A position encoded sensing device having a display panel, a light guiding layer disposed on the display panel. The light guiding layer is configured to have encoded information therein. In addition, the position encoded sensing device includes a transceiver for detecting light and the encoded information that are guided out of the light guiding layer.

1. Field of the Invention
The present invention relates to a position encoded sensing device (PESD) and a method of sensing a position with respect to a display device. In particular, the present invention relates to a liquid crystal display sensing device having a position encoded light guide plate, together with a transceiver for emitting light to the light guide plate and receiving light reflected from the light guide plate, such that the present invention senses or determines the precise position of the transceiver with respect to the display, based on the encoded information disposed within the light guide plate.
2. Related Art
Flat panel displays have become very popular in the electronic industry. Flat panel displays are generally provided in electronic products such as notebook computers, desktop monitors, televisions, digital cameras, DVD players, PDAs, mobile phones, portable games, and car navigation systems, among other applications. Some flat panel displays are position sensible liquid crystal display (PSLCD) devices whereby the PSLCD can sense the position of a stylus only when the stylus is in a direct contact with the display panel.
For instance, FIG. 1 shows an LCD with an electromagnetic digitizer. FIG. 1 illustrates a flat panel display 10 having a cover and protective glass layer 11, an LCD layer 12, and an electromagnetic digitizer layer 13. The electromagnetic digitizer layer 13 contains a sensor board 15 made up wires in a grid format. The electromagnetic digitizer layer 13 is disposed at the bottom layer of the flat screen display 10. The flat screen display 10 of FIG. 1 is pressure sensitive such that the stylus 14 must be in a direct contact with the display 10. Pressure must be applied onto and detected by the sensor board of the electromagnetic digitizer layer 13 of the display 10 in order for the display 10 to sense the position of the stylus. The display 10 as shown in FIG. 2 is a complicated structure since the sensor board 15 contains a complicated grid of wires.
FIG. 2 shows another example of a PSLCD 20 having an integrated resistive touch sensor disposed therewith. The PSLCD 20 includes an LCD 21 and a polarizing filter 22. Moreover, the PSLCD 20 includes a flexible conductive layer 23 disposed on the polarizing filter 22. A stylus 24 is provided to make direct physical contact with the flexible conductive layer 23 of the PSLCD 20. In order for the PSLCD 20 to sense the position of the stylus 24, the flexible conductive layer 23 must sense the resistive touch applied by the stylus 24 on the display. Since the flexible conductive layer 23 is disposed on the polarizing filter 22 of the PSLCD 20 of FIG. 2, a substantial amount of processing is made on the polarizing filter 23. As such, the transparency of the display is significantly decreased.
In addition, FIG. 3 shows another example of a PSLCD device 30 which includes a LCD 31 and a stylus 32. In addition, the PSLCD device 30 includes a plurality of detecting units 33 disposed on two corners of the LCD 31. The PSLCD device 30 of FIG. 3 is a pressure sensitive device such that the stylus 32 must make physical contact with the LCD 31 in order for the PSLCD device 30 to function. Specifically, pressure must be applied to the LCD 31 from the stylus, and the detecting units 33 must detect the stylus and the applied pressure in order for the PSLCD device 30 to function properly. Given the configuration as shown in FIG. 3, the PSLCD device 30 contains numerous disadvantages. For example, the PSLCD device 30 requires a plurality of detecting units 33 mounted on the corners of the LCD 31 which causes the device to be ergonomically awkward and cumbersome. Moreover, the detecting units 33 increase the weight of the device. Also, the functional accuracy of the PSCLD device 30 is easily diminished by extraneous light and particles that comes into contact with the PSLCD device 30, and in particular in contact with the detecting units 33.
In view of the aforementioned PSLCD devices with their disadvantages, there is a need to have a flat screen display device that can employ a liquid crystal display sensing device having a position encoded light guide plate (LGP), together with a transceiver so that the display device can have a simplified module structure without requiring additional control circuitries. Moreover, there is also a need as well as market demand for a position encoded liquid crystal display sensing device that can be thinner in size and lighter in weight.

Position encoded sensing device and a method thereof


The invention relates to a cutting tool having twisted edge in a blade part, having a sintered compact with higher hardness and higher wear resistance than a base sintered body buried and affixed along the twisted edge, and its manufacturing method. The blade part of the cutting tool comprises the base sintered body having a twisted groove in the position of forming the twisted edge on the outer circumference, and the sintered compact of high hardness and high wear resistance applied and buried in the twisted groove and affixed to the base sintered body by sintering, and the twisted edge is formed on the sintered compact of high hardness and high wear resistance. Its manufacturing method comprises a step of forming a presintered or a sintered base material of the blade part with material powder, a step of forming a twisted groove on the outer circumferenced of the base material, a step of filling the twisted groove with material powder of sinter of high hardness and high wear resistance, a step of heating and pressurizing the base material with the material powder, and sintering and affixing the material powder to the base material, and a step of machining thus sintered and united base material to form a twisted edge on the sintered compact of high hardness and high wear resistance.

1. Field of the Invention
The present invention relates to an improvement of cutting tool such as end mill and reamer having a twisted edge in the blade part, and more particularly to a cutting tool comprising a sintered compact of high hardness and high wear resistance buried and affixed in the blade part along the twisted edge, the sintered compact, such as polycrystalline diamond sinter and cubic boron nitride sinter, being higher in hardness and wear-resistance than its base material, and the manufacturing method of the cutting tool.
2. Description of the Prior Art
Hitherto, in order to meet the demands for enhancing cutting efficiency and prolonging tool life, cutting tools such as end mill and reamer having a sintered compact of diamond or cubic boron nitride in the blade part, the sintered compact being very high in hardness and excellent in wear resistance, have been developed and employed.
The sintered compact of high hardness and high wear resistance used in such conventional cutting tools is in a chip form shaped by sintering fine powder of diamond or cubic boron nitride at high temperature and high pressure. Besides, to facilitate bonding to the base material of the blade part such as cemented carbide and steel, the material powder of diamond or cubic boron nitride is not sintered alone, but it is sintered and formed on a substrate made of cemented carbide or the like. Thus formed sintered chip is about 0.5 mm in thickness, and is shaped in circular, semicircular, sector, triangular, rectangular or other thin plate form, and this sintered chip is soldered to the buried and affixed in part of the base material of the blade part.
Examples of such conventional cutting tools are shown in FIG. 6 and FIG. 7.
A straight edge end mill 1 in FIG. 6 comprises a blade 2 and a shank 3, and the blade 2 made of cemented carbide, steel or the like is provided with a front edge 4a and a side straight edge 4b. In the blade 2, moreover, two sintered chips 5 of high hardness and high wear resistance in semicircular plate form are buried and affixed by soldering so as to form part of the edges 4a, 4b at positions where much load is applied while machining, in particular.
A straight edge end mill 1a shown in FIG. 7 is formed exactly the same, in which two bar-shaped sintered chips 5 of high hardness and high wear resistance are buried and affixed so as to form part of the front edge 4a and the side straight edge 4b.
Such structure is quite the same in other cutting tools.
Thus, in all conventional cutting tools, a high hardness sintered chip such as diamond sinter and cubic boron nitride sinter is buried and affixed so as to form part of the straight edge, and the other part of this straight edge is made of its base material itself.
Besides, such cutting tools composed of the sintered chips of high hardness and high were resistance buried therein are almost limited to straight edge type, and can not have twisted edge such as end mill and reamer. This is because such a sintered chip is formed by sintering material particles at high temperature and superhigh pressure, and as a matter of course thus formed sintered chip is limited in its shape and size, and can not be in a twisted shape or be buried to form part of the twisted edge.
Moreover, when burying and affixing the sintered chip of diamond or cubic boron nitride to the base material of the blade by soldering, the chip is heated to a considerably high temperature, and the adverse effect by the heat cannot be ignored. In particular, in the case of a diamond sintered chip, heating may cause to form a graphite layer on the sintered chip surface and to burn the chip, so a sufficient caution is needed during work.
Yet, whether in diamond or in cubic boron nitride, soldering of the sintered chip and the base material may be peeled off by the heat during the process of machining.
On the other hand, cutting tools having a twisted edge on the flank of the blade part, for example, spiral end mills, are known to be more excellent in the cutting performance and the dimensional precision after cutting than the straight edge end mills.

Cutting tool with twisted edge and manufacturing method thereof


This invention is directed to novel (N-substituted) indole ICE/ced-3-inhibitor compounds. The invention is also directed to pharmaceutical compositions of such indole compounds, plus the use of such compositions in the treatment of patients suffering inflammatory, autoimmune and neurodegenerative diseases, for the prevention of ischemic injury.

1. Field of the Invention
The present invention relates to novel classes of compounds which are inhibitors of interleukin-1xcex2 converting enzyme and related proteases (xe2x80x9cICE/ced-3 family of cysteine proteasesxe2x80x9d). This invention also relates to pharmaceutical compositions comprising these compounds and to methods of using such pharmaceutical compositions. The compounds, pharmaceutical compositions and methods of this invention are particularly well suited for inhibiting the protease activity of the ICE/ced-3 family and consequently. may be advantageously used as agents against interleukin-1 (xe2x80x9cIL-1xe2x80x9d) mediated diseases, including inflammatory diseases, autoimmune diseases and neurodegenerative diseases and for inhibiting unwanted apoptosis in various disease states such as ischemic injury to the heart (e.g., myocardial infarction), brain (e.g., stroke), and kidney (e.g., ischemic kidney disease).
2. Background Information
Interleukin 1 (xe2x80x9cIL-1xe2x80x9d) is a major pro-inflammatory and immunoregulatory protein that stimulates fibroblast differentiation and proliferation, the production of prostaglandins, collagenase and phospholipase by synovial cells and chondrocytes, basophil and eosinophil degranulation and neutrophil activation. Oppenheim, J. H. et al., Immunology Today, 7:45-56 (1986). As such, it is involved in the pathogenesis of chronic and acute inflammatory and autoimmune diseases. IL-1 is predominantly produced by peripheral blood monocytes as part of the inflammatory response. Mosely, B. S. et al., Proc. Nat. Acad. Sci., 84:4572-4576 (1987); Lonnemann, G. et al., Eur. J. Immunol., 19:1531-1536 (1989).
IL-1xcex2 is synthesized as a biologically inactive precursor, proIL-1xcex2. ProIL-1xcex2 is cleaved by a cysteine protease called interleukin-1xcex2 converting enzyme (xe2x80x9cICExe2x80x9d) between Asp-116 and Ala-117 to produce the biologically active C-terminal fragment found in human serum and synovial fluid. Sleath, P. R. et al., J. Biol. Chem., 265:14526-14528 (1992); A. D. Howard et al., J. Immunol., 147:2964-2969 (1991).
ICE is a cysteine protease localized primarily in monocytes. In addition to promoting the pro-inflammatory and immunoregulatory properties of IL-1xcex2, ICE, and particularly its homologues, also appear to be involved in the regulation of cell death or apoptosis. Yuan, J. et al., Cell, 75:641-652 (1993); Miura, M. et al., Cell, 75:653-660 (1993); Nett-Giordalisi, M. A. et al., J. Cell Biochem., 17B:117 (1993). In particular, ICE or ICE/ced-3 homologues are thought to be associated with the regulation of apoptosis in neurogenerative diseases, such as Alzheimer""s and Parkinson""s disease. Marx, J. and M. Baringa, Science, 259:760-762 (1993); Gagliardini, V. et al., Science, 263:826-828 (1994).
Thus, disease states in which inhibitors of the ICE/ced-3 family of cysteine proteases may be useful as therapeutic agents include: infectious diseases, such as meningitis and salpingitis; septic shock, respiratory diseases; inflammatory conditions, such as arthritis, cholangitis, colitis, encephalitis, endocerolitis, hepatitis, pancreatitis and reperfusion injury, ischemic diseases such as the myocardial infarction, stroke and ischemic kidney disease; immune-based diseases, such as hypersensitivity; auto-immune diseases, such as multiple sclerosis; bone diseases; and certain neurodegenerative diseases, such as Alzheimer""s and Parkinson""s disease.
ICE/ced-3 inhibitors represent a class of compounds useful for the control of the above-listed disease states. Peptide and peptidyl inhibitors of ICE have been described. However, such inhibitors have been typically characterized by undesirable pharmacologic properties, such as poor oral absorption, poor stability and rapid metabolism. Plattner, J. J. and D. W. Norbeck, in Drug Discovery Technologies, C. R. Clark and W. H. Moos, Eds. (Ellis Horwood, Chichester, England, 1990), pp. 92-126. These undesirable properties have hampered their development into effective drugs.
Accordingly, the need exists for compounds that can effectively inhibit the action of the ICE/ced-3 family of proteases, for use as agents for preventing unwanted apoptosis and for treating chronic and acute forms of IL-1 mediated diseases, such as inflammatory, autoimmune or neurodegenerative diseases. The present invention satisfies this need and provide related advantages as well.
One aspect of the instant invention is the compounds of Formula 1, set forth below.
A further aspect of the instant invention is pharmaceutical compositions comprising a compound of the above Formula 1 and a pharmaceutically-acceptable carrier therefor.
Other aspects of this invention involve a method for treating an autoimmune disease, an inflammatory disease, or a neurodegenerative disease comprising administering an effective amount of a pharmaceutical composition discussed above to a patient in need of such treatment.
Another aspect of the instant invention is a method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury comprising administering an effective amount of the pharmaceutical composition discussed above to a patient in need of such treatment.
The compounds of this invention incorporate an N-substituted indole ring as a peptidomimetic structural fragment. Despite lacking a hydrogen bond donor equivalent to the P3 amide nitrogen of known peptidic inhibitors of ICE, the N-substituted indole compounds of the instant invention have high activity as inhibitors of ICE/ced-3 protease family of enzymes. These compounds also demonstrate other advantages relative to known peptidic inhibitors.
One aspect of the instant invention is the compounds of the Formula 1:
wherein:
n is 1 or 2;
R1 is alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl or (CH2)mCO2R4, wherein m=1-4, and R4 is as defined below;
R2 is a hydrogen atom, chloro, alkyl, cycloalkyl, cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl or (CH2)pCO2R5, wherein p=0-4, and R5 is as defined below;
R3 is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;
R4 is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;
R5 is a hydrogen atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenylalkyl, or (substituted)phenylalkyl;
A is a natural or unnatural amino acid;
B is a hydrogen atom, a deuterium atom, alkyl, cycloalkyl, (cycloalkyl)alkyl, phenyl, (substituted)phenyl, phenylalkyl, (substituted)phenylalkyl, heteroaryl, (heteroaryl)alkyl, halomethyl, CH2ZR6, CH2OCO(aryl), or CH2OCO(heteroaryl), or CH2OPO(R7)R8, where Z is an oxygen, OC(xe2x95x90O) or a sulfur atom;
R6 is phenyl, substituted phenyl, phenylalkyl, (substituted phenyl)alkyl, heteroaryl or (heteroaryl)alkyl;
R7 and R8 are independently selected from a group consistent of alkyl, cycloalkyl, phenyl, substituted phenyl, phenylalkyl, (substituted phenyl) alkyl and (cycloalkyl)alkyl; and
X and Y are independently selected from the group consisting of a hydrogen atom, halo, trihalomethyl, amino, protected amino, an amino salt, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, a carboxylate salt, hydroxy, protected hydroxy, a salt of a hydroxy group, lower alkoxy, lower alkylthio, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and (substituted phenyl)alkyl;
or a pharmaceutically acceptable salt or stereoisomer thereof.
As used in the above formula, the term xe2x80x9calkylxe2x80x9d means a straight or branched C1 to C8 carbon chain such as methyl, ethyl, tert-butyl, iso-propyl, iso-butyl, n-octyl, and the like.
The term xe2x80x9ccycloalkylxe2x80x9d means a mono-, bi-, or tricyclic ring that is either fully saturated or partially unsaturated. Examples of such a ring include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl, cis- or trans decalin, bicyclo[2.2.1]hept-2-ene, cyclohex-1-enyl, cyclopent-1-enyl,1,4-cyclooctadienyl, and the like.
The term xe2x80x9c(cycloalkyl)alkylxe2x80x9d means the above-defined alkyl group substituted with one of the above cycloalkyl rings. Examples of such a group include (cyclohexyl)methyl, 3-(cyclopropyl)-n-propyl, 5-(cyclopentyl)hexyl, 6-(adamantyl)hexyl, and the like.
The term xe2x80x9csubstituted phenylxe2x80x9d specifies a phenyl group substituted with one or more, and preferably one or two, moieties chosen from the groups consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, trifluoromethyl, C1 to C7 alkyl, C1 to C7 alkoxy, C1 to C7 acyl, C1 to C7 acyloxy, heteroaryl, carboxy, protected carboxy, carboxymethyl, protected carboxymethyl, hydroxymethyl, protected hydroxymethyl, amino, protected amino, (monosubstituted) amino, protected (monosubstituted) amino, (disubstituted)amino, carboxamide, protected carboxamide, N-(C1 to C6 alkyl or alkoxy)carboxamide, protected N-(C1 to C6 alkyl or alkoxy)carboxamide, N,N-di(C1 to C6 alkyl or alkoxy)carboxamide, N-((C1 to C6 alkyl)sulfonyl)amino, N-(phenylsulfonyl)amino or by a substituted or unsubstituted phenyl group, such that in the latter case a biphenyl or naphthyl group results, including biphenyl or naphthyl groups optionally substituted with one or more substituents as identified above.
Examples of the term xe2x80x9csubstituted phenylxe2x80x9d includes a mono- or di(halo)phenyl group such as 2-, 3- or 4-chlorophenyl, 2,6-dichlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 2-,3- or 4-bromophenyl, 3,4-dibromophenyl, 3-chloro-4-fluorophenyl, 2-, 3- or 4-fluorophenyl and the like, as well as tri- or tetra(halo)phenyl groups such as 2,3,5,6-fluorophenyl; a mono or di(hydroxy)phenyl group such as 2-, 3-, or 4-hydroxyphenyl, 2,4-dihydroxyphenyl, the protected-hydroxy derivatives thereof and the like; a nitrophenyl group such as 2-, 3-, or 4-nitrophenyl; a cyanophenyl group, for example, 2-,3- or 4-cyanophenyl; a mono- or di(alkyl)phenyl group such as 2-, 3-, or 4-methylphenyl, 2,4-dimethylphenyl, 2-, 3- or 4-(isopropyl)phenyl, 2-, 3-, or 4-ethylphenyl, 2-, 3- or 4-(n-propyl)phenyl and the like; a mono or di(alkoxy)phenyl group, for example, 2,6-dimethoxyphenyl, 2-, 3- or 4-(isopropoxy)phenyl, 2-, 3- or 4-(t-butoxy)phenyl, 3-ethoxy-4-methoxyphenyl and the like; 2-, 3- or 4-trifluoromethylphenyl; a mono- or dicarboxyphenyl or (protected carboxy)phenyl group such as 2-, 3- or 4-carboxyphenyl or 2,4-di(protected carboxy)phenyl; a mono- or di(hydroxymethyl)phenyl or (protected hydroxymethyl)phenyl such as 2-, 3- or 4-(protected hydroxymethyl)phenyl or 3,4-di(hydroxymethyl)phenyl; a mono- or di(aminomethyl)phenyl or (protected aminomethyl)phenyl such as 2-, 3- or 4-(aminomethyl)phenyl or 2,4-(protected aminomethyl)phenyl; or a mono- or di(N-(methylsulfonylamino))phenyl such as 2,3 or 4-(N-(methylsulfonylamino))phenyl. Also, the term xe2x80x9csubstituted phenylxe2x80x9d represents disubstituted phenyl groups wherein the substituents are different, for example, 3-methyl-4-hydroxyphenyl, 3-chloro-4-hydroxyphenyl, 2-methoxy-4-bromophenyl, 4-ethyl-2-hydroxyphenyl, 3-hydroxy-4-nitrophenyl, 2-hydroxy-4-chlorophenyl, and the like.
The term xe2x80x9c(substituted phenyl)alkylxe2x80x9d means one of the above substituted phenyl groups attached to one of the above-described alkyl groups. Examples of such groups include 2-phenyl-1-chloroethyl, 2-(4xe2x80x2-methoxyphenyl)ethyl, 4-(2xe2x80x2,6xe2x80x2-dihydroxy phenyl)n-hexyl, 2-(5xe2x80x2-cyano-3xe2x80x2-methoxyphenyl)n-pentyl, 3-(2xe2x80x2,6xe2x80x2-dimethylphenyl)n-propyl, 4-chloro-3-aminobenzyl, 6-(4xe2x80x2-methoxyphenyl)-3-carboxy(n-hexyl), 5-(4xe2x80x2-aminomethylphenyl)-3-(aminomethyl)n-pentyl, 5-phenyl-3-oxo-n-pent-1-yl, (4-hydroxynapth-2-yl)methyl, and the like.
The terms xe2x80x9chaloxe2x80x9d and xe2x80x9chalogenxe2x80x9d refer to the fluoro, chloro, bromo or iodo groups. There can be one or more halogen, which are the same or different. Preferred halogens are chloro and fluoro.
The term xe2x80x9carylxe2x80x9d refers to aromatic five and six membered carbocyclic rings. Six membered rings are preferred.
The term xe2x80x9cheteroarylxe2x80x9d denotes optionally substituted five-membered or six-membered rings that have 1 to 4 heteroatoms, such as oxygen, sulfur and/or nitrogen atoms, in particular nitrogen, either alone or in conjunction with sulfur or oxygen ring atoms. These five-membered or six-membered rings are fully unsaturated.
The following ring systems are examples of the heterocyclic (whether substituted or unsubstituted) radicals denoted by the term xe2x80x9cheteroarylxe2x80x9d: thienyl, fluryl, pyrrolyl, pyrrolidinyl, imidazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, oxazinyl, triazinyl, thiadiazinyl tetrazolo, 1,5-[b]pyridazinyl and purinyl, as well as benzo-fused derivatives, for example, benzoxazolyl, benzothiazolyl, benzimidazolyl and indolyl.
Substituents for the above optionally substituted heteroaryl rings are from one to three halo, trihalomethyl, carboxamide, amino, protected amino, amino salts, mono-substituted amino, di-substituted amino, carboxy, protected carboxy, carboxylate salts, hydroxy, protected hydroxy, salts of a hydroxy group, lower alkoxy, lower alkylthio, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, (cycloalkyl)alkyl, substituted (cycloalkyl)alkyl, phenyl, substituted phenyl, phenylalkyl, and (substituted phenyl)alkyl groups. Substituents for the heteroaryl group are as heretofore defined, or as set forth below. As used in conjunction with the above substituents for heteroaryl rings, xe2x80x9ctrihalomethylxe2x80x9d can be trifluoromethyl, trichloromethyl, tribromomethyl or triiodomethyl, xe2x80x9clower alkoxyxe2x80x9d means a C1 to C4 alkoxy group, similarly, xe2x80x9clower alkylthioxe2x80x9d means a C1 to C4 alkylthio group. The term xe2x80x9csubstituted alkylxe2x80x9d means the above-defined alkyl group substituted from one to three times by a hydroxy, protected hydroxy, amino, protected amino, cyano, halo, trifluoromethyl, mono-substituted amino, di-substituted amino, lower alkoxy, lower alkylthio, carboxy, protected carboxy, or a carboxy, amino, and/or hydroxy salt. As used in conjunction with the substituents for the heteroaryl rings, the terms xe2x80x9csubstituted (cycloalkyl)alkylxe2x80x9d and xe2x80x9csubstituted cycloalkylxe2x80x9d are as defined above substituted with the same groups as listed for a xe2x80x9csubstituted alkylxe2x80x9d group. The term xe2x80x9c(monosubstituted)aminoxe2x80x9d refers to an amino group with one substituent chosen from the group consisting of phenyl, substituted phenyl, alkyl, substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 substituted alkenyl, C2 to C7 alkynyl, C7 to C16 alkylaryl, C7 to C16 substituted alkylaryl and heteroaryl group. The (monosubstituted)amino can additionally have an amino-protecting group as encompassed by the term xe2x80x9cprotected (monosubstituted)amino.xe2x80x9d The term xe2x80x9c(disubstituted)aminoxe2x80x9d refers to amino groups with two substituents chosen from the group consisting of phenyl, substituted phenyl, alkyl, substituted alkyl, C1 to C7 acyl, C2 to C7 alkenyl, C2 to C7 alkynyl, C7 to C16 alkylaryl, C7 to C16 substituted alkylaryl and heteroaryl. The two substituents can be the same or different. The term xe2x80x9cheteroaryl(alkyl)xe2x80x9d denotes an alkyl group as defined above, substituted at any position by a heteroaryl group, as above defined.
Furthermore, the above optionally substituted five-membered or six-membered heterocyclic rings can optionally be fused to a aromatic 5-membered or 6-membered aryl or heteroaryl ring system. For example, the rings can be optionally fused to an aromatic 5-membered or 6-membered ring system such as a pyridine or a triazole system, and preferably to a benzene ring.
The term xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d encompasses those salts that form with the carboxylate anions and includes salts formed with the organic and inorganic cations such as those chosen from the alkali and alkaline earth metals, (for example, lithium, sodium, potassium, magnesium, barium and calcium); and ammonium ion; and the organic cations (for example, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium, bis(2-hydroxyethyl)ammonium, phenylethylbenzylammonium, dibenzylethylenediammonium, and like cations.) Other cations encompassed by the above term include the protonated form of procaine, quinine and N-methylglucosamine, the protonated forms of basic amino acids such as glycine, omithine, histidine, phenylglycine, lysine, and arginine. Furthermore, any zwitterionic form of the instant compounds formed by a carboxylic acid and an amino group is referred to by this term. A preferred cation for the carboxylate anion is the sodium cation. Furthermore, the term includes salts that form by standard acid-base reactions with basic groups (such as amino groups) and includes organic or inorganic acids. Such acids include hydrochloric, sulfuric, phosphoric, acetic, succinic, citric, lactic, maleic, fumaric, palmitic, cholic, pamoic, mucic, D-glutamic, D-camphoric, glutaric, phthalic, tartaric, lauric, stearic, salicyclic, methanesulfonic, benzenesulfonic, sorbic, picric, benzoic, cinnamic, and the like acids.
The compounds of Formula I may also exist as solvates and hydrates. Thus, these compounds may crystallize with, for example, waters of hydration, or one, a number of, or any fraction thereof of molecules of the mother liquor solvent. The solvates and hydrates of such compounds are included within the scope of this invention.
The term xe2x80x9ccarboxy-protecting groupxe2x80x9d as used herein refers to one of the ester derivatives of the carboxylic acid group commonly employed to block or protect the carboxylic acid group while reactions are carried out on other functional groups on the compound. Examples of such carboxylic acid protecting groups include t-butyl, 4-nitrobenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,4,6-trimethoxybenzyl, 2,4,6-trimethylbenzyl, pentamethylbenzyl, 3,4-methylenedioxybenzyl, benzhydryl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, 2-phenylpropyl, trimethylsilyl, t-butyldimethylsilyl, phenacyl, 2,2,2-trichloroethyl, xcex2-(trimethylsilyl)ethyl, xcex2-(di(n-butyl)methylsilyl)ethyl, p-toluenesulfonylethyl, 4-nitrobenzylsulfonylethyl, allyl, cinnamyl, 1-(trimethylsilylmethyl)-propenyl and like moieties. The species of carboxy-protecting group employed is not critical so long as the derivatized carboxylic acid is stable to the conditions of subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Further examples of these groups are found in C. B. Reese and E. Haslam, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapter 5, respectively, and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 5, each of which is incorporated herein by reference. A related term is xe2x80x9cprotected carboxy,xe2x80x9d which refers to a carboxy group substituted with one of the above carboxy-protecting groups.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d refers to readily cleavable groups bonded to hydroxyl groups, such as the tetrahydropyranyl, 2-methoxyprop-2-yl, 1-ethoxyeth-1-yl, methoxymethyl, xcex2-methoxyethoxymethyl, methylthiomethyl, t-butyl, t-amyl, trityl, 4-methoxytrityl, 4,4xe2x80x2-dimethoxytrityl, 4,4xe2x80x2,4xe2x80x3-trimethoxytrityl, benzyl, allyl, trimethylsilyl, (t-butyl)dimethylsilyl, 2,2,2-trichloroethoxycarbonyl, and the like.
Further examples of hydroxy-protecting groups are described by C. B. Reese and E. Haslam, xe2x80x9cProtective Groups in Organic Chemistry,xe2x80x9d J. G. W. McOmie, Ed., Plenum Press, New York, N.Y., 1973, Chapters 3 and 4, respectively, and T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d Second Edition, John Wiley and Sons, New York, N.Y., 1991, Chapters 2 and 3. A preferred hydroxy-protecting group is the tert-butyl group. The related term xe2x80x9cprotected hydroxyxe2x80x9d denotes a hydroxy group bonded to one of the above hydroxy-protecting groups.
The term xe2x80x9camino-protecting groupxe2x80x9d as used herein refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups of the molecule. The term xe2x80x9cprotected (monosubstituted)aminoxe2x80x9d means there is an amino-protecting group on the monosubstituted amino nitrogen atom.
Examples of such amino-protecting groups include the formyl (xe2x80x9cForxe2x80x9d) group, the trityl group, the phthalimido group, the trichloroacetyl group, the trifluoroacetyl group, the chloroacetyl, bromoacetyl, and iodoacetyl groups, urethane-type protecting groups, such as t-butoxycarbonyl (xe2x80x9cBocxe2x80x9d), 2-(4-biphenylyl)propyl-2-oxycarbonyl (xe2x80x9cBpocxe2x80x9d), 2-phenylpropyl-2-oxycarbonyl (xe2x80x9cPocxe2x80x9d), 2-(4-xenyl)isopropoxycarbonyl, 1,1-diphenylethyl-1-oxycarbonyl, 1,1-diphenylpropyl-1-oxycarbonyl, 2-(3,5-dimethoxyphenyl)propyl-2-oxycarbonyl (xe2x80x9cDdzxe2x80x9d), 2-(p-toluyl)propyl-2-oxycarbonyl, cyclopentanyloxycarbonyl, 1-methylcyclopentanyl-oxycarbonyl, cyclohexanyloxy-carbonyl, 1-methyl-cyclohexanyloxycarbonyl, 2-methylcyclohexanyl-oxycarbonyl, 2-(4-toluylsulfonyl)ethoxycarbonyl, 2-(methylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphino)-ethoxycarbonyl, 9-fluorenylmethoxycarbonyl (xe2x80x9cFmocxe2x80x9d), 2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl, 1-(trimethylsilylmethyl)prop-1-enyloxycarbonyl, 5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyl-oxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl, cyclopropylmethoxycarbonyl, isobornyloxycarbonyl, 1-piperidyloxycarbonyl, benzyloxycarbonyl (xe2x80x9cCbzxe2x80x9d), 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, xcex1-2,4,5,-tetramethylbenzyl-oxycarbonyl (xe2x80x9cTmzxe2x80x9d), 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, 2,4-dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 4-cyanobenzyloxycarbonyl, 4-(decyloxy)benzyloxycarbonyl and the like; the benzoylmethylsulfonyl group, the 2,2,5,7,8-pentamethylchroman-6-sulfonyl group (xe2x80x9cPMCxe2x80x9d), the dithiasuccinoyl (xe2x80x9cDtsxe2x80x9d) group, the 2-(nitro)phenyl-sulfenyl group (xe2x80x9cNpsxe2x80x9d), the diphenylphosphine oxide group, and like amino-protecting groups. The species of amino-protecting group employed is not critical so long as the derivatized amino group is stable to the conditions of the subsequent reaction(s) and can be removed at the appropriate point without disrupting the remainder of the molecule. Preferred amino-protecting groups are Boc, Cbz and Fmoc. Further examples of amino-protecting groups embraced by the above term are well known in organic synthesis and the peptide art and are described by, for example, T. W. Greene and P. G. M. Wuts, xe2x80x9cProtective Groups in Organic Synthesis,xe2x80x9d 2nd ed., John Wiley and Sons, New York, N.Y., 1991, Chapter 7, M. Bodanzsky, xe2x80x9cPrinciples of Peptide Synthesis,xe2x80x9d 1st and 2nd revised Ed., Springer-Verlag, New York, N.Y., 1984 and 1993, and J. M. Stewart and J. D. Young, xe2x80x9cSolid Phase Peptide Synthesis,xe2x80x9d 2nd Ed., Pierce Chemical Co., Rockford, Ill., 1984, E. Atherton and R. C. Shephard, xe2x80x9cSolid Phase Peptide Synthesisxe2x80x94A Practical Approachxe2x80x9d IRL Press, Oxford, England (1989), each of which is incorporated herein by reference. The related term xe2x80x9cprotected aminoxe2x80x9d defines an amino group substituted with an amino-protecting group discussed above.
The terms xe2x80x9cnatural and unnatural amino acidxe2x80x9d refers to both the naturally occurring amino acids and other non-proteinogenic xcex1-amino acids commonly utilized by those in the peptide chemistry arts when preparing synthetic analogues of naturally occurring peptides, including D and L forms. The naturally occurring amino acids are glycine, alanine, valine, leucine, isoleucine, serine, methionine, threonine, phenylalanine, tyrosine, tryptophan, cysteine, proline, histidine, aspartic acid, asparagine, glutamic acid, glutamine, xcex3-carboxyglutamic acid, arginine, omithine and lysine. Examples of unnatural alpha-amino acids include hydroxylysine, citrulline, kynurenine, (4-aminophenyl)alanine, 3-(2xe2x80x2-naphthyl)alanine, 3-(1xe2x80x2-naphthyl)alanine, methionine sulfone, (t-butyl)alanine, (t-butyl)glycine, 4-hydroxyphenyl-glycine, aminoalanine, phenylglycine, vinylalanine, propargyl-gylcine, 1,2,4-triazolo-3-alanine, thyronine, 6-hydroxytryptophan, 5-hydroxytryptophan, 3-hydroxy-kynurenine, 3-aminotyrosine, trifluoromethylalanine, 2-thienylalanine, (2-(4-pyridyl)ethyl)cysteine, 3,4-dimethoxy-phenylalanine, 3-(2xe2x80x2-thiazolyl)alanine, ibotenic acid, 1-amino-1-cyclopentane-carboxylic acid, 1-amino-1-cyclohexanecarboxylic acid, quisqualic acid, 3-(trifluoromethylphenyl)alanine, (cyclohexyl)glycine, thiohistidine, 3-methoxytyrosine, norleucine, norvaline, alloisoleucine, homoarginine, thioproline, dehydro-proline, hydroxyproline, homoproline, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydroquinoline-2-carboxylic acid, xcex1-amino-n-butyric acid, cyclohexylalanine, 2-amino-3-phenylbutyric acid, phenylalanine substituted at the ortho, meta, or para position of the phenyl moiety with one or two of the following groups: a (C1 to C4)alkyl, a (C1 to C4)alkoxy, a halogen or a nitro group, or substituted once with a methylenedioxy group; xcex2-2- and 3-thienylalanine; xcex2-2- and 3-furanylalanine; xcex2-2-, 3- and 4-pyridylalanine; xcex2-(benzothienyl-2- and 3-yl)alanine; xcex2-(1- and 2-naphthyl)alanine; O-alkylated derivatives of serine, threonine or tyrosine; S-alkylated cysteine, S-alkylated homocysteine, the O-sulfate, O-phosphate and O-carboxylate esters of tyrosine; 3-(sulfo)tyrosine, 3-(carboxy)tyrosine, 3-(phospho)tyrosine, the 4-methane-sulfonic acid ester of tyrosine, 4-methanephosphonic acid ester of tyrosine, 3,5-diiodotyrosine, 3-nitrotyrosine, xcex5-alkyllysine, and delta-alkyl omithine. Any of these xcex1-amino acids may be substituted with a methyl group at the alpha position, a halogen at any position of the aromatic residue on the xcex1-amino side chain, or an appropriate protective group at the O, N, or S atoms of the side chain residues. Appropriate protective groups are discussed above.
Depending on the choice of solvent and other conditions known to the practitioner skilled in the art, compounds of this invention may also take the hemi-ketal, hemi-acetal, ketal or acetal form, which forms are included in the instant invention.
In addition, it should be understood that the equilibrium forms of the compounds of this invention may include tautomeric forms. All such forms of these compounds are expressly included in the present invention.
Also, it will be understood by those skilled in the art that when B in Formula 1 is a hydrogen atom, a semicarbazone may be formed with the resulting aldehyde. Such semicarbazones are also included as compounds of Formula 1, as well as the pharmaceutical compositions containing those compounds. Such semicarbazones also include, for example, semicarbazone derivatives of the optimal groups and embodiments of the 4-oxo-butanoic acid derivatives of the compounds of Formula 1 set forth below.
The compounds of this invention may be modified by appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of exertion. In addition, the compounds may be altered to pro-drug form such that the desired compound is created in the body of the patient as the result of the action of metabolic or other biochemical processes on the pro-drug. Some examples of pro-drug forms include ketal, acetal, oxime, and hydrazone forms of compounds which contain ketone or aldehyde groups, especially where they occur in the group donated as xe2x80x9cAxe2x80x9d in Formula 1 or the modified aspartic or glutamic residues attached to the group denoted as xe2x80x9cAxe2x80x9d.
In the above Formula 1, a group of optimal compounds occurs when n is one, more so when G is carbonyl group and B is a hydrogen atom, and especially so when R3 is a hydrogen atom or a t-butyl group. Of note within this group of compounds as those when A is naturally-occurring amino acid. This latter group of compounds will be referred to herein as the xe2x80x9c4-oxobutanoic compoundsxe2x80x9d.
Within this group of 4-oxobutanoic compounds is a group of optimal compounds wherein R1 is a methyl group, that is, the N-methylindole compounds. One embodiment of this group of N-methylindole compounds occurs when A is an alanine, valine, leucine, phenylalanine, glycine or a proline residue. Compounds of note within each one of these groups of natural amino acid, N-methylindole compounds occur when the N-methylindole is otherwise unsubstituted, that is, wherein X, Y and R2 are each a hydrogen atom, and optimally so when R3 is a hydrogen atom.
Another optimal group of 4-oxobutanoic compounds consists of the N-benzylindole compounds. For example, one group of the N-benzylindole compounds occurs when A is an alanine residue. Of note within this group of alanine compounds are those in which X, Y and R2 are each a hydrogen atom, and especially so where R3 is a hydrogen atom.
An alternate optimal group of 4-oxobutanoic compounds occurs when the N-substituent of the indole group is a 1-butenyl group. An embodiment of this group of N-(1-butenyl)indole compounds occurs when A is a valine residue, and especially so when X, Y and R2 are each a hydrogen atom. An optimal group of this. latter group of compounds occurs when R3 is a hydrogen atom.
Yet another group of optimal 4-oxobutanoic compounds occurs when the N-substituent of the indole ring is a 2xe2x80x2-acetic acid residue. An exemplary group of the N-(2xe2x80x2-acetic acid compounds) occurs when A is an alanine residue. An embodiment of this particular group of alanine compounds occurs when X, Y and R2 are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
A group of the 4-oxobutanoic compounds when the indole group is substituted on the nitrogen with 3xe2x80x2-propionic acid residue is another example of this invention. An optimal group of such N-(propionic acid)indole compounds occurs when A is an alanine residue. Of note within this group of alanine compounds are those when X, Y and R2 are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Another optimal group of compounds of Formula 1 occurs wherein n is one and more so when B is a monofluoromethyl group. An embodiment of these monofluoromethyl compounds occurs when R3 is a hydrogen atom or a t-butyl group, and an even more so when A is a natural amino acid. An example of these compounds wherein A is a natural amino acid occurs when A is a valine residue. This latter group of valine compounds will be referred to herein as the xe2x80x9c4-oxo-5-(fluoropentanoic acid) compoundsxe2x80x9d.
One optimal group of 4-oxo-5-(fluoropentanoic acid) compounds occurs when R1 is a methyl group, in other words, the N-methylindole compounds. An exemplary group of such N-methylindole compounds occurs when R2 is a methyl group and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom. Another exemplary group of such N-methylindole compounds occurs when R2 is a chloro atom and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom. A third exemplary group of N-methylindole compounds occurs when R2 is a chloro group, X is a 5-fluoro group, and Y is a hydrogen atom, and especially so when R3 is a hydrogen atom. A fourth exemplary group of N-methylindole compounds occurs when R2 is iso-butyl and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Another optimal group of 4-oxo-5-(fluoro-pentanoic acid) compounds is composed of N-(3xe2x80x2-phenylprop-1-yl) indole compounds. A group of note within this latter class of compounds occurs when R2, X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
A third optimal group of 4-oxo-5-(fluoro-pentanoic acid) compounds has an N-(carboxymethyl or protected carboxymethyl) indole moiety. An embodiment of this group occurs wherein R2, X and Y are each a hydrogen atom, and especially so wherein R3 is a hydrogen atom and the nitrogen atom of the indole ring is substituted with a carboxymethyl group.
A fourth optimal group of 4-oxo-5(fluoropentanoic acid) compounds has an N-(homoallyl)indole moiety. One embodiment of note within this group occurs when R2, X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Yet another optimal group of compounds of Formula 1 occurs wherein n is one and more so when B is a (2,6-dichorobenzyloxy)-methyl group. An embodiment of these (2,6-dichorobenzyloxy)methyl compounds occurs when R3 is a hydrogen atom or a t-butyl group, and even more so when A is a natural amino acid. An example of these compounds wherein A is a natural amino acid occurs when A is a valine residue. This latter group of valine compounds will be referred to herein as the xe2x80x9c(dichlorobenzyloxy)methylxe2x80x9d compounds.
One optimal group of (dichlorobenzyloxy)methyl compounds occurs when R1 is a methyl group, in other words, the N-methylindole compounds. An exemplary group of such N-methylindole compounds occurs when R2 is a methyl group and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Another optimal group of compounds of Formula 1 occurs wherein n is one and more so when B is a group of the formula CH2OPO(R7)R8. An embodiment of these phosphinyloxy-substituted compounds occurs when R3 is a hydrogen atom or a t-butyl group, and an even more so when A is a natural amino acid. An example of these compounds wherein A is a natural amino acid occurs when A is a valine residue. This latter group of valine compounds will be referred to herein as the xe2x80x9cphosphinyloxymethylxe2x80x9d compounds.
One optimal group of phosphinyloxymethyl compounds occurs when R7 and R8 are each a phenyl group, and more so when R1 is a methyl group, in other words, the N-methylindole compounds. An exemplary group of such N-methylindole compounds occurs when R2 is a methyl group and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Still another optimal group of compounds of Formula 1 occurs wherein n is one and more so when B is a group CH2ZR6. Optimal embodiment further occurs when R6 is a heteroaryl group, and more so when Z in an oxygen atom. An embodiment of these (heteroaryl) oxymethyl compounds occurs when R3 is a hydrogen atom or a t-butyl group, and an even more so when A is a natural amino acid. An example of these compounds wherein A is a natural amino acid occurs when A is a valine residue. This latter group of valine compounds will be referred to herein as the xe2x80x9cheteroaryloxyxe2x80x9d compounds.
One optimal group of heteroaryloxy compounds occurs when the heteroaryloxy group is substituted or unsubstituted pyrazol-5-yloxymethyl, and especially so when this group is (1-phenyl-3-(trifluoromethyl)pyrazol-5-yl)oxymethyl, and even more so when R1 is a methyl group, in other words, the N-methyliindole compounds. An exemplary group of such N-methylindole compounds occurs when R2 is a methyl group and X and Y are each a hydrogen atom, and especially so when R3 is a hydrogen atom.
Another optimal group of compounds of Formula 1 occurs when B is CH2ZR6 and Z is oxygen or OC(xe2x95x90O).
The compounds of Formula 1 may be synthesized using conventional techniques as discussed below. Advantageously, these compounds are conveniently synthesized from readily available starting materials.
One synthetic route for synthesizing the instant compounds is set forth in the following Scheme I:
In the above Scheme I, Formula (2), that is H2Nxe2x80x94Z, is a modified aspartic or glutamic acid residue of Formulas 2a through 2d:
In the above Scheme I, xe2x80x9cPGxe2x80x9d stands for an amino protecting group and xe2x80x9cAxe2x80x9d stands for a natural or unnatural amino acid, as discussed above.
The modified aspartic or glutamic acids of Formula 2a-d can be prepared by methods well known in the art. See, for example, European Patent Application 519,748; PCT Patent Application No. PCT/EP92/02472; PCT Patent Application No. PCT/US91/06595; PCT Patent Application No. PCT/US91/02339; European Patent Application No. 623,592; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US94/08868; European Patent Application No. 623,606; European Patent Application No. 618,223; European Patent Application No. 533,226; European Patent Application No. 528,487; European Patent Application No. 618,233; PCT Patent Application No. PCT/EP92/02472; World Patent Application No. WO 93/09135; PCT Patent Application No. PCT/US93/03589; and PCT Patent Application No. PCT/US93/00481, all of which are herein incorporated by reference.
The coupling reactions carried out under Step A are performed in the presence of a standard peptide coupling agent such as the combination of the combination of dicyclohexylcarbodiimide(DCC) and 1-hydroxy-benzotriazole(HOBt), as well as the BOP(benzotriazolyloxy-trio-(dimethylamino)phosphonium hexafluorophosphate) reagent, pyBOP (benzotriazolyloxy-tris(N-pyrolidinyl)phosphoniumhexafluorophosphate), HBTU (O-benzotriazolyly-tetramethylisouronium-hexafluorophosphate), and EEDQ (1-ethyloxycarbonyl-2-ethyloxy-1,2-dihydroquinoline) reagents, the combination of 1-ethyl(3,3xe2x80x2-dimethyl-1-1xe2x80x2-aminopropyl)carbodiimide (EDAC) and HOBt, and the like, as discussed in J. Jones, xe2x80x9cAmino Acid and Peptide Synthesis,xe2x80x9d Steven G. Davis ed., Oxford University Press, Oxford, pp. 25-41 (1992); M. Bodanzky, xe2x80x9cPrinciples of Peptide Synthesis,xe2x80x9d Hafner et al. ed., Springer-Verlag, Berlin Heidelberg, pp. 9-52 and pp. 202-251 (1984); M. Bodanzky, xe2x80x9cPeptide Chemistry, A Practical Textbook,xe2x80x9d Springer-Verlag, Berlin Heidelberg, pp. 55-73 and pp. 129-180; and Stewart and Young, xe2x80x9cSolid Phase Peptide Synthesis,xe2x80x9d Pierce Chemical Company, (1984), all of which are herein incorporated by reference. The amino protecting group is then removed and the resulting amine is coupled to the 2-(carboxy)indole of Formula 4 (Step B). Again, this coupling reaction uses the standard peptide coupling reactions mentioned above. The indole ring of Formula 4 can be substituted before the reaction in Step B or afterwards. The synthesis and substitution reactions of such an indole ring is well known, as is described, for example, in Brown, R. T. and Joule, J. A. in xe2x80x9cHeterocyclic chemistry (ed. P. G. Sammes) (Vol 4 of Comprehensive Organic Chemistry, ed. D. Barton and W. D. Ollis), (1979), Pergamon Press, Oxford; Houlihan, W. J., (ed.) in xe2x80x9cIndoles (The Chemistry of Heterocyclic Compounds [ed. A. Weissburger and E. C. Taylor], Vol. 25, Parts 1-3), Wiley Interscience, New York (1972); and Saxton, J. E. (ed.) in xe2x80x9cIndoles (The Chemistry of Heterocyclic Compounds),xe2x80x9d [ed. A. Weissburger and E. C. Taylor], Vol. 25, Part 4), Wiley Interscience, New York, (1979); all of which are incorporated herewith by reference.
In the case where the coupling reaction was carried out with the amino alcohol of Formula 2c, the alcohol moiety must be oxidized to the corresponding carbonyl compound prior to removal of the protecting groups. Preferred methods for the oxidation reaction include Swem oxidation (oxalyl chloride-dimethyl sulfoxide, methylene chloride at xe2x88x9278xc2x0 C. followed by triethylamine); and Dess-Martin oxidation (Dess-Martin periodinane, t-butanol, and methylene chloride.) The protecting groups contained in substructures of the Formula 2a-d and A are removed by methods well known in the art. These reactions and removal of some or all of the protecting groups are involved in Step C in the above Scheme.
Pharmaceutical compositions of this invention comprise any of the compounds of Formula 1, of the present invention, and pharmaceutically acceptable salts thereof, with any pharmaceutically acceptable carrier, adjuvant or vehicle (hereinafter collectively referred to as xe2x80x9cpharmaceutically-acceptable carriersxe2x80x9d). These compositions also include the groups and embodiments of compounds discussed above, as well as the compounds of the Examples discussed below. Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchange, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin; buffer substances such as the various phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids; water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, and zinc salts; colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethyicellulose, polyarylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat, and the like.
Such pharmaceutical compositions will be understood to include the optimal groups and embodiments of the compounds of Formula 1 set forth above.
The pharmaceutical compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or by an implanted reservoir. Oral and parenteral administration are preferred. The term xe2x80x9cparenteralxe2x80x9d as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrastemal, intrathecal, intralesional and intracranial injection or infusion techniques.
The pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, and aqueous suspensions and solutions. In the case of tablets for oral use, carrier which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
The pharmaceutical compositions of this invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of this invention with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature. Such materials include, but are not limited to, cocoa butter, beeswax and polyethylene glycols.
Topical administration of the pharmaceutical compositions of this invention is especially useful when the desired treatment involves areas or organs readily accessible to topical application. For application topically to the skin, the pharmaceutical composition should be formulated with a suitable ointment containing the active components suspended or dissolved in a carrier. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petroleum, white petroleum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical composition can be formulated with a suitable lotion or cream containing the active compound suspended or dissolved in a carrier. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. The pharmaceutical compositions of this invention may also be topically applied to the lower intestinal tract by rectal suppository formulation or in a suitable enema formulation. Topically-applied transdermal patches are also included in this invention.
The pharmaceutical compositions of this invention may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques wel-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilizing or dispersing agents known in the art.
The compounds of this invention may be used in combination with either conventional anti-inflammatory agents or with matrix metalloprotease inhibitors, lipoxygenase inhibitors and antagonists of cytokines other than IL-1xcex2.
The compounds of this invention can also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, GM-CSF, methionine enkephalin, interferon alpha, diethyldithiocarbamate, tumor necrosis factor, naltrexons and rEPO) or with prostaglandins, to prevent or combat IL-1-mediated disease symptoms such as inflammation.
When the compounds of this invention are administered in combination therapies with other agents, they may be administered sequentially or concurrently to the patient. Alternatively, pharmaceutical compositions according to this invention may be comprised of a combination of a compound of Formula 1 and another therapeutic or prophylactic agent mentioned above.
The disease states which may be treated or prevented by the instant pharmaceutical compositions include, but are not limited to, inflammatory diseases, autoimmune diseases and neurodegenerative diseases, and for inhibiting unwanted apoptosis involved in ischemic injury, such as ischemic injury to the heart (e.g., myocardial infarction), brain (e.g., stroke), and kidney (e.g., ischemic kidney disease). Methods of administering an effective amount of the above-described pharmaceutical compositions to mammals, also referred to herein as patients, in need of such treatment (that is, those suffering from inflammatory diseases, autoimmune diseases, and neurodegenerative diseases are further aspects of the instant invention.
Another aspect of the instant invention is a method of preventing ischemic injury to a patient suffering from a disease associated with ischemic injury comprising administering an effective amount of the pharmaceutical composition discussed above to a patient in need of such treatment.
Also, each of the methods directed to methods for treating inflammatory diseases, autoimmune diseases, neurodegenerative disease and preventing ischemic injury encompass using any of the optimal groups and embodiments of pharmaceutical compositions set forth above.
Inflammatory disease which may be treated or prevented include, for example, septic shock, septicemia, and adult respiratory distress syndrome. Target autoimmune diseases include, for example, rheumatoid, arthritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves"" disease, autoimmune gastritis, insulin-dependent diabetes mellitus, autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasthenia gravis and multiple sclerosis. Target neurodegenerative diseases include, for example, amyotrophic lateral sclerosis, Alzheimer""s disease, Parkinson""s disease, and primary lateral sclerosis. The pharmaceutical compositions of this invention may also be used to promote wound healing. Target diseases associated with harmful, apoptosis, in other words, those associated with ischemic injury, includes myocardial infarction, stroke, and ischemic kidney disease. The pharmaceutical compositions of this invention may also be used to treat infectious diseases, especially those involved with viral infections.
The term xe2x80x9ceffective amountxe2x80x9d refers to dosage levels of the order of from about 0.05 milligrams to about 140 milligrams per kilogram of body weight per day for use in the treatment of the above-indicated conditions (typically about 2.5 milligrams to about 7 grams per patient per day). For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 milligrams of the compound per kilogram of body weight per day (about 0.5 milligrams to about 3.5 grams per patient per day).
The amount of the compounds of Formula 1 that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 milligrams to 5 grams of a compound of Formula 1 combined with an appropriate and convenient amount of a pharmaceutically-acceptable carrier which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 milligram to about 500 milligrams of an active compound of Formula 1.
It will be understood, however, that the specific xe2x80x9ceffective amountxe2x80x9d for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing prevention or therapy.
Although this invention focuses on the use of the compounds disclosed herein for preventing and treating IL-1-mediated diseases, the compounds of this invention can also be used as inhibitory agents for other cysteine proteases.
The compounds of this invention are also useful as commercial reagents which effectively bind to the ICE/ced-3 family of cysteine protease or other cysteine proteases. As commercial reagents, the compounds of this invention, and their derivatives, may be used to block proteolysis of a target peptide or may be derivatized to bind to a stable resin as a tethered substrate for affinity chromatography applications. These and other uses which characterize commercial cysteine protease inhibitors will be evident to those of ordinary skill in the art.

C-terminal modified (N-substituted)-2-indolyl dipeptides as inhibitors of the ICE/ced-3 family of cysteine proteases


In general, techniques are described for providing a continuous feedback system that dynamically updates data collection criteria and subscriber policies based on aggregated subscriber-specific and network usage data. For example, a method includes applying one or more subscriber specific policy and charging control (PCC) rules to network traffic to collect network traffic data for a plurality of subscribers, aggregating the network traffic data, and determining, based on the aggregated traffic data, whether subscriber independent data collection criteria need to be updated. The method may also include, responsive to determining that the data collection criteria need to be updated: updating the data collection criteria, translating the updated data collection criteria from updated subscriber independent data collection criteria into updated subscriber specific PCC rules, and applying the updated subscriber specific policy and charging control rules to additional network traffic to collect additional network traffic data.

A cellular radio access network is a collection of cells that each includes at least one base station capable of transmitting and relaying signals to subscribers' wireless devices. A "cell" generally denotes a distinct area of a mobile network that utilizes a particular frequency or range of frequencies for transmission of data. A typical base station is a tower to which are affixed a number of antennas that transmit and receive the data over the particular frequency. Wireless devices, such as cellular or mobile phones, smart phones, camera phones, personal digital assistants (PDAs) and laptop computers, may initiate or otherwise transmit a signal at the designated frequency to the base station to initiate a call or data session and begin transmitting data.
Mobile networks convert cellular signals, e.g., Time Division Multiple Access (TDMA) signals, Orthogonal Frequency-Division Multiplexing (OFDM) signals or Code Division Multiple Access (CDMA) signals, received at a base station from wireless devices into Internet protocol (IP) packets for transmission within packet-based networks. A number of standards have been proposed to facilitate this conversion and transmission of cellular signals to IP packets, such as a general packet radio service (GPRS) standardized by the Global System for Mobile Communications (GSM) Association, an evolution of Universal Mobile Telecommunications System (UMTS) referred to as Long Term Evolution (LTE), mobile IP standardized by the Internet Engineering Task Force (IETF), as well as other standards proposed by the 3rd Generation Partnership Project (3GPP), 3rd Generation Partnership Project 2 (3GGP/2) and the Worldwide Interoperability for Microwave Access (WiMAX) forum.
A typical mobile service provider network, or "mobile network," includes a core packet-switched network, a transport network, and one or more radio access networks. The core packet-switched network for the mobile network establishes logical connections, known as bearers, among the many service nodes on a path between a wireless device, attached to one of the radio access networks, and a packet data network (PDN). The service nodes then utilize the bearers to transport subscriber traffic exchanged between the wireless device and the PDN, which may include, for example, the Internet, an enterprise intranet, a layer 3 VPN, and a service provider's private network. Various PDNs provide a variety of packet-based data services to wireless devices to enable the wireless devices to exchange service data with application or other servers of the PDNs. In addition, while primarily described with respect to service providers and mobile service provider networks, many different types of entities, including enterprises and government agencies, may deploy a mobile network. Accordingly, the term "mobile network" may be used herein to encompass many different types of cellular network architectures and operators.
Mobile networks perform detailed and accurate monitoring of service usage so that proper charging information can be generated for potentially millions of customers in order to provide revenue for the service providers. A mobile network gateway collects charging information related to the external data network usage and to network resource usage, such as the amount of data categorized by quality of service (QoS), the user protocols, and the usage of the packet data protocol (PDP) address. However, the amount and granularity of data that may be collected is typically limited by the capabilities of the mobile network gateway. In addition, the collected data is typically used to manage individual subscriber access (e.g., denying a subscriber access to the requested service in the absence of adequate credit).


A battery pack is disclosed. In one aspect, the battery pack includes a plurality of battery cells electrically connected to each other and comprising first and second outermost battery cells positioned at opposite ends thereof and a case accommodating the battery cells. The battery pack also includes a barrier wall formed between the battery cells and the case and a traversing tab positioned between the case and the barrier wall and electrically connecting the first and second outermost battery cells. At least one embodiment can facilitate a welding process while preventing a conductive tab connecting battery cells to a protective circuit module from being short-circuited.

1. Field
The described technology generally relates to a battery pack.
2. Description of the Related Technology
In general, a battery pack used in a portable electronic device, such as a notebook computer, a personal digital assistant (PDA) or a camcorder is manufactured by incorporating multiple battery cells into the battery pack to provide sufficient energy storage to power the device. The battery pack generally includes i) a lower case, ii) a plurality of battery cells accommodated in the lower case, iii) a protective circuit module (PCM) electrically connected to the battery cells and controlling charge/discharge operation of the battery cells, and iv) an upper case covering the lower case and protecting the battery cells and the PCM from external surroundings. Here, the battery cells may be high-capacity cylindrical lithium ion batteries. The PCM is electrically connected to the battery cells by a tab made of, for example, nickel (Ni) or a conductive wire.


Disclosed herein is a novel retinoblastoma binding protein-related gene that encodes an antigenic epitope, IKPSLGSKK (SEQ ID NO:3), which is differentially expressed in cancers, such as breast, lung, colon, pancreas, and ovarian cancer. Polynucleotides that encode and polypeptides that comprise the antigenic epitope and variants thereof are disclosed. Also, disclosed are methods of using the polynucleotides and polypeptides of the present invention in immunotherapies and immunoassays.

1. Field of the Invention
This invention relates generally to methods of detecting or diagnosing a plurality of different cancers. In particular, the present invention relates to a retinoblastoma binding protein-related gene that is differentially expressed in cancer cells as compared to normal cells.
2. Description of the Related Art
Breast, lung, colon, pancreas, and ovarian cancers are aggressive forms of cancer, difficult to diagnose, or both. In order to detect breast cancer by physical examination, a breast tumor must be of a large enough size and mammography is limited by the skill of the observer, the quality of the mammogram, often result in over 80% false positives and over 10% false negatives. See Wright, et al. (1995) Lancet 346:29-32. Generally, there are no observable clinical symptoms of lung cancer until the advanced stage. In fact, only 16% of lung cancers are discovered before the disease has spread. Likewise, colon cancer is difficult to diagnose as clinical symptoms such as rectal bleeding, pain, abdominal distension, or weight loss are observable only after the disease is advanced and not surgically curable. Fecal occult blood tests are difficult to conduct due to lack of compliance, are poorly sensitive, exhibit little predicative value, and often lead to colonoscopic examination which is an expensive and invasive procedure. Pancreatic cancer produces few specific symptoms in its early stages and usually is detected at an advanced and incurable stage. Thus, pancreatic cancer exhibits the lowest survival rate of any major cancer. Specifically, the average survival after diagnosis is less than 6 months and fewer than 5% of patients survive 5 years. See Rosenberg, L. (1997) Pancreatol. 22:81-93; and Flanders and Foulkes (1996) J. Med. Genet. 33:889-898). Likewise, ovarian cancer is difficult to diagnose and effective treatment depends on early detection.
Molecular identification of tumor antigens that can elicit both antibody and cellular immune responses in humans has been an important focus in the development of therapeutic methods that are active and specific against various cancers and tumors. Many strategies have been used to characterize and detect tumor antigens. See e.g. DePlaen et al. (1988) PNAS USA 85:2275-2280; Mandelboim, et al. (1994) Nature 369:69; and Sahin, et al. (1995) PNAS USA 92:11810-11913.
Numerous human tumor antigens have been identified. See e.g., Van der Bruggen, et al. (1991) Science 254:1643-1647 (MAGE-1); Brichard, et al. (1993) J. Exp. Med. 178:489-495; Coulie, et al. (1994) J. Exp. Med. 180:35-42; Kawakami, et al. (1994) PNAS USA 91:3515-3519; Clark, et al. (1994) Nature Genetics 7:502-508 (SSX-2); Crew, et al. (1995) EMBO J. 144:2333-2340 (SSX-1); DeLeeuw, et al. (1996) Cytogenet. Genet. 73:179-183 (SSX-3); Gure, et al. (1997) Int. J. Cancer, 72:965-971 (SSX4); Meuwissen, et al. (1992) EMBO J. 11(13):5091-5100 (SCP-1); Tureci, et al. (1996) Cancer Res. 56:4766-4772 (HOM-MEL-40); Chen, et al. (1997) PNAS USA 94:1914-1918 (NY-ESO-1); Boel, et al. (1995) Immunity 2:167-175 (BAGE); and U.S. Pat. Nos. 5,610,013 and 5,648,226 (GAGE). Many of these tumor antigens have been the focus of cancer immunotherapy. Unfortunately, for a variety of reasons, many of the tumor antigens known in the art are not useful in cancer immunotherapy.
Thus, a need still exists for effective and accurate cancer diagnostics and therapies.

RBP1L1, a novel retinoblastoma binding protein-related gene encoding an antigenic epitope and methods of using thereof


A method for preventing collisions between robots by causing a first robot to stop or pause so that a second robot may safely pass by or perform a specified operation. Once the second robot has completed its operation then the first robot is allowed to resume operation. Each robot automatically stops when it reaches a certain point in its job. The robots communicate with a central controller which allows the robots to resume operation when the central controller has determined that all of the robots have reached their respective correct positions. This prevents collisions between robots which are operating in the same area, especially those robots operating on the same workpiece. This method works with existing robot welders, does not require modifications to the robots, and does not require expensive spatial analysis computer programs, which may not even be available for the type of processor used in a particular robot. The present invention also provides a method for specifying a compartment entry point for a welding operation based upon data provided from a CAD program. The present invention also provides a method for automatically determining the starting and ending coordinates of a weld using a touch-sensing capability of the robot. The present invention also provides a method for automatically tracking the joint for a welding seam by periodically measuring the coordinates of the components by using the touchsensing feature of the robot. The present invention also provides a method for automatically determining the position of a torch to provide for an optimum angle of attack for a welding operation based upon data, such as beam height and flange overhang, provided from a CAD program. The present invention also provides a method for automatically tracking the joint for a welding seam by weaving (dithering) the torch along the desired path, measuring the arc welding current at peak deviations from the travel path, and comparing the measured current on the two different sides of the weld to determine whether the torch is on the seam. The present invention also uses this method to automatically track the edge of a component for applying a welding bead to the edge of the component. The present invention also provides for automatically selecting a welding program from a standard set of welding programs based upon data from a CAD program.

Robot welders are automated welding machines which operate under the control of a microprocessor. They are being used in more and more applications because they provide several advantages with respect to human welders. Some, but not all, of the advantages are that they do not need to take breaks, they can tolerate adverse environmental conditions, they can work in very tight areas, and they yield a consistent, quality weld.
However, a robot, like a human, must be told what to weld. A program for a robot welder can be written which specifies the exact spot or line that must be welded. Typically, an operator specifies the starting point of a weld and the length of the weld or the ending point of the weld. This information is given in precise coordinates, for example, start at point x=1.05 inches, y=1.77 inches, and z=0.0 inches and end at x=2.00 inches, y=2.00 inches, and z=0.5 inches. In this case the robot will weld on a seam defined by a line between the given starting and ending points. This procedure is simple and straightforward, but is very time consuming because the operator must determine the starting and ending points of the weld. This procedure is also prone to errors because the operator must manually enter these starting and ending points into the program and the operator may make errors in measuring the points or in entering the points into the program. Further, some points may be difficult or impossible for the operator to measure manually.
The robots have sensing devices, often referred to as touch sensors, which indicate that contact has been made with an object. In welding environments, the workpiece is typically a conductive material, such as iron or steel. Therefore, in these environments, the touch sensor is often the tip of the welding torch, or the welding wire, and the robot senses when the tip or wire has reached the workpiece by simply monitoring the output voltage or current at the tip or wire. When contact is made, the output voltage will drop and the output current will increase. The operator can therefore operate the robot to determine the coordinates of the starting and ending points of the weld, and then enter these coordinates into a welding program. This procedure is simple and straightforward, but is also very time consuming and prone to errors because, even through the robot makes the measurements precisely, the operator may make errors in entering the measurements.
Thus, each weld requires a substantial amount of attention by the operator. In some cases, the amount of time required to determine the coordinates of the weld and enter the points into the welding program can easily exceed the amount of time required for the robot to perform the weld. Also, because of human measurement and data entry, errors are quite possible. Therefore, there is a need for a method of operating a robot welder so as to reduce or eliminate the amount of attention required from the operator.
Further, once a welding program is written it will generally be useful for only one specified weld. That is, as long as the coordinates of the welds are identical (same starting and ending points(, then the robot will faithfully repeat the weld. This is most useful on assembly lines where the robot performs the same welding operation on each workpiece which comes down the assembly line. However, if the coordinates of the welds are not identical then a different program is required. This may occur where one robot is required to make several welds on the same workpiece. Thus, the amount of memory required to store the several programs necessary for multiple welding operations can be substantial or even beyond the capability of the robot.
Robot welders, although useful, do only what the programmer instructs them to do. This is of little concern if there is only one robot performing a welding operation because, other than hitting the workpiece, there is little danger of the robot hitting anything. However, speed of assembly is frequently a customer requirement so it would be beneficial if two or more robots could be assigned to weld on the same workpiece at the same time. The problem with two or more robot welders is that they may try to occupy the same space at the same time. Two humans assigned to perform conflicting welding operations may be able to discuss and resolve the problem among themselves. They may also contact a supervisor to determine whose work will be done first. However, robots do not have the capability to recognize that a problem exists, much less discuss and resolve the problem or seek the guidance of a superior authority. Therefore, each robot follows its own program, mindless of the presence of any other robot. The result at some point, with some programs, will be a collision. The resulting damage to the robots and possibly even the workpiece can be extensive and expensive, and can cause serious delays.
It is difficult, if not impossible, to known in advance of the performance of an operation whether or not there will be a collision between the two robots. When programming a robot to perform a welding operation, the operator may specify a series of points to which the robot must move, with or without specifying exactly how the robot will get there. However, the microprocessor which controls the robot has its own set of manufacturer-installed operating instructions as to how the robot should operate. This problem is compounded by the fact that a robot typically has numerous degrees of freedom. For example, the Panasonic industrial robot model AW-010A has 6 degrees of freedom (rotation, upper arm, front arm, rotating wrist, bending wrist, twisting wrist), and two directions of linear motion (forward-backward, up-down). The particular moves generated by these operating instructions are frequently not the same moves, or in the same sequence, that the operator would have thought to use to accomplish the same result. Therefore, even if the operator specifies that a robot is to go from one point to another point, the operator has no information on what motions the robot may implement to do so. Further, the operator may have to particularly specify parts of the sequence to get the welding torch in the right position and at the right angle while avoiding parts of the workpiece, for example, an overhanging flange from a T-beam.
This problem is made worse if one attempts to simultaneously operate more than one robot on the same workpiece. None of the robots knows, or has the capability to know, where the other robots are located, what the other robots are doing, what the other robots are preparing to do, or how the other robots are going to accomplish whatever their next actions may be. Therefore, in the past, the only certain ways to avoid a collision were to put only a single robot on a workpiece, or to space the robots far enough apart to where it was impossible for one robot to intrude into the operating area of another robot. However, a single robot provides for slow operation. Further, in some situations, the small size of the workpiece may prevent spacing the robots such that they cannot hit each other. Also, operating space is like any other resource; it has a value and should be conserved whenever possible. There is therefore a need for a method which provides for simultaneous operation of the robots in close proximity to each other while preventing the collisions which, with the current state of the art, are probable.
A sophisticated spatial analysis computer program could be used to generate a computer model of each robot and the workpiece and perform a mathematical computation to determine if any robot will attempt to occupy the same space as any other robot at the same time. However, such a program is expensive and requires a substantial amount of time for programming of the dimensions and variables. Such a program is also very computation-intensive and requires a large amount of memory. This may tie up the resources of a company which as its own computer, or increase the computer time rental costs for a company. Furthermore, a spatial analysis program may not have been written for the particular processor being used to control a robot. In addition, there may be inadequate time, at a processing speed which is not cost prohibitive, to perform the calculations in real time. Also, any change to any program may require running the analysis again to verify that the change has not caused a collision.
Welding robots typically have current sensors associated with each driving motor. Therefore, if the robot contacts an object and a driving motor stalls out, then the current will increase. This feature is often referred to as an amp-out condition and can be used to determine if the robot has hit an object or another robot. However, at the speeds at which robots operate, the damage will still be serious. It is, of course, possible to program the robots to move at a very slow rate so that the amp-out condition can be used to determine if a collision is occurring and to stop movement of the robots so that the collision will not cause further damage. However, this only prevents further damage, it does not prevent any damage caused by the initial contact nor resolve the original problem: both robots trying to be in the same space at the same time. Also, by moving at this slow speed, the time needed for a welding operation is greatly increased. Further, the slow movement approach is only useful for positioning. A welding operation must usually occur at a predetermined speed. Moving the robot arm at a slower speed during a welding operation may result in the workpiece being damaged by excessive heat. The workpiece may be warped or even burned through, or an excessively large welding bead may be deposited. Therefore, there is a need for a method of operating robot welders in a manner which avoids collisions between the robots.
Before beginning a welding operation, the robot must know how to get the torch into the compartment in which the welding operation is to be performed. This can be done by the operator, by manually measuring the coordinates, or by manually positioning the robot in the compartment. However, manual measurement of the coordinates is time prone to errors, and manual positioning is time consuming. In many cases, the workpiece is designed using a computer aided design (CAD) program. This CAD program contains information which could be used to determine the entry point into a compartment for the torch. This would eliminate the need for manual measurement or control, would improve speed, and would eliminate errors. Therefore, there is a need for a method for specifying a compartment entry point for a welding operation based upon data provided from a CAD program.
Even after the torch is guided into the compartment in which a welding operation is to be performed, the starting and ending points of the weld must be determined. This can be done by the operator, by manually measuring the coordinates, or by manually positioning the torch to determine the coordinates, and then loading these coordinates into the robot. However, these procedures are time consuming and may introduce errors. Some robots have a "touch-sensing" capability. That is, the ability to locate the boundaries or walls which limit the operation area of the robot. This capability could be used to define the coordinates of the weld. Therefore, there is a need for a method for automatically determining the starting and ending coordinates of a weld. There is also a need for a method for automatically determining the starting and ending coordinates of a weld using the touch-sensing capability of the robot.
Programming a robot by going out on the shop floor and using a pendant to teach the robot the steps necessary for the welding operation is useful, but is time consuming and, therefore, inefficient and expensive. Further, it requires the operator to go into an environment which is not climate controlled. If the weather is particularly adverse then the time that the operator can sped on the shop floor may be very limited. To circumvent this problem, some facilities use programmers to write the welding program by looking at the CAD design, rather than by going out on the shop floor. The programmer is thus in a climate-controlled environment and is not affected by the weather. However, this approach is often unsuccessful on the first attempt at programming. This occurs because there are limits on the agility of a robot. The robot may be able to turn its wrist through most of, all of, or even slightly more than, a 360 degree arc but there will be a limit. This limit condition is installed in the robot by the manufacturer and prevents excessive turning so that wires, hoses, and cables do not get wrapped around the robot arm and/or broken. If this limit is implemented by software it is frequently referred to as a soft limit condition and if it is implemented by hardware, such as a switch, it is frequently referred to as a hard limit condition. If a program instructs the robot to move more than the soft limit conditions allows, the soft/hard limit causes the robot to disregard the program instruction. A programmer may unknowingly write a program which attempts to cause the robot to exceed a limit conditions. When the offending program instruction is reached then the robot simply stops operating. The programmer may have to run the program several times to determine why the robot stopped. Then, the programmer will have to modify or completely rewrite the program in order to avoid reaching the limit switch condition. In some cases, the programmer may have to modify or rewrite the program by going out on the shop floor and using the pendant. There is therefore a need for a method of generating a welding program which avoids the limit switch problem and which also prevents the operator from having to go to the shop floor for the programming.
Before the welding operation is performed, the angle of attack of the torch of the robot must be specified. There is an optimum angle of attack for most welding operations. However, merely specifying that angle in the welding job for a robot is not useful because the compartment in which the welding is to be done may be too deep, or have a beam with too much of a flange overhang, to obtain the desired angle of attack and the robot may merely jam the torch into the workpiece in a vain attempt to achieve the desired angle of attack. Therefore, there is a need for a method for automatically determining the positioning of a torch to provide for an optimum angle of attack for a welding operation.
Further, the optimum angle of attack for the torch is not fixed, even for a known compartment design. If the orientation (pitch or roll) of the compartment is changed then the optimum angle of attack for the torch will vary to compensate for the tendency of the molten metal to flow downhill. Also, if one takes the program for a compartment which has no pitch (inclination) and tires to use the program for a compartment which has some pitch, the robot may be able to get into position to start the weld but may encounter a limit condition as the robot attempts to perform the weld. Thus, a different orientation (yaw, pitch, roll) may require the robot to use a different approach path in order to get the torch into the compartment and be able to complete the weld. Therefore, there is a need for a method for generating a program which is responsive to the orientation of the workpiece.
Once the robot has successfully placed the torch within the desired compartment and the torch is positioned at the best available angle of attack, the robot must move the torch along the joint of the pieces to be welded together. Point-to-point specifications are very useful if the joint is along a straight line. However, if the joint is along a curve or bend, or there is a change in the direction of the joint, then point-to-point specifications become less useful. Attempting to create a curve by a series of point-to-point specifications is time consuming and also prone to errors because the ending point of one path must precisely correspond to the starting point of the next path. Also, if the curve is severe, then numerous point-to-point specifications may be necessary to simulate the curve closely enough to keep the torch on the joint. There exists a method for automatically tracking the joint for a welding seam where the seam is a joint between two planar surfaces. However, in some cases, the weld to be made is not a joint between two planar surfaces but is a joint between two perpendicular surfaces. The prior art seam tracking method frequently fails to provide the desired results in the case of perpendicular surfaces. Therefore, there is a need for a method for automatically tracking the seam between two perpendicular surfaces.
In some cases, the weld to be made is not a joint between two surfaces but, rather, is simply a welding bead placed along the edge of a piece to eliminate the rough edge, or provide for rust prevention, or provide a better edge for a later welding operation, etc. As in the case of a seam, point-to-point specifications are very useful if the edge is a straight line. However, if the edge is curved or bent, or there is a change in the direction of the edge, then point-to-point specifications become less useful. Attempting to create a curve by a series of point-to-point specifications is time consuming and also prone to errors because the ending point of one path must precisely correspond to the starting point of the next path. Also, if the curve is severe, then numerous point-to-point specifications may be necessary to simulate the curve closely enough to keep the torch on the edge. Therefore, there is a need for a method for automatically tracking the edge of a component so that a welding bead can be applied to the edge.

Method of determining weld path for a robot welder