A nitrogen-containing silicon carbide material may be deposited on the basis of a single frequency or mixed frequency deposition recipe with a high internal compressive stress level up to 1.6 GPa or higher. Thus, this dielectric material may be advantageously used in the contact level of sophisticated integrated circuits, thereby providing high strain levels while not unduly contributing to signal propagation delay.

1. Field of the Disclosure
Generally, the present disclosure relates to the fabrication of microstructure devices, such as integrated circuits, and, more particularly, to the formation of dielectric layers of reduced permittivity having etch stop capabilities.
2. Description of the Related Art
Semiconductor devices are typically formed on substantially disc-shaped substrates made of any appropriate material. The majority of semiconductor devices including highly complex electronic circuits are currently, and in the foreseeable future will be, manufactured on the basis of silicon, thereby rendering silicon substrates and silicon-containing substrates, such as silicon-on-insulator (SOI) substrates, viable carriers for forming semiconductor devices, such as microprocessors, SRAMs, ASICs (application specific ICs) and the like. The individual integrated circuits are arranged in an array form, wherein most of the manufacturing steps, which may involve several hundred individual process steps in sophisticated integrated circuits, are performed simultaneously for all chip areas on the substrate, except for photolithography processes, metrology processes and packaging of the individual devices after dicing the substrate. Thus, economical constraints drive semiconductor manufacturers to steadily increase the substrate dimensions, thereby also increasing the area available for producing actual semiconductor devices and thus increasing production yield. On the other hand, device dimensions are continuously reduced in view of performance criteria, as, typically, reduced transistor dimensions provide increased operating speed.
In modern integrated circuits, the circuit elements are formed in and on a semiconductor layer, while most of the electrical connections are established in one or more "wiring" layers, also referred to as metallization layers, wherein the electrical characteristics, such as resistivity, electromigration, etc., of the metallization layers significantly affect the overall performance of the integrated circuit. Due to the ongoing demand for shrinking the feature sizes of highly sophisticated semiconductor devices, copper, in combination with a low-k dielectric material, has become a frequently used alternative in the formation of so-called wiring structures comprising metallization layers having metal line layers and intermediate via layers. Metal lines act as intra-layer connections and vias act as inter-layer connections, which commonly connect individual circuit elements to provide the required functionality of the integrated circuit. Typically, a plurality of metal line layers and via layers stacked on top of each other are necessary to realize the connections between all internal circuit elements and I/O (input/output), power and ground pads of the circuit design under consideration.
For extremely scaled integrated circuits, the signal propagation delay may no longer be limited by the circuit elements, for instance by field effect transistors, but may be limited, owing to the increased density of circuit elements, which requires an even more increased number of electrical connections, by the close proximity of the metal lines and vias, since the line-to-line capacitance increases as the spacing decreases. This fact, in combination with a restricted conductivity of the lines due to a reduced cross-sectional area, even though highly conductive metals may be used, results in increased resistance capacitance (RC) time constants. For this reason, traditional dielectrics such as silicon dioxide (k>4) and silicon nitride (k>7) are increasingly replaced in metallization layers by dielectric materials having a lower permittivity, which are therefore also referred to as low-k dielectrics having a relative permittivity of approximately 3 or significantly less. However, the density and mechanical stability or strength of the low-k materials may be significantly less compared to the well-approved dielectrics silicon dioxide and silicon nitride. Additionally, copper may readily diffuse in many low-k dielectrics, while also reactive components, such as oxygen, fluorine and the like, may come into contact with copper due to the limited diffusion blocking capabilities of the low-k dielectric materials.
For this reason, low-k dielectric materials may have to be used in combination with appropriate materials which may provide the desired copper-confining effect and may also be used as efficient etch stop materials during the patterning of the low-k dielectric materials. For example, silicon nitride may be used in combination with low-k dielectric materials, since silicon nitride may act as an efficient diffusion blocking material, for instance, with respect to copper and other reactive components, thereby maintaining integrity of a copper-based metal region. On the other hand, a plurality of plasma-assisted etch processes, as well as wet chemical etch processes, may be available in which silicon nitride exhibits a significantly reduced etch rate compared to other dielectric materials, such as silicon dioxide and a plurality of low-k dielectric materials. In sophisticated semiconductor devices, however, the overall permittivity of the metallization system may be affected by the provision of silicon nitride material, which may have a moderately high dielectric constant of approximately 6 or higher, which may therefore reduce performance gain obtained by the introduction of low-k dielectric materials. For this reason, great efforts have been made in order to develop material compositions that may provide the desired barrier capabilities, while also having a high etch resistance against a plurality of well-established plasma-assisted etch techniques for patterning low-k dielectric materials. One promising candidate in this respect is a nitrogen-containing silicon carbide layer which may be formed on the basis of plasma-assisted chemical vapor deposition (CVD) techniques on the basis of ammonia and trimethyl silane (TMS), which may have a dielectric constant of approximately 5, while at the same time providing the required diffusion blocking capabilities and etch stop qualities. Consequently, significant performance gain may be accomplished in the metallization level of sophisticated semiconductor devices.
The continuing shrinkage of transistor dimensions, however, also involves a plurality of issues at the transistor level that had to be addressed so as to not unduly offset the advantages obtained by steadily decreasing critical dimensions, such as the gate length of MOS transistors. The gate length, that may be highly correlated to the respective channel length, represents a dominant design criterion for enhancing performance of integrated circuits, since, in CMOS technology, transistor characteristics are substantially determined by the electrical behavior of a channel region, which separates drain and source regions and which is controlled on the basis of a gate electrode, which is separated from the channel region by a thin gate dielectric layer. One major problem in scaled transistor structures is to maintain channel controllability, which may be addressed by a plurality of design measures, many of which may be associated with a reduction of charge carrier mobility in the channel region, thereby reducing the overall gain in performance obtained by further reducing device dimensions. It has, therefore, been proposed to improve transistor performance by enhancing the channel conductivity of the transistor elements by increasing charge carrier mobility in the channel region for a given channel length. One efficient mechanism for increasing the charge carrier mobility is the modification of the lattice structure in the channel region, for instance by creating compressive stress in the vicinity of the channel region to produce a corresponding strain in the channel region, which may result in a modified mobility of holes. Thus, performance of P-channel transistors may be efficiently increased by introducing appropriate stress or strain engineering techniques into the fabrication process for sophisticated semiconductor devices. According to one promising approach for creating strain in the channel region of the transistor, the dielectric material that is formed above the basic transistor structure may be provided in a highly stressed state, for instance in a highly compressive state, in order to induce strain at the transistor and in particular in the channel region thereof. For example, the transistor structures are typically enclosed in an interlayer dielectric material, which may provide the desired mechanical and electrical integrity of the individual transistor structures and which may provide a platform for the formation of the additional wiring layers of the metallization system. The interlayer dielectric material may then be appropriately patterned to provide respective openings connected to the contact areas of the transistors, wherein the patterning process, which may represent one of the most critical processes, may be performed on the basis of an etch stop material in combination with the actual interlayer dielectric material.
For example, silicon dioxide is a well-established interlayer dielectric material in combination with silicon nitride, which may act as an efficient etch stop material during the formation of the contact openings. Consequently, the etch stop material, i.e., the silicon nitride material, is in close contact with the basic transistor structure and thus may be efficiently used for inducing strain in the transistors, in particular as silicon nitride may be deposited on the basis of well-established CVD techniques with high internal stress. For instance, silicon nitride may be deposited with high internal compressive stress of up to 2 GPa (Giga Pascal) or higher by selecting appropriate deposition parameters. On the other hand, a moderately high internal tensile stress level may be created up to 1 GPa and higher by appropriately adjusting the process parameters, such as pressure, temperature, gas flow rates and ion bombardment, during the deposition of the silicon nitride material. Consequently, in an attempt to increase the magnitude of strain created in the adjacent channel region, the internal stress level may be increased and the amount of stress material provided around the basic transistor structure may also be increased. It appears, however, that, in sophisticated applications, the dielectric characteristics of the silicon nitride material may reduce overall performance gain, since, in sophisticated device geometries, the stressed silicon nitride material may also be close to metal lines of the very first metallization layer as well as to the gate electrode structures and the contact elements, which may thus result in an increase of the parasitic capacitance, thereby contributing to significant signal propagation delays, as is previously described with reference to the metallization system. For this reason, the thickness of the highly stressed silicon nitride material may be reduced so as to find a compromise between a desired high strain level and an acceptable overall permittivity within the contact level of the semiconductor device under consideration, thereby, however, restricting the degree of performance gain that could be obtained by more fully exploiting the capabilities of stress liner approaches.
The present disclosure is directed to various methods and devices that may avoid, or at least reduce, the effects of one or more of the problems identified above.

Microstructure device including a compressively stressed low-k material layer


A connector is provided and includes a barrel, an end bell, an assembly nut, and a securing mechanism. The end bell includes a spring arm and a seat portion. The assembly nut includes a projection disposed on the seat portion and engaging the spring arm to couple the barrel to the end bell. The securing mechanism secures the barrel and the assembly nut to each other.

There are well-known connectors that couple a barrel of a plug with a plurality of contacts to an end bell attached to an end portion of a cable using an assembly nut.
For example, such a known connector is disclosed in Japanese Patent Application No. JP2001-267006A. The known connector shown in JP2001-267006A includes a barrel, an end bell, and an assembly nut coupling the barrel and the end bell to each other. The barrel is positioned along an end portion of the plug receiving a plurality of contacts. The barrel includes a plurality of keys projecting in a radial direction. Alternatively, the end bell includes an end portion having a plurality of key grooves to engage with keys of the barrel. The end bell also includes another end portion provided with a port for drawing out a cable connected to the plurality of contacts. Further, the assembly nut is formed with a plurality of key grooves into which the keys of the barrel are inserted and is held by the end bell to be rotatable by a predetermined angle.
When the connector is assembled, first, the assembly nut is inserted into a distal end portion of the end bell such that key grooves of the end bell and the key grooves of the assembly nut are aligned with each other along a predetermined angle relationship. Next, the keys of the barrel are caused to pass through the key grooves of the assembly nut to be inserted into the key grooves of the end bell, so that locating of the cables in the cable drawing-out direction is performed. Thereafter, the assembly nut is rotated by a predetermined angle so that the barrel and the end bell are secured to each other.
In the known connector shown in JP2001-267006A, however, there is the following problem.
That is, in the case of the known connector shown in JP2001-267006A, when the assembly nut is inserted into the distal end portion of the end bell, a projection of the assembly nut is substantially press-fit into a slot of the end bell. Therefore, a large force is required upon initial assembling, and when disassembling and assembling are repeated, the end bell is scraped, which results in such a problem that a retaining force of the assembly nut to the end bell is lowered.

Connector having a barrel and an end bell


An LCD with power consumption reduction and a method of driving the same. In one embodiment, the LCD has a plurality of pixels spatially arranged in the form of a matrix having N pixel rows, each pixel row defined between two neighboring scanning lines Gn and Gn+1, and having an auxiliary common electrode, and a plurality of common voltage driving circuits, each common voltage driving circuit electrically coupled between the scanning line Gn and the corresponding auxiliary common electrode for providing a two-level lift-up coupling voltage to the auxiliary common electrode.

A liquid crystal display (LCD) device includes an LCD panel formed with liquid crystal cells and pixel elements with each associating with a corresponding liquid crystal cell and having a liquid crystal (LC) capacitor and a storage capacitor, a thin film transistor (TFT) electrically coupled with the liquid crystal capacitor and the storage capacitor. These pixel elements are substantially arranged in the form of a matrix having a number of pixel rows and a number of pixel columns. Typically, scanning signals are sequentially applied to the number of pixel rows for sequentially turning on the pixel elements row-by-row. When a scanning signal is applied to a pixel row to turn on corresponding TFTs of the pixel elements of a pixel row, source signals (i.e., image signals) for the pixel row are simultaneously applied to the number of pixel columns so as to charge the corresponding liquid crystal capacitor and storage capacitor of the pixel row for aligning orientations of the corresponding liquid crystal cells associated with the pixel row to control light transmittance therethrough. By repeating the procedure for all pixel rows, all pixel elements are supplied with corresponding source signals of the image signal, thereby displaying the image signal thereon.
Liquid crystal molecules have a definite orientational alignment as a result of their long, thin shapes. The orientations of liquid crystal molecules in liquid crystal cells of an LCD panel play a crucial role in the transmittance of light therethrough. It is known if a substantially high voltage potential is applied between the liquid crystal layer for a long period of time, the optical transmission characteristics of the liquid crystal molecules may change. This change may be permanent, causing an irreversible degradation in the display quality of the LCD panel. In order to prevent the LC molecules from being deteriorated, an LCD device is usually driven by using techniques that alternate the polarity of the voltages applied across a LC cell. These techniques may include inversion schemes such as frame inversion, row inversion, column inversion, and dot inversion. Typically, notwithstanding the inversion schemes, a higher image quality requires higher power consumption because of frequent polarity conversions. For example, the conventional design with row inversion lost much more power consumption. For the conventional DC Vcom solution, it needs higher data voltage to be column inversion.
Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.

LCD with common voltage driving circuits


A liquid crystal display apparatus has horizontal and vertical scanning circuits for scanning an array of pixels. An image signal applied to an image signal supply circuit in the form of series of pixel signals is transferred to pixels in the array of pixels designated by the horizontal and vertical scanning circuits. Each of the horizontal and vertical scanning circuits have a series connection of bidirectional shift register stages and are capable of bidirectional scanning. Each of the bidirectional shift register stages includes a pair of latches connected in tandem and is capable of providing an intermediate output and a shift register stage output. The pair of latches of each of the bidirectional shift register stages except those located at both ends of the series connection have respective intermediate and bidirectional shift register stage outputs contributing to designation of pixels to which pixel signals are to be supplied, while the pair of latches of the shift register stages located at each end of the series connection have their bidirectional shift register stage outputs contributing to such designation of pixels and their intermediate output terminals not contributing to such designation of pixels.

The present invention relates to a liquid crystal display apparatus, and more particularly to a technology which is effective when applied to a liquid crystal display apparatus in which a display pixel of an active matrix-driven type and a driving circuit therefor are formed on a glass substrate or a silicon chip.
A liquid crystal panel is being widely used as a television set, a monitor of information devices such as a personal computer, and a display apparatus for the other various kinds of display apparatuses.
This kind of liquid crystal panel is constituted as follows: A driving electrode, which serves as an electrode of a switching element for selecting a pixel, is formed on one substrate, and a common electrode is formed on the other substrate. Then, sides of both the electrodes are opposed and laminated to each other with a gap, and a liquid crystal layer is disposed in the gap, to thereby constituting the panel.
In a structure in which an amorphous silicon thin film is employed for a channel layer of a FET switching element, there will be a limit to the characteristics as a transistor. If such structure is used to constitute a driving circuit, resulting characteristics will be insufficient, thus making it necessary to provide a peripheral driving circuit outside the glass substrate.
Meanwhile, the following type of display apparatus has been developed: A thin film transistor (hereinafter, referred to as TFT) is formed using a poly-silicon film, so that a driving circuit, as well as switching elements for selecting display pixels, is formed on one and the same glass substrate. Incidentally, concerning the TFT elements formed using the polysilicon film, a product manufactured therefrom, about which the number of pixels is about one hundred thousand and diagonal length of a display area is 0.7 inches, is used as a color finder of a small-sized video camera.
Moreover, concerning the above-described TFT display apparatus in which the poly-silicon film is used, the utilization thereof has been developed as a display source of a projector or as a panel for a head mount (glasses-shaped) display designed for a virtual reality.
Furthermore, a polymer dispersion type liquid crystal (hereinafter, referred to as PDLC) display element has been developed in the following way: A common electrode is formed on a transparent substrate and a driving electrode is formed on a silicon substrate. Then, a liquid crystal layer of a macromolecule dispersion type is sandwiched in a lamination gap between both the electrodes, thus forming the PDLC.
In connection with the above-described methods of utilizing the TFT display apparatus in which the poly-silicon film is used or a display apparatus in which the PDLC is used, there is a liquid crystal projector optical system based on a three-color plates system. The three-plates system is a system employing a display apparatus which allows an image to be formed for each of colors of red, green and blue.
FIG. 1 shows a schematic diagram of the liquid crystal projector optical system based on the three-plates system. A light launched from a light source 850, which comprises, for example, a metal halide lamp and a parabolic surface mirror, reaches a dichroic mirror 851. Here, the dichroic mirror 851 has a function of allowing a light in a specific wavelength range to be reflected or to pass through. Thus, only a blue light is reflected with its direction changed by 90 degrees, and the other lights are permitted to pass through. The other lights which have passed through, i.e. transmitting lights, are launched into a dichroic mirror 852. Only a green light is reflected there, and a transmitting light turns out to be a red one. In this way, the lights resolved in the order of blue, green and red are each launched into specifically designed liquid crystal panels 853, 854 and 855. On each of the liquid crystal panels 853, 854 and 855, an image corresponding to each of the colors has been reproduced. Then, each of the incoming lights, after being modulated for each color, is superimposed.
At a dichroic mirror 856, the green light is reflected. The reflected green light is superimposed with the blue light which has passed through the liquid crystal panel 853. The superimposed light is further superimposed with the red light reflected by a dichroic mirror 857. The superimposed light is projected onto a screen by a projection lens.
In the optical system as described above, first, the blue transmitting light from the liquid crystal panel 853 has never been reflected even one time. Accordingly, the blue transmitting light is superimposed in such a state that the pattern on the liquid crystal panel remains unchanged, and then is launched into the projection lens. Then, the red transmitting light from the liquid crystal panel 855 undergoes a direction conversion by 90 degrees two times at a reflection mirror 858 and at the dichroic mirror 857. Consequently, as is the case with the blue transmitting light, the red transmitting light is superimposed in such a state that the pattern on the liquid crystal panel remains unchanged, and then is launched into the projection lens.
Moreover, the green transmitting light from the liquid crystal panel 854 undergoes a direction conversion by 90 degrees only one time at the dichroic mirror 856. Accordingly, the green transmitting light is launched into the projection lens with the pattern on the liquid crystal panel inverted from top to bottom or from right to left. On account of this, in order to make the images coincide with each other, it becomes necessary for the green liquid crystal panel 854 to display an image which is, in advance, inverted from top to bottom or from right to left. Incidentally, reference numeral 859 designates a reflection mirror.
In the green liquid crystal panel 854, in order to invert an image thereon from right to left or from top to bottom, the following methods are generally employed: An inversion driving circuit is newly provided, the green liquid crystal panel 854 is specially manufactured so that, in order to display the inverted image, it can scan in a direction opposite to that of the red and the blue liquid crystal panels 853, 855, image data is stored once in a memory and is then read out so that the image is inverted, and so on.
Namely, in the liquid crystal projector based on the three primary colors-separating system, only one color component of the color images differs in the number of times of inversion from the other color components. This situation causes the component through a usual liquid crystal panel to be inverted from right to left or from top to bottom, and thus it turns out that the usual liquid crystal panel outputs the inverted image. Accordingly, a specific structure is added to the usual liquid crystal panel so that it can output an inverted image independently. An example of such a liquid crystal panel as outputting the inverted image is indicated on pages 383-386 of SID 93 DIGEST (1993).
According to one aspect of the present invention, in a liquid crystal display apparatus having horizontal and vertical scanning circuits capable of bidirectionally scanning an array of pixels and an image signal supply circuit to which an image signal is applied in the form of series of pixel signals, the horizontal and vertical scanning circuits have a series connection of bidirectional shift register stages. Each of the bidirectional shift register stages includes a pair of latches connected in tandem and is capable of providing an intermediate output and a shift register stage output. The pair of latches of each of the bidirectional shift register stages except those located at both ends of the series connection have respective intermediate and bidirectional shift register stage outputs contributing to designation of pixels to which pixel signals are to be supplied, while the pair of latches of the shift register stages located at each end of the series connection have their bidirectional shift register stage outputs contributing to such designation of pixels and their intermediate outputs not contributing to such designation of pixels.
According to another aspect of the present invention, at least one of the horizontal scanning circuit and vertical scanning circuit of the liquid crystal display apparatus further includes a reset circuit.
According to another aspect of the present invention, each of the horizontal scanning circuit and vertical scanning circuit of the liquid crystal display apparatus operate with clock signals, and has a structure such that a shift operation of each of the shift register stages is responsive to the duty ratio of its associated clock signal.

Liquid crystal display apparatus including scanning circuit having bidirectional shift register stages


In a heavy closed-shed dobby of a weaving machine having oscillating levers which are selectively connected to one of two oppositely movable actuation knives by rocking double hooks mounted thereto so as to control the movement of heddle frames to which the levers are connected, a pair of locking members pivotally mounted to each lever. An elastic element is provided to urge one end of each locking member toward abutting engagement with a double hook thereby preventing pivotable movement of the double hook when engaged by one of the knives. The locking members are released from engagement with the double hook upon simultaneous engagement of the knives with a lever.

1. Field of the Invention
The present invention relates to heavy dobbies used for forming the shed in weaving machines of very large width, of the type particularly employed for manufacturing tubular fabrics for the production of endless dryer felts or filters for the paper-making industry.
2. History of the Related Art
Due to the considerable amplitude of the stroke of the heddle frames associated with these dobbies, the conventional open-shed systems cannot be used and closed-shed dobbies must be employed in which each frame moves downwardly or upwardly from a mean position corresponding to the point of crossing of the assembly of the frames.
FIG. 1 of the accompanying drawings schematically shows the general arrangement of the heavy closed-shed dobbies known in practice. Each of the heddle frames CL mounted on the weaving machine is connected by a system of rods 1 to a corresponding oscillating lever 2, articulated at 2a on the fixed frame. One of the ends of each lever 2 is provided with a freely rotatable stop 2b. Each lever is connected with a double rocking hook 3 whose pivoting movement is controlled by pushers (arrows 4) of the reading mechanism of the dobby in order to selectively engage with one or the other of two actuation knives 5. The knives are controlled to move reciprocally in unison in opposite directions.
Actuation of the assembly of the double hooks 3 by the reading mechanism is effected when the two knives 5 lie in a central position (levers 2 oriented vertically) and it will be understood that, depending on whether a hook cooperates with one or the other of the knives 5, the corresponding frame CL moves vertically upwardly or downwardly from the position corresponding to the closure of the shed.
Although such a system functions relatively correctly when the work speed is reduced, this does not apply when the dobby is associated with a weaving machine driven at the high rates now required in practice. In such a case, the double hooks are subjected to the effects of rebound and vibrations which render their engagement by the driving knives random. Furthermore, the pushers 4 have only a very short period of time to act on the double hooks and it happens that the double hooks pivot with a very slight delay. Now, in either case, any defective engagement of one of the double hooks 4 by a knife 5 results in a defect in weaving in the article being made.
It is a principal object of the present invention to overcome these drawbacks.

Locking mechanisms for selective retention of oscillating levers engaged by knives in a dobby


Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Inhibition of histone deacetylase can lead to the histone deacetylase-mediated transcriptional repression of tumor suppressor genes. For example, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, such as hematopoiesis, and genetic related metabolic disorders, such as, cystic fibrosis and adrenoleukodystrophy.

This invention relates to enzyme inhibitors, and more particularly to histone deacetylase inhibitors.
DNA in the nucleus of the cell exists as a hierarchy of compacted chromatin structures. The basic repeating unit in chromatin is the nucleosome. The nucleosome consists of a histone octomer of proteins in the nucleus of the cell around which DNA is twice wrapped. The orderly packaging of DNA in the nucleus plays an important role in the functional aspects of gene regulation. Covalent modifications of the histones have a key role in altering chromatin higher order structure and function and ultimately gene expression. The covalent modification of histones occurs by enzymatically mediated processes, such as acetylation.
Regulation of gene expression through the inhibition of the nuclear enzyme histone deacetylase (HDAC) is one of several possible regulatory mechanisms whereby chromatin activity can be affected. The dynamic homeostasis of the nuclear acetylation of histones can be regulated by the opposing activity of the enzymes histone acetyl transferase (HAT) and histone deacetylase (HDAC). Transcriptionally silent chromatin can be characterized by nucleosomes with low levels of acetylated histones. Acetylation of histones reduces its positive charge, thereby expanding the structure of the nucleosome and facilitating the interaction of transcription factors to the DNA. Removal the acetyl group restores the positive charge condensing the structure of the nucleosome. Acetylation of histone-DNA activates transcription of DNA""s message, an enhancement of gene expression. Histone deacetylase can reverse the process and can serve to repress gene expression. See, for example, Grunstein, Nature 389, 349-352 (1997); Pazin et al., Cell 89, 325-328 (1997); Wade et al., Trends Biochem. Sci. 22, 128-132 (1997); and Wolffe, Science 272, 371-372 (1996).
Histone deacetylase is a metallo-enzyme with zinc at the active site. Compounds having a zinc-binding moiety, such as, for example, a hydroxamic acid group, can inhibit histone deacetylase. Histone deacetylase inhibition can repress gene expression, including expression of genes related to tumor suppression. Accordingly, inhibition of histone deacetylase can provide an alternate route for treating cancer, hematological disorders, e.g., hemoglobinopathies, and genetic related metabolic disorders, e.g., cystic fibrosis and adrenoleukodystrophy.
In one aspect, hydroxamic acid-containing compounds have a structure of formula (I):
A is a cyclic moiety selected from the group consisting of C3-14 cycloalkyl, 3-14 membered heterocycloalkyl, C4-14 cycloalkenyl, 3-14 membered heterocycloalkenyl (e.g., C3-8 cycloalkyl, 3-8 membered heterocycloalkyl, C4-8 cycloalkenyl, 3-8 membered heterocycloalkenyl), monocyclic aryl, or monocyclic heteroaryl. Each of these cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl. Each of X1 and X2, independently, is O or S. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, or a bond wherein each of Ra and Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. Y2 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94N(Rd)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein each of Rc and Rd, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. L is (1) a saturated straight C1-12 hydrocarbon chain substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, halo, carboxyl, amino, nitro, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, formyl, C1-4 alkylcarbonylamino, or C1-4 aminocarbonyl, or at least two hydroxyl; and further optionally interrupted by xe2x80x94Oxe2x80x94, xe2x80x94N(Re)xe2x80x94, xe2x80x94N(Re)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Re)xe2x80x94, xe2x80x94N(Re)xe2x80x94C(O)xe2x80x94N(Rf)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein each of Re and Rf, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl; or L is (2) an unsaturated straight C4-12 hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond, where the unsaturated hydrocarbon chain is optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, formyl, C1-4 alkylcarbonylamino, or C1-4 aminocarbonyl; and further being optionally interrupted by xe2x80x94Oxe2x80x94, xe2x80x94N(Rg)xe2x80x94, xe2x80x94N(Rg)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Rg)xe2x80x94, xe2x80x94N(Rg)xe2x80x94C(O)xe2x80x94N(Rh)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94 wherein each of Rg and Rh, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and R2 is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group.
In another aspect, hydroxamic acid-containing compounds have a structure of formula (I), supra. A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl. Each of the cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino. Each of X1 and X2, independently, is O or S. Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, or a bond, where each of Ra and Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. Y2 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94N(Rd)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94; each of Rc and Rd, independently, being hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. L is (1) a saturated straight C3-10 hydrocarbon chain substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, or amino, and further optionally interrupted by xe2x80x94Oxe2x80x94 or xe2x80x94N(Re)xe2x80x94, where Re is hydrogen, alkyl, hydroxylalkyl, or haloalkyl; or L is (2) an unsaturated straight C4-10 hydrocarbon chain containing at least two double bonds, at least one triple bond, or at least one double bond and one triple bond; said unsaturated hydrocarbon chain being optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, or amino, and further optionally interrupted by xe2x80x94Oxe2x80x94 or xe2x80x94N(Rf)xe2x80x94, where Rf is hydrogen, alkyl, hydroxylalkyl, or haloalkyl. Each of R1 and R2, independently, is hydrogen, alkyl, hydroxylalkyl, or haloalkyl.
In certain embodiments, R1 is hydrogen, R2 is hydrogen, X1 is O, X2 is O, or Y1 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(Raxe2x80x94, or a bond, and Y2 is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94N(Rc)xe2x80x94. L can be a saturated straight C4-10 hydrocarbon chain, or C5-8 hydrocarbon chain (e.g., a saturated straight C5 hydrocarbon chain, a saturated straight C6 hydrocarbon chain, or a saturated straight C7 hydrocarbon chain), substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, or amino, and further optionally interrupted by xe2x80x94Oxe2x80x94 or xe2x80x94N(Rc)xe2x80x94. In other embodiments, L is an unsaturated straight C4-10 hydrocarbon chain, or an unsaturated straight C4-8 hydrocarbon chain, containing 2-5 double bonds, or 1-2 double bonds and 1-2 triple bonds, optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, or C1-4 alkoxy, and further being optionally interrupted by xe2x80x94Oxe2x80x94 or xe2x80x94N(Rg)xe2x80x94. In certain embodiments, L can be xe2x80x94(CHxe2x95x90CH)mxe2x80x94 where m is 2 or 3 or L can be xe2x80x94Cxe2x89xa1Cxe2x80x94(CHxe2x95x90CH)nxe2x80x94 where n is 1 or 2. A can be phenyl, furyl, thienyl, pyrrolyl, or pyridyl or A can be phenyl optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino.
In a further aspect, hydroxamic acid-containing compounds have a structure of formula (II):
A is a cyclic moiety selected from the group consisting of monocyclic aryl or monocyclic heteroaryl. Each of the cyclic moieties is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, or amino. Each of X1 and X2, independently, is O or S. Each of R1 and R2, independently, is hydrogen, alkyl, hydroxylalkyl, or haloalkyl. Each of R3, R4, R5, R6, R7, R8, R9 and R10, independently, is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, hydroxylC1-4 alkyl, haloC1-4 alkyl, or amino, and each of a, b, c, d, e, and f, independently, is 0 or 1. Note that at least one of b, c, d, and e cannot be zero. In certain embodiments, a is 0, f is 0, or the total number of b, c, d, and e is 3 or 4. In other embodiments, each of R3, R4, R5, R6, R7, R8, R9 and R10, independently, is hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxylC1-4 alkyl, or amino. Each of R5, R6, R7, and R8, independently can be hydrogen, C1-4 alkyl, C1-4 alkoxy, hydroxyl, hydroxylC1-4 alkyl, or amino, Each of R3, R4, R9 and R10, independently, can be hydrogen.
In another aspect hydroxamic acid-containing compounds have the structure of formula (I), supra. A is a saturated branched C3-14 hydrocarbon chain or an unsaturated branched C3-14 hydrocarbon chain optionally interrupted by xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(Ra)xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94SO2xe2x80x94, xe2x80x94SO2xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Ra)xe2x80x94, xe2x80x94N(Ra)xe2x80x94C(O)xe2x80x94N(Rb)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, where each of Ra and Rb, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. Each of the saturated and the unsaturated branched hydrocarbon chain is optionally substituted with alkyl, alkenyl, alkynyl, alkoxy, hydroxyl, hydroxylalkyl, halo, haloalkyl, amino, alkylcarbonyloxy, alkyloxycarbonyl, alkylcarbonyl, alkylcarbonylamino, aminocarbonyl, alkylsulfonylamino, aminosulfonyl, or alkylsulfonyl. Each of X1 and X2, independently, is O or S. Each of Y1 and Y2, independently, is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Rc)xe2x80x94, xe2x80x94N(Rc)xe2x80x94C(O)xe2x80x94N(Rd)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, or a bond, where each of Rc and Rd, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. L is a saturated straight C3-12 hydrocarbon or an unsaturated straight C4-12 hydrocarbon chain, said hydrocarbon chain being optionally substituted with C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, hydroxyl, halo, carboxyl, amino, nitro, cyano, C3-6 cycloalkyl, 3-6 membered heterocycloalkyl, monocyclic aryl, 5-6 membered heteroaryl, C1-4 alkylcarbonyloxy, C1-4 alkyloxycarbonyl, C1-4 alkylcarbonyl, formyl, C1-4 alkylcarbonylamino, or C1-4 aminocarbonyl; and further optionally interrupted by xe2x80x94Oxe2x80x94, xe2x80x94N(Re)xe2x80x94, xe2x80x94N(Re)xe2x80x94C(O)xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94N(Re)xe2x80x94, xe2x80x94N(Re)xe2x80x94C(O)xe2x80x94N(Rf)xe2x80x94, xe2x80x94Oxe2x80x94C(O)xe2x80x94, xe2x80x94C(O)xe2x80x94Oxe2x80x94, or xe2x80x94Oxe2x80x94C(O)xe2x80x94Oxe2x80x94, where each of Re and Rf, independently, is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, or haloalkyl. R1 is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxylalkyl, hydroxyl, haloalkyl, or an amino protecting group; and R2 is hydrogen, alkyl, hydroxylalkyl, haloalkyl, or a hydroxyl protecting group.
Set forth below are some examples of a hydroxamic acid-containing compound of the present invention: benzylthioglycoloylhydroxamic acid, N-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 3-methyl-5-phenyl-2,4-pentadienoyl hydroxamic acid, 4-methyl-5-phenyl-2,4-pentadienoylhydroxamic acid, 4-chloro-5-phenyl-2,4-pentadienoylhydroxamic acid, 5-(4-dimethylaminophenyl)-2,4-pentadienoylhydroxamic acid, 5-phenyl-2-en-4-yn-pentanoylhydroxamic acid, 5-(2-furyl)-2,4-pentadienoylhydroxamic acid, N-methyl-6-phenyl-3,5-hexadienoylhydroxamic acid, and 7-phenyl-2,4,6-hepta-trienoylhydroxamic acid.
A salt of any of the compounds of the invention can be prepared. For example, a pharmaceutically acceptable salt can be formed when an amino-containing compound of this invention reacts with an inorganic or organic acid. Some examples of such an acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid. Examples of pharmaceutically acceptable salts thus formed include sulfate, pyrosulfate bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, and maleate. A compound of this invention may also form a pharmaceutically acceptable salt when a compound of this invention having an acid moiety reacts with an inorganic or organic base. Such salts include those derived from inorganic or organic bases, e.g., alkali metal salts such as sodium, potassium, or lithium salts; alkaline earth metal salts such as calcium or magnesium salts; or ammonium salts or salts of organic bases such as morpholine, piperidine, pyridine, dimethylamine, or diethylamine salts.
It should be recognized that a compound of the invention can contain chiral carbon atoms. In other words, it may have optical isomers or diastereoisomers.
Alkyl is a straight or branched hydrocarbon chain containing 1 to 10 (preferably, 1 to 6; more preferably 1 to 4) carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylhexyl, and 3-ethyloctyl.
The terms xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d refer to a straight or branched hydrocarbon chain containing 2 to 10 carbon atoms and one or more (preferably, 1-4 or more preferably 1-2) double or triple bonds, respectively. Some examples of alkenyl and alkynyl are allyl, 2-butenyl, 2-pentenyl, 2-hexenyl, 2-butynyl, 2-pentynyl, and 2-hexynyl.
Cycloalkyl is a monocyclic, bicyclic or tricyclic alkyl group containing 3 to 14 carbon atoms. Some examples of cycloalkyl are cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, and norbornyl. Heterocycloalkyl is a cycloalkyl group containing at least one heteroatom (e.g., 1-3) such as nitrogen, oxygen, or sulfur. The nitrogen or sulfur may optionally be oxidized and the nitrogen may optionally be quaternized. Examples of beterocycloalkyl include piperidinyl, piperazinyl, tetrahydropyranyl, tetrahydrofuryl, and morpholinyl. Cycloalkenyl is a cycloalkyl group containing at least one (e.g., 1-3) double bond. Examples of such a group include cyclopentenyl, 1,4-cyclohexa-di-enyl, cycloheptenyl, and cyclooctenyl groups. By the same token, heterocycloalkenyl is a cycloalkenyl group containing at least one heteroatom selected from the group of oxygen, nitrogen or sulfur.
Aryl is an aromatic group containing a 5-14 ring and can contain fused rings, which may be saturated, unsaturated, or aromatic. Examples of an aryl group include phenyl, naphthyl, biphenyl, phenanthryl, and anthracyl. If the aryl is specified as xe2x80x9cmonocyclic aryl,xe2x80x9d if refers to an aromatic group containing only a single ring, i.e., not a fused ring.
Heteroaryl is aryl containing at least one (e.g., 1-3) heteroatom such as nitrogen, oxygen, or sulfur and can contain fused rings. Some examples of heteroaryl are pyridyl, furanyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl, and benzthiazolyl.
The cyclic moiety can be a fused ring formed from two or more of the just-mentioned groups. Examples of a cyclic moiety having fused rings include fluorenyl, dihydrodibenzoazepine, dibenzocycloheptenyl, 7H-pyrazino[2,3-c]carbazole, or 9,10-dihydro-9,10-[2]buteno-anthracene.
Amino protecting groups and hydroxy protecting groups are well-known to those in the art. In general, the species of protecting group is not critical, provided that it is stable to the conditions of any subsequent reaction(s) on other positions of the compound and can be removed without adversely affecting the remainder of the molecule. In addition, a protecting group may be substituted for another after substantive synthetic transformations are complete. Examples of an amino protecting group include, but not limited to, carbamates such as 2,2,2-trichloroethylcarbamate or tertbutylcarbamate. Examples of a hydroxyl protecting group include, but not limited to, ethers such as methyl, t-butyl, benzyl, p-methoxybenzyl, p-nitrobenzyl, allyl, trityl, methoxymethyl, 2-methoxypropyl, methoxyethoxymethyl, ethoxyethyl, tetrahydropyranyl, tetrahydrothiopyranyl, and trialkylsilyl ethers such as trimethylsilyl ether, triethylsilyl ether, dimethylarylsilyl ether, triisopropylsilyl ether and t-butyldimethylsilyl ether; esters such as benzoyl, acetyl, phenylacetyl, formyl, mono-, di-, and trihaloacetyl such as chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl; and carbonates including but not limited to alkyl carbonates having from one to six carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl; isobutyl, and n-pentyl; alkyl carbonates having from one to six carbon atoms and substituted with one or more halogen atoms such as 2,2,2-trichloroethoxymethyl and 2,2,2-trichloro-ethyl; alkenyl carbonates having from two to six carbon atoms such as vinyl and allyl; cycloalkyl carbonates having from three to six carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and phenyl or benzyl carbonates optionally substituted on the ring with one or more C1-6 alkoxy, or nitro. Other protecting groups and reaction conditions can be found in T. W. Greene, Protective Groups in Organic Synthesis, (3rd, 1999, John Wiley and Sons, New York, N.Y.).
Note that an amino group can be unsubstituted (i.e., xe2x80x94NH2), mono-substituted (i.e., xe2x80x94NHR), or di-substituted (i.e., xe2x80x94NR2). It can be substituted with groups (R) such as alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl. Halo refers to fluoro, chloro, bromo, or iodo.
Inhibition of a histone deacetylase in a cell is determined by measuring the level of acetylated histones in the treated cells and measuring the level of acetylated histones in untreated cells and comparing the levels. If the level of histone acetylation in the treated cells increases relative to the untreated cells, histone deacetylase has been inhibited.
Some disorders or physiological conditions may be mediated by hyperactive histone deacetylase activity. A disorder or physiological condition that is mediated by histone deacetylase refers to a disorder or condition wherein histone deacetylase plays a role in triggering the onset thereof. Examples of such disorders or conditions include, but not limited to, cancer, hemoglobinopathies (e.g., thalassemia or sickle cell anemia), cystic fibrosis, protozoan infection, adrenoleukodystrophy, alpha-1 anti-trypsin, retrovirus gene vector reactivation, wound healing, hair growth, peroxisome biogenesis disorder, and adrenoleukodystrophy.
Other features or advantages will be apparent from the following detailed description of several embodiments, and also from the appended claims.
A carboxylic acid-containing compound of the present invention can be prepared by any known methods in the art. For example, a compound of the invention having an unsaturated hydrocarbon chain between A and xe2x80x94C(xe2x95x90X1)xe2x80x94 can be prepared according to the following scheme:
where Lxe2x80x2 is a saturated or unsaturated hydrocarbon linker between A and xe2x80x94CHxe2x95x90CHxe2x80x94 in a compound of the invention, and A and X1 has the same meaning as defined above. See Coutrot et al., Syn. Comm. 133-134 (1978). Briefly, butyllithium was added to an appropriate amount of anhydrous tetrahydrofuran (THF) at a very low temperature (e.g., xe2x88x9265xc2x0 C.). A second solution having diethylphosphonoacetic acid in anhydrous THF was added dropwise to the stirred butyllithium solution at the same low temperature. The resulting solution is stirred at the same temperature for an additional 30-45 minutes which is followed by the addition of a solution containing an aromatic acrylaldehyde in anhydrous THF over 1-2 hours. The reaction mixture is then warmed to room temperature and stirred overnight. It is then acidified (e.g., with HCl) which allows the organic phase to be separated. The organic phase is then dried, concentrated, and purified (e.g., by recrystallization) to form an unsaturated carboxylic acid-containing intermediate.
Alternatively, a carboxylic acid-containing compound can be prepared by reacting an acid ester of the formula Axe2x80x94Lxe2x80x2xe2x80x94C(xe2x95x90O)xe2x80x94O-lower alkyl with a Grignard reagent (e.g., methyl magnesium iodide) and a phosphorus oxychloride to form a corresponding aldehyde, which can be further oxidized (e.g., by reacting with silver nitrate and aqueous NaOH) to form an unsaturated carboxylic acid-containing intermediate.
Other types of carboxylic acid-containing compounds (e.g., those containing a linker with multiple double bonds or triple bonds) can be prepared according to published procedures such as those described in Parameswara et al., Synthesis, 815-818 (1980) and Denny et al., J. Org. Chem., 27, 3404 (1962).
Carboxylic acid-containing compounds described above can then be converted to hydroxamic acid-containing compounds according to the following scheme:
Triethylamine (TEA) is added to a cooled (e.g., 0-5xc2x0 C.) anhydrous THF solution containing the carboxylic acid. Isobutyl chloroformate is then added to the solution having carboxylic acid, which is followed by the addition of hydroxylamine hydrochloride and TEA. After acidification, the solution was filtered to collect the desired hydroxamic acid-containing compounds.
An N-substituted hydroxamic acid can be prepared in a similar manner as described above. A corresponding carboxylic acid Axe2x80x94Lxe2x80x2xe2x80x94C(xe2x95x90O)xe2x80x94OH can be converted to an acid chloride by reacting with oxalyl chloride (in appropriate solvents such as methylene chloride and dimethylformamide), which in turn, can be converted to a desired N-substituted hydroxamic acid by reacting the acid chloride with an N-substituted hydroxylamine hydrochloride (e.g., CH3NHOH.HCl) in an alkaline medium (e.g., 40% NaOH (aq)) at a low temperature (e.g., 0-5xc2x0 C.). The desired N-substituted hydroxamic acid can be collected after acidifying the reaction mixture after the reaction has completed (e.g., in 2-3 hours).
As to compounds of the invention wherein X1 is S, they can be prepared according to procedures described in Sandler, S. R. and Karo, W., Organic Functional Group Preparations, Volume III (Academic Press, 1972) at pages 436-437. For preparation of compounds of the invention wherein X2 is xe2x80x94N(Rc)OHxe2x80x94 and X1 is S, see procedures described in U.S. Pat. Nos. 5,112,846; 5,075,330 and 4,981,865.
Compounds of the invention containing an xcex1-keto acid moiety (e.g., when X1 is oxygen and X2 is xe2x80x94C(xe2x95x90O)OM or Axe2x80x94Lxe2x80x2xe2x80x94C(xe2x95x90O)xe2x80x94C(xe2x95x90O)xe2x80x94OM, where A and Lxe2x80x2have been defined above and M can be hydrogen, lower alkyl or a cation such as K+), these compounds can be prepared by procedures based on that described in Schummer et al., Tetrahedron, 43, 9019 (1991). Briefly, the procedure starts with a corresponding aldehyde-containing compound (e.g., Axe2x80x94Lxe2x80x2xe2x80x94C(xe2x95x90O)xe2x80x94H), which is allowed to react with a pyruvic acid in a basic condition (KOH/methanol) at a low temperature (e.g., 0-5xc2x0 C.). Desired products (in the form of a potassium salt) are formed upon warming of the reaction mixture to room temperature.
The compounds described above, as well as their (thio)hydroxamic acid or xcex1-keto acid counterparts, can possess histone deacetylase inhibitory properties.
Note that appropriate protecting groups may be needed to avoid forming side products during the preparation of a compound of the invention. For example, if the linker Lxe2x80x2 contains an amino substituent, it can be first protected by a suitable amino protecting group such as trifluoroacetyl or tert-butoxycarbonyl prior to being treated with reagents such as butyllithium. See, e.g., T. W. Greene, supra, for other suitable protecting groups.
A compound produced by the methods shown above can be purified by flash column chromatography, preparative high performance liquid chromatography, or crystallization.
A pharmaceutical composition can be used to inhibit histone deacetylase in cells and can be used to treat disorders associated with abnormal histone deacetylase activity. Some examples of these disorders are cancers (e.g., leukemia, lung cancer, colon cancer, CNS cancer, melanoma, ovarian cancer, cervical cancer, renal cancer, prostate cancer, and breast cancer), hematological disorders (e.g., hemoglobinopathies, thalassemia, and sickle cell anemia) and genetic related metabolic disorders (e.g., cystic fibrosis, peroxisome biogenesis disorder, alpha-l anti-trypsin, and adrenoleukodystrophy). The compounds of this invention can also stimulate hematopoietic cells ex vivo, ameliorating protozoal parasitic infection, accelerate wound healing, and protecting hair follicles.
An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 50, 219 (1966). Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, New York, 537 (1970). An effective amount of a compound described herein can range from about 1 mg/kg to about 300 mg/kg. Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage, pre-treatment, or post-treatment, with other therapeutic treatments including use of other chemotherapeutic agents and radiation therapy. Other chemotherapeutic agents that can be co-administered (either simultaneously or sequentially) include, but not limited to, paclitaxel and its derivatives (e.g., taxotere), doxorubicin, L-asparaginase, dacarbazine, amascrine, procarbazine, hexamethylmelamine, mitoxantrone, and gemicitabine.
The pharmaceutical composition may be administered via the parenteral route, including orally, topically, subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active agent, in a isotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds. Because some of the compounds described herein can have limited water solubility, a solubilizing agent can be included in the composition to improve the solubility of the compound. For example, the compounds can be solubilized in polyethoxylated castor oil (Cremophor EL(copyright)) and may further contain other solvents, e.g., ethanol. Furthermore, compounds described herein can also be entrapped in liposomes that may contain tumor-directing agents (e.g., monoclonal antibodies having affinity towards tumor cells).
A compound described herein can be formulated into dosage forms for other routes of administration utilizing conventional methods. For example, it can be formulated in a capsule, a gel seal, or a tablet for oral administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a compound described herein with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. Compounds of this invention can also be administered in a form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent.
The activities of a compound described herein can be evaluated by methods known in the art, e.g., MTT (3-[4,5-dimehtythiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay, clonogenic assay, ATP assay, or Extreme Drug Resistance (EDR) assay. See Freuhauf, J. P. and Manetta, A., Chemosensitivity Testing in Gynecologic Malignancies and Breast Cancer 19, 39-52 (1994). The EDR assay, in particular, is useful for evaluating the antitumor and antiproliferative activity of a compound of this invention (see Example 28 below). Cells are treated for four days with compound of the invention. Both untreated and treated cells are pulsed with tritiated thymidine for 24 hours. Radioactivity of each type of cells is then measured and compared. The results are then plotted to generate drug response curves, which allow IC50 values (the concentration of a compound required to inhibit 50% of the population of the treated cells) to be determined.
The histone acetylation activity of a compound described herein can be evaluated in an assay using mouse erythroleukemia cells. Studies are performed with the DS19 mouse erythroleukemia cells maintained in RPMI 1640 medium with 25 mM HEPES buffer and 5% fetal calf serum. The cells are incubated at 37xc2x0 C.
Histones are isolated from cells after incubation for periods of 2 and 24 hours. The cells are centrifuged for 5 minutes at 2000 rpm in the Sorvall SS34 rotor and washed once with phosphate buffered saline. The pellets are suspended in 10 ml lysis buffer (10 mM Tris, 50 mM sodium bisulfite, 1% Triton X-100, 10 mM magnesium chloride, 8.6% sucrose, pH 6.5) and homogenized with six strokes of a Teflon pestle. The solution is centrifuged and the pellet washed once with 5 ml of the lysis buffer and once with 5 ml 10 mM Tris, 13 mM EDTA, pH 7.4. The pellets are extracted with 2xc3x971 mL 0.25N HCl. Histones are precipitated from the combined extracts by the addition of 20 mL acetone and refrigeration overnight. The histones are pelleted by centrifuging at 5000 rpm for 20 minutes in the Sorvall SS34 rotor. The pellets are washed once with 5 mL acetone and protein concentration are quantitated by the Bradford procedure.
Separation of acetylated histones is usually performed with an acetic acid-urea polyacrylamide gel electrophoresis procedure. Resolution of acetylated H4 histones is achieved with 6,25N urea and no detergent as originally described by Panyim and Chalkley, Arch. Biochem. Biophys. 130, 337-346 (1969). 25 xcexcg total histones are applied to a slab gel which is run at 20 ma. The run is continued for a further two hours after the Pyronon Y tracking dye has run off the gel. The gel is stained with Coomassie Blue R. The most rapidly migrating protein band is the unacetylated H4 histone followed by bands with 1, 2, 3 and 4 acetyl groups which can be quantitated by densitometry. The procedure for densitometry involves digital recording using the Alpha Imager 2000, enlargement of the image using the PHOTOSHOP program (Adobe Corp.) on a MACINTOSH computer (Apple Corp.), creation of a hard copy using a laser printer and densitometry by reflectance using the Shimadzu CS9000U densitometer. The percentage of H4 histone in the various acetylated states is expressed as a percentage of the total H4 histone.
The concentration of a compound of the invention required to decrease the unacetylated H4 histone by 50% (i.e., EC50) can then be determined from data obtained using different concentrations of test compounds.
Histone deacetylase inhibitory activity can be measured based on procedures described by Hoffmann et al., Nucleic Acids Res., 27, 2057-2058 (1999). See Example 30 below. Briefly, the assay starts with incubating the isolated histone deacetylase enzyme with a compound of the invention, followed by the addition of a fluorescent-labeled lysine substrate (contains an amino group at the side chain which is available for acetylation). HPLC is used to monitor the labeled substrate. The range of activity of each test compound is preliminarily determined using results obtained from HPLC analyses. IC50 values can then be determined from HPLC results using different concentrations of compounds of this invention. All assays are duplicated or triplicated for accuracy. The histone deacetylase inhibitory activity can be compared with the increased activity of acetylated histone for confirmation.
Compounds of this invention are also evaluated for effects on treating X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disorder with impaired very long-chain fatty acid (VLCFA) metabolism. In such an assay, cell lines derived from human primary fibroblasts and (EBV-transformed lymphocytes) derived from X-ALD patients grown on RPMI are employed. Tissue culture cells are grown in the presence or absence of test compounds. For VLCFA measurements, total lipids are extracted, converted to methyl esters, purified by TLC and subjected to capillary GC analysis as described in Moser et al., Technique in Diagnostic Biochemical Genetics: A Laboratory Manual (ed A., H. F) 177-191 (Wiley-Liss, New York, 1991). C24:0 xcex2-oxidation activity of lyophoclastoid cells are determined by measuring their capacity to degrade [1-14C]-C24:0 fatty acid to water-soluble products as described in Watkins et al., Arch. Biochem. Biophys. 289, 329-336 (1991). The statistical significance of measured biochemical differences between untreated and treated X-ALD cells can be determined by a two-tailed Student""s t-test. See Example 31 below.
Further, compounds of the present invention are evaluated for their effects in treating cystic fibrosis (CF). Since the initial defect in the majority of cases of CF is the inability of mutant CF protein (CFTR) to fold properly and exit the ER, compounds of the invention are tested to evaluate their efficacy in increasing the trafficking of the CF protein out of the ER and its maturation through the Golgi. During its biosynthesis, CFTR is initially synthesized as a nascent polypeptide chain in the rough ER, with a molecular weight of around 120 kDa (Band A). It rapidly receives a core glycosylation in the ER, giving it a molecular weight of around 140 kDa (Band B). As CFTR exits the ER and matures through the Golgi stacks, its glycosylation is modified until it achieves a terminal mature glycosylation, affording it a molecular weight of around 170 kDa (Band C). Thus, the extent to which CFTR exits the ER and traverses the Golgi to reach the plasma membrane may be reflected in the ratio of Band B to Band C protein. CFTR is immunoprecipitated from control cells, and cells exposed to test compounds. Both wt CFTR and xcex94F508 CFTR expressing cells are tested. Following lysis, CFTR are immunoprecipitated using various CFTR antibodies. Immunoprecipitates are then subjected to in vitro phosphorylation using radioactive ATP and exogenous protein kinase A. Samples are subsequently solubilized and resolved by SDS-PAGE. Gels are then dried and subject to autoradiography and phosphor image analysis for quantitation of Bands B and C are determined on a BioRad personal fix image station. See Example 32 below. Furthermore, compounds of this invention can be used to treat homozygous xcex2 thalassemia, a disease in which there is inadequate production of xcex2 globin leading to severe anemia. See Collins et al., Blood, 85(1), 43-49 (1995).
Still further, compounds of the present invention are evaluated for their use as antiprotozoal or antiparasitic agents. The evaluation can be conducted using parasite cultures (e.g., Asexual P. falciparum). See Trager, W. and Jensen, J. B., Science 193, 673-675 (1976). Test compounds of the invention are dissolved in dimethyl sulfoxide (DMSO) and added to wells of a flat-bottomed 96-well microtitre plate containing human serum. Parasite cultures are then added to the wells, whereas control wells only contain parasite cultures. After at least one invasion cycle, and addition of labeled hypoxanthine monohydrochloride, the level of incorporation of labeled hypoxanthine is detected. IC50 values can be calculated from data using a non-linear regression analysis.
The toxicity of a compound described herein is evaluated when a compound of the invention is administered by single intraperitoneal dose to test mice. See Example 33 below. After administration of a predetermined dose to three groups of test mice and untreated controls, mortality/morbidity checks are made daily. Body weight and gross necropsy findings are also monitored. For reference, see Gad, S. C. (ed.), Safety Assessment for Pharmaceuticals (Van Nostrand Reinhold, New York, 1995).
Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific examples, which described syntheses, screening, and biological testing of various compounds of this invention, are therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications recited herein, including patents, are hereby incorporated by reference in their entirety.


A computer-implemented graphics program for drawing a spline. The spline is drawn using a first method in the graphics program. Thereafter, the graphics program seamlessly switches from drawing the spline using the first method to drawing the spline using a second method, in response to a first user command. Further, the graphics program may also seamlessly switch from drawing the spline using the second method to drawing the spline using the first method, in response to a second user command.

1. Field of the Invention
The present invention relates generally to computer-implemented graphics systems, and in particular, to a method, apparatus, and article of manufacture for improved spline drawing in a computer-implemented graphics program.
2. Description of the Related Art
Splines are free-form, smooth, irregular curves. Splines are used in computer-implemented graphics programs to represent lines, surfaces, edges, and other geometric shapes.
Typically, a spline is comprised of one or more curves connected by a series of vertices, which may or may not include control points. The vertices determine the location of the spline, while the control points contain the curve information for the spline. The curves in the splines can be reshaped by moving the vertices and/or control points. A fit tolerance can be used to control how closely the spline conforms to the vertices, wherein a low tolerance value causes the spline to form close to vertices and a tolerance of 0 (zero) forces the spline to pass through the vertices.
There is a need in the art for a way to generate splines that is more intuitive than current methods. There is also a need in the art for a way to quickly generate splines from the selection of vertices as well as by drawing the splines in freehand. There is also a need in the art to be able to quickly switch between the selection of vertices and the freehand drawing of splines. The present invention satisfies those needs.

Spline drawing in a computer-implemented graphics program


The present invention relates to markers manufactured from skis. In accordance with the invention, the structure of a ski is modified to enable its use as an object which may be driven into soil or snow to designate the presence of underground objects, to delineate or identify a border or as a post for signage or fencing. The process of the invention relates to the modification of a ski by treating or removing the existing outer surfaces of a ski and providing new outer surfaces to the ski which may include graphics or notices specific to its new use. In order to inhibit the removal of a marker from soil or snow after placement, the marker may be provided with a barb system on its underground portion.

The ski industry discards thousands of skis each year either as factory seconds from the manufacturing process or as old skis at the end of their useful life. Throughout North America and Europe, these discarded skis generally make their way to land fill sites creating a significant volume of waste.
With thousands of skis being discarded each year there are obviously environmental concerns with respect to such wasteful activities and, accordingly, there is a need for new and innovative uses for discarded skis in order to reduce the number of skis which ultimately end up at a land fill site. However, as a basic raw material, old or factory second skis come in a huge variety of lengths, colors, designs and shapes and previously, have not been considered useful as a raw material source for proposed consumer products.
Common amongst skis, however, is the fact that they are generally manufactured as highly durable and structurally-strong objects for their intended use as recreational items in a demanding environment. Accordingly, under the basic exterior structure of a ski is an underlying raw material of significant strength and uniformity which could be used in new products. One such use is as marker which may be used for the identification of underground cables (i.e. utility markers), as highway or railway markers, as miscellaneous use markers for delineating boundaries such as driveways or gardens or as a boundary marker at ski resorts or any open area where it is required to create or mark off specific boundaries. Another use would be in support for signage or fencing.
Hereinbefore, however, skis have not been considered for such an applications. A review of the prior art has shown utility or road markers specifically manufactured from raw materials for such purposes and are described as such in U.S. Pat. 4,249,357 (Cornou) as a synthetic-resin road marker having a specific extruded form. Examples of other utility markers include those disclosed in U.S. Pat. No. 4,078,867, which describes the specific structure of a traffic marker post specifically manufactured for such a use.
A still further example of a utility road marker is that which is described in re-issued Pat. No. 32,045 (Schmanski, re-issued Dec. 10, 1985) which also describes a flexible highway maker having a specific form.
Still further and related to ground marker systems, U.S. Pat. No. 4,939,877 (Claffey) describes an anchor device for supporting the post of signs, flags, road markers and the like.
An example of a use for factory second skis is described in U.S. Design Pat. No. 345,656 (Theobald) which describes the ornamental design of a "Adirondack" type chair in which the back of said chair is manufactured from a plurality of skis cut to different lengths.
However, the above mentioned patents do not describe the modification of a ski in order to facilitate its use as a marker.


There is proposed a mechanism for monitoring optical fibers (1) in an optical backhaul network that connects nodes (10, 20) of a distributed radio base station system. The nodes carry data streams using the Common Public Radio Interface (CPRI) protocol. The method includes: receiving from at least one node a CPRI alarm indicative of a transmission failure in a CPRI data stream, and triggering fault analysis of an optical fiber identified as carrying the CPRI data stream. Using CPRI alarms that are generated by transmission failures between nodes as a trigger for monitoring the physical fiber carrying the CPRI streams provides a targeted mechanism for determining fiber failures, which had a low response time and thus enables rapid repair of any fault and minimal disruption to the network.

In mobile communication networks, the radio base stations (RBS) are increasingly designed in such a way that the air interface is physically separated from the baseband signal processing. In practice, this means that radio equipment controllers (REC), which perform the baseband processing, are arranged at one location while the radio equipments (RE) are arranged at locations remote from the RECs, often on antenna masts, rooftops, roadsides, etc. In a distributed RBS, an RE is also referred to as a remote radio unit (RRU). This configuration allows the bulk of the processing to be performed remotely in a centralised fashion, which simplifies the design of the radio site. In effect, it enables all RECs to be located in a single physical site within a controlled environment. This kind of system architecture with centralised processing units is often referred to as Centralised Baseband (CBB), but is also often referred to as Centralised Radio Access Network (C-RAN) or baseband hotel.
In a distributed RBS or CBB, an REC is connected to REs via a backhaul network, which is typically an optical fiber network. The backhaul network must comply with the necessary requirements for data rates, bit error rate (BER), delay and delay variation. One manner of achieving this is to use the Common Public Radio Interface protocol or CPRI defined in "CPRI Specification V5.0 (2011 Sep. 21)" available at http://www.cpri.info/spec.html. CPRI is a layer 2 protocol which defines the signalling and control operations for transmitting digitised radio signal samples from REs to the processing units and vice-versa. Providing that the bandwidth, maximum delay, delay variation and BER requirements are met, CPRI can be run over different physical media, such as optical fibers, copper wires or even microwave links.
As each optical fiber in the backhaul network may be used to carry traffic from multiple mobile subscribers, it is essential that any failure in the backhaul network is detected promptly and communication restored with minimum delay.
Conventional fiber monitoring systems use reflectometry techniques to detect faults by transmitting test signals through a fiber and analysing the reflections. They are generally stand alone systems which can be customised to interact with an operator's Operations, Administration and Maintenance (OAM) system. For example, it is known to provide a manually operated fiber monitoring system in an access network that is configured as a passive optical network (PON), where the fiber condition is tested after a customer has complained. A fiber monitoring system operated in this way is not suitable for mobile backhaul optical fiber networks, because the downtime caused by a fiber fault can affect many mobile subscribers and cause substantial losses for the operator.
U.S. patent application No. US 2011/0311220 A1 and U.S. Pat. No. 7,738,787 both describe optical transmission line monitoring apparatus that use optical time domain reflectometry (OTDR) to continuously poll the status of each optical fiber in turn. Whilst these arrangements may react faster than a manually operated monitoring system, they are subject to scalability problems, as the time needed to poll all fibers increases with each additional managed fiber. A reduction in the total testing time can only be achieved by reducing the sampling rate for each fiber and thus at the expense of OTDR accuracy.
A further fiber monitoring arrangement and method is described in WO 2012/087205. In this arrangement a test procedure is triggered by an alarm received from a terminal device as a result of non-standardized performance parameters measured as part of an Optical Transceiver Monitoring (OTM) arrangement. The detection trigger is based on hard thresholds, e.g. absolute received power levels, which requires careful control of the operating conditions of such a system. Optical power measurements made using the same equipment, but at different operating temperatures can differ substantially.

Method and arrangement for monitoring optical transmission lines


In a stator core having a plurality of teeth, which elongate in an inner radial direction and slots, which are configured among the teeth, powder is caused to adhere to the stator core, the powder adhering to an inner peripheral face of the stator core is removed, and the stator core is heated to melt and harden the powder.

1. Field of the Invention
The present invention relates to a powder-coated stator core, a coating method for the stator core, and a coating apparatus for the stator core, and more particularly to powder coating of a stator core of a vehicular rotary electric machine.
2. Description of the Related Art
FIG. 10 is a section view showing the configuration of a vehicular alternator, which is disclosed in, for example, JP-A-2001-238419. In FIG. 10, 1 denotes a front bracket, 2 denotes a rear bracket, 3 denotes a stator, which is interposed between the front bracket 1 and the rear bracket 2 and is configured by a stator core 4 and a stator coil 5, and 6 denotes a rotor. The rotor includes a rotation shaft 7 in which the both ends thereof are supported by the front bracket 1 and the rear bracket 2, respectively, rotor cores 8 and 9, which are attached to the rotation shaft 7, a field coil 10, which is wound between the rotor cores 8 and 9, fans 11 and 12, which are disposed on the back sides of the rotor cores 8 and 9, respectively, and a slip ring 13, which is disposed on the rotation shaft 7 to supply a current to the field coil 10.
The outer peripheries of the rotor cores 8 and 9 are opposed via an air gap to the inner periphery of the stator core 4. The reference numeral 14 denotes a pulley, which is disposed on the rotation shaft 7. The reference numeral 15 denotes a brush for supplying a current to the slip ring 13, 16 denotes a brush holder, which holds the brush 15, 17 denotes a three-phase full-wave rectifier, which rectifies the AC output of the stator coil 5, and 18 denotes a regulator, which adjusts the current of the field coil 10 to control the output voltage of the stator coil 5. These components are attached to the rear bracket 2. The stator coil 5, which is wound and inserted into the stator core 4, is extended toward the rear bracket 2, and a joining terminal 19 is welded to the tip end. The terminal is connected and fixed to a terminal 17a of the rectifier 17.
In the thus configured vehicular alternator, the stator 3 is formed by applying an insulating process on the stator core 4, and then inserting or winding the stator coil 5 on the stator core. The insulating process can be conducted by a method such as that insulating paper is interposed between the stator core 4 and the stator coil 5, or that powder coating for insulation is applied to the surface of the stator core 4. As disclosed in, for example, JP-A-Sho.57-135655, a method in which powder coating is conducted after a jig is mounted on the inner radial side of the stator core 4 to take a measure (masking) for preventing powder from adhering to a portion not to be powder-coated is usually employed as a method of producing a stator of a vehicular alternator or the like that is requested to be mass-produced at a lower cost.
The stator core 4 of the vehicular alternator is powder-coated as described above. When the number of the slots or the dimensions of the stator core are changed, therefore, the jig must be changed, and a work of replacing the jig with another one is necessary. When a large clearance is formed between the stator core 4 and the jig, masking may not be surely performed, thereby raising the possibility that powder adhering to the inner peripheral face of the stator core 4 rubs against the outer peripheral faces of the rotor cores 8 and 9. When the air gap is increased in order to cope with this, the performance of the alternator is lowered. Alternatively, a work of removing the excess powder adhering to the inner peripheral face of the stator core 4 must be additionally conducted. By contrast, when the clearance between the stator core and the jig is too small, the jig cannot be smoothly mounted or dismounted, and positioning between the jig and the stator core 4 must be conducted. Furthermore, the removal of powder adhering to the jig must be conducted after the jig is dismounted from the stator core 4. In this way, the method has also a problem with productivity.
In the method according to the related art in which the inner peripheral face of the stator core 4 is masked by the jig, powder can be applied only from the side of the axial end faces of the stator core 4. In the case where the slot area is reduced as a result of an increased number of slots or the axial length of the stator core 4 is prolonged, therefore, powder coating is ununiformly conducted in such a manner that, for example, the film thickness on the axial end faces of the stator core, 4 is large but that in a slot in the vicinity of the axial center is small. This causes a coil failure such as that the insulation property is lowered, that the stator coil 5 cannot be accommodated in the slots, or that the stator coil 5 is damaged. When a thin stator coil 5 is used in order to prevent such a failure from occurring, there arises a problem such as that the performance is lowered.

Stator core, and method and apparatus for producing the same