydroxymethyl group. Both intermediates 11 and 12 can be derivatized to confer peripheral selectivity.
The 5xe2x80x2-substituted series can be prepared via Schemes 3 and 4. Starting from N-t-Boc-O-MEM-D-serine, the 5xe2x80x2-(S) series can be prepared, and starting from from N-t Boc-O-MEM-L-serine allows the preparation of the 5xe2x80x2-(R) series.
wherein Ar, R1R2, and n are defined in formula I.
wherein Ar, R1, R2, and n are as defined is formula I.
wherein Ar, R1, R2, and n are as defined in formula I.
wherein Ar, R1R2, and n are as defined is formula I.
Using Schemes 1-4 the following example compounds are made.
Intermediate 3 can be treated with t-butyl bromoacetate and deprotected to produce {4-[1-(3,4-Dichlorophenyl)acetyl-2R(1-pyrrolidinyl)-methyl] piperazinyl}acetic acid (26).
Intermediate 3 can be reacted with methane sulfonyl chloride to produce [1-(3,4-Dichlorophenyl)acetyl-4-methanesulfonyl-2R-(1-pyrrolidinyl)methyl] piperazine (27).
Intermediate 3 can be coupled to N-t-Boc-L-aspartic acid xcex2-benzyl ester and deprotected to produce [4-5-Aspartic acid-a-amido-1-(3,4-dichlorophenyl)acetyl-2R-(1-pyrrolidinyl)methyl] piperazine (28).
Intermediate 11 can be treated with t-butyl bromoacetate and deprotected to produce Methyl-[2R-(O-2-acetic acid) hydroxymethyl-4-(3,4-dichlorophenyl acetyl-3R-(1-pyrrolidinyl)methl]-1-piperazinecarboxylate (29).
Intermediate 11 can be coupled to to N-t-Boc-L-aspartic acid-b-benzyl ester and deprotected to produce Methyl-[2R-(O-5-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (30).
Intermediate 12 can be treated with methanesulfonyl chloride to produce Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-3R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (31).
Intermediate 12 can be coupled to 2S-isothiocyanato-succinic acid-debenzyl ester and deprotected to yield Methyl-{4-[3,4-dichlorophenyl] acetyl-3R-[1-pyrrolidiayl] methyl-2R-[N-(succinic acid-2S-thioureido)] aminomethyl}-1-piperazinecarboxylate (32).
Intermediate 21 can be treated with t-butyl bromoacetate and deprotected to produce Methyl-[2S-(O-2-acetic acid) hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (33).
Intermediate 21 can be coupled to to N-t-Boc-L-aspartic acid-b-benzyl ester and deprotected to produce Methyl-[2S-(O-5-aspartic acid-a-acetyl)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (34).
Intermediate 22 can be treated with methanesulfonyl chloride to produce Methyl-[4-(3,4-dichlorophenyl)acetyl-2S-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl
nethyl]-1-piperazinecarboxylate (35).
Intermediate 22 can be coupled to 2S-isothiocyanato-succinic acid-dibenzyl ester and deprotected to yield Methyl-{4-[3,4-dichlorophenyl] acetyl-5R-[1-pyrrolidinyl] methyl-2S-[N-(succinic add-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (36).
The 2R isomers of 33-34 and 35-36 can be prepared from intermediates 24 and 25, respectively to produce
Methyl-[2R-(O-2-acetic acid)hydroxymethyl-4-(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (37).
Methyl-[2R(O-5-aspartic acid-a-acetyl)hydroxymethyl-4(3,4-dichlorophenyl)acetyl-5R-(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (38).
Methyl-[4-(3,4-dichlorophenyl)acetyl-2R-(N-methanesulfonamido)aminomethyl-5R-(1-pyrrolidinyl) methyl]-1-piperazinecarboxylate (39).
Methyl-{4-[3,4-dichlorophenyl] acetyl-5R-[1-pyrrolidinyl] methyl-2R-[N-(succinic acid-2S-thioureido)]aminomethyl}-1-piperazinecarboxylate (40).
The corresponding structural formulas are shown hereunder.
Compounds of formula II of the present invention are made by peripheralization by substitutions of the benzo portion of the tetrahydronaphthyl ring of DuPont aeries of compounds with polar groups.
Starting material or precursors of the starting material are commercially available and thus allows regiospecific substitutions of the tetrahydronaphthyl ring (Scheme 5). While 5-hydroxytetralone, 6-hydroxytetralone, 7-hydroxytetralone, and 7-aminotetralone derivatives are readily available, 5-aminotetralone could be prepared from 5-hydroxytetralone (J. Org. Chem. 1972, 37, 3570).
The tetralone derivatives can be converted to dihydronaphthyl derivatives and subjected to chemistry similar to that employed in the preparation or U50,488 derivatives. The resulting compounds are racemic mixtures that can be derivatized to confer peripheral selectivity. If necessary, the final compounds or one of the intermediates can be resolved to test both enantiomers.
wherein R1, R2, and n are as defined in formula I.
Following the procedure shown is Schemes 5-7, the following example compounds are prepared:
Intermediate (xc2x1)-64 can be treated with t-butyl bromoacetate and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(O-2-acetic acid)-hydroxy-2(1-pyrrolidinyl)naphthyl]acetamide (72).
Intermediate (xc2x1)-65 can be treated with t-butyl bromoacetate and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(O-2-acetic acid)-hydroxy-2-(1-pyrrolidinyl)naphthyl]acetamide (73).
Intermediate (xc2x1)-66 can be treated with methanesulfonyl chloride to produce (xc2x1)-2xe2x80x94(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-methanesulfonamido)amino-2-(1 pyrrolidinyl)naphthyl]acetamide (74).
Intermediate (xc2x1)-67 can be treated with methanesulfonyl chloride to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-methanesulfonamido)amino-2-(1-pyrrolidinyl)naphthyl]acetamide (75).
Intermediate (xc2x1)-68 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl]acetamide (76).
Intermediate (xc2x1)-69 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-5-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl]acetamide (77).
Intermediate (xc2x1)-70 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-acetic acid)-carboxamido-2-(1-pyrrolidinyl)naphthyl] acetamide (78).
Intermediate (xc2x1)-71 can be treated with glycine benzyl ester and deprotected to produce (xc2x1)-2-(3,4-dichlorophenyl)-N-methyl-N-1-[1,2,3,4-tetrahydro-7-(N-2-acetic acid)-sulfonamido-2-(1-pyrrolidinyl)naphthyl] acetamide (79).
The compounds of formula III of the present invention an prepared by substituting the central phenyl ring with polar groups.
Compound 80 and analogues undergo a variety of diazonium-involving reactions for the attachment of polar groups (Scheme 7).
Using the procedure shown in Scheme 7, the following compounds are made.
Intermediate 81 can be treated with dibenzyl phosphoryl chloride followed by deprotection to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-3-(O-phosphoryl) hydroxyphenyl-2-(1-pyrrolidinyl)ethyl}acetamide (87).
Intermediate 85 can be coupled to methanesulfonyl chloride to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-methanesulfonamido)aminomethyl] phenyl-2-(1-pyrrolidinyl)ethyl}acetamide (88).
Intermediate 85 can be coupled to 2S-isothiocyanato succinic acid and deprotected to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-[3-(N-succinic acid-2S-thioureido)aminomethyl] phenyl-2-(1-pyrrolidinyl) ethyl}acetamide (89).
Intermediate 80 can be treated with dibenzyl phosphoryl chloride followed by deprotection to produce 2-(3,4-dichlorophenyl)-N-methyl-N-{1-3-(N-phosphoramido) aminophenyl-2-(1-pyrrolidinyl)ethyl}acetamide (90).
The compounds of formula IV may be prepared by Scheme 8.
wherein R1, R2, R3, and R4 are defined in formulas III and IV.
The diamino intermediate 91 (J. Med. Chem. 1990, 33, 286) can be coupled to different regioisomers of nitrophenylacetic acid, which are all commercially available. Reduction of the nitro group provides an amino group for the attachment of polar groups. Alternatively, the amino intermediates 95-97 readily undergo diazonium chemistry that converts the amino groups to carboxyl and sulfonyl chloride groups. This allows the polar groups to be attached via different linkers.
Following the procedure in Scheme 8, the following compounds are made.
Intermediate 96 can be treated with methanesulfonyl chloride to produce (xe2x88x92)-(5xcex1,7xcex1,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5] dec-8-yl]-3-(N-methanesulfonamido)aminophenylacetamide (104).
Intermediate 98 can be coupled to glycine benzyl ester and deprotected to yield (xe2x88x92)-(5xcex1,7xcex1,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5] dec-8-yl]-3-(N-2-acetic acid)sulfonamidophenylacetamide (105).
Intermediate 99 can be coupled to glycine benzyl ester and deprotected to yield (xe2x88x92)-(5xcex1,7xcex1,8xcex2)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro-[4,5] dec-8-yl]-3-(N-2-acid) carboxamidophenylacetamide (106).
Compounds of the above formulas may have one or more asymmetric carbon atoms. Pure sterochemically isomeric forms of the above compounds may be obtained, and diastereoisomers isolated by physical separation methods, including, but not limited to crystallization and chromatographic methods. Cis and traps diasteriomeric racemates may be further resolved into their isomers. If separated, active isomers may be identified by their activity. Such purification is not, however, necessary for preparation of the compositions or practice of the methods herein.
As used herein, the compounds provided herein also include pharmaceutically acceptable salts, adds and esters thereof, stereoisomers, and also metabolites or prodrugs thereof that possess activity as analgesics but do not cause substantial CNS effects when administered or applied. Metabolites include any compound that is produced upon administration of the compound and metabolism thereof.
More detailed preparations of the compounds of the present invention follow.
Preparatory for the compounds of formula I, the following intermediates wore prepared. Computing . . .
N-Benzyl-D-serine(1)1:
1 Ref. (1) Ohfume, Y.; Kurokawa, N.; Higuichi, N.; Saito, M.; Hasnimoto, M.; Tanaka, T. An efficient one-step reductive N-monoalkyation of a-amino acids. Chemistry Letters. 1984, 441-444.
To a mixture of D-serine (25.0 g, 0.237 mol) and 200 mL anhydrous methanol was added sodium cyanoborohydride (11.95 g, 0.190 mol), while maintaining the temperature at 0xc2x0 C. with an ice bath. Then, benzaldehyde (26.5 mL, 0.261 mol) was added to the reaction flask, dropwise, at 30xc2x0 C. The mixture was stirred for 60 Hr. at room temperature. Then, the mixture was filtered and rinsed with methanol (50 mL). The white solid was dried in a vacuum oven at 40xc2x0 C. and 10 mmHg over 2 nights: 24.5 g. The filtrate was retained and the solvent was evaporated. This oil was passed through a silica gel column (10% MeOH/CH2Cl2) and 3.4 g of the desired compound was isolated. The total amount of the product was 27.9 g (60.0% yield). 1H NMR (DMSO-d6) 3.25 (m, 1H, CH), 3.85 (m, 2H, CH2), 4.11 (d, 2H, benzylic CH2), 7.45-7.53 (m, 5H, ArH).
N-Benzyl-D-serine methyl ester(2):
Hydrogen chloride (gas) was bubbled into anhydrous methanol for 10 minutes. Then, the solution was allowed to cool to room temperature. Then, N-benzyl-D-serine (24.6 gm, 0.126 mol) was added to the reaction flask and refluxed aver night under dry nitrogen. Then, the solvent was evaporated and dissolved in dichloromethane (200 mL), and washed with a saturated solution of sodium bicarbonate. The dichloromethane layer was dried with magnesium sulfate and the solvent was evaporated. (23 gm, 87.2% yield). 1H NMR (CDCl3) xcex4 3.41 (d, 1H, CH), 3.52-3.80 (dd, 2H, benzylic 3.69 (s, 3H, OMe), 7.27 (s, 3H, ArH).
N-[(1,1-Dimethylethoxy)carbonyl-D-Ser-(O-Bzl)-N-benzyl-D-Ser-OMe (3):
To a solution of N-boc-D-serine-(O-bzl)OH (15 g, 50.76 mmol) in anhydryous dichloromethane (200 mL) was added HOBt (7.54 g, 55.8 mmol) at 0xc2x0 C. under dry nitrogen. Then, DCC (11.5 g, 55.7 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flask. Then, this mixture was stirred for 1 Hr. Then, N-benzyl-D-serine-OMe (10 g, 47.8 mmol) in dichloromethane (100 mL) was added dropwise to the reaction flash. Then, stirred for 4 days. Then, filtered and rinsed with dichloromethane (100 ml). The white precipitate was DCU and HOBt. The filtrate was evaporated and re-dissolved in ethyl acetate (100 mL). Then, this was allowed to precipitate, overnight-more DCU. This was filtered and rinsed with ethyl acetate. Then, this was isolated on a silica gel column (20% ethyl acetate/hexanes): an oil-173 g, 74.3% yield. 1H NMR (CDCl3) xcex4 1.43 (s, 9H, t-Bu), 3.54 (t, 1H, OH), 3.72 (s, 3H, OMe), 3.75 (dd, 2H, CH2), 3.79 (dd, 2H, CH2), 4.41 (d, 2H, CH2 benzylic 4.43 (d, 2H, CH2 benzylic), 7.27-7.30 (m, 10H, ArH). (2R,5R)-2-((Benzyloxy)methyl)-5-(Hydroxymethyl)-4-(phenylmethyl)-3,6-piperazine dione(4)2:
Ref. (2) Williams, T. M.; Ciccarone, T. M.; MacTough, S. C. and et al. 2-Substituted piperazines or constrained amino acids. J. Med. Chem. 1996, 39, 1345-1348.
Into anhydrous chloroform (300 mL) was bubbled hydrogen chloride (gas). Then, the dipeptide (3) (13.5 g, 27.7 mmol) in chloroform (100 ml) was added to the reaction flask. The Bask was stoppered and stirred for 64 Hr. Then, a saturated solution (100 ml) of sodium bicarbonate was added and stirred vigorously for 48 Hr. The cyclization was completed at this point. The organic layer was separated from the aqueous layer in a 1 L separatory funnel. The product was isolated from a silica gel column, eluting with dichloromethane-methanol-0.88 ammonia (96:2:2) to give (4) as an amorphous solid (6.0 g, 61.1% yield). 1H NMR (CDCl3) xcex4 3.72-3.96 (m, 7H), 3.97-5.24 (dd, 2H, CH2 benzylic 4.45 (dd, 2H, CH2 benzylic 7.15-7.30 (m, 10H, ArH); MS (FAB) m/e 355 (MH+).
(2S,5S)-2-((Benzyloxy)methyl)-4-(phenylmethyl)-5-piperazinemethanol(5):
A suspension of lithium aluminum hydride (0.9 g, 23.7 mmol) in anhydrous tetrahydrofuran (40 mL) was treated with a solution of piperazinedione 4 (2.1 g, 5.92 mmol) in anhydrous tetrahydrofuran (200 mL). The reaction mixture was heated at reflux for 24 Hr and then, stirred at room temperature for 12 Hr. Water (10 ml) was added followed by aqueous sodium hydroxide (1N, 10 mL) and water (10 mL). The mixture was filtered, and the filtrate was evaporated to give 5 (1.67 g, 86.4% yield) as a viscous oil. 1H NMR (CDCl3) xcex4 2.58 (dd, 2H, CH2), 2.61 (t, 1H, OH), 3.10 (dd, 2H, CH2), 3.25 (dd, 2H, CH2), 3.50 (dd, 2H, CH2), 3.74 (s, 2H, CH2), 4.41 (dd, 2H, CH2benzylic), 7.20-7.30 (m, 10H, ArH).
(2S,5S)-Methyl 2-[(Benzyloxy)methyl]-5-(hydroxymethyl)-4-(phenylmethyl)-1-piperazine carboxylate (6)3:
(3) Naylor, A.; Judd, D. B.: Lloyd, J. H.; Scopes, D. I. C.; Hayes, A. G.; Birch, P. J. A potent new class of k-Receptor agonist : 4-substituted 1-(arylacetyl)-2-[(dialkylamino)methyl]piperazines. J. Med Chem. 1993, 36, 2075-2083.
A solution of 5 (1.67 g, 5.11 mmol.) is acetonitrile (20 mL) was treated with a solution of methyl chloroformate (0.532 g, 5.63 mmol) in acetonitrile (10 mL) at 0xc2x0 C. The mixture was stirred at ambient temperature for 30 min., and then aqueous sodium carbonate solution (15 mL) was added. The organic solvent was removed, and the aqueous residue was extracted with chloroform (3xc3x9710 mL). The combined organic extracts were washed with aqueous sodium carbonate solution (10 mL), dried, and evaporated to give 6 (1.52 g, 773% yield) as an oil. 1H NMR (CDCl3) xcex4 2.54 (dd, 2H, CH2), 2.45 (t, 1H, OH), 2.72 (dd, 2H, CH2), 3.51 (dd, 2H, CH2), 3.67 (dd, 2H, CH2), 3.69 (s, 3H, OMe), 3.81 (dd, 2H, CH2), 4.44 (dd, 2H, CH2benzylic), 7.17-7.31 (10H, ArH).
(2S,5S)-Methyl 2-[(Benzyloxy)methyl]-5-(1-pyrrolidinyl) methyl)-4-(phenylmethyl]-1-piperazine carboxylate(7)3:
A solution of oxalyl chloride (0.545 mL, 6.24 mmol) in dichloromethane (10 mL at xe2x88x9265xc2x0 C. was treated with a solution of dimethyl sulfoxide (1.14 mL, 16.0 mmol) in dichloromethane (5 ml) taming the reaction temperature below xe2x88x9265xc2x0 C. The mixture was stirred at xe2x88x9270xc2x0 C. for 10 min, and then a solution of the piperazinemethanol (6: 2 g, 5.19 mmol) in dichloromethane (20 mL) was added at such a rate that the reaction temperature was maintained below xe2x88x9265xc2x0 C. The reaction mixture was stirred at xe2x88x9265xc2x0 C. for 3 Hr, and a solution of N-methylmorpholine (1.42 mL, 12.91 mmol) in dichloromethane (5 mL) was added. The mixture was stirred at xe2x88x9220xc2x0 C. for 45 min and then washed with ice-cold hydrochloric add (0.01 N, 100 mL and 50 mL), dried, evaporated, and placed on a high vacuum pump overnight. The residue was dissolved in methanol (10 mL) and was added to a solution of pyrrolidine (0.91 mL, 10.94 mmol) in methanol (10 mL) at xe2x88x9210xc2x0 C., which had been adjusted to pH 6.0 by the addition of methanolic hydrogen chloride. Sodium cyanoborohydride (0.67 g, 10.66 mmol) and 4-xc3x85molecular sieves (0.66 g) were added, and the mixture was stirred at ambient temperature for 18 Hr. The mixture was filtered, and the filtrate was evaporated to dryness. The residue was dissolved in aqueous sodium carbonate (1M, 25 mL) and extracted with dichloromethane (2xc3x9750 mL). The product was isolated from a silica gel column, eluting with dichloromethane-methanol (98:2) to give (7:1.0 g, 23.0% yield). 1H NMR (CDCl3) xcex4 1.75 (m, 4H, CH2CH2), 2.46 (m, 3H), 2.48 (m, 4H, CH2CH2), 2.55 (dd, 2H, CH2), 2.70-2.85 (m, 3H), 3.41 (dd, 2H, CH2), 3.69 (s, 3H, OMe), 4.10 (m, 1H), 4.20 (m, 1H), 4.41 (dd, 2H, CH2benzylic), 7.10-7.31 (m, 10H, ArH); MS (FAB) m/e 438 (M+).
(2S,5S)-Methyl 2-(Hydroxymethyl)-5-[(1-pyrrolidinyl) methyl]-1-piperazine carboxylate(8):
A solution of 7 (0.25 g, 0.571 mmol) in ethanol (200 mL) was hydrogenated over 10% palladium on carbon (Degussa type E101 NE/W) at 50 psi for 7 days. Then, filtered through celite and filtrate was evaporated. (0.13 g, 0.3 mmol: 87% yield).
(2S,5S)-Methyl 4-[(3,4-dichlorophenyl)acetal]-2-(hydroxy) methyl-5-[(1-pyrrolidinyl)methyl]-1-piperazinecarboxylate (9):
To a solution of 1,1xe2x80x2-carbonyldiimiazole (0.20 g, 1.26 mmol) in dichloromethane (10 mL) was added portionwise 3,4-dichlorophenylacetic acid (0.25 g, 1.26 mmol) and the resulting solution stirred under nitrogen for 1 Hr, at room temperature. A solution of 8 (0.13 g, 0.5 mmol) in dichloromethane (10 mL) was added and the mixture at room temperature for 18 Hr. The reaction mixture was washed with sodium carbonate solution (2N, 2xc3x9710 mL), dried, and evaporated to give a viscous oil. This material was dissolved in a mixture of tetrahydrofuran (5 mL) and water (5 mL) and treated with lithium hydroxide (42 mg, 1.0 mmol). The reaction mixture was removed, and the aqueous residue was extracted with dichloromethane (3xc3x9710 mL). The combined organic extracts were dried and evaporated to give a colorless gum which was purified by flash column chromatography on silica gel, eluting with ethyl acetate-methanol (40:1) to give 9 (155 mg, 70%) as a colorless foam
Utilizing the above-denoted intermediates, the following compounds were prepared.

Kappa agonist compounds and pharmaceutical formulations thereof

Abstract: The compounds of formulae I, II, III and IV have the structure:

Abstract: wherein:

Abstract: X, X4, X5, X7, X9;

Abstract: R1, R2, R3, R4; and

Abstract: Y, Z and n are as described in the specification.


A designing method is provided for designing an electric circuit including a clock output circuit for delivering a clock signal and a plurality of processing circuits for receiving the clock signal from the clock output circuit via wirings for clock transmission so as to perform a predetermined process based on the clock signal. The method includes, as a method for designing the wirings for clock transmission to have a predetermined length, a first step of connecting wirings between each of the processing circuits and an arbitrary point (as a “first point”) so that the wirings have substantially the same length (as a “first length”), and a second step of connecting the first point to the clock output circuit by a single wire having the length that is obtained by subtracting the first length from the predetermined length. Thus, lengths of the wirings for transmitting the clock signal to the plurality of circuits are adjustable while the entire length of the wirings is minimized.

1. Field of the Invention
The present invention relates to an electric circuit associated with transmission of a clock signal and a method for designing the electric circuit.
2. Description of Related Art
Conventionally, electronic equipment including a personal computer or the like uses a memory device of a standard such as Double Data Rate 2 (DDR2) SDRAM, for instance. A plurality of such memory devices may be disposed in electronic equipment for a purpose of securing sufficient memory capacity or other purposes. A schematic structure of an example of the electric circuit having such the structure is shown in FIG. 2.
The electric circuit includes a control IC 101 and a plurality of (e.g., four) SDRAMs 102a to 102d, which are connected to each other via wirings 103 and 104. In addition, the control IC 101 is provided with a clock signal output portion 111 for outputting a predetermined clock signal and a data input and output portion 112 for supplying or receiving various data to or from the SDRAMs 102a to 102d.
Such the electric circuit enables the SDRAMs 102a to 102d to read or write data in synchronization with a clock signal (external clock) that is sent from the clock signal output portion 111 via the wiring 103. Note that the clock signal is delivered from the clock signal output portion 111 and is imparted to the SDRAMs 102a to 102d after branching at a branch node 103b.
In addition, the data input and output portion 112 is supplied with the clock signal from the clock signal output portion 111 and performs input and output of data from or to the SDRAMs 102a to 102d via the wiring 104 in synchronization with the clock signal.
Noting an operation of writing data in the SDRAMs 102a to 102d, for instance, it is desirable that the writing operation should be performed in the SDRAMs 102a to 102d at timings delayed as little as possible from the timing when the data to be written reaches the SDRAMs 102a to 102d via the wirings 104.
However, even if a clock signal that is common to individual operations is used, there may be the case where a time difference occurs between the time period from reception of the clock signal by the data input and output portion 112 until arrival of the data at the SDRAMs 102a to 102d via the wiring 104 and the time period until reception of the clock signal by the SDRAMs 102a to 102d via the wiring 103, due to a delay time of transmission.
Therefore, when such the electric circuit is designed, a wiring length adjustment portion 103a is disposed at each branch of the individual wirings 103 as shown in FIG. 2. This wiring length adjustment portion 103a is disposed for adjusting the length of the wiring 103 so as to adjust transmission delay time of the clock signal (the longer the wiring, the longer the delay time is). According to the wiring length adjustment portion 103a shown in FIG. 2, a meandering pattern is adopted so that the wiring 103 is adjusted to be longer intentionally and that the transmission delay times of the clock signal to the SDRAMs 102a to 102d are increased.
Thus, it is possible to minimize the time difference by adjusting the wiring lengths as described above, so that the operation of writing data in the SDRAMs 102a to 102d can be performed more appropriately. Note that the documents below disclose conventional techniques in the art of the present invention.    JP-A-2004-110103    JP-A-2000-267756    JP-A-2006-54348    JP-A-2000-122751    JP-A-2000-148282
However, if it is necessary to increase the length of the wiring length adjustment portion 103a in the case where the wiring length adjustment portion 103a is disposed at each branch as described above, it is necessary to increase all the plurality of wiring lengths 103a of the individual branches. Therefore, the entire length of the wiring 103 becomes very long, so that power loss will increase due to an increase in wiring resistance. As a result, quantity of current of the clock signal to be supplied to the SDRAMs 102a to 102d may be insufficient.
If the quantity of current of the clock signal is insufficient, it causes drop of an amplitude level of the clock signal or deterioration of a waveform of the clock signal, so that the clock signal cannot be transmitted accurately. Therefore, a malfunction may occur in writing or the like of the data in the SDRAMs 102a to 102d.

Electric circuit and method for adjusting wirelength of clock signal in electric circuit


The present invention relates to a monofilament with a segmented pie structure formed by conjugated spinning of degradable polymers and non-degradable polymers, a hernia mesh having improved flexibility and biocompatibility, and a preparation method of the monofilament. More specifically, the hernia mesh of the present invention having improved flexibility and biocompatibility is prepared using the monofilament obtained by conjugated spinning of degradable polymers and non-degradable polymers into a segmented pie form, to control it to be gradually degraded in the body, whereby the stiffness of the early stage is removed, and thereby the foreign body sensation is also removed.

(a) Field of the Invention
The present invention relates to a monofilament having a segmented pie structure formed by conjugated spinning of degradable polymers and non-degradable polymers, a hernia mesh comprising the monofilament having improved flexibility and biocompatibility, and a method for preparing the same. More specifically, the present invention relates to a monofilament prepared by conjugated spinning of degradable polymers and non-degradable polymers in the form of a segmented pie; a hernia mesh that is prepared with the monofilament and that is controlled to be gradually degraded in the body while losing the stiffness of the early stage, causing no misfeelings, and having improved flexibility and biocompatibility; and a method of preparation thereof.
(b) Description of the Related Art
Tension-free hernioplasty (Lichtenstein I L, Am J Surg 1989; 157; 188-193) is considered to be a useful method for reparation of hernias, because the relapse ratio thereafter is low, the operative time is short, and the operative wound heals quickly, and thereby the patient can rapidly return to normal life. Conventionally, since the mesh used for hernia repair is required to have the capability of maintaining its chemical and physical properties for several years to strengthen the peritoneum, polypropylene monofilaments have been used as the material for a hernia mesh. However, it has been reported that the polypropylene mesh may have the potential to generate fistulas in the intestine (Seelig M H, "A rare complication after incisional hernia repair". Chirurg 1995; 66(7); 739-741, Leber G E, "Long-term complications associated with prosthetic repair of incisional hernias", Arch Surg 1988; 133(4); 378-382). Further, as general side effects of the polypropylene mesh, an edema, a restriction of abdominal wall mobility due to stiffness of the peritoneum where the artificial membrane is located and pain from misfeelings caused by the stiffness, a chronic inflammatory response between the polypropylene fibers and tissues in body, and the like have been reported (Amid P K, "Biomaterials for abdominal wall hernia surgery and principles of their applications", Lagenbecks Arch Chir 1994; 379(3): 168-171, Waldrep D J, "Mature fibrous cyst formation after Marlex Vestweber K, Results of recurrent abdominal wall hernia repair using polypropylene mesh". Zentralblatt Für Chirurgie 1997; 122:885-8, Belton J M, "Integration of biomaterials implanted into abdominal wall: mesh ventral herniorrhaphy: a newly described pathologic entity". Am Surg 1993; 59(11):716-8, "Process of scar formation and macrophage response". Biomaterials 1995; 16(5):381-7, Klinge U, "Changes in abdominal wall mechanics after mesh implantation". Experimental changes in mesh stability. Lagenbecks Arch Chir 1996; 381(6): 323-32).
The hernia mesh needs stiffness in order to be positioned and fixed on the surgical wound region when performing the surgical operation. For that purpose, several methods to prepare the hernia mesh using fibers in the monofilament form have been known. U.S. Pat. No. 4,347,847, U.S. Pat. No. 4,452,245, U.S. Pat. No. 5,569,273, and U.S. Pat. No. 6,287,316 disclose a method to prepare a hernia mesh consisting of polypropylene monofilaments. However, since polypropylene is non-degradable, after performing the surgical operation using the hernia mesh, the strength and stiffness of the mesh that are necessary during the initial stage after the surgical operation are continuously maintained in the body. Therefore, the mesh has excessive stiffness even after the wound has healed, causing pain to the patient due to misfeelings. Further, U.S. Pat. No. 5,292,328 discloses a method of preparing a hernia mesh consisting of polypropylene multifilaments in order to improve the flexibility, in which the mesh has a somewhat improved initial flexibility compared with that consisting of the monofilaments. However, since the mesh consists of only non-degradable materials, there are also some problems in that the initial strength and stiffness of the mesh are continuously maintained in the body, and an excessive amount of polypropylene remains in the body.
To solve these problems, studies on development of a partially degradable mesh wherein the content of polypropylene is decreased and the strength and stiffness necessary for the initial stage is supplemented by additionally comprising degradable materials, have been disclosed in U.S. Pat. No. 4,652,264 and U.S. Pat. No. 6,162,962. Herein, the degradable materials are partially degraded after the wound has healed, to improve the flexibility of the mesh. U.S. Pat. No. 4,652,264 discloses a method to prepare a mesh by combining threads consisting of three different materials, of which two are degradable and one is non-degradable. U.S. Pat. No. 6,287,316 discloses a method of preparing a mesh using a multifilament consisting of degradable materials and non-degradable materials. However, since the meshes prepared by the above methods consist of several threads of degradable and non-degradable materials in the combined form, there is a possibility of bacterial infection within the spaces between the threads, which is an inherent defect of multifilaments. Further, since the methods employ the multifilament form wherein several strands of fiber are combined, the amount of materials required for exhibiting the necessary stiffness is larger than the case of using the monofilament. In addition, the multifilament causes a strong foreign body response due to the large surface area (Beets G L, "Foreign body reactions to monofilament and braided polypropylene mesh used as preperitoneal implants in pigs". Eur J Surg 1996; 162:823-825).
As known from the above prior art, although the use of a hernia mesh has been regarded as a basic means in performing hernia repairs, there are unsatisfactory results obtained from the studies to develop a hernia mesh for improving the convenience in performing the operation, reducing the misfeelings, and having improved biocompatibility. Therefore, it is required to develop a hernia mesh that can maintain its strength and stiffness at the early stage, thereby ensuring convenience in performing the operation, and be partially degraded as the surgical wound is healed, thereby improving the flexibility of the remaining mesh.

Process for preparing hernia mesh from monofilament


Hydroxyaromatic compounds such as phenol are carbonylated with oxygen and carbon monoxide in the presence of a catalyst system comprising a Group VIIIB metal, preferably palladium; an iodide salt, preferably sodium iodide; and at least one organic bisphosphine such as 1,3-bis(diphenylphosphino)propane or 1,4-bis(diphenylphosphino)butane. The catalyst system also preferably contains a compound of cerium or lead.

This invention relates to the preparation of diaryl carbonates by carbonylation. More particularly, it relates to the improvement of diaryl carbonate yield in the carbonylation reaction.
Diaryl carbonates are valuable intermediates for the preparation of polycarbonates by transesterification with bisphenols in the melt. This method of polycarbonate preparation has environmental advantages over methods which employ phosgene, a toxic gas, as a reagent and environmentally detrimental chlorinated aliphatic hydrocarbons such as methylene chloride as solvents.
Various methods for the preparation of diaryl carbonates by an oxidative carbonylation (hereinafter sometimes simply "carbonylation" for brevity) reaction of hydroxyaromatic compounds with carbon monoxide and oxygen have been disclosed. In general, the carbonylation reaction requires a rather complex catalyst. Reference is made, for example, to U.S. Pat. No. 4,187,242, in which the catalyst is a heavy Group VIII metal; i.e., a Group VIII metal having an atomic number of at least 44, said metals consisting of ruthenium, rhodium, palladium, osmium, iridium and platinum, or a complex thereof. Palladium catalysts have been found particularly useful; they include complexes with phosphines such as triphenylphosphine.
The production of carbonates may frequently be improved by including a metal-based cocatalyst along with the heavy Group VIII metal catalyst. Suitable metal-based cocatalysts have been described broadly in U.S. Pat. Nos. 4,187,242, 4,201,721 and 5,380,907 as compounds or complexes of copper, iron, manganese, cobalt, mercury, lead, cerium, vanadium, uranium, bismuth and chromium. Cerium compounds as cocatalysts are particularly detailed in European patent application 736,512.
Also required in general as part of the catalyst package are halides, typically quaternary ammonium or phosphonium halides, hexaalkylguanidinium halides or alkali metal or alkaline earth metal halides. According to Japanese Kokai 1/165,551 and 8/134,022, the halide can be an iodide; however, product recovery, particularly as defined in terms of "turnover number" (the number of moles of product and specifically diaryl carbonate formed per gram-atom of palladium present) was calculated to be very low, the highest being represented by a turnover number of about 3.3. In the aforementioned European application 736,512, the halide is a chloride or bromide.
Another disadvantage often encountered in the production of diaryl carbonates is the co-production of isomeric compounds. Thus, diphenyl carbonate yields are often decreased by concurrent formation of isomers such as phenyl salicylate and 4-hydroxyphenyl benzoate.
It remains of interest, therefore, to develop catalyst systems which provide improved production of diaryl carbonates. In particular, it is of interest to increase the rate of production relative to amount of catalyst employed and to decrease the proportions of isomers obtained.

Catalyst composition and method for producing diaryl carbonates, using bisphosphines


A system and method for controlling an external device from a first device include a display and a user interface associated with the first device. The first device has a first controller and a first data port. An external device has an external controller and a second data port coupled to the first data port. The external device communicates a command and a command identifier to the first controller. The first controller causes the display to display the command. When the command is selected by the user interface, the first controller transmits the command identifier to the external controller through the first and second data port.

Satellite television has become increasingly popular due to its wide variety of programming. Entertainment in automobiles such as DVD players has also become increasingly popular. It would be desirable to provide a satellite television system for a vehicle so that the wide variety of programming may be enjoyed by the rear passengers.
Both personal and residential units may be coupled to a variety of external devices. Typically, control of each device is separate in terms of controlling operating parameters of each device. A control or interface such as a remote control, keypad or buttons must be provided for each device. Providing separate interfaces increases the cost of the system.
It would therefore be desirable to provide a system that allows a receiving device to control other external devices generically without having to specifically configure for that device.

Customizable user interface for external devices


The aircraft pre-ventilation system has a ventilation unit mounted for movement along the ground. A primary and a return duct carry air between the ventilator and the aircraft door opening. The ducts are connected to a fitting which is designed to fit into and seal different size door openings for different aircraft. The fitting has a central rigid member, and a flexible bladder is attached to and surrounds the outside of the central member. The fitting is supporting by an adjustable arm for positioning the fitting in the door opening. When the fitting is properly positioned, the bladder expands to secure and seal the fitting to the aircraft door opening. The support arm that holds the fitting is hollow and carries pressurized air from the ventilator to a hose near the fitting that carries the air into the bladder.

1. Field of the Invention
This invention relates to a ground system designed to ventilate a variety of aircraft or structures especially executive and private airplanes.
2. Background of the Prior Art
When aircraft are parked on hot, sunny days, the interior temperature increases rapidly. Little ventilation is available. Many airplanes have only one door and no cooling air-conditioning. Air-conditioning must be powered, and it is uneconomical and possibly unsafe to use the main engine(s) to run an air-conditioner in a parked airplane.
The heating of the aircraft is a minor inconvenience when it is vacant, but a hot and/or humid airplane is most uncomfortable to embarking passengers. Because of the heat stored in the fuselage and contents of the airplane, the interior of the aircraft may not reach a comfortable temperature until well into the flight. Cooling does take place at higher altitudes where the air temperature is lower, but it may take many minutes to reach that altitude. The problem is compounded at major airports because there may be traffic delays in taking off. The problem is especially acute in executive jets and turboprop airplanes that may have pressurized cabins for flight at high altitudes. In those airplanes, the cabin is sealed before takeoff and the aircraft ventilation system cannot handle the preload of the heat in the plane. Occasionally also, an aircraft parked outside on a very cold day may be very cold inside and it may take many minutes into a flight before the passenger cabin is comfortably warm.
Various shelters may be used as warehouses, construction offices or the like. It may be uneconomical to provide these structures with permanent heating or cooling, but it may be desirable to heat or cool the structures on occasion.
Commercial airplanes have ground ventilation systems to ventilate parked airplanes. One of the earlier ones used a stand-alone air-conditioning unit mounted on a chassis for movement between aircraft parked at various gates at an airport. A flexible hose extended between the air-conditioning units and a fitting on the airplane for ventilating and cooling the interior of the airplane. Some commercial airplanes now have an auxiliary power unit APU which can be used for generating electrical power to run the ventilating systems and air-conditioning while the airplane is on the ground. The airplane may also be connected to an electrical source at the gate.
These options are not always available to executive and general aviation. They are not parked at a conventional gate, and few have an APU because of weight and cost considerations or have fittings for connection to the stand-alone air-conditioning units.


An alignment film for controlling orientation of liquid crystal molecules is formed of an organic silicon material which includes in its molecule an affinity imparting group for enhancing affinity to the liquid crystal molecules and an orientation characteristic imparting group for controlling orientation of the liquid crystal molecules. The affinity imparting group is at least one selected from the group comprising a vinyl group, an alkylene group, and a cyanoalkyl group, and the orientation characteristic group is at least one selected from the group comprising a phenyl group, a substituted phenyl group, a phenyl-alkyl group, a substituted phenyl-alkyl group, a branched alkyl group having carbon atoms of 3 to 12. Preferably, the organic silicon material includes organopolysilsesquioxane having a cage structure or a partially cleaved cage structure. A liquid crystal panel having the alignment film, and electronic equipment provided with the liquid crystal panel are also provided.

1. Field of the Invention
The present invention relates to an alignment film (orientation film), a method of forming the alignment film, a liquid crystal panel, and electronic equipment, and more particularly relates to an organic film, a method of forming the alignment film, a liquid crystal panel provided with the alignment film, and electronic equipment provided with the liquid crystal panel.
2. Description of the Related Art
There is known a projection type display apparatus that projects an image on a screen. In most of such projection type display apparatuses, a liquid crystal panel is used for forming the image.
Such a liquid crystal panel usually has alignment films (orientation films) that are set to develop a predetermined pre-tilt angle to align or orient liquid crystal molecules in a fixed direction. As a method of manufacturing such alignment films, there is known, for example, a method in which a thin film consisting of a high-molecular compound such as polyimide and formed on a substrate is subjected to rubbing treatment by rubbing the thin film in one direction with a cloth of rayon or the like (see, for example, JP-A No. H10-161133).
However, the alignment films formed of a high-molecular compound such as polyimide may cause photo-deterioration because of various factors such as an environment of use, time of use, and the like. When such photo-deterioration occurs, materials forming the alignment films, liquid crystal layers and the like are likely to decompose, and decomposition products thereof may adversely affect performance of liquid crystal. Further, in the rubbing treatment, static electricity is generated and dust is also produced, thereby lowering reliability of the liquid crystal panel.
For the purpose of solving such a problem, it is attempted to adopt an alignment film formed of an inorganic material. In general, such an inorganic alignment film is formed by an oblique vapor deposition method.
Such an inorganic alignment film is superior in light resistance and heat resistance as compared to an alignment film formed of an organic material, but in turn has a problem in that its ability of orientating liquid crystal molecules is low.

Alignment film, method of forming the alignment film, liquid crystal panel, and electronic equipment


The present invention provides slurries and methods of making slurries having improved stability comprising below about 78 weight-percent rutile titanium dioxide based on the total weight of the slurry, an amorphous alumina compound surface treated titanium dioxide, a polyacrylic acid dispersing agent having a molecular weight in the range of from about 2,000 to about 5,000 that is neutralized with a neutralizing agent having a monovalent group, and water; wherein the slurry has a pH of from about 6 to about 8. The slurries of the present invention resist gel formation.

Titanium dioxide (TiO2) pigments are important pigments in the manufacture of paints, plastics, coatings and paper laminates. Titanium dioxide (TiO2) is produced commercially in two crystalline polymorphic forms, namely the rutile form which can be produced by both the chloride and sulfate processes and the anatase form which is produced by the sulfate process. Both of these processes are well known in the art. Generally, in the xe2x80x9cchloridexe2x80x9d process, rutile crystal is produced while in the sulfate process, both rutile and anatase crystals can be produced.
With regards to rutile TiO2 it is known to add volatile aluminum compounds in the oxidation reaction of titanium tetrachloride (TiCl4), primarily to increase the rutile content of the TiO2 pigment being produced. Typically, the amount of aluminum compound added is sufficient to form about 1 to 1.5 weight-percent alumina based on the TiO2 pigment, and this amount helps achieve greater than 99 weight-percent rutile in the pigment. The resulting TiO2 from the oxidation reaction is then subjected to certain finishing and grinding treatments depending on the desired type of final TiO2 pigment product.
Finishing and grinding treatment often involve the steps of: a) dispersing the TiO2 particles in an aqueous medium to form a slurry having a relatively low TiO2 solids concentration; b) precipitating hydrous inorganic oxide coating, such as for example, alumina, silica and/or other compounds, onto the surface of the TiO2 particles; c) recovering the inorganic oxide surface-treated TiO2 particles from the aqueous medium by filtering; d) washing the TiO2 particles to remove by-product salts and impurities; e) drying the washed TiO2 pigment particles; f) dry-grinding the dried TiO2 pigment particles to a desired particle size using a fluid-energy mill, and optionally, if an aqueous TiO2 pigment slurry is desired, g) dispersing the pigment product in water to produce a slurry typically having a TiO2 solids content of below about 78 weight-percent.
The titanium dioxide may be finished depending on the end-use application (i.e., paint, plastic etc). For example, some finishing steps involve wet surface treatments with other inorganic metal oxides, such as alumina, silica, phosphate, CeO2 and the like, for processibility and/or final applications as known in the art. The surface treatment steps then follow by drying and grinding. These steps will give the finished pigment the desired particle size, distribution and properties.
Generally, concentrated rutile TiO2 slurry products are made by dispersing the finished pigment product in water to produce a slurry having a TiO2 solids content below about 78 weight-percent. Slurries with solids contents greater than 78 weight-percent typically exhibit negative effects on stability and other physical properties (i.e. difficultly pumping, flocculation, gellation and poor or no fluidity over time).
Slurry stability may be further reduced when the rutile TiO2 is treated with an inorganic oxide such as amorphous alumina. Dispersants are often added to such slurries to make it maintain viscosity and storage stability so that it can easily be handled during transport from the TiO2 manufacturers to the customers. However, some prior art slurries, even with dispersants, tend to gel during conventional storage making them difficult to pump and transport.
Based on the foregoing, there is a need for titanium dioxide slurries having improved stability which are useful in the manufacture of paper laminates, plastic, paint and other coatings systems.
The present invention relates to photodurable slurries having improved stability that comprise: i) below about 78 weight-percent rutile titanium dioxide based on the total weight of the slurry, with a surface treatment comprising an amorphous alumina compound; ii) a polyacrylic acid dispersing agent having a weight average molecular weight (Mw) in the range of from about 2,000 to about 5,000, that is neutralized with a neutralizing agent having a monovalent group, and iii) water, wherein the slurry has a pH of from about 6 to about 8.
Compared to prior art slurries, the slurries of the present invention exhibit improved stability and a reduced tendency toward gellation over time. Accordingly, one advantage of the stable slurries of the present invention is that they can be easily handled and transported to other sites such as a paper laminate manufacturing facilities, while they maintain free flowing and pumpable characteristics.
In another embodiment, the present invention provides methods of making slurries having improved stability comprising mixing rutile titanium dioxide, surface-treated with an amorphous alumina compound, with water and a polyacrylic acid dispersing agent having a molecular weight in the range of from about 2,000 to about 5,000 under conditions so as to form the slurry, wherein the dispersing agent is neutralized with a neutralizing agent having a monovalent group, the mixing is performed at a pH of from about 6 to about 8 and wherein the rutile titanium is present in an amount below about 78 weight-percent based on the total weight of the slurry.
The improved stable slurries of the present invention enable many end-use improvements and expand the limits within which many end users, such as paper manufacturers, were heretofore required to operate.

Titanium dioxide slurries having improved stability


An integrative transmission chain of hybrid-drive wind turbine and a gearbox used by the transmission chain, comprising a front housing body, a rear housing body, a main shaft and a planet carrier, and further comprising: an inner ring gear on the main shaft, N intermediate gears (N≥3), N planet gear shafts provided with a first stage planet gear and a second stage planet gear, an output shaft, and a sun gear; wherein the inner ring gear, the intermediate gear and the first stage planet gear form a first stage fixed shaft transmission pair, and the second stage planet gear and the sun gear form a second stage fixed shaft transmission pair; and wherein an upwind end of the output shaft is axially rotatably disposed on the planet carrier and a downwind end of the output shaft protrudes outside the rear housing body; the downwind end which protrudes outside is connected to an upwind end of the rotor of the generator so as to drive the rotor of the generator in rotation, and a downwind end of the rotor of the generator is supported in an inner hole of the stator of the generator via a generator stator main bearing. The transmission chain according to the invention has a high integration level, a simple structure, a light weight, a short axial length, and a high transmission ratio, etc., and is very suitable for a high power wind power generating apparatus.

In the structure of a hybrid-drive wind turbine, the rotating speed of wind wheel is increased to certain times larger by a gearbox and then is input to a generator (e.g., a permanent magnet generator). Essentially, a speed-up gearbox is additionally installed onto a direct-driven wind power generator. Through gear transmission, the hybrid-drive wind turbine increases the rotating speed input from a hub by about 25-40 times, for example, and the both the size and weight of the generator can be greatly reduced as compared to the direct-driven wind power generator. Therefore, the hybrid-drive wind turbine not only has the following advantages existing in the direct-driven wind turbine, such as making it easy to realize low-voltage passing through, being free of high-speed output shaft that is prone to failures, removing failure points such as electric brush, slip or the like from the motor, having a small impact on the power grid, outputting high-quality electrical energy, but also the hybrid-drive wind turbine can effectively avoid disadvantages such as high cost and difficult in hoisting caused by a large direct-driven wind power generator.
Meanwhile, all the current large wind power generators have requirements on lightweight, high integration and high reliability so as to reduce electricity cost. The characteristics of hybrid-drive wind turbines are particularly suitable for large wind machines, and thus have a bright prospect of development.
Currently, a transmission chain of hybrid-drive wind turbine and a gearbox used for the transmission chain typically use a conventional two stage NGW solution, which uses too many elements and has a complicated structure, thus making the processing and assembling difficult; in an existing transmission chain based on NGW solution, all the planet gears receive loads at both faces, thus increasing the possibility of gear failure; moreover, the planet gears rotate, thus increasing the complexity in lubricating solution.
Chinese patent application for invention with publication No. CN101846155A and title "a megawatt scale quasi planet gear hybrid-drive wind turbine speed-up gearbox" discloses a megawatt scale quasi planet gear hybrid-drive wind turbine speed-up gearbox which is easy to assemble and disassemble, can be repaired inside nacelles, has a light weight and a low difficulty in manufacturing process. This patent application uses such a "(input) inner ring gear-two second intermediate gears-quasi planet gear-intermediate gear-(output) center gear" single stage quasi planet structure which conducts two shunts in one plane. Due to the addition of two intermediate gears, such a hybrid-drive wind turbine speed-up gearbox structure results in a two-time shunt, and the load bearing capability can therefore be significantly improved. Meanwhile, due to the single stage transmission, the axial length is short, and the required installation space is small; however, it is obvious that the hybrid-drive wind turbine speed-up gearbox of this patent application has a disadvantage of low transmission ratio and thus cannot meet requirements imposed by high power wind turbines.

Integrative transmission chain of hybrid-drive wind turbine and a gearbox used by the transmission chain


A process for weaving using a reed having vertically aligned upper and lower reed portions with the reed portions being relatively movable in a weft direction. The process includes transferring warp yarns between the reed portions, moving the transferred warp yarns in the weft direction to define a selected array of warp yarns, and then shedding the array of warp yarns for insertion of weft yarn. A weaving loom head is also provided including a reed having vertically aligned upper and lower reed portions, a plurality of healds each releasably engagable with an individual warp yarn for moving selected warp yarns from one reed portion to the other, and a selectively operable drive mechanism for causing relative movement between the reed portions by a predetermined spacing in the weft direction. Weaves may accordingly be produced including warp threads extending parallel to and/or inclined to the fabric take-off direction. Inclination of the warp threads may be in a horizontal and/or vertical plane. The warp yarns are woven with weft yarns that may extend in a direction generally perpendicular to the take-off direction and/or may be inclined in horizontal and/or vertical plane. Also, complex weaves may be produced wherein the weave pattern can be selectively changed as the weaving process progresses.

Multi-axial woven fabric is used as reinforcement in producing constructional components. The strength requirements of a composite component varies throughout its structure and so the fabric used has to be tailored for each component. This commonly involves accurately cutting the fabric to size and layering it where required to provide a three dimensional structure. De-lamination between these layers can occur thereby weakening the component and so it is desirable for the independently formed layers to be physically tied to one another to provide inter layer strength.
A general aim of the present invention is to provide a process and loom weaving head for producing weaves including warp threads extending parallel to and/or inclined to the fabric take-off direction. Inclination of the warp threads may be in a horizontal and/or vertical plane. The warp yarns are woven with weft yarns which may extend in a direction generally perpendicular to the take-off direction and/or may be inclined in a horizontal and/or vertical plane.
In U.S. Pat. No. 4,140,156 a triaxial fabric is produced on a machine in which the two sets of bias yarns are created by displacement of heddles in the weftwise direction under the control of shifting means. Two sets of beating means that include opposing reeds are employed for beating up weft yarns to the fell of the fabric. The large number of heddles required need however to be movable weftwise, which leads to a machine of complex form.
A further aim of the invention is to provide a process and loom weaving head in which the formation of bias yarns in the weaving process can be advantageously carried out using novel yarn transfer means.
A further aim is to provide such a process and loom weaving head to enable complex weaves to be produced wherein the weave pattern can be selectively changed as the weaving process progresses. It is therefore possible to tailor the weave in order to provide desired shapes and/or strength characteristics.

Multi-axial weaving with two part reed and traversing warps


A grip heater controlling apparatus controls an amount of current supplied from a power supply to a grip heater mounted on a handle grip on the steering handle of a motorcycle. The grip heater controlling apparatus has a single momentary switch operable by the driver of the motorcycle, and an amount-of-current controller for changing the amount of current cyclically to at least three levels, including 0, depending on the number of times that the momentary switch is operated.

1. Field of the Invention
The present invention relates to an apparatus for and a method of controlling the amount of current in a grip heater mounted in a tubular steering handle of a vehicle such as a two-wheeled cycle, a snow mobile, a personal watercraft, a three-wheeled buggy, or the like, or the tubular steering handle of an outboard motor or the like.
2. Description of the Related Art
Some vehicles such as two-wheeled cycles (motorcycles, bicycles, motor-assisted bicycles, etc.), snow mobiles, personal watercrafts, three-wheeled buggies, or the like have steering handles with left and right handle grips incorporating nichrome-wire or copper-foil heaters. There have been developed grip heater controlling apparatus for supplying a current from a power supply to those heaters to make the handle grips warm for allowing the driver to drive the vehicle comfortably in winter or cold climate.
Since the amount of heat generated by the heaters should preferably be adjustable depending on the atmospheric temperature and the driver, there has been proposed a grip heater controlling apparatus having a rotary potentiometer (or rheostat) for adjusting the amount of current supplied to the heaters (see, for example, Japanese Patent No. 3,231,247). The proposed grip heater controlling apparatus allows the driver to operate the potentiometer to adjust the amount of heat generated by the heaters as desired. If the potentiometer is positioned near either one of the grip heaters, then the driver finds it easy to operate the potentiometer.
Certain motorcycles or the like have handle covers which cover the handle grips as well as a brake lever and a clutch lever for the purpose of preventing air heated by the heaters from escaping as well as protecting the driver's hands from the wind.
However, if such a handle cover is provided on the handle, the handle cover covers the handle grip combined with the above potentiometer. Since the handle cover covers the potentiometer, the driver finds it difficult to operate potentiometer.
Furthermore, since the potentiometer is of the rotary type, it needs to be operated by two fingers, e.g., a thumb and an index finger, of the driver.

Apparatus for and method of controlling grip heater