This invention relates to an optical card having a preformat portion comprising a low reflectance area having an excellent contrast to high reflectance area. An optical card original plate whose portions corresponding to preformat portions 4, 5 of an optical card 1 each have a stereostructure of an inverted pyramidal shape is prepared. An optical card is duplicated from this optical card original plate. The stereostructure in an inverted pyramidal shape can be formed by the anisotropic etching of a single crystal substrate. An original plate free from defects and surface roughnesses and ensuring a sufficiently low reflectance is obtained. An optical card produced from this original plate has a preformat portion comprising a low reflectance area with a satisfactory contrast to a high reflectance area. A replica duplicated using a molding resin from the original plate can be used as a resin original plate. Furthermore, a replica duplicated from this resin original plate by use of a molding resin can be used as a stamper for production of an optical card.

The invention relates to an optical card capable of optical information recording, and technology for producing it.
An optical card has been known as a memory card incorporating an optical recording zone, i.e., an optical information recording zone, in a plastic card. FIG. 1 shows an example of a WORM (write-once/read-many) type optical card. In an optical recording zone 2 of this optical card 1, track guides 4 and information recording pits 5, each composed of a low reflectance area, are formed as preformats along with high reflectance areas. Among optical cards of this type is an optical card whose low reflectance areas are composed of light scattering surface roughened portions. Such an optical card has been proposed as a product using an optical recording medium whose manufacturing process is relatively simple, whose material is not restricted to a particular optical recording material, and whose production cost is low enough to be suitable for mass reproduction on a commercial scale (see, for example, Japanese Patent Publication No. 64141/95). The production of this optical card begins with the preparation of a surface-roughened original plate having low reflectance areas surface roughened according to an information record pattern. The resulting original plate is duplicated and transferred to mass produce the optical card having a rough surface information record pattern.
The steps for its manufacturing process will be described with reference to the accompanying drawings.
At a first stage, a positive photoresist is uniformly coated on a transparent substrate 11 (a 400 .mu.m thick acrylic plate) to a thickness of 0.5 .mu.m by means of a rotary photoresist coater to form a photoresist layer 12, as shown in FIG. 2A. At a second stage as shown in FIG. 2B, a photomask 13 formed in accordance with an information record pattern is superimposed on the photoresist layer 12 using a mask aligner, and then initial exposure (patterning exposure) is performed. At a third stage as shown in FIG. 2C, a glass sheet 14 roughened on one surface in a finely uneven form (average roughness 0.3 .mu.m, #3000 abrasive glass) is used, and exposure is performed again (surface roughening exposure). After exposure, the photoresist layer 12 is developed at a fourth stage. Thus, as shown in FIG. 2D, the pattern of the photomask 13 is transferred onto the transparent substrate 11, with the exposed areas of the photoresist being dissolved and the unexposed areas remaining. By this measure, the surface roughened photoresist layer 12 is formed as guide tracks, for example, with a width of about 2.5 pm and a pitch of about 15 .mu.m.
Then, an optical recording medium having an information record pattern composed of low reflectance areas roughened on the surface (a medium as shown in FIG. 2D) is used as a surface roughened original plate 15. From this surface roughened original plate 15, a mother mask is duplicated using a molding press. Specifically, as shown in FIG. 3A, the surface roughened original plate 15 is superimposed on a transparent substrate 21 (an acrylic plate 12 mm in thickness) via an impression material 22 comprising a molding compound of an ionizing radiation curable resin or a thermosetting resin. The combination is pressed, and then the surface roughened original plate 15 is stripped to duplicate a pattern on the transparent substrate 21 side, thus forming a mother mask 23.
Then, the mother mask 23 is used as a duplicating original plate for mass duplication, and impression using it is performed to duplicate an optical recording medium on the back of a substrate serving as a transparent protective layer of an optical card. In detail, as shown in FIG. 4A, a molding resin 33 is interposed between the back of a transparent protective layer 32 having a surface hardening layer 31 and the pattern surface of a mother mask 23. The assembly is pressed by a pressing machine to undergo hardening. Then, as shown in FIG. 4B, the transparent protective layer 32 and the mother mask 23 are released from the mold to duplicate a pattern on the transparent protective layer 32 side. In this manner, high reflectance areas 33a and low reflectance areas 33b are formed on the duplicating resin 33 to serve as an optically transparent substrate for an optical card.
Then, as shown in FIG. 5, an optical recording material layer 34 of, say, the intermediate oxide of Te, is laminated to cover the high reflectance areas 33a and low reflectance areas 33b in the optically transparent substrate composed of the duplicating resin 33.
Separately from the foregoing series of steps, a card substrate 35 as shown in FIG. 6 is prepared. This card substrate is formed by applying a print layer 36 to one surface of a core sheet 35b comprising translucent polyvinyl chloride, and bonding overlay sheets 35a, 35c comprising transparent polyvinyl chloride to both surfaces of the core sheet 35b.
Then, the card substrate 35 is adhesion laminated to the substrate having the optical recording material layer 34 via an adhesive layer 37 comprising urethane resin, as shown in FIG. 7. The so prepared master is punched into a card form to produce an optical card as illustrated in FIG. 1.
The aforementioned production of a conventional surface roughened original plate posed the problem that the resulting roughened surface contained defective areas because of the processing method during production, the limits of the properties of the materials used, and slight changes in the manufacturing conditions. In extreme cases, the resulting original plate partially had no sufficiently low reflectance. Optical cards duplicated from such an original plate were not entirely satisfactory in the contrast of the preformat portions.


A method and an apparatus for estimating a geometric thickness of a breast in mammography/tomosynthesis or in other x-ray procedures, by imaging markers that are in the path of x-rays passing through the imaged object. The markings can be selected to be visible or to be invisible when the composite markings/breast image is viewed in clinical settings. If desired, the contribution of the markers to the image can be removed through further processing. The resulting information can be used determining the geometric thickness of the body being x-rayed and thus setting imaging parameters that are thickness-related, and for other purposes. The method and apparatus also have application in other types of x-ray imaging.

Breast cancer and other breast lesions continue to be a significant threat to women's health. X-ray mammography currently is the most widely used tool for early detection and diagnosis, and is the modality approved by the U.S. Food and Drug Administration to screen for breast cancer in women who do not show symptoms of breast disease. A typical x-ray mammography system compresses and immobilizes a patient's breast on a breast platform positioned between an x-ray source and an x-ray imager, and takes a projection x-ray image (called here a conventional mammogram or simply mammogram) using a collimated cone or pyramid beam of x-rays at appropriate factors such as mA (current), kVp (voltage) or keV (energy), and msec (exposure time). In the United States, typically two views are taken of each breast, one from above (cranial-caudal, or CC, with the image plane generally at a 0° angle to the horizontal and one from the side (mediolateral-oblique, or MLO, with the image plane at an angle of typically around 45° to the horizontal). Different typical views may be taken in other countries. The x-ray source typically is an x-ray tube operating at or in the neighborhood of 25-30 kVp, using a molybdenum, rhodium or tungsten rotating anode with a focal spot of about 0.3 to 0.4 mm and, in some cases, 0.1 mm or less. An anti-scatter grid between the breast and the imager can be used to reduce the effects of x-ray scatter. The breast is compressed to reduce patient motion and also for reasons such as reducing scatter, separating overlapping structures in the breast, reducing the x-ray thickness of the imaged breast and making it more uniform, and providing more uniform x-ray exposure. Traditionally, the imager has been a film/screen unit in which the x-rays impinging on the screen generate light that exposes the film. In the last several years, mammography systems using electronic digital flat panel x-ray receptors have made significant inroads. A Selenia™ digital mammography system with such a digital flat panel x-ray receptor or imager is offered by Lorad, a division of the assignee hereof, Hologic, Inc. of Bedford, Mass. See brochure "Lorad Selenia™" Document B-BI-SEO US/Intl (May 2006) copyright Hologic 2006. Digital mammography has significant advantages and in time may fully supplant film/screen systems. Additional information regarding digital mammography systems and processes offered by the common assignee can be found at <www.hologic.com>. Digital tomosynthesis also has made advances and the assignee hereof has exhibited breast tomosynthesis systems at trade shows and has carried out clinical testing. It is a three-dimensional process in which several two-dimensional projection views are acquired at respective different angles but lower x-ray dose than conventional mammograms, and are reconstructed into tomosynthesis slice views that can be along any desired plane in the breast. For tomosynthesis, the breast is still immobilized but may be compressed to the same or lesser extent than in conventional mammography. See, e.g., International Application WO 2006/058160 A2 published under the Patent Cooperation Treaty on Jun. 1, 2006 and Patent Application Publication No. 2001/0038681 A1, PCT application International Publication No. WO 03/020114 A2 published Mar. 13, 2003, U.S. Pat. Nos. 7,142,633, 6,885,724, 6,647092, 6,289,235, 5,051,904, 6,359,637, and 4,496,557, and published patent applications US 2004/0109529 A1, US 2004/0066884 A1, US 2005/0105679 A1, US 0050129172A1, and Digital Conical Reports, Tomosynthesis, GE Brochure 98-5493, November 1998. Reference markers can be used in x-ray imaging for purposes such as checking the rotation angle and unwanted shift of center of rotation of an x-ray source and receptor (imager), and fiducial phantoms can be used in 3D angiography to calibrate for irregular scan geometries. See, e.g., U.S. Pat. Nos. 5,051,904, 5,359,637, and 6,289,235, N. Navab, et al., Dynamic geometrical calibration for 3D cerebral angiography, SPIE Vol. 2708, pp. 361 370, and said PCT published application WO 03/020114 A2, A tomosynthesis system specifically for imaging patients' breast is disclosed in commonly owned U.S. Pat. Nos. 7,123,684 and 7,245,494. The same system can be selectively used mammography and tomography, in the same or different compressions of the patient's breast.
It is desirable to know the geometric thickness of the mobilized breast in both film/screen and digital flat panel x-ray mammography as well as in tomosynthesis in order to make appropriate setting for the imaging procedure, such as settings for the x-ray tube that control the x-ray beam. Knowing the breast thickness can also help in quantitative assessments regarding x-ray images of the breast, such as in assessing the nature and clinical significance of x-ray attenuation properties of the breast. It can also be used in tomosynthesis reconstructions such as to determine the required reconstructed field of view or desired display field of view. It has been proposed to use encoders to measure the geometric height of breast compression paddle and use the result to estimate the geometric thickness of the breast but this process typically has a relatively high error because of factors such as tilting and geometric distortions of the paddle as it compresses the breast, and because the encoders must be calibrated. The information on the paddle height is oftentimes stored in the DICOM header associated with the medical image, and this information is used for several purposes, including the calculation of body part radiation exposure. It also has been proposed to derive breast thickness information from measuring the paddle compression force versus time and to use the results to guide control factors such as kV, mAs, and filter selection, as in commonly assigned U.S. Pat. No. 7,123,684. The geometric thickness of any other body part being x-rayed also can be of interest, and one process for basing an estimate on non-contact ranging using ultrasound is discussed in U.S. Pat. No. 4,591,094. It has also been proposed to use a calibration phantom with embedded pellets of high-density material serving as markers and to use the imaged markers in calibrating the system, such as once a week. See U.S. Pat. No. 7,142,633 cited above.
Proposals have been made for automated methods of estimating breast density from mammograms, including volumetric and areal estimates. One example, using digitized film mammograms, is given in Br J Radial. 2008 May; 79 (941):378-82 16632617. These methods are understood to derive the volume of fibroglandular tissue in the breast tissue for a cross-sectional area in a mammogram. The accuracy of these methods is believed to be related to the accuracy of measurement of the actual compressed breast. In addition, information has been published proposing that breast density is related to the breast cancer risk, See Cancer Epidemiology Biomarkers & Prevention, Vol 13, 715-722, May 2004, American Association for Cancer Research.
The patents and other publications identified above, including the brochure "Lorad Selenia™" and said published application WO 2006/058160 (corresponding U.S. patent application Ser. No. 11/791,601), are hereby incorporated by reference in this patent specification.

X-ray imaging with x-ray markers that provide adjunct information but preserve image quality


Two syntheses are provided; one for the preparation of (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol, and other for the preparation of (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol. (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol is prepared using the achiral ylide prepared from benzylamine instead of phenethylamine (Scheme 3) which provides a crystalline intermediate. The synthesis of (3S,4R)-4-(hydroxymethyl)pyrrolidin-3-ol is achieved from (S)-diethylmalate as described in Scheme 4. A process for preparing camphor sultam is also provided.

Racemic and non-racemic 4-(hydroxymethyl)pyrrolidin-3-ols have been prepared and found to have an inhibitory effect on certain enzymes and on glial GABA uptake. These pyrrolidines have also been used as building blocks for the synthesis of some compounds having antibacterial activity and also for some nucleosides analogues. Recently, (3R,4R)-4-(hydroxymethyl)-pyrrolidin-3-ol was used for the synthesis of a highly potent purine nucleoside phosphorylase (PNP) inhibitor.
The first synthesis of 3-hydroxy-4-hydroxymethylpyrrolidine was reported starting from N-benzylglycinate and ethyl acrylate and was obtained as a mixture of cis/trans isomers. The trans-racemic compound was prepared starting from fumaric acid methyl ester.
The first synthesis of the pure enantiomer (3R,4R)-4-(hydroxymethyl)pyrrolidin-3-ol was reported from glucose and xylose (Schemes 1 and 2) in very low yields requiring several steps and is not practical for synthesis on a kilogram scale.
Karlsson and Hogberg reported the preparation of this compound via asymmetric 1, 3-dipolar cycloaddition using camphor sultam as a chiral auxiliary. In this synthesis, the chiral ylide used was generated from phenethylamine and the intermediates obtained were oils requiring flash chromatography for the separation of isomers.
These reported methods are considered unsuitable for various reasons. To produce kilogram quantities of these products, a practical synthesis was needed using a suitable procedure.

Process for the preparation of substituted pyrrolidine derivatives and intermediates


A system employs space-time coding characterized at the transmitter by bit-interleaved coded modulation (BICM) combined with modulating several streams of the BICM encoded data for transmission over two or more antennas. Space-time coding techniques improve transmission efficiency in radio channels by using multiple transmit and/or receive antennas and coordination of the signaling over these antennas. Bit-interleaved coded modulation provides good diversity gain with higher-order modulation schemes that employ binary convolutional codes. A receiver demodulates the received signals and applies multi-input, multi-output (MIMO) demapping to estimate the BICM encoded bitstream. After deinterleaving of the BICM encoded bitstream, maximum a posteriori (MAP) decoding is applied to the resulting bit stream to generate soft output values. By applying well-known turbo-decoding principles to iteratively demap and decode, the overall receiver performance is significantly improved. The MIMO demapping and MAP decoding processes exchange likelihood information to improve the bit error rate performance over several iterations of demapping/decoding. By generating tentative decisions for transmitted bits, the overall number of evaluations used for demapping may be reduced.

1. Field of the Invention
The present invention relates to data modulation and demodulation in a communication network, and, more particularly, to space-time coding and decoding techniques for wideband data channels.
2. Description of the Related Art
Wireless channels exhibit a number of severe impairments, among which fading is one of the most severe. For narrowband channels, the fading can often be assumed to be flat, while for wideband channels the fading is typically frequency selective. In addition, additive noise and interference contribute significantly to signal degradation. Diversity is a method to improve transmission over fading channels. Time diversity uses encoding to duplicate and spread information through an encoded bit stream (e.g., convolutional encoding) and space diversity employs multiple transmit and/or receive links to duplicate and spread information over multiple signal paths.
Coded modulation systems employ methods that utilize time diversity. Encoded data is transmitted through the path between a single transmit antenna and a single receive antenna. Some methods efficiently utilize binary convolutional codes to obtain diversity gains with higher-order, non-binary modulation symbols (e.g., 16-QAM), such as bit-interleaved coded modulation (BICM) systems using multi-level coding methods (and corresponding multistage decoding at the receiver). For example, BICM systems provide diversity gains, and, for example, higher-order, coded modulation systems use well-known binary convolutional codes separated by interleaving to encode the data. Further improvements in system performance are obtained by iterative demapping (translation of symbols to bits) and decoding at the receiver. More recently, so-called space-time coding methods have been proposed to obtain both space and time diversity by using multiple transmit and/or receive antennas along with matching coding. For example, a space-time BICM scheme for narrowband radio channels employing multiple transmit antennas in flat fading cases is described in A. M. Tonello, "Space-Time Bit-Interleaved Coded Modulation With An Iterative Decoding Strategy," Proceedings, VTC 2000 Fall, Boston, Mass., September 2000, pp473–478, which is incorporated herein in its entirety by reference.
Orthogonal Frequency Division Multiplexing (OFDM) is a form of data transmission in which a block of data is converted into a parallel form and mapped into frequency domain symbols. To generate a time domain signal for transmission over the antenna link between antennas, the inverse discrete Fourier transform (IDFT, or its fast version, the IFFT) of length F is applied to F frequency domain symbols to create F subchannels (also known as F subcarriers, since each channel is a separately modulated carrier). Each of the F subcarriers is orthogonal to each other while the frequency spectrum overlaps. The frequency spacing between the F subcarriers is minimum in OFDM, giving OFDM high spectral efficiency. At the receiver, the discrete Fourier transform (DFT, or its fast version, the FFT) is applied to the received signal over F subchannels to generate a sequence of values representing estimated frequency domain symbols. Demapping maps the estimated symbols back to the original block of user data (bits). OFDM allows for wideband transmission over frequency selective (radio) channels without adaptive equalizers. For wideband systems, OFDM has been proposed for a wide range of radio channel applications. One application is the wireless local Area Network (LAN) system defined by the IEEE 802.11a standard. This standard adopts OFDM in packet-based communications operating in unlicensed 5 GHz bands.

Reduced complexity receiver for space-time- bit-interleaved coded modulation


Provided are a computer program product, system, and method for allowing writes to complete without obtaining a write lock to a file. A lock is provided to a first request, comprising a read or write request, to access the file. A second write request is received while the first request maintains the lock. A temporary file associated with the file for the second write request is created. The second write request is controlled to write to the temporary file while the lock is held by the first request. In response to completing the first request, the lock is granted to the second write request to write the data in the temporary file to the file.

1. Field of the Invention
The present invention relates to a computer program product, system, and method for allowing writes to complete without obtaining a write lock to a file.
2. Description of the Related Art
A sequential file is a file to which write data is appended to the end of the file. When a write request is writing to a sequential file, the file is locked and other read and write requests are not allowed to access the file. When a read or write is holding a lock to a file, a subsequent writer has to wait for the first request to release the lock before the update can be applied to the file. A job may consist of multiple read and write requests that can be substantially delayed while waiting for previously received read and write requests to release their locks to the file.

This patent is subject to a terminal disclaimer.

Allowing writes to complete without obtaining a write lock to a file

INTERNATIONAL BUSINESS MACHINES CORPORATION


A signal transition control system for use in a modulated-signal communication system having a plurality of predefined signal states each representing a digital data symbol, enables a transition from one signal state to a next signal state to be executed in a smooth, bandwidth-efficient manner. The system includes circuitry for receiving a stream of data symbols and storing in succession consecutive pairs of the data symbols, each of the pairs including a last data symbol and a next data symbol, for producing data describing a vector in signal space from the last data symbol to the next data symbol, for storing data representative of a desired shape of a transition from the last data symbol to the next data symbol, means for sequentially stepping through the data representative of the desired shape, and for producing data representing a transition from the last data symbol to the next data symbol, the transition having the desired shape. The system is used to particular advantage in a number-controlled modulated oscillator that generates a signal having a numerically controlled frequency, a numerically controlled phase, a programmable shape, and a numerically controlled amplitude.

1. Field of the Invention
The present invention relates to modulated-signal communication systems and, more particularly, to signal transition control in such systems.
2. State of the Art
In modulated-signal communications systems, it is well known to impress information on a sinusoidal carrier signal by changing the carrier amplitude, frequency, phase, or combinations thereof. In digital communication systems, the information impressed on the carrier signal is a digital data stream composed of 1s and 0s. One common modulation technique in digital communication systems is phase-shift keying (PSK) in which a phase reversal of the carrier signal of 180.degree. signals a data transition from 1 to 0 or vice versa.
Referring to FIG. 1A, for example, the sequence 1, 0, 1, 0 is to be transmitted using PSK. Each bit has a duration of one and one half cycles of the carrier signal. The initial 1 is therefore represented by one and one half cycles of the carrier signal at a given phase. At the end of the first bit time, a discontinuity occurs as the phase of the carrier signal is reversed to represent the change from a 1 to a 0. Likewise, at the end of the second bit time a discontinuity occurs as the phase of the carrier signal is reversed to represent the change from a 0 to a 1, and so forth.
As is well-known from Fourier analysis, abrupt transitions such as occur between bits in FIG. 1A are inherently wide-bandwidth. In radio communications, radio energy transmitted in connection with a particular signal must be confined within a particular channel bandwidth. Furthermore, the portion of the radio spectrum allocated to any particular use is limited by F.C.C. regulations, within the United States. Therefore, within a limited portion of the radio spectrum, individual channels must be defined so as to have a relatively wide bandwidth if signals of the type shown in FIG. 1A are to be accommodated. As a result, fewer channels can be defined within the limited portion of spectrum than might otherwise be possible and thus less information can be carried.
As described with respect to FIG. 1A, discontinuities can occur in a digitally modulated signal upon transition from one signal state to another. This situation is represented in FIG. 2A, which shows a 2-dimensional signal space. Transitions between the two signal states 0 and 1 occur as "snap transitions", the intervening signal space between the two signal states being traversed almost instantaneously.

Signalling transition control in a modulated-signal communications system


Compounds of formula (I): wherein Rx is cyano or bromo; R1 is halo; R2 is C1-C3 alkyl, and pharmaceutically acceptable salts and prodrugs thereof have activity as antiretrovirals.

This invention relates to the field of antivirals and in particular to HIV reverse transcriptase inhibitors. The invention provides novel compounds, pharmaceutical compositions comprising these compounds and methods for the inhibition of HIV employing them.
Of the pharmaceuticals which have shown clinically relevant activity in the inhibition of HIV reverse transcriptase in HIV treatment, most are nucleoside analogues such as AZT, ddI, ddC and D4T. These nucleoside analogues are not as specific as is desirable and thus have to be administered at relatively high dosage levels. At these dosage levels, nucleoside analogues tend to be rather toxic, limiting their long term use.
To overcome these problems of specificity and toxicity a number of non-nucleoside inhibitors of the reverse transcriptase of HIV have been developed. For example TIBO, a reverse transcriptase from Janssen inhibits HIV at nanomolar concentrations and displays no clinically significant toxicity. Both TIBO and the non nucleotide reverse transcriptase inhibitor nevirapine proceeded rapidly to phase II clinical trials in patients. However it soon became apparent that these non-nucleoside inhibitors rapidly select out HIV mutants in vivo which are resistant to the usual dosages of the respective inhibitors. In the case of nevirapine for example, after only four weeks of therapy virus isolated from patient serum was 100 fold less sensitive to the drug compared with virus isolated from untreated patients (Drug Design and Discovery 1992 8 pp 255-263). A similar pattern has emerged for other non-nucleoside RT inhibitors which have entered clinical trials, Merck""s L-697661 and Upjohn""s delavirdine (U-87201), namely that promising in vitro activity has rapidly produced resistant HIV mutants when administered to patients. Notwithstanding this drawback nevirapine and delavirdine have recently been registered for clinical use, although limited to specific coadministration regimes in an attempt to retard resistance development.
International patent application no WO 95/06034 describes a series of novel urea derivatives which exhibit good in vitro activity against HIV reverse transcriptase and good inhibition of HIV replication in cell culture. However practical deployment of the compounds in WO 95/06034 is hampered by their poor pharmacokinetic performance. Additionally, as with many non-nucleoside reverse transcriptase inhibitors, the compounds presented in WO 95/06034 leave room for improvement in the key parameter of slow resistance development and a favourable pattern of activity against HIV mutants generated by other antiviral regimes.
A poster of xc3x96berg et al at the 1995 ICAR at Santa Fe disclosed inter alia a racemic compound nominally within the abovementioned WO 95/06034 and having the formula:
At the time the above depicted compound was regarded as of less interest than thiourea variants having a methoxy/acetyl bearing phenyl ring. However, we have now discovered that an alternative substitution pattern manifests an improved resistance pattern in comparison to these prior art compounds in conjunction with good pharmacokinetic performance and a prolonged time to virus resistance. The invention thus provides inhibitors which combine the superior specificity of non-nucleoside inhibitors with the clinical practicality missing from all prior art inhibitors.
In accordance with the invention there are provided compounds of the formula I
wherein
R1 is halo;
R2 is C,-C, alkyl;
Rx is cyano or bromo;
and pharmaceutically acceptable salts and prodrugs thereof.
The invention further provides pharmaceutical compositions comprising the compounds of formula I and pharmaceutically acceptable carriers or diluents therefor. Additional aspects of the invention provide methods for the inhibition of HIV comprising administering a compound of the formula I to a subject afflicted with HIV. The invention also extends to the use of the compounds of formula I in therapy, such as in the preparation of a medicament for the treatment of HIV infections.
In treating conditions caused by HIV, the compounds of formula I are preferably administered in an amount to achieve a plasma level of around 10 to 1000 nM and more preferably 100 to 500 nM. This corresponds to a dosage rate, depending on the bioavailability of the formulation, of the order 0.01 to 10 mg/kg/day, preferably 0.1 to 2 mg/kg/day. A typical dosage rate for a normal adult will be around 0.05 to 5 g per day, preferably 0.1 to 2 g such as 500-750 mg, in one to four dosage units per day.
A preferred subset of compounds within claim 2, particularly with regard to pharmacokinetics, has the structure IA:
where R1 and R2 are as defined above, including the pharmaceutically acceptable salts and prodrugs thereof.
A further favoured subset of compounds within Formula I, particularly with regard to ease of forming prodrugs, comprise compounds wherein Rx is bromo.
Preferably R1 is chloro and more preferably fluoro. Suitable R2 groups include methyl, isopropyl, n-propyl and preferably ethyl.
As depicted above, the cyclopropyl ring is in the cis configuration, allowing two enantiomers, 1S, 2S and 1R, 2R (respectively and non-conventionally denoted 2R,1S and 2S,1R in SE 980016-7 and SE 9800113-4):
Each of these enantiomers are potent antiretrovirals, although the different enantiomers can display subtle differences in physiological properties. For instance the 1S,2S and 1R,2R enantiomers can show a different pattern of metabolism within the P450 system. The 1S,2S enantiomer of compounds wherein Rx is cyano is particularly preferred as it appears unique in being able to avoid key components of the P450 system. Other retroviral agents such as the HIV protease inhibitor ritonavir interact extensively with the P450 system, leading to an array of undesirable physiological responses including extensive alteration of the metabolism of other co-administered drugs. This is of particular concern with pharmaceuticals administered for a chronic infection where patients can expect to take a number of pharmaceuticals for years, if not decades.
Suitable prodrugs of the compounds of formula I include those of the formula II:
wherein
R1, R1 and Rx are as defined above,
R3 is H, (CHm)nNR5R6;
R4 is H, C1-C3alkyl, (CHm)nNR5R6, (CHm)nC(xe2x95x90O)R5, (CHm)nOH, OR7, halo, CF3 or CN; or
R3, and R4 together define a 5 or 6 membered fused ring having 0-2 hetero atoms and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R5, is H, C1-C3 alkyl, C(xe2x95x90O)R7 or a peptide of 1 to 4 amino acids;
R6 is H, C1-C3 alkyl; or
R5 and R6 together define a 5 or 6 membered ring having 0 or 1 additional hetero atom and/or 0-2 unsaturated bonds and/or 0-2 substituents;
R7 is H, C1-C12 alkyl, (CHm)nNR5R6;
X and its encompassing circle define a 5 or 6 membered ring having 0 to 3 unsaturated bonds and/or 0 to 3 hetero atoms selected from S, O and N;
m is independently 1 or 2;
n is independently 0, 1 or 2;
and pharmaceutically acceptable salts thereof.
Corresponding prodrugs of compounds wherein Rx is chloro foam a further aspect of the invention.
The ring structure containing X, hereafter referred to the X-ring, may be saturated or have 1-3 unsaturated bonds, including rings with an aromatic character. Preferred X-rings include a cyclohexanyl or cyclohexenyl ring or more preferably a phenyl ring. Other preferred X-rings include morpholino or more preferably a pyridyl ring. Alternatively, X-ring may define a five membered ring such as pentenyl or pyrrolyl.
Suitable fused ring systems for the X-ring in the event that R3 and R4 join to form an optionally hetero-containing ring include napthyl, quinolyl, tetrahydroisoquinolyl, indolyl or benzimidazole ring systems. Suitable substituent rings for the X-ring in the event that R4 and R5 join to form a ring include morpholino and piperidino. These fused or substituent rings may be may be optionally substituted with halo, halomethyl, amino such as (CHm)nNR5R6, C(xe2x95x90O)NR5R6, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C1-3alkyl, C1-3alkoxy and the like.
The X-ring may be spaced from the adjacent carbonyl moiety by a methylene or ethylene group which may be optionally substituted with substituents such as halo, halomethyl, amino, amino methyl, hydroxy, hydroxymethyl, carboxy, carboxymethyl, C1-3alkyl, C1-3alkoxy and the like. It is preferred that the X-ring is adjacent the carbonyl.
Preferably the moiety represented by the X-ring system, R3, R4 and, if present R5-R7 has a somewhat basic character. This can be achieved by selecting a suitably basic heterocycle as the X-ring, such as pyridyl or benzopyridyl. Alternatively or additionally, one or more of R3 to R7 may comprise a basic substituent such as a primary, secondary or tertiary amine, an amino acid etc.
Favoured R3, and/or R1 groups include NH2, N(CH2)2 and NHC1-C3 alkyl, such as NHCH3 or NHCH2CH3. Preferably R3, is in the meta position relative to the carbonyl and its optional spacer, especially where the X-containing ring is phenyl or R3 is in the para position when the X-containing ring is heteroaromatic, such as pyrid-3-yl. The currently preferred value for p and/or n is zero, that is the respective groups are absent.
Preferred compounds of the invention include:
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylpheny)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Other preferred compounds include
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof
Other convenient compounds of the invention include:
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea,
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea,
(1R,2R)-N-[cis-2-(6-fluoro, 2-hydroxy, 3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea,
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(IR,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and their pharmaceutically acceptable salts.
Other convenient compounds include;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-cyanopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Preferred compounds of the invention include
(1S,2S)-N-[cis-2-(2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-fluoro, 2-hydroxy, 3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-aminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-ethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(3-dimethylaminophenylcarbonyloxy)-6-fluoro-3-butyrylphenyl)cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
and their pharmaceutically acceptable salts.
Further preferred compounds include:
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1S,2S)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-methylaminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R
N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-propionylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-butyrylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
(1R,2R)-N-[cis-2-(2-(6-aminopyrid-3-ylcarbonyloxy)-6-fluoro-3-acetylphenyl)-cyclopropyl]-Nxe2x80x2-(5-bromopyrid-2-yl)-urea;
and pharmaceutically acceptable salts thereof.
Appropriate pharmaceutically acceptable salts of the compounds of formula I include salts of organic carboxylic acids such as acetic, lactic, gluconic, citric, tartaric, maleic, malic, pantothenic, isethionic, oxalic, lactobionic, and succinic acids, organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toluenesulfonic acid; and inorganic acids such as hydrochloric, hydroiodic, sulfuric, phosphoric and sulfamic acids.
In keeping with the usual practice with HIV inhibitors it is advantageous to co-administer one to three additional antivirals to provide synergistic responses and to ensure complementary resistance patterns. Such additional antivirals may include AZT, ddI, ddC, D4T, 3TC, abacavir, adefovir, adefovir dipivoxil, bis-POC-PMPA, foscarnet, hydroxyurea, Hoechst-Bayer HBY 097, efavirenz, trovirdine, nevirapine, delaviridine, PFA, H2G, ABT 606, DMP-450, loviride, ritonavir, saquinavir, indinavir, amprenavir (Vertex VX 478), nelfianavir and the like, typically at molar ratios reflecting their respective activities and bioavailabilities. Generally such ratio will be of the order of 25:1 to 1:25, relative to the compound of formula I.
While it is possible for the active agent to be administered alone, it is preferable to present it as part of a pharmaceutical formulation. Such a formulation will comprise the above defined active agent together with one or more acceptable carriers and optionally other therapeutic ingredients. The carriers(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient.
The formulations include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parenteral (including subcutaneous, intramuscular, intravenous and intradermal) administration. The formulations may conveniently be presented in unit dosage form, e.g. tablets and sustained release capsules, and may be prepared by any methods well known in the art of pharmacy.
Such methods include the step of bringing into association the above defined active agent with the carrier. In general, the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
Formulations for oral administration in the present invention may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water in oil liquid emulsion and as a bolus etc.
With regard to compositions for oral administration (e.g. tablets and capsules), the term suitable carrier includes vehicles such as common excipients e.g. binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone (Povidone), methylcellulose, ethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sucrose and starch; fillers and carriers, for example corn starch, gelatin, lactose, sucrose, microcrystalline cellulose, kaolin, mannitol, dicalcium phosphate, sodium chloride and alginic acid; and lubricants such as magnesium stearate and other metallic stearates, stearic acid, silicone fluid, talc waxes, oils and colloidal silica. Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring or the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in the art.
Convenient carriers for oral dosing include liquid formulations in the form of solutions, suspensions or emulsions, optionally encapsulated or otherwise presented in unit dose form in a conventional manner. Favoured formulations include acacia/TWEEN/water, TWEEN/water, propylene glycol, vegetable oil (such as peanut, olive and the like) with 10-20% ethanol, vegetable oil/Capmul MGM, Capmul MCM/propylene glycol, methyl cellulose/water, vegetable oil/stearoyl monoester of glycerol, vegetable oil/monounsaturated fatty acid ester of glycerol and the like.
A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
Formulations suitable for topical administration include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
Formulations suitable for topical administration to the skin may be presented as ointments, creams, gels, and pastes comprising the active agent and a pharmaceutically active carrier. An exemplary topical delivery system is a transdermal patch containing the active agent. Other topical formulations include antiseptic swabs which release the active agent upon the skin prior to invasive procedures such as injection or capillary blood sampling. Such swabs neutralise HIV in the blood or serum emanating from the invasive procedure thus assisting to prevent transfer of HIV to health care workers via needle stick accidents. Such swabs may comprise sterile surgical gauze pad soaked in a solution of the active agent in a volatile solvent such as ethanol and single packed in a sealed sachet.
Formulations for rectal or vaginal administration may be presented as a suppository or pessary with a suitable base comprising, for example, cocoa butter or a salicylate. Other vaginal preparations can be presented as tampons, creams, gets, pastes, foams or spray formulations containing, in addition to the active agent, such carriers as are known in the art to be appropriate.
Formulations suitable for nasal administration wherein the carrier is a solid include a coarse powder having a particle size, for example, in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation from a container of the powder held up close to the nose. Suitable formulations wherein the carrier is a liquid for administration, for example, as a nasal spray or as nasal drops, include aqueous or oily solutions of the active agent.
Formulations suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind previously described.
A further aspect of the invention provides methods for the preparation of the compounds of Formula I, in particular the cis enantiomers, comprising the Curtius rearrangement of a compound of the formula:
followed by coupling of a compound of the formula
and deprotection, wherein R1, R2 and Rx are as defined above and PG is an hydroxy-protecting group.
The methods of the invention can further comprise the step of acylating with an activated compound of the formula III:
where R3, R4, X and n are as defined above but are optionally protected, and R8 is hydrogen or a conventional activating group. Alternatively the method of the invention may further comprise the step of alkylation with a compound of the formula IIIa
where n, R3, R4 and X are as defined above, but where exposed amine, hydroxy etc substituents being protected with conventional protecting groups.
Enantiomeric compounds of formula I may thus be prepared by the reaction scheme below:
The above scheme illustrates the preparation of a (1S,2S) compound of the invention where Rx is cyano, R1 is F and R2 is ethyl, but corresponding methodology is applicable to the other Rx, R1 and R2 variants. The chiral ligand indicated for the fourth step may comprise, for example, a compound of the formula:
To prepare the 1R, 2R enantiomer, the mirror image chiral ligand is employed. Alternatively, the chiral ligand may be omitted in order to form the racemate.
Prodrugs of the formula II wherein p is 0 can be synthesised by acylating a compound of the formula I with an activated compound of the formula III,
where R3, R4, X and n are as defined above but are optionally protected, and R8 is hydrogen or a conventional activating group.
Activated compounds of Formula III include the acid halide, acid anhydride, activated acid ester or the acid in the presence of a coupling reagent such as dicyclohexyl-carbodiimide. Representative activated acid derivatives include the acid chloride, formic and acetic acid derived mixed anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N-hydroxysuccinamide derived esters, N-hydroxyphthalimide derived esters, N-hydroxy-5-norbomene-2,3-dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters and the like. Suitable optional protecting groups for compounds of formula III, especially any constituent amines, include those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d (John Wiley and Sons, New York, 1981), which is hereby incorporated by reference. N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoracetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl, and the like, carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-vitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Favoured N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and benzyloxycarbonyl (Cbz).
The acylation is carried out with conventional esterification conditions such as DMAP and DCC in a solvent such as dimethylformamide or pyridine. Optional protecting getups may be removed with conventional techniques as comprehensively discussed in Greene above, such as TFA, HCl(aq)/dioxane or hydrogenation in the presence of a catalyst to give the compound of Formula II.
Compounds of the Formula II, wherein p is 1 can be prepared by reacting a compound of the formula III with iodochloromethane or mixed dichloro/iodochlor methane under conventional alkylating conditions to form a compound of the Formula IIIa:
where n, R3, R4, and X are as defined above, but where exposed amine, hydroxy etc substituents being protected with conventional protecting getups. The compound of formula IIIa is then preferably converted to the corresponding iodo derivative by reaction with NaI followed by coupling to the compound of formula I, typically under basic conditions, such as an organic solvent containing sodium hydride.


A method is disclosed to reconstruct multiphase MR images that accurately depict the entire cardiac cycle. A segmented, gradient-recalled-echo sequence is modified to acquire data continuously. Images are retrospectively reconstructed by selecting views from each heartbeat based on cardiac phase rather than the time elapsed from the QRS complex. Cardiac phase is calculated using a model that compensates for beat-to-beat heart rate changes.

The field of the invention is nuclear magnetic resonance imaging methods and systems. More particularly, the invention relates to the production of images in a fast cardiac MRI acquisition.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B.sub.0), the individual magnetic moments of the spins in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B.sub.1) which is in the x-y plane and which is near the Larmor frequency, the net aligned moment, M.sub.z, may be rotated, or "tipped", into the x-y plane to produce a net transverse magnetic moment M.sub.t. A signal is emitted by the excited spins after the excitation signal B.sub.1 is terminated and this signal may be received and processed to form an image.
When utilizing these signals to produce images, magnetic field gradients (G.sub.x G.sub.y and G.sub.z) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received NMR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
Most NMR scans currently used to produce medical images require many minutes to acquire the necessary data. The reduction of this scan time is an important consideration, since reduced scan time increases patient throughput, improves patient comfort, and improves image quality by reducing motion artifacts. There is a class of pulse sequences which have a very short repetition time (TR) and result in complete scans which can be conducted in seconds rather than minutes. When applied to cardiac imaging, for example, a complete scan from which a series of images showing the heart at different phases of its cycle or at different slice locations can be acquired in a single breath-hold.
There are two common techniques for acquiring cardiac MR images. The first is a prospectively gated, single-phase, multi-slice conventional spin echo sequence. In each cardiac cycle, data at different spatial locations are acquired with the same k-space phase encoding value. Images at the different spatial locations are then acquired at different temporal phase of the cardiac cycle. Since only one k-space line is acquired per cardiac trigger, a typical scan with a 128 k-space views in the phase encoding direction will take 128 heart beats to complete. The sequence repetition time (TR) is then the cardiac R--R interval time.
In gated spin echo, data for each slice location is acquired at a fixed delay from the cardiac R-wave. With variations in the cardiac rhythm, the heart may be at a different phase of the cardiac cycle when data is acquired even though the cardiac delay time may be the same. Normal variations of the cardiac cycle usually result in disproportionately larger changes in the diastolic portion of the cardiac cycle, and gated spin echo images acquired at the end of the cardiac cycle often exhibit blurring or ghosting artifacts.
Another disadvantage of gated spin echo is that images at different slice locations are acquired at different cardiac phases. Hence, it may be difficult to relate information from one spatial location to the next as the heart is pictured at different phases of the cardiac cycle. Furthermore, small structures may also be missed due to inadequate temporal and spatial coverage. Motion of the heart during the cardiac cycle can also lead to image contrast variations from slice to slice due to differential saturation or inter-slice cross-talk.
A short TR gated gradient echo pulse sequence may be used to acquire (CINE) images at multiple time frames of the cardiac cycle. As described in U.S. Pat. No. 4,710,717, conventional CINE pulse sequences run asynchronously to the cardiac cycle with the phase encoding value stepped to a new value at each R-wave trigger. In CINE, each rf excitation pulse is applied at the same spatial location and repeated at intervals of TR in the cardiac cycle. Since the sequence runs asynchronously, the rf excitation pulses may occur at varying time delays from the R-wave from one cardiac cycle to the next. On detection of the next cardiac R-wave, the acquired data from the previous R--R interval are resorted and interpolated into evenly distributed time frames within the cardiac cycle. This method of gating is also known as retrospective gating as the data for the previous R--R interval is resorted only after the current R-wave trigger is detected.
The cardiac cycle is divided into equal time points or frames at which images of the heart are to be reconstructed. In order to reconstruct images at each of these time points, data acquired asynchronously is linearly interpolated to the pre-determined time points in the cardiac cycle. In order to account for variations in the cardiac R--R interval during the scan (from changing heart rate), the interpolation varies from cardiac cycle to cardiac cycle, depending on the R--R interval time. This method allows reconstruction of images at any phase of the cardiac cycle, independent of variations in heart rate. As in gated spin echo, only one k-space phase encoding view is acquired per heart beat. The total image acquisition time is then on the order of 128 heart beats.
Faster scan times can be achieved by segmenting k-space and acquiring multiple phase encoding k-space views per R--R interval. The scan time is speeded up by a factor equal to that of the number of k-space views acquired per image per R--R interval. In this manner, a typical CINE acquisition with a matrix size of 128 pixels in the phase encoding direction can be completed in as little as 16 heart beats, when 8 k-space views per segment are acquired.
Multiple phases of the cardiac cycle can be visualized by repeated acquisition of the same k-space segment within each R--R interval but assigning the data acquired at different time points in the cardiac cycle to different cardiac phases. Thus, the cardiac cycle is sampled with a temporal resolution equal to the time needed to acquire data for a single segment, such that EQU temporal resolution=vps.times.TR,
where vps is the number of k-space lines per segment, the TR is the pulse sequence repetition time. The total scan time is then ##EQU1## where yres is the number of phase encoding views in the image. Typically, an image utilizes 128 or more phase encoding views, and 8 views per segment is also often used.
In segmented k-space scans, the total scan time can be substantially reduced by increasing the number of views per segment (vps). However, this is at the expense of reducing the image temporal resolution. As described in U.S. Pat. No. 5,377,680 the image temporal resolution can be increased by sharing views between adjacent time segments to generate images averaged over different time points. The true image temporal resolution is unchanged but the effective temporal resolution is now doubled. View sharing can thus increase the number of cardiac phase images reconstructed without affecting the manner in which the k-space data is acquired.
Prospectively gated, segmented k-space sequences have become popular for cardiac imaging mainly because images can be obtained in a breath-hold and therefore do not suffer from respiratory artifact. Images are formed by acquiring data over a series of heartbeats with data acquisition gated to the QRS complex of the ECG. For images to reconstruct properly, using current methods, the duration of image acquisition must be less than or equal to the duration of the shortest expected R--R interval. In practice, this usually means that the last 10-20% of diastole (.about.100-200 msec for a heart rate of 60 bpm) is not acquired.
Another problem with many current cardiac-gated sequences is that they sort data based on the time elapsed since the QRS complex. As described in U.S. Pat. No. 4,710,787, this strategy assumes that cardiac phase is directly proportional to time. However, in practice the relationship between cardiac phase and the time elapsed since the QRS is not strictly linear. For example, consider sinus arrhythmia where there is a normal, physiologic change in heart rate that accompanies respiration. The time between the QRS complex and end-diastole is longer for those heart beats with longer R--R intervals and in this case, end-diastole is better defined relative to the following (rather than the preceding) QRS complex. This can be seen readily in the normal ECG where the P wave (which signifies atrial contraction) is better correlated temporally to the following (rather than the preceding) QRS complex. This variation in the R--R interval and the fact that a specific cardiac phase occurs at a different delay time from the R-wave with this variation, leads to image blurring in fast segmented k-space pulse sequences and also in conventional CINE pulse sequences.

Retrospective ordering of segmented MRI cardiac data using cardiac phase


The present invention provides a TCP/IP header compression format as a label in package transmitting. The header format is used under the acknowledgement mode in wireless network to reduce the header transmission amount between the base station and the mobile station, comprising: a connecting sequence number field for storing a connecting sequence number to indicate the required TCP/IP header information related base stations; a buffer length field for storing a length value of the buffer region to indicate the acceptable package number of the buffer region in receiver; and a plurality of control flag fields for providing certain necessary information for transmission control.

In recent years, with the great progress of mobile telecommunication, digital mobile products of all kinds, such as mobile phone, laptop, PDA and so on have been the important part of human daily life. Therefore, the requirements of the wireless Internet such as receiving/sending e-mail immediately and obtaining real-time information are increasing vastly. And how to connect the wireless telecommunication with the Internet thereof becomes an important research topic in nowadays. Please refer to FIG. 1, which is a schematic diagram showing the wireless Internet scheme. To get resources in the Internet, the user needs a point-to-point link to download and upload information. In fact, from the viewpoint of the wireless Internet, a point-to-point link can be divided into two parts: the wireless telecommunication from the mobile unit to the base station, and the network communication from the base station to the Internet. Wherein, in the part of the wireless telecommunication, the data will be transmitted from the mobile product to the base station and received from the base station via wireless. It's a direct point-to-point connection. However, in the part of the line network connection, the data are transmitted to the Internet via the present framework such as telephone network and optical fiber communication, and then sent to the remote terminals such as server, personal computer, work station and so on. The network connection needs more network control information for each of the connections.
In fact, the most common point-to-point transmission protocol in the Internet is the Transmission Control Protocol/Internet Protocol (TCP/IP), which is built in the traditional point-to-point transmission protocol of network connection. For its excellent reliability as well as robustness and the growth of Word Wide Web (WWW), the TCP/IP has been utilized extensively in the Internet now.
In the traditional network connection, if the transmitted data are larger, they will be divided into several smaller portions to avoid occupying too much frequency bandwidth in each transmitting, and then transmitted successively in the packet format; finally, all the packets will be received and combined by the remote receiver. However, because the networks are extended in all directions and the network statuses are instantaneously varying, the paths of packets may be different, and thus the received sequence may be different from the original transmitting sequence. Therefore, to avoid confusing the packet sequence and to recombine all the packets correctly, we need to define certain labels on such packets, which are so-called "header". Please refer to FIG. 2, which shows the header format in typical TCP/IP packet of the prior art. The TCP/IP header can be divided into two pans: the Transmission Control Protocol (TCP) header and the Internet Protocol (IP) header.
The IP header comprises a Version field, which has 4 bits to label the using version of the TCP/IP; an Internet Header Length (IHL) field with 4 bits for specifying the length of the IP header; a Type of Service field with 8 bits, which relates to the quality service types such as the minimum delay, the maximum throughput, the maximum reliability, and the minimum cost; a Total Length field with 16 bits for indicating the total bits of the package; an Identification field with 16 bits, which gives each package an unique serial number for conveniently recombining the packages from the receiver. Next, the filed provides a 3 bits information flag set, an Indicate flag with 1 bit, a Don't Fragment (DF) flag with 1 bit, and a More Fragment (MF) flag with 1 bit. Wherein the indicate flag, shown as symbol A in FIG. 2, is used to indicate whether the information flag set is triggered; the DF flag, shown as symbol B in FIG. 2, is used to indicate whether the package may be fragmented, and the MF flag, shown as symbol C in FIG. 2, is used to indicate whether the package is the last one. And then, the next field is a Fragment Offset field with 13 bits for indicating the fragment address corresponded to the original location in the data beginning. The IP header also comprises a Time to Live field with 8 bits, which is used to indicate the maximum time the package is allowed to remain in the Internet system; a Protocol field with 8 bits for indicating the Internet protocol type the package is using; a Header Checksum field with 16 bits for detecting whether the package is transmitted correctly; a Source Address field with 32 bits for storing the address of the transmitting terminal; and a Destination Address field with 32 bits for storing the address of the receiver. In summary, the total length of the IP header is 20 bytes.
The TCP header comprises a Source Port field with 16 bits for indicating the working port of the transmitting terminal; a Destination Port field with 16 bits for indicating the working port of the receiver; a Sequence Number field with 32 bits, which corresponds to the sequence number of the package; an Acknowledgment Number field with 32 bits for indicating the sequence number of the package that has been received; a TCP Header Length field with 4 bits for specifying the figure of the TCP header length; a Reserved field with 6 bits, which is not used yet. Next the reserved field are 6 control bits, including an Urgent Flag field (URG), shown as symbol D in FIG. 2, with 1 bit for indicating whether the package carries the urgent data; an Acknowledgment Flag field (ACK), shown as symbol E in FIG. 2, with 1 bit for indicating whether the package asks the response form the receiver; a Push Flag field (PSH), shown as symbol F in FIG. 2, with 1 bit for indicating whether the package pushes the receiver to send the data to the application program; a Reset the Connection Flag field (RST), shown as symbol G in FIG. 2, with 1 bit for indicating whether the data needs to be resent; a Synchronous Flag field (SYN), shown as symbol H in FIG. 2, with 1 bit for indicating whether the synchronization needs to be carried out; a Finish Flag field (FIN), shown as symbol I in FIG. 2, with 1 bit for indicating whether the transmission is over. After these control bits is a Buffer Length field with 16 bits, which is used to indicate how much free space is remained so as to avoid the error of Overflow. The TCP header also has a Checksum field with 16 bits for detecting whether the package is transmitted correctly and an Urgent Pointer field with 16 bits for storing the urgent data when the URG control bit is set. In summary, the total TCP header is of 20 bytes. And basically, the length of TCP header is a multiple of word.
From the foregoing, the total length of general TCP/IP header is 40 bytes. That is, each packet needs to increase the transmission amount of 40 bytes, which is very bulky and wasted, and thereby several new header compression formats are continually brought out to solve such problems. In the traditional network connection, the most common header compression method is Van Jacobson TCP/IP header compression, so-called RFC 1144 compression. RFC 1144 can efficiently compress the header format by eliminating some unvaried fields such as the Version field, the Destination Address field, and the Destination Port field during the lifetime.
In the wireless communication, RFC 1144 is also the most familiar method to compress the headers at the present day. However, it is designed to aim at the traditional network connection structure, not at the wireless telecommunication, so this method does not consider the limitation of the wireless transmission such as the narrower bandwidth. In fact, the major bottleneck of the wireless Internet is the part of the wireless communication, so how to increase the efficiency of the data transmission has become a very important topic now. In the wireless communication, each unnecessary data transmitting will reduce the substantial transmission rate; therefore, if we can utilize some characters of wireless telecommunication to carry out the further data compression, the data transmission rate will be improved largely.

TCP/IP header compression format and method over wireless network


An additive manufacturing machine (900) includes a build unit (904) that is supported by an overhead gantry (918). The build unit (904) includes a powder dispenser (906) including a vibration mechanism (922) and a scan unit (908) including a powder fusing device (910) for fusing or binding portions of a layer of additive powder. A vibration isolation device (932), such as a passive rubber damper (940) or an active vibration canceling mechanism (960), is positioned between the powder dispenser (906) and the scan unit (908) to prevent vibrations in the powder dispenser (906) from causing operational issues with the scan unit (908) and inaccuracies in the additive manufacturing process.

Additive manufacturing (AM) processes generally involve the buildup of one or more materials to make a net or near net shape (NNS) object, in contrast to subtractive manufacturing methods. Though "additive manufacturing" is an industry standard term (ISO/ASTM52900), AM encompasses various manufacturing and prototyping techniques known under a variety of names, including freeform fabrication, 3D printing, rapid prototyping/tooling, etc. AM techniques are capable of fabricating complex components from a wide variety of materials. Generally, a freestanding object can be fabricated from a computer aided design (CAD) model.
A particular type of AM process uses an energy source such as an irradiation emission directing device that directs an energy beam, for example, an electron beam or a laser beam, to sinter or melt a powder material, creating a solid three-dimensional object in which particles of the powder material are bonded together. AM processes may use different material systems or additive powders, such as engineering plastics, thermoplastic elastomers, metals, and ceramics. Laser sintering or melting is a notable AM process for rapid fabrication of functional prototypes and tools. Applications include direct manufacturing of complex workpieces, patterns for investment casting, metal molds for injection molding and die casting, and molds and cores for sand casting. Fabrication of prototype objects to enhance communication and testing of concepts during the design cycle are other common usages of AM processes.
Selective laser sintering, direct laser sintering, selective laser melting, and direct laser melting are common industry terms used to refer to producing three-dimensional (3D) objects by using a laser beam to sinter or melt a fine powder. More accurately, sintering entails fusing (agglomerating) particles of a powder at a temperature below the melting point of the powder material, whereas melting entails fully melting particles of a powder to form a solid homogeneous mass. The physical processes associated with laser sintering or laser melting include heat transfer to a powder material and then either sintering or melting the powder material. Although the laser sintering and melting processes can be applied to a broad range of powder materials, the scientific and technical aspects of the production route, for example, sintering or melting rate and the effects of processing parameters on the microstructural evolution during the layer manufacturing process have not been well understood. This method of fabrication is accompanied by multiple modes of heat, mass and momentum transfer, and chemical reactions that make the process very complex.
During direct metal laser sintering (DMLS) or direct metal laser melting (DMLM), an apparatus builds objects in a layer-by-layer manner by sintering or melting a powder material using an energy beam. The powder to be melted by the energy beam is spread evenly over a powder bed on a build platform, and the energy beam sinters or melts a cross sectional layer of the object being built under control of an irradiation emission directing device. The build platform is lowered and another layer of powder is spread over the powder bed and object being built, followed by successive melting/sintering of the powder. The process is repeated until the part is completely built up from the melted/sintered powder material.
After fabrication of the part is complete, various post-processing procedures may be applied to the part. Post processing procedures include removal of excess powder by, for example, blowing or vacuuming. Other post processing procedures include a stress release process. Additionally, thermal and chemical post processing procedures can be used to finish the part.
Certain conventional AM machines include a build unit that is supported by an overhead gantry. The gantry defines a build area and facilitates movement of the build unit within the build area to repeatedly deposit layers of powder and fuse portions of each layer to build one or more components. The build unit may include powder hopper that deposits a layer of additive powder and an energy source that selectively directs an energy beam to fuse portions of that layer of additive powder. However, such machines typically include a vibration mechanism attached to the powder dispenser to prevent clogging and ensure that the additive powder is dispensed or deposited evenly. Notably, such vibrations may transfer to the scan unit and affect the accuracy of the energy source.
Accordingly, an AM machine including an improved system for precisely focusing an energy beam during an AM process would be desirable. More particularly, an AM machine including a build unit that maintains the accuracy of an energy source regardless of vibrations in the powder dispenser would be particularly beneficial.

Vibration isolation device for an additive manufacturing machine


The radome for vehicles includes a frontal layer (1) and a rear layer (2), both made from thermoplastic material, and it also includes a heating element (3) placed on the frontal layer (1), on its face opposed to the rear layer (2). The method for manufacturing the radome includes forming the frontal layer (1) with the heating element (3) placed on a face of the frontal layer (1); placing the conductive element(s) (5) in the heating element (3) ; forming the rear layer (2); assembling the frontal and rear layers (1, 2), so that the heating element (3) is on the face of the frontal layer (1) opposite to the rear layer (2). Some embodiments provide a radome with a heating function and an outstanding appearance.

Vehicles with sensors able to sense their surroundings are the key enablers to decrease of road fatalities. Through sensors, driver assistance functions are implemented, minimizing risks and increasing the probability of avoiding collisions.
Vehicles are designed to offer an aesthetically pleasant impression. Therefore, sensors must be integrated within the vehicle behind covers enabling their function, concealing them from the public view and harmonized with the aesthetic design of the vehicle.
In case of a radar sensor, such covers are known as radomes. As mentioned above, radomes must minimize the impact its presence offers to radar emitted and received waves. This is especially important in adverse weather conditions, when driving becomes more dangerous due to loss of visibility, road ground conditions and other. Obviously, water, ice and snow represent a clear danger for the functionality of the radar, as they block radar waves and can be deposited over the radome surface.
Hence, radomes must be able to remove such layers, for instance, melting them. Integrating a heating capability in a decorative radome is a difficult task given the complexity of the design, the different materials employed, and the decoration technologies required to faithfully reproduce a brand logo.
There are several inventions where the use of heating has been disclosed for automotive radomes.
DE 19724320 A1 disclose the arrangement of electrical conductor tracks in a curved dielectric body, so that the conductive structure does not lie in one plane. This document does not provide a solution for the manufacturing of the radome, only a concept that would need to be produced.
DE 2017055182 A1 discloses a flexible printed circuit board that is injection molded with a thermoplastic. Circuit tracks are used to transport current instead of conductive wires. Electrical contact elements are present in the board so that a plug-in basket can make contact with them.
Main limitation of this invention comes from the fact of employing circuit tracks, as the performance of a radome using this technology is significantly worse than using conductive wires.
DE 10156699 A1 discloses conductor paths that are applied to the rear surface of a plastic part representing a brand logo, which in turn is attached to a second plastic part so the conductor paths are sandwiched between both plastic materials.
The issue is distance between conductor paths and the front surface, where ice or snow will deposit and will need to be removed.
US 20060086710 A1 discloses a film embedding conductor strips placed in the inner surface of a polymeric part. A control unit regulates the amount of current circulating through the strips, thus controlling the heating output. Here again, the issue is distance between conductive elements and the front surface, where ice or snow will deposit and will need to be removed.
DE102014002438 A1 discloses a process for manufacturing a heatable radome, in which a thin foil with recesses embedding conductive wires is shaped and insert molded. Electric contact between an element and the wires is done at a recess in the film.
Although this solution may allow placing the foil on the outermost radome surface, thus optimizing heating transfer and efficiency, it lacks protection in the contact area. Therefore, metals at that point are subject to corrosion and degradations over time due to their exposure to the environment.
DE102013207482 A1 discloses a similar invention as in DE102014002438 A1, so the same limitations apply.
It has been shown the issues affecting design and manufacturing of heatable radome solutions. The aim of this invention is solving these problems while providing a pleasant aesthetic and functional solution that can be easily manufactured.

Radome for vehicles and method for manufacturing said radome


A composite rotor for caliper disc brakes and the like includes an outer friction portion having two ring sections, with a plurality of supports extending therebetween to fixedly interconnect the ring sections in a mutually parallel, spaced apart relationship defining a cavity therebetween. The ring sections have opposite friction surfaces which interface with associated friction members. The rotor also includes an inner hub portion having a central mounting section which mounts the same on a drive member, and a peripheral section cast into the cavity of the outer friction portion to integrally interconnect the inner hub and outer friction portions of the rotor with primarily mechanical bonds formed at an unfused interface.

The present invention relates to rotors for caliper disc brakes and the like, and in particular to a composite construction therefor.
Rotors are generally well known in the art, and are used extensively in caliper disc brakes, power transmission devices, clutches, and other similar machinery and mechanisms. Brake rotors are typically cast from a ferrous material, such as cast or grey iron, and are then machined in multiple operations to shape the rotor, to form a inner hub portion and friction surfaces. The inner hub portion of the rotor is mounted to a drive member, such as the vehicle axle, and is drivingly connected to the vehicle wheels. The friction surfaces of the rotor typically include oppositely directed friction surfaces which interface with associated brake pads for braking the vehicle. During braking, vibrations are created when the brake pads contact the friction surfaces of the rotor. Some of the vibrations are transmitted to the operator and passengers of the vehicle through the structure of the vehicle. The vibrations at the friction surfaces are transmitted through the rotor to the hub, to the axle and associated vehicle suspension components, and into the interior of the vehicle where they are manifested to the occupants as undesirable noise.
The ability of a brake rotor to quickly transfer and dissipate heat generated during the braking process is a very desirable feature, as excess heat leads to premature brake wear and/or failure. Also, the ability to readily match rotor and brake pad materials for a specific vehicle application is highly beneficial to achieve the desired braking performance at minimum cost. Corrosion is also a problem with cast iron brake rotors, particularly when used with spoked or windowed types of wheels in which rotors are normally visible, such that some rotors are painted or otherwise surface treated, which adds cost to the part. Weight is another drawback associated with most ferrous metal rotors. Cast aluminum rotors are available to reduce the weight and corrosion problems associated with ferrous metal rotors, however, the heat resistance and brake surface toughness of cast aluminum is typically less desirable than that of other types of rotors.
It is known to use composite rotors having combination of separate components including a friction portion and a hub portion, each comprised of different materials to provide a lightweight, corrosion resistant rotor as disclosed in Ihm (U.S. Pat. No. 5,509,510). However, such rotors use a combination of mechanical and metallurgical bonds to secure the rotor components together. The metallurgical bonds formed between the rotor components couples the components for the effective transmission of braking vibrations through the rotor, to the vehicle, creating noise for the people inside. It is desirable to reduce the transmission of vibrations between the composite rotor components to reduce the braking noise.


When in operation, devices for telecommunications installed in rooms generate a considerable amount of heat. This takes place continuously, and a maximum temperature must not be exceeded. In order to obtain reserve time for an air cooling system having a reserve time system with a guaranteed low temperature level of the liquid for the reserve time system, an evaporator (2) for the air cooling system is provided with a liquid circuit (2b) which is connected with a liquid tank (7). Liquid is circulated continuously through the evaporator with the liquid circuit, where it is cooled by the cooling medium for the air cooling system, at the same time as the inside air is cooled by the same evaporator. The continuous cooling and circulation of the liquid in the tank ensures that there is always the coldest possible liquid available when the ordinary cooling system is not working. In case of failure of the air cooling system, liquid is circulated by means of a liquid pump (6) from the tank via the evaporator provided with the liquid circuit, thus cooling the warm inside air. The heated liquid is returned to the tank. When the air cooling system is working again, it will start to fill the tank with cold liquid.

Equipment for telecommunication installed in rooms, during operation generates a considerable amount of heat energy. This occurs continuously and the temperatures around the equipment have to be maintained within certain limits. Particularly important is that a specified maximum temperature must not be exceeded. In order to achieve this temperature regulation, usually mechanical cooling systems e.g. compressor operated evaporation systems are used. In those the warm indoor air passes an evaporator and is cooled. Thereafter the cooled air is recirculated to the room. The continous heat generation requires continuous cooling.
In case of failure of e.g. a compressor cooling system some kind of reserve system has to be activated and provide cooling of the indoor air. One method to obtain reserve cooling is to provide cool liquid in a tank. At failure of the compressor cooling system, cold liquid is pumped from said tank to an air cooler in which the indoor air is cooled and is then pumped back to the tank again. This system however, can operate only a limited time since the liquid in the tank gradually becomes warmer. Therefore a system for obtaining reserve time for cooling indoor air is discussed.

Method and device for obtaining reserve time for a cooling system


A drum for producing a tire casing blank comprises a support and sectors forming a circumferential face of the drum.

1. Field
The disclosure relates to tires and, in particular, the production of tire casing blanks.
2. Description of Related Art
Assembly of the elements forming the tread of a tire casing blank for a wheel takes place on a production drum, which is also called a crown form. These elements principally comprise unprocessed rubber. Once assembled, the tread is removed from the drum and deposited on a separately produced carcass. The association of the two forms a green tire. Forming of the latter results in the green blank that is subsequently cured to vulcanize the rubber.
Application WO 2013/054051 in the name of the applicants discloses a drum that comprises primary and secondary sectors forming its circumferential face. These sectors are movable in a radial direction relative to the axis of rotation of the drum in order to enable removal of the tread once it has been produced and also to adapt the diameter of the drum as a function of that of the tread to be produced. The primary sectors are likewise movable in the axial direction relative to the secondary sectors. Thus, when the diameter of the drum has to be increased, all the sectors are moved away from the axis and then the secondary sectors are brought closer to the primary sectors in the axial direction in order to fill in the spaces that have arisen between the primary sectors and to restore the continuity of the circumferential face in order that it can bear the elements of the tread.
The drum is produced such that the primary sectors carry the secondary sectors in the course of their radial movement. In order, subsequently, to allow movement of the latter relative to the former in the axial direction, the primary sectors have grooves of helicoidal form in which the secondary sectors slide. The lateral faces of the sectors designed to come into mutual contact also have a helicoidal form.
This drum thus offers the advantage of providing, for the production of the tread, a continuous bearing surface that is free from holes and reliefs, which preserves the properties of the rubber. Moreover, it is possible, as desired, to modify the diameter of the drum as a function of the tire model to be produced.
It is possible, however, to improve this drum. Indeed, the presence of helicoidal faces or grooves on each sector very substantially complicates their manufacture. Furthermore, the link between the primary and secondary sectors via these grooves requires the provision of a very substantial amount of energy when it is required to move the sectors relative to one another, particularly in order to modify the diameter of the drum.

Drum for producing a tire, provided with mobile sectors

Abstract: Each sector has a circumferential outer face having a contour of general trapezoidal form and is mounted so as to be movable relative to the support in a non-radial predetermined direction relative to an axis of rotation of the drum and intercepting this axis.

COMPAGNIE GENERALE DES ETABLISSEMENTS MICHELIN