An amide of the formula I

This application is a national phase application of PCT/EP 99/02633 filed Apr. 20, 1999 which claims the priority of German patent application No. 19818615.0 filed Apr. 20, 1998.
The present invention relates to novel amides which are inhibitors of enzymes, especially cysteine proteases such as calpain (=calcium dependant cysteine proteases) and its isoenzymes and cathepsins, for example B and L.
Calpains are intracellular proteolytic enzymes from the group of cysteine proteases and are found in many cells. Calpains are activated by an increase in the calcium concentration, a distinction being made between calpain I or xcexc-calpain, which is activated by xcexc-molar concentrations of calcium ions, and calpain II or m-calpain, which is activated by m-molar concentrations of calcium ions (P. Johnson, Int. J. Biochem. 1990, 22(8), 811-22). Further calpain isoenzymes have now been postulated too (K. Suzuki et al., Biol. Chem. Hoppe-Seyler, 1995, 376(9), 523-9).
It is suspected that calpains play an important part in various physiological processes. These include cleavages of regulatory proteins such as protein kinase C, cytoskeletal proteins such as MAP 2 and spectrin, muscle proteins, protein degradation in rheumatoid arthritis, proteins in the activation of platelets, neuropeptide metabolism, proteins in mitosis and others which are listed in M. J. Barrett et al., Life Sci. 1991, 48, 1659-69 and K. K. Wang et al., Trends in Pharmacol. Sci., 1994, 15, 412-9.
Elevated calpain levels have been measured in various pathophysiological processes, for example: ischemias of the heart (e.g. myocardial infarct), of the kidney or of the central nervous system (e.g. stroke), inflammations, muscular dystrophies, cataracts of the eyes, injuries to the central nervous system (e.g. trauma), Alzheimer""s disease etc. (see K. K. Wang, above). It is suspected that there is a connection between these disorders and elevated and persistent intracellular calcium levels. This results in overactivation of calcium-dependent processes, which are then no longer subject to physiological control. Accordingly, overactivation of calpains may also induce pathophysiological processes.
It has therefore been postulated that inhibitors of calpain enzymes may be useful for treating these disorders. Various investigations have confirmed this. Thus, Seung-Chyul Hong et al., Stroke 1994, 25(3), 663-9 and R. T. Bartus et al., Neurological Res. 1995, 17, 249-58 have shown a neuroprotective effect of calpain inhibitors in acute neurodegenerative disorders or ischemias like those occurring after stroke. Likewise, calpain inhibitors improved the recovery of the memory deficits and neuromotor disturbances occurring after experimental brain trauma (K. E. Saatman et al. Proc. Natl. Acad. Sci. USA, 1996, 93, 3428-3433). C. L. Edelstein et al., Proc. Natl. Acad. Sci. USA, 1995, 92, 7662-6, found a protective effect of calpain inhibitors on kidneys damaged by hypoxia. Yoshida, Ken Ischi et al., Jap. Circ. J. 1995, 59(1), 40-8, were able to show beneficial effects of calpain inhibitors after cardiac damage produced by ischemia or reperfusion. Since the release of the xcex2-AP4 protein is inhibited by calpain inhibitors, a potential therapeutic use for Alzheimer""s disease has been proposed (J. Higaki et al., Neuron, 1995, 14, 651-59). The release of interleukin-1xcex1 is likewise inhibited by calpain inhibitors (N. Watanabe et al., Cytokine 1994, 6(6), 597-601). It has further been found that calpain inhibitors have cytotoxic effects on tumor cells (E. Shiba et al. 20th Meeting Int. Ass. Breast Cancer Res., Sendai Jp, Sep. 25-28, 1994, Int. J. Oncol. 5 (Suppl.), 1994, 381). Further possible uses of calpain inhibitors are detailed in K. K. Wang, Trends in Pharmacol. Sci., 1994, 15, 412-8.
Calpain inhibitors have already been described in the literature. However, these are predominantly either irreversible or peptide inhibitors. Irreversible inhibitors are usually alkylating substances and have the disadvantage that they react nonselectively or are unstable in the body. Thus, these inhibitors often show unwanted side effects such as toxicity, and are accordingly of limited use or unusable. The irreversible inhibitors can be said to include, for example, the epoxides E 64 (E. B. McGowan et al., Biochem. Biophys. Res. Commun. 1989, 158, 432-5), xcex1-halo ketones (H. Angliker et al., J. Med. Chem. 1992, 35, 216-20) or disulfides (R. Matsueda et al., Chem. Lett. 1990, 191-194).
Many known reversible inhibitors of cysteine proteases such as calpain are peptide aldehydes, in particular dipeptide and tripeptide aldehydes such as, for example, Z-Val-Phe-H (MDL 28170) (S. Mehdi, Trends in Biol. Sci. 1991, 16, 150-3). Under physiological conditions, peptide aldehydes have the disadvantage that, owing to the high reactivity, they are often unstable, may be rapidly metabolized and are prone to nonspecific reactions which may cause toxic effects (J. A. Fehrentz and B. Castro, Synthesis 1983, 676-78).
JP 08183771 (CA 1996, 605307) and EP 520336 have described aldehydes derived from 4-piperidinoylamides [sic] and 1-carbonyl-4-piperidinoylamides [sic] as calpain inhibitors. However, the aldehydes which are claimed herein and are derived from amides of the general structure I with heteroaromatic substituents have previously been described [sic]
Peptide ketone derivatives are likewise inhibitors of cysteine proteases, in particular calpains. Thus, for example, ketone derivatives where the keto group is activated by an electron-attracting group such as CF3 are known to be inhibitors of serine proteases. In the case of cysteine proteases, derivatives with ketones activated by CF3 or similar groups have little or no activity (M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13). Surprisingly, to date only ketone derivatives in which, on the one hand, leaving groups in the a position cause irreversible inhibition and, on the other hand, the keto group is activated by a carboxylic acid derivative have been found to be effective inhibitors of calpain (see M. R. Angelastro et al., see above; WO 92/11850; WO 92,12140; WO 94/00095 and WO 95/00535). However, only peptide derivatives of these keto amides and keto esters have to date been described as effective (Zhaozhao Li et al., J. Med. Chem. 1993, 36, 3472-80; S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 and see above M. R. Angelastro et al.).
Ketobenzamides have already been described in the literature. Thus, the keto ester PhCOxe2x80x94Abuxe2x80x94COOCH2CH3 has been described in WO 91/09801, WO 94/00095 and 92/11850. The analogous phenyl derivative Phxe2x80x94CONHxe2x80x94CH(CH2Ph)xe2x80x94COxe2x80x94COCOOCH3 was, however, found to be only a weak calpain inhibitor in M. R. Angelastro et al., J. Med. Chem. 1990, 33, 11-13. This derivative is also described in J. P. Burkhardt, Tetrahedron Lett., 1988, 3433-36. The significance of the substituted benzamides has, however, never been investigated to date.
In a number of therapies, such as for stroke, the active ingredients are administered intravenously, for example as infusion solution. To do this it is necessary to have available substances, in this case calpain inhibitors, which have adequate solubility in water so that an infusion solution can be prepared. Many of the described calpain inhibitors have, however, the disadvantage that they have only low or no solubility in water and thus are unsuitable for intravenous administration. Active ingredients of this type can be administered only with ancillary substances intended to confer solubility in water (cf. R. T. Bartus et al. J. Cereb. Blood Flow Metab. 1994, 14, 537-544). These ancillary substances, for example polyethylene glycol, often have side effects, however, or are even incompatible. A non-peptide calpain inhibitor which is soluble in water without ancillary substances would thus be a great advantage. No such inhibitor has been described to date, and it would thus be novel.
Non-peptide aldehydes, keto carboxylic esters and keto amide derivatives were described in the present invention. These compounds are novel and surprisingly show the possibility of obtaining potent non-peptide inhibitors of cysteine proteases, such as, for example, calpain, by incorporating rigid structural fragments. In addition, all the present compounds of the general formula I have at least one aliphatic amine radical and are thus able to bind [sic] salts with acids. This results in improved solubility in water and thus the compounds show the required profile for intravenous administration as is necessary, for example, for stroke therapy.
The present invention relates to amides which have heterocyclic substituents and the general formula I
and their tautomeric and isomeric forms, possible enantiomeric and diastereomeric forms, and possible physiologically tolerated salts, in which the variables have the following meanings:
A xe2x80x94(CH2)pxe2x80x94R1, where R1 can be pyrrolidine [sic], morpholine [sic], hexahydroazepine [sic], piperidine [sic], xe2x80x94NR5R6 and
xe2x80x83it also being possible for the cyclic amines to be substituted by one or two R15 radicals, and R15 are [sic] hydrogen, C1-C6-alkyl, Oxe2x80x94C1-C6-alkyl and phenyl, and R5, R6 and R7 can be, independently of one another, hydrogen, C1-C4-alkyl, cyclohexyl, cyclopentyl, CH2Ph, Ph, CH2CH2Ph, it also being possible for the phenyl rings to be substituted by R6, and p can be 1 and 2, and
can be phenyl [sic], pyridyl [sic], pyrazyl [sic], pyrimidyl [sic] and pyridazyl [sic], it also being possible for the rings to be substituted by up to 2 R8 radicals, and
A and B together can also be
xe2x80x83and R16 is hydrogen, C1-C6-alkyl and (CH2)1-4-phenyl, it also being possible for the phenyl ring to be substituted by a maximum of 2 R6 radicals, and
D can be a bond, xe2x80x94(CH2)0-2xe2x80x94Oxe2x80x94(CH2)0-2, xe2x80x94(CH2)mxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, and
R2 is chlorine, bromine, fluorine, C1-C6-alkyl, NHCOxe2x80x94C1-C4-alkyl, NHSO2xe2x80x94C1-C4-alkyl, NO2, xe2x80x94Oxe2x80x94C1-C4-alkyl and NH2, and
R3 is xe2x80x94C1-C6-alkyl, branched or unbranched, and which may also carry a SCH3 radical, a phenyl ring, imidazolyl ring, indolyl ring and cyclopentyl, cycloheptyl or cyclohexyl ring which is in turn substituted by by [sic] a maximum of two R8 radicals, where R8 is hydrogen, C1-C4-alkyl, branched or unbranched, xe2x80x94Oxe2x80x94C1-C4-alkyl, OH, Cl, F, Br, I, CF3, NO2, NH2, CN, COOH, COOxe2x80x94C1-C4-alkyl, NHCOxe2x80x94C1-C4-alkyl, xe2x80x94NHSO2xe2x80x94C1-C4-alkyl and xe2x80x94SO2xe2x80x94C1-C4-alkyl; and
Y is phenyl [sic], pyridine, pyridazine, pyrimidine and pyrazine and
R4 is hydrogen, COOR9 and COxe2x80x94Z in which Z is NR10R11 and
R9 is hydrogen, C1-C6-alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R12 radicals, and
R10 is hydrogen, C1-C6-alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which itself may also be substituted by one or two R12 radicals, and
R1 is hydrogen, C1-C6-alkyl, branched or unbranched, which may also be and [sic] substituted by a phenyl ring which may also carry an R9 radical, and
R12 can be hydrogen, C1-C4-alkyl, branched or unbranched, xe2x80x94Oxe2x80x94C1-C4-alkyl, OH, Cl, F, Br, I, CF3, NO2, NH2, CN, COOH, COOxe2x80x94C1-C4-alkyl, xe2x80x94NHCOxe2x80x94C1-C4-alkyl, xe2x80x94NHCO-phenyl, xe2x80x94NHSO2xe2x80x94C1-C4-alkyl, xe2x80x94NHSO2-phenyl, xe2x80x94SO2xe2x80x94C1-C4-alkyl and xe2x80x94SO2-phenyl,
R13 is hydrogen, C1-C6-alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R12 radicals, and
R14 is hydrogen, C1-C6-alkyl, linear or branched, and which may [lacuna] substituted by a phenyl ring which may itself also be substituted by one or two R12 radicals, and
n is a number 0, 1 or 2, and
m, q is, independently of one another, a number 0, 1, 2, 3 or 4.
Preferred compounds of the general formula I are those in which
A xe2x80x94CH2xe2x80x94R1, where R1 can be pyrrolidino, piperidino, xe2x80x94NR5R6 and
xe2x80x83and R5, R6 and R7 can be, independently of one another, hydrogen and C1-C4-alkyl, and
B phenyl [sic]
xe2x80x94CHxe2x95x90CHxe2x80x94
R2 hydrogen
R3 benzyl, CH2CH2CH2CH3, CH2CH2CH2CH2CH3 and
Y phenyl [sic] and pyridine and
R4 hydrogen and COxe2x80x94NH2 and
all the remaining variables have the same meaning as in claim 1.
The compounds of the formula I can be employed as racemates, as enantiomerically pure compounds or as diastereomers. If enantiomerically pure compounds are required, these can be obtained, for example, by carrying out a classical racemate resolution with the compounds of the formula I or their intermediates using a suitable optically active base or acid. On the other hand, the enantiomeric compounds can likewise be prepared by using commercially purchasable compounds, for example optically active amino acids such as phenylalanine, tryptophan and tyrosine.
The invention also relates to compounds which are mesomers or tautomers of compounds of the formula I, for example those in which the aldehyde or keto group in formula I is in the form of an enol tautomer.
The invention further relates to the physiologically tolerated salts of the compounds I which can be obtained by reacting compounds I with a suitable acid or base. Suitable acids and bases are listed, for example, in Fortschritte der Arzneimittelforschung, 1966, Birkhxc3xa4user Verlag, Vol. 10, pp. 224-285. These include, for example, hydrochloric acid, citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid etc., and sodium hydroxide, lithium hydroxide, potassium hydroxide and tris.
Amides I according to the invention with an aldehyde group can be prepared in various ways, as outlined in synthesis scheme 1.
Heterocyclic carboxylic acids II are linked to suitable amino alcohols III to give the corresponding amides IV. Conventional peptide coupling methods are used for this, as detailed either in C. R. Larock, Comprenhensive [sic] Organic Transformations, VCH Publisher, 1989, page 972 et seq., or in Houben-Weyl, Methoden der organischen Chemie, 4th edition, E5, Chapter V. It is preferred to use xe2x80x9cactivatedxe2x80x9d acid derivatives of II, with the acid group COOH being converted into a group COL. L is a leaving group such as, for example, Cl, imidazole and N-hydroxybenzotriazole. This activated acid is then reacted with amines to give the amides IV. The reaction takes place in anhydrous inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from xe2x88x9220 to +25xc2x0 C. These alcohol derivatives IV can be oxidized to the aldehyde derivatives I according to the invention. Various conventional oxidation reactions can be used for this (see C. R. Larock, Comprenhensive [sic] Organic Transformations, VCH Publisher, 1989, page 604 et seq.) such as, for example, Swern and Swern-analogous oxidations (T. T. Tidwell, Synthesis, 1990, 857-70), sodium hypochloride [sic]/TEMPO (S. L. Harbenson et al., see above) or Dess-Martin (J. Org. Chem. 1983, 48, 4155). Preferably used for this are inert aprotic solvents such as dimethylformamide, tetrahydrofuran or methylene chloride with oxidizing agents such as DMSO/pyxc3x97SO3 or DMSO/oxalyl chloride at temperatures from xe2x88x9250 to +25xc2x0 C., depending on the method (see above literature).
Alternatively, the carboxylic acid II can be reacted with amino hydroxamic acid derivatives VI to give benzamides VII. The reaction in this case is carried out in the same way as for preparing IV. The hydroxamic derivatives VI can be obtained from the protected amino acids V by reaction with a hydroxylamine. An amide preparation process already described is also used in this case. Elimination of the protective group X, for example Boc, takes place in a normal way, for example with trifluoroacetic acid. The amide hydroxamic acids VII obtained in this way can be converted by reduction into the aldehydes I according to the invention. The reducing agent used for this is, for example, lithium aluminum hydride at temperatures from xe2x88x9260 to 0xc2x0 C. in inert solvents such as tetrahydrofuran or ether. Carboxylic acids or acid derivatives such as esters IX (P=COORxe2x80x2, COSRxe2x80x2) can also be prepared in analogy to the last process and can likewise be converted by reduction into the aldehydes I according to the invention. These processes are listed in R. C. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, pages 619-26.
The amides I according to the invention, which have heterocyclic substituents and have a keto amide or keto ester group, can be prepared in various ways which have been outlined in synthesis schemes 2 and 3.
The carboxylic esters IIa are converted where appropriate with acids or bases such as lithium hydroxide, sodium hydroxide or potassium hydroxide in aqueous medium or in mixtures of water and organic solvents such as alcohols or tetrahydrofuran at room temperature or elevated temperatures, such as 25-100xc2x0 C., into the acids II.
These acids II are linked to an xcex1-amino acid derivative using customary conditions which are listed, for example, in Houben-Weyl, Methoden der organischen Chemie, 4th edition, E5, Chapter V, and C. R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, Ch. 9.
For example, the carboxylic acids II are converted into the xe2x80x9cactivatedxe2x80x9d acid derivatives IIb (COOHxe2x86x92COL), where L is a leaving group such as Cl, imidazole and N-hydroxybenzotriazole, and then converted into the derivative XI by adding an amino acid derivative H2Nxe2x80x94CH(R3)xe2x80x94COOR. This reaction takes place in anhydrous inert solvents such as methylene chloride, tetrahydrofuran and dimethylformamide at temperatures from xe2x88x9220 to +25xc2x0 C.
The derivatives XI, which are usually esters, are converted into the keto carboxylic acids XII by hydrolysis analogous to that described above. The keto esters Ixe2x80x2 are prepared in a Dakin-West-analogous reaction using a method of Zhaozhao Li et al., J. Med. Chem., 1993, 36, 3472-80. This entails a [sic] carboxylic acids such as XII being reacted with oxalic monoester chloride at elevated temperature (50-100xc2x0 C.) in solvents such as, for example, tetrahydrofuran, and the product obtained in this way then being reacted with bases such as sodium ethanolate in ethanol at temperatures of 25-80xc2x0 C. to give the keto ester Ixe2x80x2 according to the invention. The keto esters Ixe2x80x2 can be hydrolyzed as described above for example to keto carboxylic acids according to the invention.
The reaction to give keto benzamides Ixe2x80x2 likewise takes place in analogy to the method of ZhaoZhao Li et al. (see above). The keto group in Ixe2x80x2 is protected by adding 1,2-ethanedithiol with Lewis acid catalysis, such as, for example, boron trifluoride etherate, in inert solvents such as methylene chloride at room temperature, resulting in a dithiane. These derivatives are reacted with amines R3xe2x80x94H in polar solvents such as alcohols at temperatures of 0-80xc2x0 C., resulting in the keto amides I (R4=Z or NR10R11).
An alternative method is depicted in scheme 3. The keto carboxylic acids II are reacted with amino hydroxy carboxylic acid derivatives XIII (for preparation of XIII, see S. L. Harbenson et al., J. Med. Chem. 1994, 37, 2918-29 or J. P. Burkhardt et al. Tetrahedron Lett. 1988, 29, 3433-3436) using customary peptide coupling methods (see above, Houben-Weyl), resulting in amides XIV. These alcohol derivatives XIV can be oxidized to the keto carboxylic acid derivatives I according to the invention. It is possible to use for this various customary oxidation reactions (see C. R. Larock, Comprehensive Organic Transformations, VCH Publisher, 1989, page 604 et seq.) such as, for example, Swern and Swern-analogous oxidations, preferably dimethyl sulfoxide/pyridine-sulfur trioxide complex in solvents such as methylene chloride or tetrahydrofuran, where appropriate with the addition of dimethyl sulfoxide, at room temperature or temperatures from xe2x88x9250 to 25xc2x0 C. (T. T. Tidwell, Synthesis 1990, 857-70) or sodium hypochloride [sic]/TEMPO (S. L. Harbenson et al., see above).
In the case of xcex1-hydroxy esters XIV (X=O-alkyl), these can be hydrolyzed to carboxylic acids XV using methods analogous to those above, but preferably using lithium hydroxide in water/tetrahydrofuran mixtures at room temperature. Other esters or amides XVI are prepared by reaction with alcohols or amines under coupling conditions described above. The alcohol derivative XVI can be oxidized to give keto carboxylic acid derivatives I according to the invention.
The preparation of the carboxylic esters II have [sic] already been described for some instances, or it takes place by usual chemical methods.
Compounds in which C is a bond are prepared by conventional aromatic coupling, for example Suzuki coupling with boric acid derivatives and halides with palladium catalysis or copper-catalyzed coupling of aromatic halides. The alkyl-bridged radicals (Cxe2x95x90xe2x80x94(CH2)mxe2x80x94) can be prepared by reducing the analogous ketones or by alkylating the organolithium, e.g. ortho-phenyloxazolidines, or other organometallic compounds (cf. I. M. Dordor et al., J. Chem. Soc. Perkins Trans. I, 1984, 1247-52).
Ether-bridged derivatives are prepared by alkylating the corresponding alcohols or phenols with halides. Alkene- and alkyne-bridged compounds are prepared, for example, by the Heck reaction from aromatic halides and corresponding alkenes and alkynes (cf. I. Sakamoto et al., Chem. Pharm. Bull., 1986, 34, 2754-59).
The amides I with heterocyclic substituents of the present invention are inhibitors of cysteine proteases, especially cysteine proteases such as calpains I and II and cathepsins B and L.
The inhibitory effect of the amides I with heterocyclic substituents has been determined using enzyme assays known from the literature, determining as criterion of effect a concentration of the inhibitor at which 50% of the enzyme activity is inhibited (=IC50). The amides I were measured in this way for their inhibitory effect on calpain I, calpain II and cathepsin B.
The inhibition of cathepsin B was determined by a method analogous to that of S. Hasnain et al., J. Biol. Chem., 1993, 268, 235-40.
2 xcexcl of an inhibitor solution prepared from inhibitor and DMSO (final concentrations: 100 xcexcM to 0.01 xcexcM) are [lacuna] to 88 xcexcl of cathepsin B (cathepsin B from human liver (Calbiochem), diluted to 5 units in 500 xcexcM buffer). This mixture is preincubated at room temperature (25xc2x0 C.) for 60 minutes and then the reaction is started by adding 10 xcexcl of 10 mM Z-Arg-Arg-pNA (in buffer with 10% DMSO). The reaction is followed in a microtiter plate reader at 405 nM [sic] for 30 minutes. The IC50s are then determined from the maximum gradients.
The testing of the inhibitory properties of calpain inhibitors takes place in buffer with 50 mM tris-HCl, pH 7.5; 0.1 M NaCl; 1 mM dithiotreithol [sic]; 0.11 mM CaCl2, using the fluorogenic calpain substrate Suc-Leu-Tyr-AMC (25 mM dissolved in DMSO, Bachem/Switzerland). Human xcexc-calpain is isolated from erythrocytes, and enzyme with a purity greater than 95%, assessed by SDS-PAGE, Western blot analysis and N-terminal sequencing, is obtained after more [sic] chromatographic steps (DEAE-Sepharose, phenyl-Sepharose, Superdex 200 and blue Sepharose). The fluorescence of the cleavage product 7-amino-4-methylcoumarin (AMC) is followed in a Spex Fluorolog fluorimeter at xcexex=380 nm and xcexem=460 nm. The cleavage of the substrate is linear in a measurement range of 60 min., and the autocatalytic activity of calpain is low, if the tests are carried out at temperatures of 12xc2x0 C. The inhibitors and the calpain substrate are added to the test mixture as DMSO solutions, and the final concentration of DMSO ought not to exceed 2%.
In a test mixture, 10 xcexcl of substrate (250 xcexcM final) and then 10 xcexcl of xcexc-calpain (2 xcexcg/ml final, i.e. 18 nM) are added to a 1 ml cuvette containing buffer. The calpain-mediated cleavage of the substrate is measured for 15 to 20 min. Then 10 xcexcl of inhibitor (50 to 100 xcexcM solution in DMSO) are added and the inhibition of cleavage is measured for a further 40 min.
Ki values are determined using the classical equation for reversible inhibition:
Ki=I (v0/vi)xe2x88x921; where I=inhibitor concentration, v0=initial rate before addition of the inhibitor; vi=reaction rate at equilibrium.
The rate is calculated from v=AMC liberation/time, i.e. height/time.
Calpain is an intracellular cysteine protease. Calpain inhibitors must pass through the cell membrane in order to prevent intracellular proteins being broken down by calpain. Some known calpain inhibitors, such as, for example, E 64 and leupeptin, cross cell membranes only poorly and accordingly show only a poor effect on cells, although they are good calpain inhibitors. The aim is to find compounds better able to cross membranes. Human platelets are used to demonstrate the ability of calpain inhibitors to cross membranes.
Calpain-mediated Breakdown of Tyrosine Kinase pp60src in Platelets
Tyrosine kinase pp60src is cleaved by calpain after activation of platelets. This has been investigated in detail by Oda et al. in J. Biol. Chem., 1993, 268, 12603-12608. This revealed that the cleavage of pp60src can be prevented by calpeptin, a calpain inhibitor. The cellular efficacy of our substances was tested based on this publication. Fresh, citrated, human blood was centrifuged at 200 g for 15 min. The platelet-rich plasma was pooled and diluted 1:1 with platelet buffer (platelet buffer: 68 mM NaCl, 2.7 mM KCl, 0.5 mM MgCl2xc3x976 H2O, 0.24 mM NaH2PO4xc3x97H2O, 12 mM NaHCO3, 5.6 mM glucose, 1 mM EDTA, pH 7.4). After a centrifugation step and washing step with platelet buffer, the platelets were adjusted to 107 cells/ml. The human platelets were isolated at RT.
In the assay mixture, isolated platelets (2xc3x97106) were preincubated with various concentrations of inhibitors (dissolved in DMSO) at 37xc2x0 C. for 5 min. The platelets were then activated with 1 xcexcM ionophore A23187 and 5 mM CaCl2. After incubation for 5 min., the platelets were briefly centrifuged at 13000 rpm, and the pellet was taken up in SDS sample buffer (SDS sample buffer: 20 mM tris-HCl, 5 mM EDTA, 5 mM EGTA, 1 mM DTT, 0.5 mM PMSF, 5 xcexcg/ml leupeptin, 10 xcexcg/ml pepstatin, 10% glycerol and 1% SDS). The proteins were fractionated in a 12% gel, and pp60src and its 52 kDa and 47 kDa cleavage products were identified by Western blotting. The polyclonal rabbit antibody used, anti-Cys-src (pp60c-rc) was purchased from Biomol Feinchemikalien (Hamburg). This primary antibody was detected using a second, HRP-coupled goat antibody (Boehringer Mannheim, FRG). The Western blotting was carried out by known methods. The cleavage of pp60src was quantified by densitometry, using as controls unactivated (control 1: no cleavage) and ionophore- and calcium-treated platelets (control 2: corresponds to 100% cleavage). The ED50 corresponds to the concentration of inhibitor at which the intensity of the color reaction is reduced by 50%.
Glutamate-induced Cell Death in Cortical Neurones
The test was carried out as in Choi D. W., Maulucci-Gedde M. A. and Kriegstein A. R., xe2x80x9cGlutamate neurotoxicity in cortical cell culturexe2x80x9d. J. Neurosci. 1989 [sic], 7, 357-368. The cortex halves were dissected out of 15-day old mouse embryos and the single cells were obtained enzymatically (trypsin). These cells (glia and cortical neurones) are seeded out in 24-well plates. After three days (laminin-coated plates) or seven days (ornithine-coated plates), the mitosis treatment is carried out with FDU (5-fluoro-2-deoxyuridines). 15 days after preparation of the cells, cell death is induced by adding glutamate (15 minutes). After removal of glutamate, the calpain inhibitors are added. 24 hours later, the cell damage is estimated by determining lactate dehydrogenase (LDH) in the cell culture supernatant.
It is postulated that calpain is also involved in apoptotic cell death (M. K. T. Squier et al., J. Cell. Physiol. 1994, 159, 229-237; T. Patel et al. Faseb Journal 1996, 590, 587-597).
For this reason, in another model, cell death was induced in a human cell line with calcium in the presence of a calcium ionophore. Calpain inhibitors must get inside the cell and inhibit calpain there in order to prevent the induced cell death.
Calcium-mediated Cell Death in NT2 Cells
Cell death can be induced in the human cell line NT2 by calcium in the presence of the ionophore A 23187. 105 cells/well were plated out in microtiter plates 20 hours before the test. After this period, the cells were incubated with various concentrations of inhibitors in the presence of 2.5 xcexcM ionophore and 5 mM calcium. 0.05 ml of XTT (Cell Proliferation Kit II, Boehringer Mannheim) was added to the reaction mixture after 5 hours. The optical density is determined approximately 17 hours later, in accordance with the manufacturer""s information, in an SLT Easy Reader EAR 400. The optical density at which half the cells have died is calculated from the two controls with cells without inhibitors incubated in the absence and presence of ionophore.
Elevated glutamate activities occur in a number of neurological disorders or psychological disturbances and lead to states of overexcitation or toxic effects in the central nervous system (CNS). The effects of glutamate are mediated by various receptors. Two of these receptors are classified, in accordance with the specific agonists, as NMDA receptor and AMPA receptor. Antagonists to these glutamate-mediated effects can thus be employed for treating these disorders, in particular for therapeutic use for neurodegenerative disorders such as Huntington""s chorea and Parkinson""s disease, neurotoxic impairments after hypoxia, anoxia, ischemia and after lesions like those occurring after stroke and trauma, or else as antiepileptics (cf. Arzneim. Forschung 1990, 40, 511-514; TIPS, 1990, 11, 334-338; Drugs of the Future 1989, 14, 1059-1071).
Protection From Cerebral Overexcitation by Excitatory Amino Acids (NMDA and AMPA Antagonism in Mice)
Intracerebral administration of excitatory amino acids (EAA) induces such drastic overexcitation that it leads to convulsions and death of the animals (mice) within a short time. These signs can be inhibited by systemic, e.g. intraperitoneal, administration of centrally acting substances (EAA antagonists). Since excessive activation of EAA receptors in the central nervous system plays a significant part in the pathogenesis of various neurological disorders, it is possible to infer from the detected EAA antagonism in vivo that the substances may have therapeutic uses for such CNS disorders. As a measure of the efficacy of the substances, an ED50 was determined, at which 50% of the animals are free of signs, owing to the previous i.p. administration of the measured substance, by a fixed dose of either NMDA or AMPA.
The amides I with heterocyclic substituents are inhibitors of cysteine derivatives [sic] like calpain I and II and cathepsin B and L, and can thus be used to control diseases associated with an elevated activity of calpain enzymes or cathepsin enzymes. The present amides I can accordingly be used to treat neurodegenerative disorders occurring after ischemia, damage due to reperfusion after vascular occlusions, trauma, subarachnoid hemorrhages and stroke, and neurodegenerative disorders such as multi-infarct dementia, Alzheimer""s disease, Huntington""s disease and epilepsies and, in addition, to treat damage to the heart after cardiac ischemias, damage to the kidneys after renal ischemia, skeletal muscle damage, muscular dystrophies, damage caused by proliferation of smooth muscle cells, coronary vasospasms, cerebral vasospasms, cataracts of the eyes, restenosis of the blood vessels after angioplasty. In addition, the amides I may be useful in the chemotherapy of tumors and metastasis thereof and for treating disorders in which an elevated interleukin-1 level occurs, such as inflammation and rheumatic disorders.
The pharmaceutical preparations according to the invention comprise a therapeutically effective amount of the compounds I in addition to conventional pharmaceutical ancillary substances.
The active ingredients can be present in the usual concentrations for local external use, for example in dusting powders, ointments or sprays. As a rule, the active ingredients are present in an amount of from 0.001 to 1% by weight, preferably 0.001 to 0.1% by weight.
For internal use, the preparations are administered in single doses. From 0.1 to 100 mg are given per kg of body weight in a single dose. The preparation may be administered in one or more doses each day, depending on the nature and severity of the disorders.
The pharmaceutical preparations according to the invention comprise, apart from the active ingredient, the customary excipients and diluents appropriate for the required mode of administration. For local external use it is possible to use pharmaceutical ancillary substances such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycol stearate, ethoxylated fatty alcohols, liquid paraffin, petrolatum and wool fat. Suitable examples for internal use are lactose, propylene glycol, ethanol, starch, talc and polyvinylpyrrolidone.
It is also possible for antioxidants such as tocopherol and butylated hydroxyanisole, and butylated hydroxytoluene, flavor-improving additives, stabilizers, emulsifiers and lubricants to be present.
The substances which are present in the preparation in addition to the active ingredient, and the substances used in producing the pharmaceutical preparations, are toxicologically acceptable and compatible with the active ingredient in each case. The pharmaceutical preparations are produced in a conventional way, for example by mixing the active ingredient with other customary excipients and diluents.
The pharmaceutical preparations can be administered in various ways, for example orally, parenterally, such as intravenously by infusion, subcutaneously, intraperitoneally and topically. Thus, possible presentations are tablets, emulsions, solutions for infusion and injection, pastes, ointments, gels, creams, lotions, dusting powders and sprays.

Substituted amides, their preparation and use

Abstract: An amide of the formula I

Abstract: and its tautomeric forms, possible enantiomeric and diastereomeric forms, E and Z forms, and possible physiologically tolerated salts, in which the variables have the following meanings:

Abstract: A xe2x80x94(CH2)pxe2x80x94R1, where R1 can be pyrrolidine, morpholine, piperidine, xe2x80x94NR5R6 and

Abstract: xe2x80x83and R5, R6 and R7 can, independently of one another, be hydrogen, C1-C4-alkyl, CH2Ph, Ph, CH2CH2Ph, it also being possible for the phenyl rings to be substituted by R6, and p can be 1 and 2, and

Abstract: B can be phenyl, pyridyl, pyrimidyl and pyridazyl, it also being possible for the rings to be substituted by up to 2 R8 radicals, and

Abstract: D can be a bond, xe2x80x94(CH2)m, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Cxe2x89xa1Cxe2x80x94, and

Abstract: Y is phenyl, pyridine, pyrimidine and pyrazine and

Abstract: n is a number 0, 1 or 2, and

Abstract: m,q are, independently of one another, a number 0, 1, 2, 3 or 4.


A cutter formed by detachably attaching a replaceable blade to a cutter body. The cutter body can include a main body block and slide block. The main body block includes a main body supporting section supporting the replaceable blade back face, and a main body connecting section connecting with the replaceable blade from the front face side. The slide block includes a rear side supporting section supporting the replaceable blade back face, a slide connecting section connecting with and retracting the replaceable blade toward the rear side, and a back side protruding section protruding on the back side in a thickness direction. When attached, the replaceable blade elastically deforms to curve in the thickness direction, the slide block presses toward a main body block side in the thickness direction by elastic force of the replaceable blade, and the back side protruding section engages with a main body block engaged section.

As a cutter used for a knife for medical use, a knife for pathologic use, or razors for facial shaving or haircut, there is a cutter formed by detachably attaching a replaceable blade to a cutter body.
In such a cutter, the replaceable blade is attached to the cutter body by inserting the replaceable blade into a groove section provided in the cutter body. Then, the replaceable blade can be replaced after a predetermined number of times or a period of use.
Various efforts are made to such a blade-replaceable type cutter in order to facilitate easy replacement of the replaceable blade. For example, a cutter described in patent document 1 includes an engaging member capable of sliding with respect to a cutter body, and the replaceable blade can be attached to and detached from the cutter body by using a fore end section of the cutter body and the engaging member such that an opening section provided in the replaceable blade is engaged and being pulled in a longitudinal direction.
Further, as a cutter in patent document 2, there is a type in which a replaceable blade cartridge composed of a replaceable blade and a protection cover can be detachably attached to a cutter body.


A coin mechanism comprising testing devices for testing coins as to their acceptability, a substantially upright coin store or tube adapted to contain a plurality of acceptable coins of a particular denomination up to a predetermined upper level, and a coin dispenser for dispensing coins from the lower end of the store. The coin store is provided with a coin inlet located below the predetermined upper level, and devices for delivering acceptable coins of the denomination from the testing devices through the inlet into the store. This enables the coin store to be pre-loaded to the upper level and, when its contents have been partly dispensed, to be refilled from the coin tester, through the coin inlet at the lower level.

The term "coin" when used herein includes genuine coins, tokens, counterfeit coins and any other objects which may be inserted into a coin mechanism in an attempt to obtain any kind of goods or services.
Coin mechanisms are well known, which test coins as to their acceptability and, if acceptable, indicate their denomination, and which in respect of at least some of the acceptable denominations, direct them to respective coin stores, these usually being in the form of coin tubes, which may have different diameters depending upon the particular coin denomination each is intended to contain, and which are adapted to hold the coins in a vertical stack face-to-face. A coin dispensing arrangement is provided for dispensing appropriate combinations of coins from the bottoms of the stacks for the purpose of giving change or providing prizes. Additionally, there is usually a cashbox to which are directed coins which it is not intended to dispense either as change or as prizes, and also coins which might normally be directed to specific coin stores but which are accepted when the particular coin store in question is already full.
Coin mechanisms of this general type are well known and widely sold.
It is also known that there are some situations in which a particular coin denomination will need to be dispensed, in change or as a prize, sufficiently often that the coin store for that denomination is likely to become exhausted more frequently than is desirable. In an attempt to reduce the resulting problems, some coin mechanisms have been adapted to be equipped with an "auxiliary" coin tube which is individually mountable to, and demountable from, the coin mechanism manually without the use of tools. The auxiliary coin tube is pre-loaded manually with coins of the frequently-used denomination and mounted to the coin mechanism. There are then available for dispensing whatever coins may be already in, or delivered to, the main coin tube for that denomination, plus the quantity of coins of that denomination contained in the auxiliary tube. Over a period of time, nevertheless, it is still likely that the supply of coins of that denomination will become exhausted in which case the auxiliary tube will need to be manually replenished or replaced by a new one pre-loaded with a further supply of the frequently-used denomination of coin. To minimise the frequency with which the auxiliary coin tube has to be manually replenished or exchanged for a new, full, one it is desired for its capacity to be as great as possible, that is to say for its height also to be as great as possible.


The invention includes a xe2x80x9cfloating scrollxe2x80x9d mechanism for scroll type fluid displacement apparatus. The dual orbiting scroll has spiral vanes on both sides of the end plate. In a floating scroll, the orbiting scroll is dynamically well balanced, axially and radially. The scrolls are fully or semi-axially and radially compliant for maintaining minimum contacting forces between components, hence achieving good sealing for high speed, high efficiency, low friction wear and power loss. A crank shaft-sliding knuckle and/or peripheral crank handles-sliding knuckle mechanism provide the dual orbiting scroll with radial compliant capability. A synchronizer is used to synchronize the orientation of the crank handles to avoid the mechanism from jamming during operation and start up.

This invention relates to a scroll-type positive fluid displacement apparatus and more particularly to a scroll-type apparatus having a fully compliant, i.e. axially and radially compliant, floating scroll mechanism.
There is known in the art a class of devices generally referred to as xe2x80x9cscrollxe2x80x9d pumps, compressors and expanders, wherein two interfitting spiroidal or involute spiral elements are conjugate to each other and are mounted on separate end plates forming what may be termed as fixed and orbiting scrolls. These elements are interfitted to form line contacts between spiral elements.
A pair of line contacts and the surfaces of end plates form at least one sealed off pocket. When one scroll, i.e. the orbiting scroll, makes relative orbiting motion, i.e. circular translation, with respect to the other, the line contacts on the spiral walls move along the walls and thus changes the volume of the sealed off pocket. The volume change of the pocket will expand or compress the fluid in the pocket, depending on the direction of the orbiting motion.
An early patent to Creux (U.S. Pat. No. 801,182) describes this general type of device. Subsequent patents which have disclosed scroll compressors, expanders and vacuum pumps are: U.S. Pat. Nos. 6,123,529, 6,068,459, 5,961,297, 5,855,473, 5,788,470, 5,775,893, 5,755,564, 5,690,480, 5,632,611, 5,624,247, 5,616,015, 5,556,269, 5,322,426, 5,304,047, 5,247,795, 5,171,140, 5,098,265, 4,731,000, 4,677,949, 4,558,997, 3,989,422, 3,802,809, 3,600,114, 3,560,119, 3,011,694, 2,494,100, 2,475,247, 1,041,721. These prior patents provide so-called xe2x80x9cdual scrollxe2x80x9d structure, i.e. the orbiting scroll elements extend from the opposite sides of the end plate. The dual scroll structure causes the axial forces acting on the end plate of the orbiting scroll from the compressed fluid pressure to be substantially reduced or balanced. Hence, the need for a thrust bearing to support the orbiting scroll is eliminated and so is the corresponding friction wear and power loss.
However, in the prior art, the orbiting scroll, no matter whether it is centrally driven or peripherally driven, makes orbiting motion with a fixed orbiting radius. U.S. Pat. No. 4,192,152 to Allen E. Armstrong et al. discloses a radial compliant linking means to accommodate the thermal expansion differences between the scroll members and frame of the housing. This so-called xe2x80x9cradial compliantxe2x80x9d linking means is not a true radial compliant mechanism in the sense of being typically and commonly accepted in the industry. A typical xe2x80x9cradial compliant mechanismxe2x80x9d refers to a mechanism that can provide the orbiting scroll with freedom to travel radially until flank-flank contact between the orbiting scroll and the fixed scroll takes place to seal off the compression or expansion pocket. When incompressible fluid is trapped in the compression pocket or debris is involved between the scrolls, the orbiting scroll can yield radially backwards from the fixed scroll to accommodate the situation.
U.S. Pat. No. 3,817,664 discloses a pivot shaft and coupling means, i.e. a mechanical radial compliant mechanism, where the orbiting scroll is compliant radially through a coupling mechanism driven by a pivot shaft, which in turn is urged by a mechanical spring. This patent also discloses an axial compliant mechanism where the orbiting scrolls are urged towards the fixed scroll to achieve tip-base contact between scrolls by the pressure of the discharge fluid for better radial sealing. This radial compliant mechanism is not practical due to the pivotal shaft and is not convenient for high rotation speed, such as a couple of thousand RPM (revolutions per minute) or higher.
In oil-free and large horsepower applications, due to the severe working conditions for the former and heavy load for the later, both call for stronger anti-rotation and coupling mechanisms than an Oldham ring mechanism, which is currently widely used in air conditioning and oil flooded scroll applications. The peripheral crank handles, as taught in U.S. Pat. No. 3,802,809, provide a strong and reliable anti-rotation and coupling mechanism. However, it restricts the orbiting scroll from radial compliance, thus sacrificing the tangential sealing between the fluid pockets formed between orbiting and fixed scrolls.
To overcome the shortcomings of conventional scroll-type fluid displacement apparatus, the present invention provides a xe2x80x9cfloating scrollxe2x80x9d mechanism for scroll type fluid displacement apparatus. The dual orbiting scroll has spiral vanes on both sides of the end plate. In a floating scroll, the orbiting scroll is dynamically well balanced, axially and radially. The scrolls are fully or semi-axially and radially compliant for maintaining minimum contacting forces between components, hence achieving good sealing for high speed, high efficiency, low friction wear and power loss. A crank shaft-sliding knuckle and/or peripheral crank handles-sliding knuckle mechanism provide the dual orbiting scroll with radial compliant capability. A synchronizer is used to synchronize the orientation of the crank handles to prevent the mechanism from jamming during operation and start up. The scroll can be single stage or multi-stage, depending on the compression ratio, working media and other factors of the applications.
An object of the invention is to provide an improved scroll-type positive fluid displacement apparatus, which uses peripheral multiple crank handles to assure the circular translation, i.e. orbiting motion, of the orbiting scroll relative to the fixed scroll. At the same time, the scroll-type apparatus provides the orbiting scroll with the freedom to adjust its orbiting radius compliant to the fixed scroll spiral element by synchronizing the peripheral crank handles to eliminate possible mechanical jam of the handles.
It is another object of this invention to provide an improved scroll-type apparatus in which the orbiting scroll has spiral elements extending from the opposite sides of the end plate, a so called xe2x80x9cDual Orbiting Scrollxe2x80x9d. Both sides of the dual orbiting scroll are dynamically similar or identical, i.e. the axial forces acting on both sides of the dual orbiting scroll are balanced or its difference is minimized. An axial compliant mechanism, by pressurizing a plenum, urges one scroll member towards the other scroll member with a controlled axial force that is just enough to overcome the opposite forces to maintain very light tip-base contact and thus, to achieve the radial sealing. The orbiting scroll with axial and radial compliant mechanisms is xe2x80x9cfloatingxe2x80x9d in the sense of force balance. The floating scroll technology allows the scroll apparatus to operate at higher rotating speeds to achieve higher fluid displacement capacity with a relatively small size and weight of the apparatus. This results in a reduced friction, reduced wear, highly efficient, compact and light scroll-type fluid displacement apparatus.
Other objects of the invention will in part be obvious and will in part be apparent hereinafter.

Scroll type fluid displacement apparatus with fully compliant floating scrolls


A new Pentas plant named ‘PEZZ0013’ particularly distinguished by the large sized inflorescences and flowers, with light violet flowers, dark-green foliage, upright, sturdy and vigorous growth habit, thick stems and branches on a well-branched plant, tolerates hot summer conditions with continuous summer flowering.

The present invention comprises a new Pentas, botanically known as Pentas lanceolata, and hereinafter referred to by the variety name 'PEZZ0013'.
'PEZZ0013' is a product of a planned breeding program. The new cultivar 'PEZZ0013' has large sized inflorescences and flowers, with light violet colored flowers, dark green foliage, upright, sturdy and vigorous growth habit, thick stems and branches on a well-branched plant, tolerates hot summer conditions with continuous summer flowering.
'PEZZ0013' originates from a cross hybridization of two (2) sibling seedlings in a breeding program made in September 2012 in a greenhouse in Gilroy, Calif. The female parent was an unpatented plant identified as '319-4' with darker violet flower color.
The male parent was an unpatented plant identified as '308-5' with rose colored flowers. The resultant seed was sown in June 2013 in Gilroy, Calif.
'PEZZ0013' was selected as one flowering plant within the progeny of the stated cross in November 2013 in a greenhouse in Gilroy, Calif.
The first act of asexual reproduction of 'PEZZ0013' was accomplished when vegetative cuttings were propagated from the initial selection in November 2013 in a greenhouse in Gilroy, Calif.


A binding device includes binding rings, a holding member having a length that enables the binding rings to be arranged at a distance from each other, and an operating member movably fixed inside the holding member such that the respective bases of the binding rings are secured onto a surface of the operating member at a distance to secure the binding rings to the holding member. In this binding device, the operating member includes a pair of operating pieces which move within the holding member in a longitudinal direction of the holding member. The base of one of the binding rings is secured to one of the operating piece, and the base of the other binding ring is secured to the other operating piece. The operating pieces are fixed to the holding member such that abutting edges thereof are maintained in an abutting state at a location spaced from an inner surface of the holding member when the binding rings are closed, and the abutting edges are maintained at a location closer to the inner surface of the holding member when the binding rings are opened, and an opening/closing member is provided for shifting the binding rings in an opening direction such that the operating pieces are moved in the longitudinal direction of the holding member within the holding member and are maintained at the location closer to the inner surface of the holding member when the binding rings are opened.

1. Field of the Invention
The present invention relates to a binding device, and in particular, for example, to a binding device used for a ring binder or file.
2. Description of the Related Art
A conventional binding device is configured such that an approximately annular binding ring is engaged at its center so as to be closed. For example, if the ring is manually opened or closed, a pair of approximately semicircular binding half rings which together define an approximately annular binding ring are pulled apart with fingers so as to be separated from each other, thereby opening the binding ring.
When the approximately annular binding ring is opened with fingers, however, it is difficult to open the pair of approximately semicircular binding half rings defining the binding ring when a relatively large number of sheets of a document are bound.
Therefore, for example, a ring file disclosed in Japanese Patent Laid-Open Publication No. Hei 10-337988 has been proposed.
The so-called lever type binder of a conventional ring file disclosed in the above-cited patent publication, however, has the following problem. When a large amount of an object is to be bound by approximately annular binding rings of the ring file, the inner sides of levers are pushed outwardly and down so as to open the binding rings. However, when the levers are pushed outwardly and down from the bound article side so as to open the binding rings, the bound article is an obstacle, which makes it difficult to push down the levers with fingers.


For use in transferring goods into and from a cargo compartment of a vehicle, trailer, container or the like, a hoist apparatus has a first frame having a pair of opposite side members extending in a first horizontal direction, the I-beams each having a vertical web and horizontal upper and lower flanges. The first frame is supported on rollers beneath the roof of the cargo compartment so as to allow displacement of the first frame in the first horizontal direction between a first, retracted position, in which the first frame is accommodated entirely within the cargo compartment, and a second, extended position, in which the first frame protrudes from the cargo compartment. A second frame or bridge extends horizontally between the opposite side members of the first frame and is supported on rollers on the first frame for movement along the side members. The second frame has a pair of opposite side members extending transversely of the first horizontal direction and a hoist carriage is mounted on the second frame for movement along the side members thereof. At least a major portion of the depths of the second frame and of the hoist carriage are located above the underside of the first frame, so as to counteract obstruction of the headroom within the compartment.

1. Field of the Invention
The present invention relates to hoist apparatus for use in transferring goods into and from a cargo compartment of e.g. a truck, trailer or other vehicle or the floor of a container.
2. Description of the Related Art
In U.S. Pat. No. 5,062,760, issued Nov. 5, 1991 to Felix Samaniego, there is disclosed a material handling system mounted adjacent the roof of a cargo compartment of an enclosed van or trailer. This prior system has a so-called X-axis frame, which traverses the length of the compartment, a series of Y-axis frames, which traverse the width of the compartment, and a hoist which traverses the vertical axis of the compartment and is mounted on the X-axis frame. The X-axis frame is suspended from the Y-axis frames by a carriage assembly, which allows the X-axis frame to move throughout the longitudinal or X-axis and the transverse or Y-axis of the compartment and drive means are provided for moving the X-axis frame through the X- and Y-axes of the compartment.
In this prior apparatus, since the X-axis frame is located entirely beneath the Y-axis frames, the headroom available within the compartment is obstructed or reduced by the height of the X-axis frame plus the height of the Y-axis frames.


Provided are an additive and a surface treatment agent capable of suppressing agglutination of latex particles contained in a reagent for a latex agglutination reaction during storage of the reagent although a synthetic polymer is contained as an active component.

A latex agglutination method using an agglutination reaction occurring between a target substance such as an antigen (antibody) and an antibody (antigen) against the target substance is widely utilized in regions, for example, of a clinical test and biochemical studies (Patent Literature 1). This latex agglutination method is performed, for example, by mixing a specimen that may contain a target substance with a first reagent such as a buffer and mixing this mixed solution with a reagent for a latex agglutination reaction (second reagent) containing latex particles to which an antibody (antigen) against the target substance is immobilized. In a case where the target substance is present in the specimen, an agglutination reaction of the latex particles occurring as a result of an antigen-antibody reaction is detected.
However, in the latex agglutination method, insufficient detection sensitivity may be pointed out in a case where latex particles having small particle sizes are used, for example.
Therefore, a sensitizer that promotes a latex agglutination reaction has been proposed. As such a sensitizer, a water-soluble polymer such as polyethylene glycol, a polyhydric alcohol, polyvinyl pyrrolidone, carboxymethyl cellulose, dextran, alginic acid, an aminoethanesulfonic acid derivative, or an aminopropanesulfonic acid derivative is known (Patent Literatures 2 to 4). Detection sensitivity is enhanced by adding the water-soluble polymer to a reagent and keeping the resulting mixture under certain conditions.
However, the above water-soluble polymer causes agglutination of latex particles due to a factor other than an antigen-antibody reaction (for example, nonspecific adsorption) disadvantageously. There are problems, for example, noise is generated by this agglutination, and latex particles in a reagent for a latex agglutination reaction agglutinate in a case where the water-soluble polymer is blended with the reagent and stored.

Additive, surface treatment agent, surface-modified latex particles, method for producing surface-modified latex particles, reagent for latex agglutination reaction, kit, and method for detecting target substance

Abstract: An additive is to be added to latex particles used in a reagent for a latex agglutination reaction. The latex particles have not been subjected to blocking treatment. The additive includes a polymer containing more than 60% by mass and 99% by mass or less of hydrophilic repeating units (A) relative to all repeating units and 1% by mass or more and less than 40% by mass of hydrophobic repeating units (B) relative to all repeating units, and having a weight average molecular weight of 3,000 or more.


An active layer of the index includes a first shard group, and shards in the first shard group are configured to store indexes of a part of data objects in a streaming storage system. In response to determining that the state of the first shard group meets a predetermined expansion condition, a second shard group is created in the index, and shards in the second shard group are configured to store indexes of data objects that will enter the storage system. The storage system is managed based on the shards in an active layer (where the second shard group is located) and frozen layers (where the second shard group) in the index. The number of shards in the storage system can be dynamically set to process streaming data at a relatively high speed, and it is suitable for processing streaming data that continuously enters the storage system.

Streaming data is a continuous and endless data stream generated by various data sources. Generally speaking, the generation of streaming data is fast and the amount of data is large. Common examples of streaming data include log data of various application systems, measurement data of various sensors in the Internet of Things, various real-time data collected by monitoring systems, and the like. Streaming data may include a large amount of information and is usually stored in a time series.
In order to facilitate data search, technical solutions for creating an index for streaming data have been proposed at present. However, the existing technical solutions have poor expandability. With the passage of time, when the amount of streaming data continues to grow, the existing indexing technology cannot effectively manage more and more streaming data, which will cause the decrease of data access performance and further reduce the efficiency of later data analysis. At this moment, how to manage the index in the streaming data storage system in a more convenient and effective way has become a research hotspot.

Method, device, and program product for managing index of streaming data storage system


A semiconductor structure including an electrostatic discharge (ESD) diode with an increased junction area and a vertical field effect transistor (FET) formed on a same substrate is provided. The ESD diode is formed by forming a first doped semiconductor segment merging bottom portions of a pair of semiconductor fins and then forming a second doped semiconductor segment having a conductivity type opposite to that of each of the first doped semiconductor segment and the pair of semiconductor fins. A U-shaped p-n junction is present between the second doped semiconductor segment and the first doped semiconductor segment and the second doped semiconductor segment and the pair of semiconductor fins.

The present application relates to semiconductor device fabrication, and more specifically to integration of vertical transistors and electrostatic discharge (ESD) diodes with increased junction areas.
As the advance of semiconductor technology, semiconductor devices are continually becoming more compact and circuit layouts are continually becoming more complex. As a result, semiconductor devices in circuits are more susceptible to burn-out by ESD events. ESD diodes are often required to prevent such burn-out. Since effectiveness of the protection provided by an ESD diode is associated with the junction area of the ESD diode, an ESD diode with larger junction area are desirable.
Vertical field effect transistors (FETs) are attractive candidates for 5 nm node and beyond due to better density scaling and better control of electrostatics. It is therefore desirable to have an improved structure and fabrication process for forming ESD diodes with increased junction areas that are compatible with the formation of vertical FETs.

Large area electrostatic dischage for vertical transistor structures

INTERNATIONAL BUSINESS MACHINES CORPORATION


Various embodiments of the present technology may provide methods and apparatus for optical image stabilization. A system may include an actuator control circuit responsive to a sensor and a feedback signal from an actuator. The actuator control circuit may be configured to calibrate a gain applied to a drive signal based on a measured difference value of the feedback signal generated by the actuator control circuit and a predetermined difference value.

Many electronic devices have an imaging system integrated within them, and in some cases, the electronic device may be turned and/or rotated for the purpose of a desired image capture. In many cases, the imaging system may be controlled by an optical imaging stabilization (OIS) system. In particular, the OIS system may operate to stabilize various components of the imaging system, such as a lens, and to correct for involuntary movements of the electronic device caused by external disturbances, for example movements caused by a shaking hand (hand tremors). However, as the position of the electronic device changes, gravity may influence the optical image stabilization system and/or a position of the lens. In addition, as the electronic device ages, deterioration may further influence the optical image stabilization system and/or the position of the lens. This influence may be due, in part, to how the stroke sensitivity of various components in the imaging system, such as coils, magnets, springs, etc. varies over time. As a result, given a particular position instruction (code) associated with a respective target position and drive signal, the magnitude of the drive signal needed to move the lens to the target position may be different than the one specified by the position instruction value (code).

Methods and apparatus for optical image stabilization

SEMICONDUCTOR COMPONENTS INDUSTRIES, LLC


A driver circuit for a voltage-switching, high frequency Class-D power amplifier provides an input sinewave power signal and controls the transition time between switching the two active devices thereof, resulting in substantially lossless switching. The transition time is optimized by controlling the amplitude of the voltage signals at the inputs of the two active devices, depending on the output capacitance of the switching devices, the threshold voltage of the switching devices, the power output requirement, and the impedance of the resonant load network of the Class-D power amplifier.

A Class-D power amplifier employs two active switching devices as a single-pole double-throw switch for generating a square wave signal. An output load network includes a resonant circuit which is tuned to the switching frequency of the devices, thus removing the harmonics of the square wave signal and resulting in a sinusoidal output signal. There are two types of Class-D power amplifiers, a voltage-switching type and a current-switching type. In the voltage-switching type, the switching devices are connected in series with a power supply, and the supply voltage is switched alternately between the respective inputs thereof. The current-switching type, which is the dual of the voltage-switching type, employs the devices in a parallel or push-pull configuration, and the supply current is alternately switched therebetween. For either type, since the switching devices of Class-D power amplifiers are driven alternately between cutoff and saturation such that one is conducting while the other one is turned off and vice versa, Class-D power amplifiers are conveniently driven by square wave signals. An input isolation transformer is conventionally used to provide the two out-of-phase driving signals.
Switching power losses at low frequencies are generally negligible for Class-D power amplifiers. However, at higher operating frequencies, switching losses are significant, thus decreasing efficiency. In particular, for a voltage-switching amplifier, the power dissipated by each switching device in discharging the output capacitance of the other switching device increases with increasing operating frequency. Moreover, as frequency increases, isolation transformers which are capable of passing the higher harmonics of the square wave drive signals must be more complex. It is generally accepted that the aforesaid shortcomings impose an upper limit on attainable efficiency for Class-D power amplifiers, e.g. 80% for high frequency, low power applications and less than 70% for high frequency, high power applications.

Driver for a high efficiency, high frequency Class-D power amplifier


A technique for transmitting and receiving data in a radio communication from a second radio device to a first radio device is described. As to a method aspect of the technique, one or more radio resources are determined based on radio signals received at the first radio device. The one or more radio resources comprise at least one spatial stream among different spatial streams receivable at the first radio device. A status message indicative of the one or more determined radio resources is transmitted to the second radio device. The data from the second radio device is received at the first radio device on at least one radio resource depending on the one or more radio resources indicated in the transmitted status message.

Radio communication for road traffic can actively avoid accidents and improve traffic efficiency. To this end, vehicle-to-vehicle (V2V), vehicle-to-pedestrian (V2P) and vehicle-to-infrastructure (V21) communication, collectively referred as vehicle-to-anything (V2X) communication, requires high reliability and low end-to-end (E2E) latency, which is achievable by device-to-device (D2D) communication, i.e., direct communication including packet transmission directly among radio devices participating in the traffic.
The Third Generation Partnership Project (3GPP) has expanded the Long Term Evolution (LTE) platform by building V2X communication upon Proximity-based Services (ProSe, also referred to as LTE D2D) since Release 12 of LTE. The V2X communication, e.g., according to the document 3GPP TS 22.185, version 14.3.0, includes enhancements targeting specific characteristics of vehicular communications such as high velocity (e.g., up to 250 km/h) and high density of radio devices (e.g., thousands of neighboring nodes).
To enhance system level performance under high density while meeting the latency requirements of V2X communication, 3GPP introduced sidelink (SL) transmission modes 3 and 4 (also referred to as resource allocation modes) for V2X communication with and without the infrastructure of a radio access network (RAN) being involved, respectively. The RAN is in charge of allocating radio resources to a transmitting radio device (i.e., centralized scheduling) in mode 3, whereas the transmitting radio device autonomously selects the radio resources for its own transmissions (i.e., distributed scheduling) in mode 4.
Since distributed scheduling requires a transmitting radio device to perform an access mechanism for carrier-sense multiple access (CSMA), distributed scheduling is susceptible to a "hidden node problem" (HNP), which occurs if a transmitting radio device is within range of a receiving radio device and out of range of another transmitting radio device (i.e., the "hidden" node) in radio communication with the receiving radio device. Q. Gao et al. suggest in the document "Radio resource management of D2D communication," IEEE International Conference on Communication Systems, Macau, 2014, pp. 6-10, modifying the access mechanism at the transmitting radio devices to mitigate the HNP.
However, existing access mechanisms rely upon a contention window, which causes a loss of radio resources in the time domain and adds to the latency of the radio communication. Furthermore, existing access mechanisms can still lead to the HNP if the radio communication includes a directional radio transmission directed towards the receiving radio device. Thus, the HNP can occur even if the hidden node is a neighboring node of the transmitting radio device of the radio communication.

Technique for device-to-device communication based on radio signals received from one or more radio sources


A pair of horizontal-step-including trenches are formed in a semiconductor layer by forming a pair of first trenches having a first depth around a gate structure on the semiconductor layer, forming a disposable spacer around the gate structure to cover proximal portions of the first trenches, and by forming a pair of second trenches to a second depth greater than the first depth. The disposable spacer is removed, and selective epitaxy is performed to form an integrated epitaxial source and source extension region and an integrated epitaxial drain and drain extension region. A replacement gate structure can be formed after deposition and planarization of a planarization dielectric layer and subsequent removal of the gate structure and laterally expand the gate cavity over epitaxial source and drain extension regions. Alternately, a contact-level dielectric layer can be deposited directly on the integrated epitaxial regions and contact via structures can be formed therein.

The present disclosure generally relates to semiconductor devices, and particularly to complementary metal-oxide-semiconductor (CMOS) field effect transistors including epitaxial source and drain extension regions, and methods of manufacturing the same.
With scaling of semiconductor devices, the distribution of electrically active dopants in source and drain extension regions of a metal-oxide-semiconductor field effect transistor (MOSFET) is statistically determined. Further, the extent of the source and drain regions becomes more difficult to control with the reduction of lateral dimensions for the source and drain regions. Thus, the resistance of the source and drain regions is subjected to greater statistical variation, i.e., control of the resistance of source and drain extension regions becomes more difficult with the scaling.
However, the performance of a MOSFET is often critically dependent on the resistance of the source and drain extension regions. Specifically, high source or drain resistance in a MOSFET results in degradation in the on-current and the switching speed of the MOSFET. Thus, the resistance of the source and drain extension regions needs to be kept low in order to provide a high performance MOSFET.
Further, ion scattering effect that accompanies conventional ion implantation process employed to doped source and drain extension regions causes short channel effect (SCE) performance degradation in high performance MOSFETs. The stochastic nature of the path of the implanted electrical dopants (which are either p-type dopants or n-type dopants) causes the dopant concentration profile around interfaces between a body region of a MOSFET and source and drain extension regions of the MOSFET to vary gradually due to significant interdiffusion of electrical dopants between the body region and the source and drain extension regions, thereby exacerbating the short channel effect.

International Business Machines Corporation


A radiation-sensitive composition includes a photoacid generator represented by a general formula (1), and a solvent. Each R0 independently represents a hydrogen atom, a fluorine atom, or a substituted or unsubstituted monovalent organic group. R1 represents a fluorine atom or a substituted or unsubstituted monovalent organic group. R2 represents a fluorine atom or a substituted or unsubstituted monovalent organic group. Rf represents a fluoromethylene group or a divalent fluoroalkylene group. M+ represents a monovalent onium cation. Optionally R1 bonds to Rf or R2 to form a cyclic structure.

1. Field of the Invention
The present invention relates to a radiation-sensitive composition and a compound.
2. Discussion of the Background
When deep ultraviolet rays (e.g., KrF excimer laser light or ArF excimer laser light) or the like are applied to a chemically-amplified radiation-sensitive resin composition, an acid is generated in the exposed area, and a difference in solubility rate in a developer occurs between the exposed area and the unexposed area due to chemical reactions catalyzed by the generated acid. A resist pattern is formed on a substrate by utilizing the difference in solubility rate (see Japanese Patent Application Publication (KOKAI) No. 59-45439 and Perfluorooctyl Sulfonates; Proposed Significant New Use Rule).
A photoacid generator included in the chemically-amplified radiation-sensitive resin composition is required to exhibit excellent transparency to radiation and have a high quantum yield when generating an acid. An acid generated by the photoacid generator is required to have sufficient acidity, a sufficiently high boiling point, and an appropriate diffusion distance (hereinafter may be referred to as "diffusion length") in the resist film, for example.
When using an ionic photoacid generator, the structure of the anion moiety is important in order to obtain sufficient acidity, a sufficiently high boiling point, and an appropriate diffusion length.
For example, a photoacid generator having a trifluoromethanesulfonyl structure generates an acid having sufficient acidity, and sufficiently increases the resolution of the photoresist.
A photoacid generator having a sulfonyl structure bonded to a large organic group (e.g., 10-camphorsulfonyl structure) generates an acid having a sufficiently high boiling point and an appropriate diffusion length (i.e., a sufficiently short diffusion length).
When precisely controlling the line width (e.g., when the device design dimensions are equal to or less than sub-half micrometers), it is important for a chemically-amplified resist to exhibit an excellent resolution and provide excellent surface flatness. When using a chemically-amplified resist that provides poor surface flatness, elevations and depressions (hereinafter may be referred to as "nano edge roughness") formed on the surface of the resist film may be transferred to a substrate when transferring the resist pattern to the substrate by etching or the like, so that the dimensional accuracy of the pattern may deteriorate. This may impair the electrical properties of the resulting device (see J. Photopolym. Sci. Tech., p. 571 (1998), Proc. SPIE, Vol. 3333, p. 313, Proc. SPIE, Vol. 3333, p. 634 and J. Vac. Sci. Technol. B16 (1), p. 69 (1998), for example).

Radiation-sensitive composition and compound


A method of a mobile station receiving data packets from a serving base station via a multicast or broadcast connection in a wireless network is provided for performing a handover from the serving base station to a target base station. The method comprises, at the level of the mobile station, the steps of: upon the detection of the quantity of buffered data packets in the mobile station being lower than a first threshold value, establishing a unicast connection with the serving base station to receive data packets from the serving base station; and upon detection of the level of buffered data packets reaching the predetermined threshold level, performing a handover from the serving base station to the target base station. According to the invention, a seamless handover of a mobile station in a wireless network providing Multicast and Broadcast Service (MBS service) can be achieved to prevent the MBS service interruption during the handover.

MBS is a point-to-multipoint service transmitting data from a service source to a plurality of receivers through a common wireless channel. The IEEE802.16e-2005 standard has defined the MBS in a mobile WiMAX (Worldwide Interoperability for Microwave Access) network, which can be implemented as a cost-effective way to provide mobile TV or Video on Demand (VOD) services.
According to the definition in the IEEE802.16e standard, a multi-base-station MBS can be supported by constructing separate regions in the downlink frame.
FIG. 1 is an exemplary diagram showing the network architecture of multi-base-station MBS in a wireless network in the prior art. As shown in FIG. 1, a system for providing a MBS comprises a content pool, an MBS controller, a plurality of base stations (three, BS1, BS2 and BS3 in this example) and a plurality of mobile stations. The MBS controller provides the plurality of base stations with MBS data from the content pool and performs authentication of mobile stations and distribution of encryption key for the MBS. The plurality of base stations provide the plurality of mobile stations with the MBS data transferred from a backbone network through common air interface. The plurality of mobile stations receive the MBS data transmitted from the serving base station they connect.
For the access mode of multi-base-station MBS, a single frequency network (SFN) with flexible duration of MBS regions is employed to permit the scalable assignment of radio resources to MBS traffic. Each base station is capable of providing MBSs belonging to the same MBS zone where a set of base stations with the same connection index (CID) and the same security association (SA) are used for transmitting content of certain service flows. The multi-base-station MBS in SFN does not require a mobile station to register with a new base station during a roaming process, which can reduce a handover delay and a service broken.
To enable a mobile station to receive MBSs from a plurality of base stations, MBSs need to be strictly synchronized across these base stations. However, the synchronization of MBS among multiple base stations is hard to achieve because of the following four constrains: the identical Packet Data Unit (PDU) format and CID assignment; the identical Orthogonal Frequency Division Multiple Access (OFDMA) frame; the identical OFDMA data region; and the identical channel coding scheme.
Except for the overhead for the content synchronization such as functions of classification, fragmentation and centralized scheduling, there are the following drawbacks for deployment of MBS in SFN.
(1) Waste of MBS Bandwidth
As long as a MBS zone is created, a multicast service that starts up inside one base station should be extended to all base stations belonging to the same MBS zone. Obviously, for some non-popular programs with limited subscribers located inside a small amount of base stations, the bandwidth will be wasted in the cell where there is no subscriber for this program.
(2) No Flexibility for Link Adaption Among Multiple Base Stations
How to fulfil a link adaption for MBS in a single-base-station access is a challenging task because of the great amount of overhead for feedback channel maintenance. It is nearly impossible to have the link adaption among multiple base stations since there is a remarkable variation of subscriber distribution. Accordingly, the conventional method skips the link adaption and chooses the most robust (fixed) modulation and coding scheme for MBS. The disadvantage is that the system utility will be reduced a lot due to the poor spectrum efficiency of low level modulation and coding scheme.
(3) Affection on Unicast Service
Normally, the MBS will cover partial downlink sub-frame. And in a WiMAX system, a base station needs to allocate uplink transmission opportunity for a mobile station when there is traffic originating from the mobile station. It is difficult for the base station to assign a symbol and a subchannel for a unicast service in the SFN because of the unpredictable interference from neighboring base stations operating in the same frequency band. As shown in the FIG. 1, there are overlapping areas among neighboring base stations BS1, BS2 and BS3 in the backbone network. For those mobile stations located in these overlapping areas, the transmission of unicast service to/from its serving base station is inevitably interfered with the unitcast traffic in the area of the neighboring base stations. Thus the overall system utility will also be affected.
A multiple frequency network (MFN) is another approach for multi-base-station access. Although the MFN can overcome the above described disadvantages of the SFN, a distinct challenge is the uncertain handover processing time during the course of a mobile station switching from one base station to another. In such case the mobile station needs to terminate the existing connection with the serving base station, go through the network entry procedure and then re-establish the service connection with a new base station. Because the content synchronization is not a mandatory requirement in MFN environment, even the content source is from the same MBS controller via the backbone network, the delay from MBS controller to each base station might be different. Thus the following two problems should be considered for the MBS handover process in WiMAX network:
(1) Minimizing the switching time for handover
(2) Minimizing the service interruption.
For the problem 1, there are some mechanisms already defined in the IEEE802.16e standard to reduce the switching time. For example, according to one mechanism, if a mobile station have previously received neighboring advertisement message from its serving base station, it can acquire the information including the ID, the physical frequency and the downlink/uplink channel description of the candidate target base station. Thus the synchronization to the target base station can be achieved in a quick way. Furthermore, the network re-entry proceeds may also be shortened if the target base station can possess information of the mobile station from the serving base station over the backbone network, by which the authentication and registration phases can be skipped.
For the problem 2, there is no method mentioned in the IEEE802.16e standard for data and service integrity. A mobile station must terminate the connection with the serving base station before the handover processing. No function model is defined for the base station to support seamless MBS handover in MFN mode.
Full information of the MBS in a mobile WiMAX network cab be referred by the IEEE802.16e standard.
In summary, the current definition in the IEEE802.16e standard uses the SFN for multicast and broadcast service among multi-base station access. However, such method will not only bring great overhead for content and frame synchronization among base stations grouped in the same MBS zone, but also cause bandwidth waste and efficiency descending for unicast services. By contrast, the MFN as described above can reduce overhead for content synchronization and minimize the interference for unicast services in the cell boundary and overlapping area. But the major problem of the MFN is the possible interruption of service during the handover processing when switching from one base station to another.
Therefore, the problem of an efficient and seamless MBS handover for multi-base-station access in MFN needs to be addressed.

Handover method of multicast and broadcast service based on buffer fullness


An Information Source 600 provides information to a Data Service element 602. A Directory Service Update Decision element 604 registers 606 with a Directory Service element 608. The client 610 provides a request to a Personal Lookup Agent element 612. The Directory Service Poll Decisions 614 queries the Directory Service element 608 with a Lookup 616 request. The Personal Lookup Agent 612 implements an interface to the Directory Service element 608 that allows the client 610 to ingest application-specific objects that encapsulates control functions for Directory Service Polling Decisions 614 for Candidate Service Filtering 618, and subsequent Target Service Filtering 620.

As data collection and dissemination technology continues to mature, there is an ever-widening chasm between data collection capabilities and data analysis and delivery capabilities. The result of ineffective data analysis is poor utilization of data resources and loss of opportunities to access useful data. For instance, a motorist, upon leaving work may want to know if the road home has ice on it. Alternatively, a motorist may desire information concerning traffic flow patterns along a specific stretch of roadway. Existing technology, available in many metropolitan areas, provides radio reports which include superficial data pertaining to traffic and generalized weather forecasts, Unfortunately, often the data provided is usually neither sufficiently detailed nor timely delivered. Part of this problem stems from the fact that there is simply too much data collected and too little time, and bandwidth, for complete dissemination, the result is poor utilization of data collection resources, and missed opportunities to provide data to potential users. Such missed opportunities, raise the price of data collection resources because fewer users must bear the costs associated with the data collection resources. Because of the nature of many types of situational-awareness data, the failure to provide timely delivery can mean that the data is essentially worthless, except for possible subsequent statistical evaluation.
Therefore it would be desirable to disseminate detailed data to users quickly, thereby allowing the users to consider the data and make better decisions, and lower the cost associated with data collection.

Apparatus and method for context-sensitive dynamic information service composition via mobile and wireless network communication


In a semiconductor device, a body thick film transistor and a body thin film transistor having a different body film thickness are formed on the same SOI substrate (silicon support substrate, buried oxide film and silicon layer). The body film is formed to be relatively thick in the body thick film transistor, which has a recess structure where the level of the surface of the source/drain regions is lower than the level of the surface of the body region, and thus, the SOI film in the source/drain regions is formed to be as thin as the SOI film in the body thin film transistor. On the other hand, the entirety of the SOI film is formed to have a relatively thin film thickness in the body thin film transistor. In addition, the source/drain regions are formed to penetrate through the silicon layer.

1. Field of the Invention
The present invention relates to a semiconductor device having a structure which is adaptable to various types of devices, mainly a semiconductor device having an SOI (silicon on insulator) structure, as well as a manufacturing method for the same.
2. Description of the Background Art
FIGS. 102 to 111 are cross sectional views showing a manufacturing method for a conventional MOS transistor formed on an SOI substrate. Hereinafter, the manufacturing method is described with reference to these drawings.
First, as shown in FIG. 102, a buried oxide film 2 having a film thickness of 10 nm to 1000 nm and a silicon layer 3 having a film thickness of 30 nm to 200 nm are formed in sequence on a silicon support substrate 1, which is a semiconductor substrate, and thereby, an SOI substrate (structure) composed of the silicon support substrate, the buried oxide film and the silicon layer 3 is obtained. Furthermore, a silicon oxide film 7 having a film thickness of 5 nm to 400 nm is formed on the silicon layer 3, and a silicon nitride film 4 having a film thickness of 10 nm to 200 nm is formed on the silicon oxide film 7.
Next, as shown in FIG. 103, a resist film is applied on the entire surface, and a resist pattern 9 (pattern for element isolation) for forming trenches is formed through photolithography.
After that, as shown in FIG. 104, the silicon nitride film 4, the silicon oxide film 7 and the silicon layer 3 are etched using the resist pattern 9 as a mask to form trenches. This etching process is performed in such a manner that the silicon layer 3 partially remains (partial trench isolation (PTI)). Furthermore, the inner walls of the trenches in the silicon layer 3 are oxidized to form inner wall oxide films 25 having a film thickness of 5 nm to 50 nm on the exposed surfaces of the silicon layer 3. Here, the process for forming inner wall oxide films 25 may be omitted.
Then, as shown in FIG. 105, silicon oxide films 10 bury in the trenches an annealing process at 500° C. to 1300° C. is performed. Then, a CMP (chemical mechanical polishing) process is performed using the silicon nitride film 4 as a stopper, and thereby, the silicon oxide films 10 are flattened. Here, the annealing process may be omitted.
Subsequently, as shown in FIG. 106, after the silicon oxide films 10 is etched to set the film thickness of the silicon oxide films 10 to a predetermined thickness, as shown in FIG. 107, the silicon nitride film 4 and a silicon oxide film 6 are removed.
Next, as shown in FIG. 108, silicon oxide films 12 are formed on the exposed surfaces of the silicon layer 3 between the silicon oxide films 10 and 10.
After that, as shown in FIG. 109, a polysilicon film is formed and patterned through photolithography, and thereby, gate electrodes 13 are formed, silicon oxide film spacers 14 are formed on the sides of the gate electrodes 13, and after that, impurity ions 15 are injected into the silicon layer 3 using the gate electrodes 13 and the silicon oxide film spacers 14 as a mask to form diffusion regions 37 which later become extension & pocket regions.
Then, as shown in FIG. 110, silicon oxide film side walls 16 and silicon nitride film side walls 17 are formed in sequence on the sides of the silicon oxide film spacers 14, and impurity ions are injected using the gate electrodes 13, the silicon oxide film spacers 14, the silicon oxide film side walls 16 and the silicon nitride film side walls 17 as a mask to form source/drain regions 38. At this time, the source/drain regions 38 penetrate through the silicon layer 3 to reach the silicon layer 3, so that the diffusion regions 37 mainly beneath the silicon nitride film side walls 17 becomes extension/pocket regions 37e. Furthermore, metal silicide regions 18 and 29 of cobalt (Co) silicide and the like are formed on the gate electrodes 13 and the source/drain regions 38, respectively.
Finally, as shown in FIG. 111, a silicon nitride film 42 is formed on the entire surface, and after the formation of an interlayer insulating film 19 on the silicon nitride film 42, a CMP process is performed to flatten the interlayer insulating film 19. In addition, a resist pattern (not shown) for etching is formed through photolithography, and contact holes are formed using this resist pattern as a mask, the contact holes are filled in with a metal so that metal plugs 20 are formed. Furthermore, the metal plugs 20 are electrically connected to the interlayer insulating film 19 to form metal wires 21. Al (aluminum), copper (Cu) and the like are considered as materials of the metal wires 21.
In this manner, MOS transistors are formed on the SOI substrate. The body regions of these MOS transistors are electrically connected to body contact regions (not shown) to which a predetermined body potential is provided via the silicon layer 3 beneath the silicon oxide films 10.
When the film thickness of the SOI film (film thickness of the silicon layer 3) becomes smaller by scaling, there is a problem that increases in the body resistance and cannot satisfy characteristics required for the devices used in I/O circuits or analog circuits. In addition, in the case where the thickness of the SOI film is great, the larger parasitic capacitance decrease in speed performance, and thus there is a problem that cannot satisfy speed characteristics required for the devices used in logic circuits and the like.
As a semiconductor device for solving these problems, there are transistors formed to have an SOI structure as that disclosed in, for example, Japanese Patent Application Laid-Open No. 2005-19453. According to the structure disclosed in Japanese Patent Application Laid-Open No. 2005-19453, an SOI structure can be cited, where a first semiconductor layer is provided on top of a buried insulating film in a memory cell region, and a second semiconductor layer is provided on a buried insulating film in a peripheral circuit region. The first and second semiconductor layers are made to have a different film thickness, so that transistors in the memory cell region become of a complete depletion type and transistors in the peripheral circuit region become of a partial depletion type.
However, there is a problem that cannot satisfy requirements for various device characteristics used in a variety of circuits even if semiconductor layers with an SOI structure having simply two types of SOI film thicknesses is provided.

Semiconductor device and manufacturing method for the same


A system and method facilitate drilling of a lateral wellbore by eliminating one or more trips downhole. The system comprises a drill bit optimized for the drilling operation. The drill bit is coupled to a whipstock via a connector, which minimizes interference with the cutting elements of the drill bit. The connector includes a separation device which facilitates disconnection of the drill bit from the whipstock after the whipstock is anchored at a desired downhole location. The separation device is disposed in the connector to minimize the remaining portions of the connector existing after separation of the drill bit from the whipstock which must be milled by the drill bit prior to drilling the lateral wellbore.

Directional drilling has proven useful in facilitating production of formation fluid, e.g., hydrocarbon-based fluid, from a variety of reservoirs. In application, a vertical wellbore is drilled, and directional drilling is employed to create one or more deviated or lateral wellbores extending outwardly from the vertical wellbore. Often, a whipstock is employed to facilitate the drilling of lateral wellbores in a method referred to as sidetracking.
Whipstocks are designed with a face, or ramp surface, oriented to guide the drill bit in a lateral direction into the sidewall of the wellbore to establish a lateral or deviated wellbore, which branches from the existing vertical wellbore. The whipstock is positioned at a desired depth in the wellbore and oriented to facilitate directional drilling, i.e., sidetracking, of the lateral wellbore along the desired drill path. In many applications, sidetracking requires at least two trips downhole. In the initial trip, the whipstock is delivered downhole, oriented and set at the desired wellbore location. The second trip is used to deliver a bottomhole assembly with a conventional drill bit to drill the deviated secondary, lateral borehole. However, each trip downhole increases both the time and cost associated with the drilling operation.

System and method for coupling a drill bit to a whipstock