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<SOH> SUMMARY OF THE INVENTION <EOH>The object of the present invention is solved with the metal solution-diffusion membrane according to claim 1 and the method according to claim 11 . Advantageous embodiments of the membrane and the method are the subject matter of the subclaims. The present metal solution-diffusion membrane comprises a macroporous hollow fiber as the base on which a thin metal membrane layer is formed over at least one thin, metal material-containing intermediate layer. The combination of a hollow fiber as the base with a thin metal coating yields a completely encompassing metal membrane layer which does not lose its filter property even due to detachments of the base at not optimum joints. Such type local detachment therefore does not lead to function failure of the membrane. Optimum function of the thin membrane layer requires a uniform, homogeneous substructure which, in the present membrane, is formed as an intermediate layer between the hollow fiber and the metal membrane layer. Especially this intermediate layer permits realizing a very thin metal membrane layer on the hollow fiber. The very thin membrane layer, for its part, leads to very high permeability of the membrane, for example for hydrogen. Furthermore, the use of a hollow fiber as the base yields a very good surface/volume ratio. A multiplicity of such type coated hollow fibers can be used in a filter element. The metal membrane layer can, for example, form a layer thickness in the range between 0.1 and 10 μm. Preferably, it has a layer thickness in the range between 0.7 and 1 μm. The intermediate layer can possess a layer thickness between 1 and 10 μm, preferably the layer thickness of the intermediate layer is between 2 to 3 μm. In the preferred embodiment, this intermediate layer is formed of particles of a sol, which are coated with a salt of the metal of the metal membrane layer. The pore size of the intermediate layer lies preferably in the range of approximately 6 nm. The production of such a type intermediate layer is, for example described in J. Zhao et al's above mentioned publication. The layer produced as a membrane layer therein acts in the present membrane as an intermediate layer. The employed hollow fibers preferably have an outer diameter in the range between 80 and 1500 μm, a wall thickness in the range between 10 and 200 μm as well as an average pore size of about 0.2 μm. A smaller outer diameter is associated with less wall thickness. The hollow fibers can, for example, be formed from a ceramic or a metallic material. For this purpose, Al 2 0 3 is especially suited as the ceramic material. Metals for the metal membrane-layer are preferably palladium, nickel, platinum or alloys thereof. Other metals can also be employed for gas separation processes. Examples therefor are copper, iron, silver, aluminum or alloys thereof. In the present method for producing the metal solution-diffusion membrane, one or a multiplicity of macroporous hollow fibers are provided or produced on whose surface a homogeneous intermediate layer is applied which contains metal nuclei for subsequent currentless deposition of a metal membrane layer. The intermediate layer is then passivated. Finally, the thin metal membrane layer is applied onto this intermediate layer by means of currentless deposition. Preferably the application of the homogenous intermediate layer occurs using a method according to J. Zhao et al's above mentioned publication, i.e. application of a Böhmit sol modified with metal complexes and followed by calcination. In a preferred embodiment in which the pore size of the macroporous hollow bodies for direct application of the sol is too large, an additional intermediate layer with a smaller pore size is applied onto the hollow fiber, so that the sol particles cannot or only to a small extent penetrate into the pores. |
Dynamic reduction of the moisture layer during the displacement of a viscoelastic fluid using a fluid with lower viscosity |
The invention relates to a method of optimizing the displacement of a viscoelastic fluid in a pore, tube, duct, channel, fracture, porous medium or interconnected latticework or in an interconnected assembly of pores, tubes, ducts, channels, cavities and/or fractures using a fluid with a lower viscosity. The inventive method consists in displacing the viscoelastic fluid using a displacing fluid which supplies a signal thereto comprising pressure pulses at an optimum frequency. In this way, the moisture layer between the displaced fluid and the walls of the pores, tubes, channels, cavities, fractures or porous medium is dynamically reduced during said displacement, thereby facilitating optimum extraction. |
1. Process for driving a moisture layer reducing viscoelastic fluid between the viscoelastic fluid and the walls of the medium containing it, when the driving fluid has lower viscosity than the driven fluid, the process is characterized by: Injection of the low viscosity fluid to displace the viscoelastic fluid with a signal that contain pressure pulses at a certain optimum frequency, or in the production of a signal that contains such pressure pulses inside or outside the low viscosity fluid, so that it comunicates them to the viscoelastic fluid when being driven, with the corresponding injection of low viscosity fluid to replace the volume of driven fluid: 2. Process according to claim 1, characterized in that the medium that contain the viscoelastic fluid is a pore, tube, duct, channel, fracture, porous medium or a interconnected latticework or interconnected set of pores, tubes, channels and/or fractures of equal or different geometries and equal or different sizes. 3. Process according to claim 2, characterized in that the porous medium is an oil well. 4. Process according to claim 2, characterized in that the porous medium is an oil well naturally fractured. 5. Process according to claim 1 characterized in that the pressure pulses are generated by mechanical, electromechanical, hydraulic, pneumatic, magnetic, optical, acoustical, thermo-acoustical means, or any means generating vibrations. 6. Process according to claim 1, characterized in that the signal comprises only pressure pulses to the optimum frequency. 7. Process according to claim 1, characterized in that the signal is a signal at constant flow to which are overlapped pressure pulses at the optimum frequency. 8. Process according to claim 1, characterized by the signal comprises a signal with constant pressure gradient, to which are overlapped pressure pulses at the optimum frequency. 9. Process according to claim 1, characterized by the signal comprises any signal to which are overlapped pressure pulses at the optimum frequency. |
<SOH> A) BACKGROUNDS <EOH>When a low viscosity fluid drives a high viscosity fluid, the interphase between both fluids is not flat, rather becomes unstable and creates structures called viscous fingers. In a pore, tube or channel when a viscous fluid is driven under constant flow or constant pressure gradient by a lower viscosity fluid, the driving fluid penetrates the driven fluid forming a front in the shape of a single finger within the driven fluid leaving a viscous fluid layer “glued” to the walls of the pore, tube or channel. Fluid behavior inside tubes, Hele-Shaw cells and porous medium is described by Darcy'Law, which relates fluid pressure and velocity through fluid permeability in the medium, therefore the results obtained in tubes and Hele-Shaw cells extrapolate with minor modifications to porous media. |
Pharmaceutical formulations comprising ketoconazole |
The present invention relates to pharmaceutical compositions comprising ketoconazole or a derivative thereof, one or more low melting point lipid excipients and a sufficient quantity of one or more high melting point lipid excipients to provide a liquid and a solid phase within said composition after heating to 35° C. for 18 hours more particularly to pharmaceutical compositions comprising ketoconazole or a derivative thereof and a lipid excipient, at least 85% by weight of said lipid excipient consisting or one or more low melting point lipids and 1-15% by weight of said lipid excipient consisting of one or more high melting point lipids, polymeric excipients are also described as are the use of these formulations in the treatment of metabolic syndrome and related conditions. |
1. A pharmaceutical composition comprising ketoconazole or a derivative thereof and a lipid excipient, at least 85% by weight of said lipid excipient consisting of one or more low melting point lipids and 1-15% by weight of said lipid excipient consisting of one or more high melting point lipids. 2. A composition as claimed in claim 1 wherein 2-10% by weight of said lipid excipient consists of one or more high melting point lipids. 3. A composition as claimed in claim 1 wherein 2-5% by weight of said lipid excipient consists of one or more high melting point lipids. 4. A composition as claimed in claim 1 wherein said low melting point lipid (s) are esters of fatty acids having more than 6 carbon atoms. 5. A composition as claimed in claim 4 wherein said low melting point lipid (s) are esters of fatty acids having between 16 and 22 carbon atoms. 6. A composition as claimed in claim 4 wherein said low melting point lipid (s) are esters of unsaturated fatty acids. 7. A composition as claimed in claim 4 wherein said low melting point lipid (s) are monoglycerides. 8. A composition as claimed in claim 4 wherein said low melting point lipid (s) are glycerol monooleate and/or glycerol monolinoleate. 9. A composition as claimed in claim 4 wherein said low melting point lipid is glycerol monooleate. 10. A composition as claimed claim 1 wherein said high melting point lipid (s) are esters of fatty acids having more than 6 carbon atoms. 11. A composition as claimed in claim 10 wherein said high melting point lipid (s) are esters of fatty acids having more than 12 carbon atoms. 12. A composition as claimed in claim 11 wherein said high melting point lipid (s) are esters of fatty acids having between 16 and 22 carbon atoms. 13. A composition as claimed in claim 10 wherein said high melting point lipid (s) are esters of saturated fatty acids. 14. A composition as claimed in claim 13 wherein said saturated fatty acids are selected from the group comprising lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, lignoceric acid and nervonic acid. 15. A composition as claimed in claim 10 wherein said high melting point lipid (s) are glycerides. 16. A composition as claimed in claim 10 wherein said high melting point lipid (s) are monoglycerides. 17. A composition as claimed in claim 10 wherein said high melting point lipid (s) are selected from the group comprising glycerol monopalmitate, glycerol monostearate and glycerol monobehate. 18. A composition as claimed in claim 1 which comprises 5-30% by weight of ketoconazole in the form of a racemic or other mixture of the two cis isomers or one of the cis isomers. 19. A pharmaceutical composition comprising ketoconazole or a derivative thereof, one or more low melting point lipid excipients and a sufficient quantity of a further excipient to provide a liquid and a solid phase within said composition after heating to 35° C. for 18 hours. 20. A pharmaceutical composition comprising ketoconazole or a derivative thereof, one or more low melting point lipid excipients and a sufficient quantity of one or more high melting point lipid excipients to provide a liquid and a solid phase within said composition after heating to 35° C. for 18 hours. 21. A method of preparing a composition as claimed in claim 1 which comprises melting and mixing the excipients and simultaneously or subsequently adding the ketoconazole or derivative thereof. 22. A method for treating or preventing metabolic syndrome or diabetes mellitus type II or symptoms or complications thereof in a mammal, comprising administering to the mammal the composition of claim 1. 23. A pharmaceutical composition comprising ketoconazole or a derivative thereof and a polymer excipient selected from amphiphilic polymers such as amphiphilic block copolymers, pluronics and tetronics such as poloxamer 407 (pluronic RTM.F127), poloxamer 188 (Pluronic RTM. F68) and polyacrylic acids having molecular weights from 1500 to 600, polysaccharides, such as cellulose based polymers e.g. hydroxypropyl methylcellulose (HPMC), hydroxyethyl methylcellulose (HEMC) and hydroxypropyl cellulose (HPC) and carboxyvinyl polymers. 24. A composition as claimed in claim 23 wherein said polymer is the sole excipient. |
Antagonistic anti-htnfsf13b human antibodies |
Human monoclonal antibodies that specifically bind to TNFSF13b polypeptides are disclosed. These antibodies have high affinity for hTNFSF13b (e.g., KD=10−8 M or less), a slow off rate for TNFSF13b dissociation (e.g., Koff=10−3 sec−1 or less) and neutralize TNFSF13b activity in vitro and in vivo. The antibodies of the invention are useful in one embodiment for inhibiting TNFSF13b activity in a human subject suffering from a disorder in which hTNFSF13b activity is detrimental. Nucleic acids encoding the antibodies of the present invention, as well as, vectors and host cells for expressing them are also encompassed by the invention. |
1. An anti-hTNFSF13b human antibody comprising at least three sequences selected from the group consisting of: a. SEQ ID NO: 4 located at CDR1 of the light chain variable region (LCVR); b. SEQ ID NO: 6 located at CDR2 of the LCVR; c. SEQ ID NO: 8 located at CDR3 of the LCVR; d. SEQ ID NO: 12 located at CDR1 of the heavy chain variable region (HCVR); e. SEQ ID NO: 14 located at CDR2 of the HCVR; and f. SEQ ID NO: 16 located at CDR3 of the HCVR. 2. The antibody of claim 1 comprising at least four sequences selected from the group consisting of: a. SEQ ID NO: 4 located at CDR1 of the light chain variable region (LCVR); b. SEQ ID NO: 6 located at CDR2 of the LCVR; c. SEQ ID NO: 8 located at CDR3 of the LCVR; d. SEQ ID NO: 12 located at CDR1 of the heavy chain variable region (HCVR); e. SEQ ID NO: 14 located at CDR2 of the HCVR; and f. SEQ ID NO: 16 located at CDR3 of the HCVR. 3. The antibody of claim 1 comprising at least five sequences selected from the group consisting of: a. SEQ ID NO: 4 located at CDR1 of the light chain variable region (LCVR); b. SEQ ID NO: 6 located at CDR2 of the LCVR; c. SEQ ID NO: 8 located at CDR3 of the LCVR; d. SEQ ID NO: 12 located at CDR1 of the heavy chain variable region (HCVR); e. SEQ ID NO: 14 located at CDR2 of the HCVR; and f. SEQ ID NO: 16 located at CDR3 of the. HCVR. 4. The antibody of claim 1 comprising the sequences: a. SEQ ID NO: 4 located at CDR1 of the light chain variable region (LCVR); b. SEQ ID NO: 6 located at CDR2 of the LCVR; c. SEQ ID NO: 8 located at CDR3 of the LCVR; d. SEQ ID NO: 12 located at CDR1 of the heavy chain variable region (HCVR); e. SEQ ID NO: 14 located at CDR2 of the HCVR; and f. SEQ ID NO: 16 located at CDR3 of the HCVR. 5. An anti-hTNFSF13b human antibody comprising a light chain variable region (LCVR) polypeptide as shown in SEQ ID NO: 2 or a heavy chain variable region (HCVR) polypeptide as shown in SEQ ID NO: 10. 6. The antibody of claim 5 comprising the LCVR polypeptide as shown in SEQ ID NO: 2 and the HCVR polypeptide as shown in SEQ ID NO: 10. 7-13. (cancelled) 14. The antibody of any one of claims 1 to 13 which comprises a heavy chain constant region selected from the group consisting of IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM, IgE, and IgD. 15. The antibody of claim 14 wherein the heavy chain constant region is IgG1 or IgG4. 16. The antibody of claim 15 wherein the heavy chain constant region is IgG4. 17. The antibody of claim 16 wherein the IgG4 has a proline substituted for serine at position 231. 18. The antibody of any one of claims 1 to 17 which comprises a kappa or lambda light chain constant region. 19. The antibody of claim 18 which comprises a kappa light chain constant region. 20. The antibody of any one of claims 1 to 19 wherein a CDR has three or less conservative amino acid substitutions. 21. The antibody of claim 20 wherein a CDR has two or less conservative amino acid substitutions. 22. The antibody of claim 21 wherein a CDR has one conservative amino acid substitution. 23. An anti-hTNFSF13b human antibody comprising a light chain comprising a LCVR polypeptide as shown in SEQ ID NO: 2 and a kappa constant region and a heavy chain comprising the HCVR polypeptide as shown in SEQ ID NO: 10 and a IgG4 constant region with a proline substituted for serine at position 231. 24. An isolated nucleic acid that encodes for the amino acid sequence of any of the antibodies of claims 1 to 23. 25. A recombinant expression vectors encoding an antibody of any one of claims 1 to 23. 26. A pharmaceutical composition comprising the antibody of any of claims 1-23. 27. The pharmaceutical composition of claim 26 further comprising a pharmaceutically acceptable carrier. 28. A method for inhibiting TNFSF13b activity in a subject suffering from a disorder in which TNFSF13b activity is detrimental comprising administering the antibody of any one of claims 1-23. 29. The method of claim 28 wherein the disorder is selected from the group consisting of systemic lupus erythematosus, rheumatoid arthritis, juvenile chronic arthritis, Lyme arthritis, Crohn's disease, ulcerative colitis, inflammatory bowel disease, asthma, allergic diseases, psoriasis, acute or chronic immune disease associated with organ transplantation, organ transplant rejection, graft-versus-host disease, sarcoidosis, infectious diseases, parasitic diseases, female infertility, autoimmune thrombocytopenia, autoimmune thyroid disease, Hashimoto's disease, Sjogren's syndrome, and cancer. 30. The method of claim 29 wherein the disorder cancer. 31. The method of claim 29 wherein the disorder is organ transplant rejection or graft-versus-host disease. 32. The method of claim 29 wherein the disorder is systemic lupus erythematosus. 33-38. (cancelled) 39. An article of manufacture comprising a packaging material and an antibody contained within said packaging material, wherein the antibody neutralizes TNFSF13b activity for treatment or prevention of a human subject suffering from a disorder in which TNFSF13b activity is detrimental, and wherein the packaging material comprises a package insert which indicates that the antibody neutralizes by binding an epitope of TNFSF13b, wherein the epitope comprises lysine at position 71, threonine at position 72, tyrosine at position 73, and glutamic acid at position 105. 40. The article of manufacture of claim 39, wherein the antibody is any of claims 1-23. 41. The article of manufacture of claim 40, wherein the antibody comprises the LCVR polypeptide as shown in SEQ ID NO: 2 and the HCVR polypeptide as shown in SEQ ID NO: 10. 42. An antibody or fragment thereof comprising SEQ ID NO: 17. 43. An antibody or fragment thereof comprising SEQ ID NO: 18. 44. An antibody or fragment thereof comprising SEQ ID NO: 19. 45. An antibody or fragment thereof comprising SEQ ID NO: 17 and SEQ ID NO: 19. 46. An antibody or fragment thereof comprising SEQ ID NO: 18 and SEQ ID NO: 19. |
Method for dispersing fog and/or clouds |
The invention relates to a method for dispersing fog and/or clouds. The aim of the invention is to develop a method, by means of which the dispersion of fog and/or the generation of precipitation from clouds may be rapidly and efficiently carried out in an environmentally-friendly manner. Said aim is achieved, whereby ice particles (solid H2O) are applied to the fog and/or the cloud with an initial speed of between ca 10 m/s and ca. 300 m/s, preferably between ca 100 m/s and ca. 200 m/s, whereby the ON particle size is chosen to be larger than the droplet size, thus causing dispersion of the fog and/or a precipitation from the cloud. |
1. Method for dispersing fog and/or for forming precipitation from clouds by using water ice, characterized in that the water ice particles (solid H2O) are introduced into the fbg and/or the cloud with an initial velocity of between approximately 10 m/s and approximately 300 m/s, preferably between approximately 100 m/s and approximately 200 m/s, whereby the particle diameter is selected to be greater than the droplet diameter. 2. Method acing to claim 1, characterized in that the water ice particles are surrounded and/or mixed with additional chemical substances that aid in the dispersion of the fog and/or the formation of precipitation from the cloud. 3. Method according to claim 1, characterized in that the water ice particles are surrounded and/or mixed with additional chemical substances that slow down the sublimation process of the water ice and thereby increase the range of the water ice particles. 4. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud by an air or gas flow that is generated by a compressor. 5. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud by an air or gas flow that is provided from a pressurized container. 6. Method according to the claims 1, characterized in that a container containing water ice is caused to burst in the fog and/or in the cloud, thereby introducing the water ice particles into the fog and/or the cloud. 7. Method according to the claims 1, characterized in that the water ice is caused to burst in the fog and/or in the cloud by an explosion and/or a high gas pressure, thereby introducing the water ice particles into the fog and/or the cloud. 8. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a stationary device. 9. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a mobile device. 10. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a ground-based vehicle. 11. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from an airplane. 12. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a boat. 13. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a rail vehicle. 14. Method according to the claims 1, characterized in that the water ice particles are introduced into the fog and/or the cloud from a portable device. 15. Method according to claim 1, characterized in that the water ice particles of filled into the device. 16. Method according to claim 1, characterized in that the water ice particles are produced in the device. |
Identification of specific tumor antigens by means of the selection of cdna libraries with sera and the use of said antigena in the treatment of tumors |
A method is described for the identification of specific tumour antigens by means of the selection of CND display libraries by using sera, characterised in that said selection is accomplished with the phage display technique, and in particular said selection is accomplished by means of the SEREX technique (serological analysis of autologous tumor antigens through the expression of recombinant cDNA). The method according to the invention described herein advantageously combines the SEREX approach with the potency of the phage display technique defined above, at the same time avoiding the drawbacks characteristic of the SEREX technique. The so identified antigens are useful for the preparation of medicaments for the treatment of tumors. |
1-19. (Canceled) 20. Specific tumor antigens obtainable by selection of cDNA libraries with sera, characterised in that said selection is accomplished with the phage display technique. 21. Tumor antigens according to claim 20, in which said selection is accomplished by means of the SEREX technique (serological analysis of autologous tumor antigens through expression of recombinant cDNA). 22. Tumor antigens according to claim 20, in which said selection is accomplished by means of the affinity selection technique. 23. Tumor antigens according to claim 20, in which said libraries are obtained from tumor biopsies. 24. Tumor antigens according to claim 20, in which said libraries are obtained from cultured tumor cell lines. 25. Antigen according to claim 20 selected from the group consiting of: MGTSRPANREAKQLHHQPHSIELIQSSGR; (SEQ ID NO: 49) MGTSRPANSEVYKPTLLYSSGR; (SEQ ID NO: 50) MGTSGRPTVGFTLD FTVDPPSGR; (SEQ ID NO: 51) MGTSRAGQLYRTTLTYTSGR; (SEQ ID NO: 52) MGTSRAOQLHAFPLHSTTLYYTTPSGR; (SEQ ID NO: 48) MRYYTATKTYELMLDATTQTSGR; (SEQ ID NO: 53) and MRVIDRAQAFVDEIFGGGDDAHNLNQHNSSGR. (SEQ ID NO: 54) 26. A tumor antigen of a sequence or entire sequence, or nucleic acid sequence encoding said antigen or entire sequence, said entire sequence being selected from the group consisting of: VLVAGQRYQSRSGHDQKNHRKHHGKKRMKSKRST (SEQ ID NO: 46) SLSSPRNGTSGR, MGTSRAGQQREQEKKRSPQDVEVLKTTTELFHSN (SEQ ID NO: 55) EESGFFNELEALRAESVATKAELASYKEKAEKLQ EELLVKETNMTSLQKDLSQVR DHQGRG, AGTSRAGQHAFEQIPSRQKKILEEAHELSEDHYK (SEQ ID NO: 56) KYLAKLRSTNPPCVPFFGIYLTNLLKTEEGNPEV LKRHGKELINFSKRRKVAEITGEIQQYQNQYCLR VESDTKRFFENLNPMGNSMEKEFTDYLFNKSLEI EPRKPSGR, MGTSRAQQQERSLALCEPGVNPEEQLIIIQSRLD (SEQ ID NO: 57) QSLEENQDLKKELLKCKQEARNLQGIKDALQQRL TQQDTSVLQLKQELLRANMDKD ELHNQNVDLQR KLDERTQRP, MGTSRAGQPMSGHGSFQEVPRLHTSAQLRSASLH (SEQ ID NO: 58) SEGLSCCQEGQVGQCQSPETDQQQPKMHQPSGR, TSRAGQLARIPSVTASEQGRT, (SEQ ID NO: 60) TSGPANAAPPSADDNIKTPAERLRGPLPPSADDN (SEQ ID NO: 61) LKTPSERQLTPLPPAAAK, TSRAGQRELGRTGLYPSYKVREKIETVKYPTYPE (SEQ ID NO: 62) AEK, TSVLEPTKVTFSVSPIEATEKCKKVEKGNRGLKN (SEQ ID NO: 63) IPDSKEAPVNLCKPSLGKSTIKTNTPIGCKVRKT EIISYPSTS GR, MDLTAVYRTFHPTITEYTFYLTVHGTFSKIDHMI (SEQ ID NO: 64) GHKTSLNKSKKTEIISSTLSDHSGIKLESNSKRN PQHIASGR, MPIDVVYTWVNGTDLELLKELQQVREQMEEEQKA (SEQ ID NO: 65) MREILGKNTTEPTKKRSYFVNFLAVSSGR, TSGRPTYKVNISKAKTAVTELPSARTDTTPVITS (SEQ ID NO: 66) VMSLAKIPATLSTGNTNSVLKGAVTKEAAKIIQD ESTQEDAMKFPSSQSSQPSRLLKNK GISCKPVT HPSGR, TSRAGQLRFSDHAVLKSLSPVDPVEPISNSEPSM (SEQ ID NO: 67) NSDMGKVSKNDTEEESNKSATTDNEISRTEYLCE NSLEGKNKDNSSNEVFPQYASGR, TSRAGQRKQSFPNSDPLIIQSDTSKAPGFRPPLQ (SEQ ID NO: 68) RPAPSPSGIVNTVIDSPYGSVTPSSTHLGNFASN ISGGQMYGPGAPLGGAPTSGR, MGTSRAGQPTSENYLAVTTKTKHKHSLQPSNASI (SEQ ID NO: 69) SLLGIYPTPSGR, and TSRAGQRDTQTHAHVSVCVHTPHHTYKYPTSGR. (SEQ ID NO: 70) 27. An antigen of a sequence or of the entire sequence, or nucleic acid sequence encoding said antigen or entire sequence, said entire sequence being selected from the group consisting of: TSRAGQRYEKSDSSDSEYISDDEQKSKNEPEDTE (SEQ ID NO: 59) DKEGCQMDKE-PSAVKKKPKPTNPVEIKEELKST PPA, and MGTSRAGQLVEELDKVFSQEREDVLAGMSGKSSF (SEQ ID NO: 49) QRSEGDFLLRSLTSGR. 28. A method of manufacturing a medicament for treatment of tumors comprising preparing an antigen of claim 20 in the form of a medicament. 29. Specific ligand for an antigen of claim 20. 30. Anti-antigen antibody of an antigen of claim 20. 31. A medicament comprising a ligand for and/or anti-antigen antibody of an antigen of claim 20 in a diluent. 32. A carrier for an active agent for the treatment of tumors comprising a ligand for and/or anti-antigen antibody of an antigen of claim 20. 33. An expression/display vector (λKM4) which expresses and/or displays an antigen of claim 20. 34. An antitumor vaccine comprising at least an antigen of claim 20. 35. An antitumor medicament comprising a ligand of claim 29. 36. An antitumor medicament comprising an antibody of claim 30. 37. Vaccine for treating breast cancer comprising the antigen of claim 27 and/or a specific ligand thereof and/or a specific antibody thereof. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Tumor therapy is practised according to multiple approaches of tumor attack. Other then the use of cytotoxic substances, immunotherapeutic approach is gaining even higher interest. In this context, tumor immunotherapy knows a constant increase of efforts in research, with the aim to find more effective methods for the identification of specific tumor antigens, useful for the preparation of medicaments for the treatment of tumors. In particular, antitumor vaccines constitute a kind of immunotherapy having the goal to stimulate immune system of the same patient to react against tumor antigens. For this reason, the research has recently focused also on the target of identifying, isolating and cloning specific tumor-associated antigens, which can be recognized by the host immune system. A review of arguments and related problems can be found, for example in EP 0 496 074 and WO 00/25813 and the references cited therein. The identification of tumor antigens may then provide new and better target-specific therapeutic means and more effective methods for the treatment of tumors. More or less specific tumor antigens are known, which have been obtained using tumor cells as antigens-immunogens to stimulate antibodies in laboratory animals. Also known are a number of tumor antigens that stimulate the formation of antibodies in the patients themselves (for example, p53 mutants, HER-2/neu, CEA, PSA). Their identification, however, is difficult when using conventional methods. The recent development of a method of analysing (screening) cDNA libraries with sera of patients suffering from various types of tumors, known as SEREX (serological analysis of autologous tumor antigens through the expression of recombinant cDNA, see P.N.A.S. 92, 11810-1995), has led to the identification of a large number of tumor antigens. The SEREX technology is undoubtedly useful for identifying new tumor antigens, but it presents a number of drawbacks consisting in the very laborious nature of the library screening operations, the high degree of background noise and the large amounts of material necessary. Since 1993, the year the first tumor antigen (carbonic anhydrase) was characterised, more than 600 different proteins specifically expressed in tumors and to which an immune response is generated have been identified (M. Pfreundschuch et al. Cancer Vaccine Week, International Symposium, Oct. 5-9, 1998, S03) and this number is destined to rise still further further [as today SEREX database contains 1695 public sequences (www.licr.org/SEREX.html)]. It is interesting to note that 20-30% of the sequences isolated are as yet unknown gene products. Further research, however, is necessary to improve the techniques for identifying specific tumor antigens for the treatment of tumors. |
Paget disease of bone |
Mutations in the atypical protein kinase C-interacting protein p62/sequestosome 1 (p62/SQSTM1) causing Paget disease of bone are described. Methods of detecting and treating Paget disease of bone are also disclosed. |
1. A method of detecting a condition associated with a mutated p62/SQSTM1 protein comprising assaying a sample for (a) a nucleic acid molecule encoding a mutated p62/SQSTM1 protein or a fragment thereof; or (b) a mutated p62/SQSTM1 protein or a fragment thereof. 2. A method according to claim 1 wherein the nucleic acid encoding the mutated p62/SQSTM1 protein has the sequence shown in SEQ. ID. NO.:3. 3. A method according to claim 1 wherein the mutated p62/SQSTM1 protein has the sequence shown in SEQ. ID. NO.:4. 4. A method according to claim 1 wherein the condition is Paget disease of bone. 5. A method according to claim 1, wherein the method comprises contacting the sample with a nucleotide probe capable of hybridizing with the nucleic acid molecule to form a hybridization product, under conditions which permit the formation of the hybridization product, and assaying for the hybridization product. 6. A method according to claim 1, wherein the method comprises contacting the sample with an antibody that binds to mutated p62/SQSTM1 which is capable of being detected after it becomes bound to the mutated p62/SQSTM1 in the sample. 7. An isolated nucleic acid molecule encoding a p62/SQSTM1 protein having the amino acid sequence as shown in SEQ. ID. NO.:4 or a fragment thereof. 8. A nucleic acid molecule according to claim 7 wherein said fragment comprises amino acid position 392 shown in SEQ. ID. NO.:4. 9. A nucleic acid molecule according to claim 7 wherein said fragment comprises a ubiquitin associated domain. 10. A nucleic acid molecule according to claim 7 comprising: (a) a nucleic acid sequence as shown in SEQ. ID. NO.:3 wherein T can also be U; (b) a nucleic acid sequence that is complimentary to a nucleic acid sequence of (a); (c) a nucleic acid sequence that has substantial sequence homology to a nucleic acid sequence of (a) or (b); (d) a nucleic acid sequence that is an analog of a nucleic acid sequence of (a), (b) or (c); or (e) a nucleic acid sequence that hybridizes to a nucleic acid sequence of (a), (b), (c) or (d) under stringent hybridization conditions. 11. An isolated protein having the amino acid sequence as shown in SEQ. ID. NO.:4 or a fragment, analog, homolog, derivative or mimetic thereof. 12. A protein according to claim 11 wherein said fragment comprises amino acid position 392 shown in SEQ. ID. NO.:4. 13. A protein according to claim 11 wherein said fragment comprises a ubiquitin associated domain. 14-15. (deleted). 16. An antisense oligonucleotide that is complimentary to a nucleic acid sequence according to claim 7. 17. An expression vector comprising a nucleic acid molecule of claim 7. 18. A host cell transformed with an expression vector of claim 17. 19. An antibody that can bind a protein according to claim 11. 20. A method of identifying a substance which can bind with a mutated p62/SQSTM1 protein, comprising the steps of: (a) incubating a mutated p62/SQSTM1 protein and a test substance, under conditions which allow for formation of a complex between the p62/SQSTM1 protein and the test substance, and (b) assaying for complexes of the mutated p62/SQSTM1 protein and the test substance, for free substance or for non complexed mutated p62/SQSTM1 protein, wherein the presence of complexes indicates that the test substance is capable of binding to the mutated p62/SQSTM1 protein. 21. A method for identifying a compound that affects mutated p62/SQSTM1 protein activity or expression comprising: (a) incubating a test compound with a mutated p62/SQSTM1 protein or a nucleic acid encoding a mutated p62/SQSTM1 protein; and (b) determining an amount of mutated p62/SQSTM1 protein activity or expression and comparing with a control, wherein a change in the mutated p62/SQSTM1 protein activity or expression as compared to the control indicates that the test compound has an effect on mutated p62/SQSTM1 protein activity or expression. 22. (deleted). 23. A method according to claim 26 wherein the agent is selected from the group consisting of: a nucleic acid molecule encoding wild type p62/SQSTM1; the wild type p62/SQSTM1 protein as well as fragments, analogs, derivatives or homologs thereof; antibodies; antisense nucleic acids and peptide mimetics. 24. A use method according to claim 26 wherein the bone disease is Paget disease of bone. 25. A non-human animal carrying a mutation in a gene encoding a p62/SQSTM1 protein, wherein said mutation corresponds to the human p62/SQSTM1 protein shown in SEQ. ID. NO.:4. 26. A method of treating a bone disease comprising of administering to a cell or animal in need thereof, an effective amount of agent that modulates p62/SQSTM1 expression and/or activity. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Paget disease of bone (Mendelian Inheritance in Man, MIM 167250) is a localized monostotic (only one site is affected) or polyostotic (several sites are affected) progressive metabolic bone disorder. The disease is characterized by an increased remodeling process in which abnormal bone resorption remains coupled to new osteoblastic bone formation. The process is initiated by increases in osteoclast-mediated bone resorption, with subsequent compensatory increases in new bone formation, resulting in a disorganized mosaic of woven and lamellar bone at affected sites. This structural change produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than is normal (Siris and Canfield 1990). Clinical signs and symptoms will vary from one patient to the next depending on the number and location of affected skeletal sites, as well as on the rapidity of the abnormal bone turnover. It is believed that most patients are asymptomatic, but about 5% of pagetic patients present symptoms requiring treatment (Kanis 1998). The most frequent complaints are bone pain, enlargement and deformities (Kanis 1998). Other manifestations of the disease include increased susceptibility to fractures, excessive warmth over bone from hypervascularity, deafness and neurological complications caused in most instances by compression of neural tissues adjacent to pagetic bone, as well as an increased susceptibility to osteosarcomas (Hamdy 1995). Paget disease of bone usually appears after 40 years of age (Klein and Norman 1995) and mainly affects the axial skeleton. In Western countries, Paget disease of bone is the second most common metabolic bone disorder after osteoporosis. In the United States, the disorder has an estimated frequency of 1-3% in the population over age 40 and of 8-10% for those over age 80 (Siris and Canfield 1990). The etiology of Paget disease of bone remains unknown. However, there is compelling evidence that genetic factors play a major role in the etiology of the disorder. The disease is most common in Western Europe (Detheridge et al. 1983), North America (Rosenbaum and Hanson 1969; Guyer and Chamberlain 1980), Australia (Barker 1984) and New Zealand (Reasbeck et al. 1983) with the highest prevalence in the United Kingdom, particularly in Lancashire (prevalence >6.3%) (Barker et al. 1980). Familial risk for Paget disease of bone has been evaluated by several authors. Sofaer et al. observed a tenfold increased prevalence among the parents and siblings of patients compared to their spouses (Sofaer et al. 1983). In the United States, Siris et al. further reported an affected first-degree relative in 12% of pagetic patients and calculated a seven-fold increased risk of developing the disease for first-degree relatives (Siris et al. 1991). In Spain, Mirales-Piga et al. observed that 40% of their index cases had at least one first-degree relative affected with Paget disease of bone (Morales-Piga et al. 1995). Familial clustering of Paget disease of bone was also frequently documented (Sofaer et al. 1983; Siris et al. 1991; Morales-Piga et al. 1995; Haslam et al. 1998; Hocking et al. 2000). In the kindreds investigated to date, Paget disease of bone appeared to be transmitted with an autosomal dominant mode of inheritance with incomplete penetrance. Suggestive evidence for linkage was first reported between Paget disease of bone and the HLA locus at 6p (Fotino et al. 1977; Tilyard et al. 1982). This potential locus was named PDB1 (MIM 167250). However, further studies did not confirm linkage at this site (Breanndan Moore and Hoffman 1988; Nance et al. 2000; Good et al. 2001), suggesting that the role of the HLA locus may be of minor importance in the etiology of Paget disease of bone. A rare bone disorder, familial expansile osteolysis [FEO (MIM #174810)], has been mapped to chromosome 18q21-q22 (Hughes et al. 1994). Using a candidate locus approach and a large pagetic family, Cody et al. reported evidence for linkage between Paget disease of bone and the same 18q region with a LOD score of 3.40 at D18S42 (Cody et al. 1997). This locus was called PDB2 (MIM 602080). These authors proposed that the gene(s) responsible for FEO and Paget disease of bone were either closely linked or were allelic variants of the same mutant gene. Subsequently, Haslam et al. confirmed linkage to 18q in five pagetic families and observed genetic heterogeneity in three other kindreds (Haslam et al. 1998). More recent studies confirmed genetic heterogeneity of the disorder and suggested that linkage of Paget at 18q21-q22 was relatively uncommon (Hocking et al. 2000; Nance et al. 2000; Good et al. 2001). Recently, the FEO disease gene has been identified as the TNFRSF11A gene (MIM 603499) that encodes RANK, the receptor activator of nuclear factor-κB (Hughes et al. 2000). The same heterozygotic insertion (84dup18) was detected in TNFRSF11A exon 1 in three families with FEO or FEO-related cases. One pedigree of Japanese origin with atypical Paget disease of bone also carried a 27 bp insertion (75dup27) in the TNFRSF11A gene. Their uncommon symptoms included early onset and dental problems, suggesting that these patients may suffer from a milder form of FEO or a particular early-onset form of Paget disease of bone (Leach et al. 2001). No RANK mutations have yet been reported for patients manifesting typical cases of Paget disease of bone (Hughes et al. 2000; Sparks et al. 2001). These observations show that the gene(s) causing the typical form of Paget disease of bone still remains to be characterized. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to methods and materials used to isolate and detect a human gene located at the PDB3 locus causing Paget disease of bone. The gene encodes the atypical protein kinase C-interacting protein p62 which is also referred to as sequestosome 1 (SQSTM1), some alleles of which cause Paget disease of bone. More specifically, the present invention relates to germline mutations in the atypical protein kinase C-interacting protein/sequestosome 1 (p62/SQSTM1) and their use in the diagnosis and predisposition to Paget disease of bone. The invention also relates to presymptomatic therapy of individuals who carry deleterious alleles of the p62/SQSTM1 gene. The invention also relates to the therapy of Paget disease of bone of individuals who have mutations in the p62/SQSTM1 gene (including gene therapy, protein replacement therapy, protein mimetics and inhibitors, RNA interference and antisense). The invention also relates to presymptomatic therapy of individuals who carry deleterious alleles of the p62/SQSTM1 gene. The invention further relates to the screening of drugs for Paget disease of bone. Finally, the invention relates to the screening of the p62/SQSTM1 gene for mutations, which are useful for diagnosing Paget disease of bone. Accordingly, the present invention provides an isolated nucleic acid molecule comprising a sequence encoding an atypical protein kinase C interacting protein having a molecular weight of approximately 62 kD (p62/SQSTM1) that is diagnostic of a disease of the bone. In a preferred embodiment, the isolated nucleic acid molecule encodes a mutated p62/SQSTM1 protein that is diagnostic of Paget disease of bone. In another embodiment, the invention provides an isolated atypical protein kinase C interacting protein having a molecular weight of approximately 62 kD (p62/SQSTM1) that is diagnostic of a disease of the bone. In a preferred embodiment, the protein is a mutated from of p62/SQSTM1 that is diagnostic of Paget disease of bone. In a further embodiment, the invention provides for a method of identifying substances which can bind with a mutated p62/SQSTM1 protein, comprising the steps of: (a) incubating a mutated p62/SQSTM1 protein and a test substrate, under conditions which allow for formation of a complex between the p62/SQSTM1 protein and the test substance, and (b) assaying for complexes of the mutated p62/SQSTM1 protein and a test substance, for free substance or for non complexed mutated p62/SQSTM1 protein, wherein the presence of complexes indicates that the test substance is capable of binding to the mutated p62/SQSTM1 protein. The invention also provides for methods for identifying a compound that affects mutated p62/SQSTM1 protein activity or expression comprising: (a) incubating a test compound with a mutated p62/SQSTM1 protein or a nucleic acid encoding a mutated p62/SQSTM1 protein; and (b) determining an amount of mutated p62/SQSTM1 protein activity or expression and comparing with a control, wherein a change in the mutated p62/SQSTM1 protein activity or expression as compared to the control indicates that the test compound has an effect on mutated p62/SQSTM1 protein activity or expression. In another embodiment, the invention provides a method of detecting a condition associated with a mutated p62/SQSTM1 protein comprising assaying a sample for (a) a nucleic acid molecule encoding a mutated p62/SQSTM1 protein or a fragment thereof or (b) a mutated p62/SQSTM1 protein or a fragment thereof. In a further embodiment, the invention provides a method of treating a bone disease comprising of administering to a cell or animal in need thereof, an effective amount of agent that modulates p62/SQSTM1 expression and/or activity. The invention also provides a use of an effective amount of an agent that modulates p62/SQSTM1 expression and/or activity to treat a bone. disease. In a preferred embodiment, the bone disease is Paget disease of bone. In yet another embodiment, the invention provides for a non-human animal carrying a mutation in the gene encoding a p62/SQSTM1 protein corresponding to a human P392L residue wherein the animal is a model for bone disease. Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description. |
Method for the continuous production and coating of self-adhesive compounds on the basis of sbc that includes at least one pharmaceutically active substance |
A process for the solvent-free and mastication-free production of a self-adhesive composition which is based on SBC and comprises a pharmaceutically active substance, in a continuously operating apparatus which comprises a feeding section and a compounding section. The SBC is added to the feeding section and the pharmaceutically active substance is added to the feed section and/or the compounding section, and the composition is homogenized in the compounding section. |
1-11. (canceled) 12. A process for a solvent-free and mastication-free production of a self-adhesive SBC-based composition which comprises at least one pharmaceutically active substance, in a continuously operating apparatus which comprises a feeding section and a compounding section, said process comprising (a) feeding an initial batch which comprises SBC, at least a part of the at least one pharmaceutically active substance and, optionally, at least a part of any further components of the composition into the feeding section of the apparatus; (b) transferring the initial batch from the feeding section to the compounding section of the apparatus; (c) optionally, adding any remaining part of the at least one pharmaceutically active substance and any remaining part of the further components of the composition which have not been added to the feeding section, to the compounding section; (d) treating the composition in the compounding section to prepare a homogeneous self-adhesive composition; and (e) discharging the homogeneous self-adhesive composition from the apparatus. 13. The process of claim 12, wherein the further components of the composition are selected from one or more of low molecular weight SBCs, fillers, plasiticizers, tackifiers, resins, release aids and additives. 14. The process of claim 12, wherein the apparatus comprises a twin-screw extruder. 15. The process of claim 14, wherein the twin-screw extruder comprises at least one metering port and at least one degassing port. 16. The process of claim 15, wherein the twin-screw extruder comprises from two to seven metering ports. 17. The process of claim 12, wherein a temperature inside the apparatus is from 85° C. to 120° C. 18. The process of claim 17, wherein the temperature is up to 110° C. 19. The process of claim 18, wherein the temperature is up to 100° C. 20. The process of claim 12, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.001% to 0.70% by weight, based on the weight of the composition. 21. The process of claim 20, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.01% to 0.67% by weight. 22. The process of claim 21, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.03% to 0.63% by weight. 23. The process of claim 12, wherein the SBC is used in a concentration of from 5% to 90% by weight. 24. The process of claim 22, wherein the SBC is used in a concentration of from 10% to 85% by weight. 25. A process for a solvent-free and mastication-free production of a self-adhesive SBC-based composition which comprises at least one pharmaceutically active substance, in a continuously operating apparatus which comprises a feeding section and a compounding section, said process comprising (a) feeding an initial batch which comprises SBC and, optionally, at least a part of any further components of the composition with the exception of the at least one pharmaceutically active substance into the feeding section of the apparatus; (b) transferring the initial batch from the feeding section to the compounding section of the apparatus; (c) adding the at least one pharmaceutically active substance and, optionally, any remaining part of the further components of the composition which has not been added to the feeding section to the compounding section; (d) treating the composition in the compounding section to prepare a homogeneous self-adhesive composition; and (e) discharging the homogeneous self-adhesive composition from the apparatus. 26. The process of claim 25, wherein the further components of the composition are selected from one or more of low molecular weight SBCs, fillers, plasiticizers, tackifiers, resins, release aids and additives. 27. The process of claim 25, wherein the apparatus comprises a twin-screw extruder. 28. The process of claim 27, wherein the twin-screw extruder comprises at least one metering port and at least one degassing port. 29. The process of claim 28, wherein the twin-screw extruder comprises from two to seven metering ports. 30. The process of claim 25, wherein a temperature inside the apparatus is from 85° C. to 120° C. 31. The process of claim 30, wherein the temperature is up to 110° C. 32. The process of claim 31, wherein the temperature is up to 100° C. 33. The process of claim 25, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.001% to 0.70% by weight, based on the weight of the composition. 34. The process of claim 33, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.01% to 0.67% by weight. 35. The process of claim 34, wherein the at least one pharmaceutically active substance is used in a concentration of from 0.03% to 0.63% by weight. 36. The process of claim 25, wherein the SBC is used in a concentration of from 5% to 90% by weight. 37. The process of claim 35, wherein the SBC is used in a concentration of from 10% to 85% by weight. 38. A self-adhesive composition which is obtainable by the process of claim 12. 39. A self-adhesive composition which is obtainable by the process of claim 25. 40. A process for producing a self-adhesive composition on a carrier material, which process comprises carrying out the process of claim 12, transferring the self-adhesive composition to a coating device and thereafter, coating the carrier material with the self-adhesive coating composition. 41. The process of claim 40, wherein the transfer of the coating composition to the coating device involves at least one of a melt pump and an extruder. 42. The process of claim 40, wherein the carrier material comprises a web material. 43. The process of claim 40, wherein the carrier material comprises at least one of a release film and a release paper. 44. The process of claim 43, wherein the process further comprises covering the coated composition with a release film or release paper. 45. The process of claim 40, wherein the coating device comprises an extrusion die. 46. The process of claim 40, wherein the coating device comprises at least one of a roll unit and a calender unit. 47. The process of claim 46, wherein a coating thickness of the composition is adjusted by allowing it to pass through one or more roll nips of the at least one of a roll unit and a calender unit. 48. The process of claim 46, wherein the coating device further comprises an extrusion die. 49. The process of claim 40, wherein a thickness of the self-adhesive composition on the carrier material is adjusted to from 10 μm to 2,000 μm. 50. The process of claim 49, wherein the thickness is from 20 μm to 500 μm. 51. The process of claim 50, wherein the thickness is from 50 μm to 400 μm. 52. A process for producing a self-adhesive composition on a carrier material, which process comprises carrying out the process of claim 25, transferring the self-adhesive composition to a coating device and thereafter, coating the carrier material with the self-adhesive coating composition. 53. The process of claim 52, wherein the transfer of the coating composition to the coating device involves at least one of a melt pump and an extruder. 54. The process of claim 52, wherein the carrier material comprises a web material. 55. The process of claim 52, wherein the carrier material comprises at least one of a release film and a release paper. 56. The process of claim 45, wherein the process further comprises covering the coated composition with one of a release film and a release paper. 57. The process of claim 52, wherein the coating device comprises an extrusion die. 58. The process of claim 52, wherein the coating device comprises at least one of a roll unit and a calender unit. 59. The process of claim 58, wherein a coating thickness of the composition is adjusted by allowing it to pass through one or more roll nips of the at least one of a roll unit and a calender unit. 60. The process of claim 48, wherein the coating device further comprises an extrusion die. 61. The process of claim 52, wherein a thickness of the self-adhesive composition on the carrier material is adjusted to from 10 μm to 2,000 μm. 62. The process of claim 61, wherein the thickness is from 20 μm to 500 μm. 63. The process of claim 62, wherein the thickness is from 50 μm to 400 μm. 64. A self-adhesive composition on a carrier material which is obtainable by the process of claim 40. 65. A self-adhesive composition on a carrier material which is obtainable by the process of claim 52. |
Use of stilbene compounds in preparing medicaments for treating or preventing diabetes and diseases associated with retrovirus |
This invention relates to a new use of stilbene derivatives or pharmaceutically acceptable salts thereof, especially in the manufacture of medicament for the prevention and treatment of diabetes or retrovirus associated diseases. |
1. A use of at least one stilbene derivatives of formula I or pharmaceutically acceptable salts thereof in the manufacture of medicament for the prevention and treatment of diabetes or retrovirus-associated diseases, wherein R1, R2, R3 and R4 be independently H, —OH, alkyl, aryl such phenyl or naphthalenyl alkylhydroxyl-, alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. 2. A composition for the prevention or treatment of diabetes or retrovirus-associated diseases which comprising at least one stilbene derivatives of formula I or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carrier or excipient, wherein R1, R2, R3 and R4 be independently H, —OH, alkyl C6-10 aryl such as phenyl or naphthalenyl, alkylhydroxyl-, alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. 3. A method for the prevention or treatment of diabetes or retrovirus D-associated diseases which including administrating effective amount of stilbene derivatives of formula I or pharmaceutically acceptable salts thereof to the patients, wherein R1, R2, R3 and R4 be independently H, —OH, alkyl C6-10 aryl such as phenyl or naphthalenyl, alkylhydroxyl-, alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. 4. Use as claimed in claim 1, wherein said compounds are selected from: 3,4,5-trihydroxystilbene (compound E), 3,3′,4′,5-quadrahydroxystilbene -4′-O-β-D-glucopyranoside (Compound E1) 3,4′,5-trihydroxy-3′-methyloxy stilbene-3-O-β-D glucoside (compound E2) 3,5-dihydroxy-4′-methyloxy stilbene-3-O-β-O-D glucoside (compound E3) 3,4′,5-trihydroxy stilbene-3′-O-D-glucoside (compound E5) |
<SOH> TECHNOLOGY OF THE BACKGROUND <EOH>Diabetes is a common metabolic disorder in human beings. Recently, along with the improvement of living standard, and the changing of foodstuff structure, the incidence of diabetes are increasing rapidly. In the world there are around 0.12 billion of patients suffering from this disease. It is a serious threat to mankind. Therefore the prevention and treatment of diabetes is a hot focus in the field of medicinal research work. Now the anti-diabetic medicament used in clinics such as sulfanylureas, biguanidins etc are effective yet with some side effects. Some formulation derived from Chinese traditional herbs are effective, less toxic. Up to now no hypoglycemic monomer derived from natural plants which is used in clinics is reported. |
<SOH> SUMMARY OF THIS INVENTION <EOH>The investigation of the inventors has discovered that the stilbene derivatives of formula I or pharmaceutically acceptable salts thereof have positive hypoglycemic effect and anti-retrovirus effect, then they could be useful for prevention and treatment of diabetes and retrovirus-associated diseases. Therefore, the first aspect of this invention relates to a use of at least one stilbene derivatives of formula I or pharmaceutically acceptable salts thereof in the manufacture of medicament for the prevention and treatment of diabetes or retrovirus-associated diseases, wherein, R 1 , R 2 , R 3 and R 4 are individually H, —OH, alkyl, C 6-10 aryl such as phenyl or naphthalenyl, alkylhydroxyl- , alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. The second aspect of this invention relates to a composition for the prevention and treatment of diabetes or retrovirus-associated diseases which comprising at least one stilbene derivatives of formula I or pharmaceutically acceptable salts thereof, pharmaceutically acceptable carrier or excipient, Wherein, R 1 , R 2 , R 3 and R 4 are independently H, —OH, alkyl, C 6-10 aryl such as phenyl or naphthalenyl, alkylhydroxyl-, alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. Furthermore, this invention relates to a method of the prevention and treatment of diabetes or retrovirus-associated diseases which comprising administrating a effective amount of stilbene derivatives of formula I or pharmaceutically acceptable salts thereof to the patient. wherein R 1 , R 2 , R 3 and R 4 are independently H, —OH, alkyl, C 6-10 aryl such as phenyl or naphthalenyl, alkylhydroxyl-, alkoxyl and sugar containing glycosides such as —O-glucosyl or -glucosyl. detailed-description description="Detailed Description" end="lead"? |
Transformation method for obtaining marker-free plants and plants obtained therewith |
The invention relates to a transformation method for obtaining transgenic plants and plants obtained with said method. The invention provides a method for transforming a plant cell comprising providing a plant cell with a recombinant nucleic acid comprising a T-DNA construct allowing for transfer of said construct into the genome of a plant cell, said construct provided with a foreign nucleic acid that is free of nucleic acid encoding a selective marker. |
1. A method for obtaining a market-free, uniform transgenic plant, comprising transforming a plant cell with a recombinant nucleic acid comprising a T-DNA construct wherein said T-DNA is provided with a foreign nucleic acid that is free of a nucleic acid encoding a selective marker regeneration of said cell under no selective pressure testing said cell or progeny thereof for the presence or absence of at least a functional part of said foreign nucleic acid and identify transformed plant cells or progeny thereof growing a plant from said identified cell or progeny thereof, testing the obtained plant for uniformness and selecting a uniform plant. 2. A method according to claim 1, wherein said nucleic acid that comprises a foreign nucleic acid that is free of nucleic acid encoding a selective marker is delivered to said plant cell by an Agrobacterium strain. 3. A method according to claim 3, wherein said Agrobacterium strain is a virulent Agrobacterium strain. 4. A method according to claim 2 wherein said Agrobacterium strain carries a DNA region originating from the virulence region of the Ti plasmid pTiBo542. 5. A method according to claim 2, wherein said Agrobacterium strain is selected from EHA 101, AGL-0, AGL-1. 6. A method according to claim 1 wherein said foreign nucleic acid allows for regulation of the expression of a target gene in the genome of said plant cell. 7. A method according to claim 6 wherein said regulation comprises downregulation. 8. A method according to claim 6 wherein said foreign nucleic acid includes an inverted repeat of at least part of a polynucleotide region of said target gene. 9. A method according to claim 6, wherein said target gene encodes a granule-bound starch synthase (GBSSI) enzyme. 10. A method according to claim 1, wherein said foreign nucleic acid allows for expression of a heterologous polypeptide in the genome of said plant cell. 11. A method according to claim 10, wherein said heterologous polypeptide comprises an enzyme. 12. A method according to claim 11, wherein said enzyme comprises a-, preferably feedback-insensitive, dihydrodipicolinate synthase (DHPS). 13. A method according to claim 1, wherein said testing for the presence or absence of at least a functional part of said foreign nucleic acid is performed by nucleic acid techniques, ELISA, bioassay or chemical analytical methods. 14. A method according to claim 13, wherein said testing is performed by PCR. 15. A method according to claim 1, further comprising testing said cell or progeny thereof for the presence or absence of undesired vector material such as vector backbone sequences. 16. A method according to claim 1, further comprising determining the amount of copies of said foreign nucleic acid and selecting the one that contains only one insert of said T-DNA. 17. A plant cell obtainable with a method according to claim 1. 18. A plant, or part thereof, derived from a plant cell according to claim 17. 19. A tuberous plant, or part thereof, according to claim 18. 20. A plant, or part thereof, according to claim 19 which is selected from potato or cassava plants. |
Splicing tape application device with rigid electrostatic charge eliminator |
The invention is in the field of devices enabling the sticking of splicing tapes to the ends of strips put into rolls, to prevent their later unwinding. The present invention relates to a device (1) for applying splicing tapes (22) on a strip (30) made of flexible material. The device (1) is equipped with a passive device (50) enabling the elimination of the electrostatic forces that disturb the operation of the device. The device (1) according to the invention is mainly used on photographic film or paper slitters. |
1. A device for applying precut splicing tapes 3 initially attached successively to a first strip serving as support made of flexible material, onto a second strip made of flexible material of an end of a roll, by successively separating the splicing tapes from the first strip, said device comprising: a frame in which are arranged an unwinding device, a winding device, a guide, and a mechanical tension checker of the first strip, a pressure part enabling the splicing tape separated from the first strip to be applied to a second strip of the end of the roll when said roll is approached by the pressure part; a passive device of electrostatic discharge acting by an electrical field effect and attached to one of the guides of the device, said passive device having an end placed in a sticking zone just before an intersection of paths of the separated slicing tape and the second strip to be stuck, as close as possible to the path of the separated slicing tape without touching said tape, and without touching the second strip to be stuck, so as to generate the electrostatic discharge of the sticking zone and prevent attraction of the separated tape by the pressure part. 2. A device according to claim 1, wherein the passive device of electrostatic discharge is an electrically conductive foil. 3. A device according to claim 2, wherein a thickness of the foil is between 0.05 mm and 0.10 mm. 4. A device according to claim 3, wherein a preferred thickness of the foil is 0.06 mm. 5. A device according to claim 1, wherein the first support strip made of flexible material is a paper strip coated with a thin layer of solid saturated hydrocarbons. 6. A device according to claim 1, wherein the splicing tapes pre-glued and fixed successively to the first support strip comprise at least one pre-glued zone on the side opposite the support strip. 7. A device according to claim 1, wherein the second strip of flexible material is a photographic paper strip. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The use of slitters is universally known in the photographic industry. Slitters enable the simultaneous cutting into several strips with preset widths of a wider strip or axis of film or paper previously coated with a photosensitive emulsion layer. The wider strip to be cut has a programmed length itself. The cut strips obtained from the wider strip are wound around a central core. Each of the rolls thus obtained ends with a free strand. The free strand is intended to take a pre-glued splicing tape of flexible material, to fix this free strand of the strip end onto its roll, in order to prevent the roll from unwinding during later manipulations or operations in the process, in particular during the operation of packaging the rolls and transport of the rolls. The splicing tape is applied to the roll using an automatic sticking device, attached to an annexed part of the slitter. This sticking device automatically places and sticks the splicing tapes onto the free strands of the respective rolls. Before the sticking operation of the splicing tapes to the roll, they are previously unstuck or separated from a support strip. The unsticking generates electrostatic forces that cause quality faults, because the separated splicing tape is deviated from its planned path towards the free strand of the strip end to be stuck. Therefore, it does not stick the free strand onto its roll. In addition the deviated splicing tape is often found, for example, inside the sticking device and disturbs its operation It is an object of the present invention to eliminate the effect of electrostatic forces in sticking devices used on slitters. The principle enabling electrostatic forces to be eliminated is well known to those skilled in the art. It includes using ionization of the air. To eliminate electrostatic forces, passive induction means, comprising points linked to ground for example are used, as described in Patent EP 708,580. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention relates to a splicing tape sticking or application device equipped with a passive means that enables the elimination of the electrostatic forces that disturb the operation of the device as far as stopping the operation. Stopping the operation of the sticking device causes the slitter to stop; these stops generate significant productivity losses that the device according to the invention eliminates. The present invention relates to a device for applying precut splicing tapes initially attached successively to a first strip serving as support made of flexible material, onto a second strip made of flexible material of the roll end, by successively separating the splicing tapes of the first strip. The device comprises a frame in which are arranged the means for unwinding, winding, guiding, and mechanical tension check of the first strip, and a pressure part that enables the splicing tape separated from the first strip to be applied to the second strip of the roll end when the roll is approached by the pressure part. The device is characterized in that it further comprises a passive means of electrostatic discharge acting by the electrical field effect and attached to one of the device's guiding means. The passive means has its end placed in the sticking zone just before the intersection of the paths of the separated slicing tape and the second strip to be stuck, as close as possible to the path of the separated slicing tape without touching the tape, and without touching the second strip to be stuck, so as to generate the electrostatic discharge of the zone and prevent attraction of the separated tape by the pressure means. Other advantages and characteristics of the present invention will appear in the following description and more particularly in a preferred embodiment of the invention illustrated in the following figures. |
Method, network element, and terminal device for making data packets |
The present invention relates to a method and a network element 3 for marking data packets to be transmitted in a packet switched network 10 with a priority information I, said packets being treated in said network 10 according to said priority information I. The priority information I is determined depending on a nominal bit rate NBR allocated to a certain service connection and a momentary bit rate MBR of said connection that is calculated depending on an importance marking IU contained in a received data packet indicating an importance level of said data packet. Thus, the nominal bit rate NBR allocated to an end-user can be shared between a plurality of applications with different characteristics in order to give certain applications a higher priority than other applications. The present invention relates to a corresponding terminal device 9 to be used with such a network element 3. |
1. A method for marking data packets to be transmitted in a packet switched network (10) with a priority information (I) for treating said packets in said network (10) according to said priority information (I), comprising the steps of: determining an importance marking (IU) contained in a received data packet indicating an importance level of said data packet, determining a nominal bit rate (NBR) allocated to a certain service connection, calculating a momentary bit rate (MBR) of said connection depending on said importance marking (IU), and determining said priority information (I) depending on said nominal bit rate (NBR) and said momentary bit rate (MBR). 2. A method according to claim 1, wherein said importance marking (ĨU) is generated by means of a terminal device (9). 3. A method according to claim 1, wherein said importance marking (ĨU) is generated by an end-user input (12) input to said terminal device (9). 4. A method according to claim 1, wherein said nominal bit rate (NBR) allocated to an end-user and/or a terminal device (9) is shared between a plurality of applications of said end-user and/or terminal device (9) depending on said importance marking (ĨU) of said end-user and/or terminal device (9). 5. A method according to claim 4, wherein a data packet received from an individual terminal device (9) is marked prior transmission through said network (10) with an individual priority information depending on the respective application having generated said packet. 6. A method according to claim 1, wherein said momentary bit rate (MBR) is calculated further depending on: a packet size (S) of a received data packet and an interarrival time (dt) between a packet under consideration and a previous packet. 7. A method according to claim 1, wherein said momentary bit rate (MBR) is increased for more important data packets and/or decreased for less important data packets within in given traffic class, said increasing and/or decreasing is performed depending on said importance marking (IU). 8. A method according to claim 1, wherein an overall network capacity is divided between different end-users and/or terminal devices (9) substantially depending on said nominal bit rate (NBR) of each end-user and/or terminal device (9). 9. A method according to claim 1, wherein network traffic is counted individually for each individual traffic class. 10. A method according to claim 1, wherein an overall network traffic is counted irrespective of the traffic in said individual traffic classes. 11. A network element for marking data packets to be transmitted in a packet switched network (10) with a priority information (I) for treating said packets in said network (10) according to said priority information (I), comprising: importance marking determining means (11) for determining an importance marking (IU) in an data packet receivable from a terminal device (9), said importance marking (IU) indicating an importance level of said data packet, nominal bit rate determining means (4) for determining a nominal bit rate (NBR) allocated to a certain service connection, calculation means (7) for calculating a momentary bit rate (MBR) of said connection depending on said importance marking (IU) being in connection with said importance marking determining means (11), and priority information determining means (8) for determining said priority information (I) depending on said nominal bit rate (NBR) and said momentary bit rate (MBR), said priority information determining means (8) being in connection with said nominal bit rate determining means (4) and said calculation means (7). 12. A network element according to claim 11, wherein said calculation means (7) being capable of calculating said momentary bit rate (MBR) further depending on a packet size (S) of a received data packet and an interarrival time (dt) between a packet under consideration and previous packet. 13. (Cancelled) 14. A terminal device for generating data packets to be transmitted in a packet switched network (10), said packets being treated in said network (10) according to a priority information (I) being attached to said packets by means of a network element (3) according to claim 11, said terminal device (9) comprising: means for generating data packets, and means (12) for generating an importance marking (ĨU) attached to or inserted in said data packets indicating an importance level of said data packets. 15. A terminal device according to claim 14, wherein said importance marking (ĨU) generation means (12) are generating an importance marking (ĨU) depending on an application being allocated to a current data packet. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In common communication networks, in particular in mobile communication networks two main techniques for a data transmission are used: circuit switched data transmission and packet switched data transmission. In the circuit switched domain a network establishes a service connection for data transmission by allocating a (radio) channel to a terminal, e.g. a mobile station, when a network host or service provider intends to transmit data via the network. Then data is transmitted via the network after the connection has been established. The radio channel is occupied by the terminal during the entire duration of the connection, even though in many cases only a small amount of data has to be transmitted. In the packet switched domain the network transmits a data packet only when required, i.e. when data transmission has to be carried out. Thus, several terminals can use the same channel at a time. If a terminal generates a data packet, the network routes that packet via a first unattached channel to a recipient. Thus, as data transmission frequently consists of data bursts, the channels can be used in an efficient manner. This type of packet switched data transmission is used in the Internet and e.g. GPRS (General Packet Radio Service) systems and UMTS (Universal Mobile Telecommunications System) systems. Data packets are routed in packet switched networks via mostly unpredictable routes depending on the actual data traffic and depending on the configuration of the corresponding routers. Thus, packets may encounter different delays inside the network caused e.g. by variation in occupancy levels of queues inside the routers. Furthermore, as a result, the network capacity, in particular within certain routes, has to be divided between different flows (or connections, or customers). The division of the capacity between the different glows is controlled by the so-called SIMA (Simple Integrated Media Access) system as being described in U.S. Pat. No. 6,047,326 and U.S. Pat. No. 6,081,505. SIMA is a way to provide QoS (Quality of Service) using differentiated services, i.e. SIMA is a complete service and implementation solution. Differentiated services is an approach to provide QoS in the internet. The basic idea is to provide relative (soft) guarantees for delivery of IP (Internet Protocol) data packets. Complex functions are left at the edges of the network. This allows simple core network routers and ensures the scalability. According to the SIMA concept each user or application shall define only two issues before a connection is established, namely a nominal bit rate (NBR) and the selection between real-time and non-real-time service classes. NBR forms the basic relationship between charging and QoS, and it defines how the network capacity is divided among different connections during overload situations. Due to the simplicity of SIMA the network operator does not guarantee the continuous availability of NBR. Furthermore, a user or application is allowed to send data with any bit rate independently of the NBR. The strength of SIMA is its wide area of applications. SIMA does not require to build complex systems with several service classes each appropriate to only certain applications. The idea of SIMA is that at the network edge packets are assigned a priority for a network domain. The packets are treated in the network domain according to the priority. The priority is depending on the ratio of a measured momentary bit rate (MBR) and NBR: If the MBR exceeds the NBR the priority is dropped and if the MBR is clearly below the NBR the priority is raised. Thereby, the NBR corresponds roughly to the bandwidth allocation for a given client. Though the SIMA model as being described in U.S. Pat. No. 6,047,326 and U.S. Pat. No. 6,081,505 has been proved to be efficient and quite flexible, it has some limitations. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is therefore an object of the present invention to improve such data packet marking systems. This object is achieved by a method for marking data packets to be transmitted in a packet switched network with a priority information for treating said packets in said network according to said priority information, comprising the steps of: determining an importance marking contained in a received data packet indicating an importance level of said data packet, determining a nominal bit rate allocated to a certain service connection, calculating a momentary bit rate of said connection depending on said importance marking, and determining said priority information depending on said nominal bit rate and said momentary bit rate. Furthermore, the above object is achieved by a network element for marking data packets to be transmitted in a packet switched network with a priority information for treating said packets in said network according to said priority information, comprising: importance marking determining means for determining an importance marking in an data packet receivable from a terminal device, said importance marking indicating an importance level of said data packet, nominal bit rate determining means for determining a nominal bit rate allocated to a certain service connection, calculation means for calculating a momentary bit rate of said connection depending on said importance marking being in connection with said importance marking determining means, and priority information determining means for determining said priority information depending on said nominal bit rate and said momentary bit rate, said priority information determining means being in connection with said nominal bit rate determining means and said calculation means. Furthermore, the above object is achieved by a terminal device for generating data packets to be transmitted in a packet switched network, said packets being treated in said network according to a priority information being attached to said packets by means of such a network element by using such a method, said terminal device comprising: means for generating data packets, and means for generating an importance marking attached to or inserted in said data packets indicating an importance level of said data packets. The main idea of the invention is to provide an extension to prior art systems for marking data packets by taking into account importance marking made by the customer, end-user and/or a terminal device particularly used by a customer or end-user. The invention thus provides a system that takes into account the relative importance level informed by a customer (end-user) and/or terminal device thereby particularly dividing the network resources between different customers (end-users) and/or terminal devices purely on the NBR of each of them. The invention furthermore allows to divide the data traffic in the network domain from one to a plurality of traffic classes for each connection between two or more end-users/terminal devices. As a result the invention enables more resources to be reserved for applications that an end-user/terminal device judges relevant. The above mentioned network element can be integrated into an integrated circuit, e.g. a ASIC (application specific IC) chip. This chip is preferably used in a router, preferably a wireless router as for use in mobile communication systems or in any other non-wireless router. It is further preferred that such a CHIP is used in a IP RAN (Internet Protocol Remote Access Node). Preferably, the importance marking is performed by means of the terminal device. Thus, the marking of the data packets can be controlled automatically, e.g. by a running application being operated e.g. in that terminal device. It is further preferred that the importance marking is generated by an end-user input to said terminal device. Thus, the marking of the data packets with the importance marking can be controlled manually by an end-user, preferably assisted by a corresponding application interacting with the end-user. As a result the end-user is able to give certain data packets a higher priority. In a further preferred embodiment the NBR allocated to an end-user and/or a terminal device is shared between a plurality of applications of said end-user and/or terminal device depending on the importance marking of the end-user and/or the terminal device. Thus, different applications may be operated with different bit rates and hence different bandwidths depending on the characteristics of the applications indicated by the corresponding importance markings. According to a further preferred embodiment a data packet received from an individual terminal device is marked prior transmission through said network with an individual priority information depending on the respective application having generated said packet. In a corresponding preferred terminal device the importance marking generating means are generating an importance marking depending on an individual application being allocated to a current data packet. Thus, it is possible to treat in the network domain each application individually with an application individual priority information. Thus, the flexibility of the system is further increased. It can be assumed that the application is the main reason for a customer to mark packets with specific importance. However, there also is the possibility that within the packet flow of an application certain packets are marked with higher importance than some other packet belonging to the same flow. In an embodiment of the invention the MBR is increased for more important data packets and/or decreased for less important data packets within a given traffic class, said increasing and/or decreasing is performed depending on said importance marking. The increasing and/or decreasing is performed after a MBR measurement so that a modified MBR is taken into account in subsequent computations. The overall effect of packet importance is smoothed by means of a common measurement for all traffic classes. It is further preferred, that an overall network capacity is divided between different end-users and/or terminal devices substantially depending on that NBR of each end-user and/or terminal device. Thus, the bandwidth of the network is shared between users based on their individual NBR that is preferably depending on the purchased network access, in particular on the type of network access fees paid by the user, e.g. a flat rate or time-depending fee and/or a transmission rate depending fee. According to a further embodiment the network traffic is counted individually for each individual traffic class. This can be performed by a network element by means of separate counters for the traffic in each of the classes. The difference between the classes is preferably in the delay characteristics (e.g., one class is intented to provide good enough delay characteristics for voice connections, while another one is suited for data connections). The number of classes shall be relatively small, preferably from 2 to 4. It is further preferred, that an overall network traffic is counted irrespective of the traffic in said individual traffic classes. Thus, a corresponding network element comprises a counter for counting the overall network traffic. Further advantageous developments are defined in dependent claims. |
Novel genetic products of ashbya gossypii, associated with the mechanisms of signal transduction and especially with the improvement of vitamin b2 production |
The invention relates to novel polynucleotides from Ashbya gossypii; to oligonucleotides hybridizing therewith; to expression cassettes and vectors which comprise these polynucleotides; to microorganisms transformed therewith; to polypeptides encoded by these polynucleotides; and to the use of the novel polypeptides and polynucleotides as targets for improving signal transduction mechanisms and, in particular, improving vitamin B2 production in microorganisms of the genus Ashbya. |
1. An isolated polynucleotide comprising a sequence that codes for a protein associated with signal transduction activity that can be isolated from a microorganism of Ashbya gossypii or a functional equivalent of said protein. 2. A The polynucleotide of claim 1, which codes for a protein selected from the group consisting of an inositol polyphosphate 5-phosphatase, a protein having ATP binding activity, and a protein having GTP binding activity. 3. The polynucleotide of claim 1, which comprises: the nucleic acid sequence of SEQ ID NO: 1 or SEQ ID NO: 5, or of fragments of either; polynucleotides complementary thereto; or sequences derived from said sequence or said polynucleotides through degeneracy of the genetic code. 4. The polynucleotide of claim 1, which comprises: the nucleic acid sequence of SEQ ID NO: 3 or SEQ ID NO: 7, or of a fragment of either; polynucleotides complementary thereto; or sequences derived from said sequences or said polynucleotides through degeneracy of the genetic code. 5. An isolated oligonucleotide that hybridizes to the polynucleotide of claim 1 under stringent hybridization conditions. 6. An isolated polynucleotide that hybridizes to the oligonucleotide of claim 5, under stringent hybridization conditions, and codes for a gene product derived from a microorganism of the genus Ashbya or a functional equivalent thereof. 7. A An isolated polypeptide encoded by the polynucleotide of claim 1 or a fragment thereof. 8. An expression cassette comprising the polynucleotide of claim 1 operatively linked to at least one regulatory nucleic acid sequence. 9. A recombinant vector comprising at least one expression cassette of claim 8. 10. A prokaryotic or eukaryotic host cell transformed with at least one vector of claim 9. 11. A recombinant prokaryotic or eukaryotic host cell that possesses a signal transduction activity wherein functional expression of a gene that codes for a polypeptide associated with said signal transduction activity is modulated; or a biological activity of a said polypeptide is reduced or increased. 12. A The host cell of claim 10, which is derived from the genus Ashbya. 13. A process for microbiological production of vitamin B2 or a precursor or derivative thereof comprising: transforming a host cell with the expression cassette of claim 8; and producing therefrom vitamin B2 or a precursor or derivative thereof. 14. A process for recombinant production of a polypeptide associated with signal transduction activity comprising expressing the expression cassette of claim 8 in a host cell. 15. A method for detecting an effector target for modulating the microbiological production of vitamin B2 or a precursor or derivative thereof, comprising: treating a microorganism capable of the microbiological production of vitamin B2 or a precursor or derivative thereof is treated with an effector that interacts with a polypeptide associated with signal transduction activity that can be isolated from a microorganism of Ashbya gossypii or a nucleic acid sequence that encodes said polypeptide, and determining an effect of the effector on the amount of the microbiologically produced vitamin B2 or a precursor or derivative thereof. 16. A method for modulating the microbiological production of vitamin B2 or a precursor or derivative thereof, comprising: treating a microorganism capable of the microbiological production of vitamin B2 or a precursor or derivative thereof with an effector that interacts with a polypeptide associated with signal transduction activity that can be isolated from a microorganism of Ashbya gossypii or a nucleic acid sequence that encodes said polypeptide. 17. An isolated effector for a polypeptide associated with signal transduction activity that can be isolated from a microorganism of Ashbya gossypii or a nucleic acid sequence that encodes said polypeptide. 18. A method for microbiological production of vitamin B2 or a precursor or derivative thereof, comprising: culturing the host cell of claim 10 in a culture under conditions favoring production of vitamin B2 or a precursor or derivative thereof; and isolating vitamin B2 or the precursor or derivative thereof from said culture. 19. The method of claim 18, wherein the host cell is treated with an effector before or during culturing. 20. The method of claim 18, wherein the host cell is a microorganism of the genus Ashbya. 21. The method of claim 19 wherein the effector is selected from the group consisting of: antibodies or antigen-binding fragments thereof; polypeptide ligands that are different from said antibodies or antigen-binding fragments thereof and interact with the polypeptide; low molecular weight effectors that modulate a biological activity of said polypeptide; antisense nucleic acid sequences; ribozymes; catalytic nucleic acids; and mixtures thereof. 22. A method for modulating production of vitamin B2 or a precursor or derivative thereof in a microorganism of the genus Ashbya comprising containing said microorganism with the effector of claim 17. 23. A method for modulating the cell wall and cytoskeleton structure of a microorganism of the genus Ashbya comprising: culturing the host cell of claim 12 for microbiological production of vitamin B2 or a precursor or derivative thereof; modulating said host cell by contacting said host cell with an effector. 24. The host cell of claim 12, which has an improved cellular response to extracellular signals as compared to an untransformed host cell. 25. A polypeptide encoded by the polynucleotide of claim 6. 26. A polynucleotide encoded by at least ten consecutive amino acid residues of the sequence of SEQ ID NOs: 2, 4, 6, or 8, or a functional equivalent of said at least ten consecutive amino acid residues. 27. The polynucleotide of claim 7, which has an activity of an enzyme protein selected from the group consisting of an inositol polyphosphate 5-phosphatase, a protein having ATP binding activity, and a protein having GTP binding activity. 28. The host cell of claim 11, wherein signal transduction activity of said polypeptide is increased as compared with a nonrecombinant host cell. 29. The host cell of claim 11, which is derived from a microorganism of Ashbya gossypii. 30. The method of claim 15, wherein the effector interacts with said polypeptide or said nucleic acid by binding. 31. The method of claim 15, further comprising isolating the effector. 32. The method of claim 16, wherein the effector interacts with said polypeptide or said nucleic acid by binding. 33. The effector of claim 17, which is selected from the group consisting of: antibodies or antigen-binding fragments thereof; polypeptide ligands that are different from said antibodies or antigen-binding fragments thereof and interact with the polypeptide; low molecular weight effectors that modulate a biological activity of said polypeptide; antisense nucleic acid sequences; ribozymes; catalytic nucleic acids; and mixtures and combinations thereof. 34. The effector of claim 33, wherein the antisense nucleic acid is an alpha-anomeric nucleic acid. 35. The method of claim 21, wherein the antisense nucleic acid is an alpha-anomeric nucleic acid. 36. The method of claim 22, wherein modulating comprising increasing the production of vitamin B2 or a precursor or derivative thereof. 37. The method of claim 23, wherein modulating comprises making said host cell more robust against external influences wherein viability or productivity is increased as compared to unmodulated host cells. 38. The host cell of claim 24, wherein the improved cellular response comprises increased signal transduction activity. |
Polyparaxylylene film, production method therefor and semiconductor device |
An organic polymer film of low dielectric constant and high heating resistance which is applicable as an insulating layer of a semiconductor devices is provided, as well as a manufacturing method for the film and a semiconductor device incorporating the film. |
1-16. (Canceled) 17. A film of porous poly-paraxylylene or a derivative thereof prepared by the process comprising: subliming paraxylylene or a derivative cyclic dimer; pyrolyzing the resulting product at 800 to 950° C.; polymerizing the product obtained by pyrolysis; and heat-treating the resulting polymer. 18. A film of porous poly-paraxylylene or a derivative thereof in accordance with claim 17, wherein said film contains a porous structure of 10 to 50% by volume. 19. A method of manufacturing a film of porous poly-paraxylylene or a derivative thereof, comprising subliming paraxylylene or a derivative cyclic dimer at 30 to 160° C.; pyrolyzing the resulting product at 800 to 950° C.; polymerizing the product obtained by pyrolysis at −40 to +25° C.; and heat-treating the resulting polymer. 20. The method of manufacturing a film poly-paraxylylene or a derivative thereof in accordance with claim 19, wherein said sublimation, pyrolysis, and polymerization processes are performed at a vacuum pressure of 0.001 to 0.1 mmHg. 21. The method of manufacturing a film of poly-paraxylylene or a derivative thereof in accordance with claim 19, wherein the heat-treating process comprises alternately heating to increase the temperature and heating to maintain the temperature in a stepwise manner, wherein a final heating is made at 390 to 410° C. 22. The method of manufacturing a film of poly-paraxylylene or a derivative thereof in accordance with claim 19, wherein the heat-treating process is performed at a vacuum pressure of 0.001 to 0.1 mmHg or in an inactive gas atmosphere. 23. The method of manufacturing a film of poly-paraxylylene or a derivative thereof in accordance with claim 19, wherein the heat-treating process comprises heating to increase the temperature to 170 to 220° C. at a heating rate of 4° C./minute or less, heating to maintain the temperature for at least 35 minutes at 170 to 220° C., heating to increase the temperature to 350 to 390° C. at a rate of 0.5° C./minute or less, heating to maintain the temperature for at least 70 minutes at 350 to 390° C., heating to increase the temperature to 390 to 410° C. at a rate of 0.5° C./minute or less, and heating to maintain the temperature for at least 70 minutes at 390 to 410° C. 24. The method of manufacturing a film of poly-paraxylylene or a derivative film thereof in accordance with claim 23, wherein the heat-treating process comprises heating to increase the temperature to 190 to 210° C. at a rate of 4° C./minute or less, heating to maintain the temperature for at least 35 minutes at 190 to 210° C., heating to increase the temperature to 370 to 380° C. at a rate of 0.5° C./minute or less, heating to maintain the temperature for at least 70 minutes at 370 to 380° C., heating to increase the temperature to 390 to 410° C. at a rate of 0.5° C./minute or less, and heating to maintain the temperature for at least 70 minutes at 390 to 410° C. 25. A film of porous poly-paraxylylene or a derivative thereof prepared by the process comprising: subliming paraxylylene or a derivative cyclic dimer at 30 to 160° C.; pyrolyzing the resulting product at 800 to 950° C.; polymerizing the product obtained by pyrolysis at −40 to +25° C.; and heat-treating the resulting polymer, wherein the polymer is removed from a polymerization tank and heat-treated after said polymerization process. 26. A semiconductor device comprising semiconductor elements electrically connected to thin-film wirings formed on an insulating film, wherein said insulating film comprises porous poly-paraxylylene or a derivative thereof prepared by subliming paraxylylene or a derivative cyclic dimer, pyrolyzing the resulting product at 800 to 950° C., polymerizing the product obtained by pyrolysis, and heat-treating the resulting polymer. 27. A semiconductor device in accordance with claim 26, wherein said insulating film comprises a fluorinated poly-paraxylylene film prepared by subliming a cyclophane compound, pyrolyzing said compound into paraxylylene monomer at 800 to 950° C., polymerizing said paraxylylene monomer into poly-paraxylylene precipitate, and heat-treating the precipitate. 28. A semiconductor device in accordance with claim 26, wherein said heat-treating comprises alternately heating to increase the temperature and heating to maintain the temperature in a stepwise manner, wherein a final heating is made at 390 to 410° C. 29. A semiconductor device in accordance with claim 26, wherein said insulating film is prepared by a method comprising: subliming paraxylylene or a derivative cyclic dimer at 30 to 160° C.; pyrolyzing the resulting product at 800 to 950° C.; polymerizing the product obtained by pyrolysis at −40 to +25° C.; and heat-treating the resulting polymer. 30. A semiconductor device whose semiconductor elements are electrically connected to thin-film wirings formed on an insulating film, wherein said insulating film is a poly-paraxylylene and its derivative film which is prepared by the method of claim 19 and contains a porous structure therein. 31. A semiconductor device in accordance with claim 30, wherein said film contains a porous structure of 25 to 50% by volume. 32. A multi-layer wiring substrate comprising laminate wiring layers having a conductive circuit on at least one side of an insulating base with an insulating layer therebetween, wherein at least one of said insulating base and said insulating layer is a film of poly-paraxylylene or a derivative thereof which is prepared by the method of claim 19 and contains a porous structure therein. |
<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates to films which have been widely used in electronic and electric fields, and particularly to poly-paraxylylene useful as an insulating layer of low dielectric constant and high heating resistance between wiring layers, manufacturing method thereof, and semiconductor device using thereof. The film of this invention means both a freestanding film and a coating film bonded to a substrate, for example an insulating film between wiring layers. With the development of high-density integration of semiconductor integrated circuits, their wiring line and space have been greatly reduced. As a result, line-to-line parasitic capacitances have become greater and affected the operation speeds of the semiconductor integrated circuits. Various suggestions have been made to solve this problem. One of such suggestions is to use a poly-paraxylylene film of a low dielectric constant as the wiring insulating film. For example, a poly-paraxylylene film is prepared by subliming 2,2-paracyclophane, which is a cyclophane compound, at 250° C., pyrolyzing the resulting product into the intermediate of paraxylylene at 600° C., polymerizing the intermediate at a maximum of 30° C. in a polymerization tank, and depositing the resulting polymer on a substrate. (K.-U. Buhler, “Heat resistant and thermostable polymers,” Moscow, “Chemistry,” pp. 166-167, 1984.) Another method of manufacturing poly-paraxylylene, its derivative file, and membrane is disclosed (H. Lee, D. Stoffey, K. Neville, “New Linear Polymers,” Moscow, “Chemistry,” pp. 74-76, 1972). This method comprises the steps of pyrolyzing cyclic poly-paraxylylene dimer (2,2-paracyclophane) and its derivative under a reduced pressure into reactive intermediates, polymerizing and depositing thereof onto substrate surfaces. The pyrolyzing process is carried out in a pyrolyzing tube connected to a polymerizing and depositing chamber. The process further comprises the steps of placing a preset quantity of cyclic poly-paraxylylene dimer or its derivative in a sublimation zone, hermetically closing the container, and reducing the pressure of the container down to 1 to 100 mmHg. Cyclic poly-paraxylylene dimer sublimes at a rate of about 0.25 to 0.35 grams/minute and moves into the sublimation zone. The sublimation zone is kept at 140 to 220° C., although the desired temperature depends upon the monomers used as raw material. The pyrolysis zone is kept at about 600° C. and the decomposed gases are fed to the polymerization chamber which is kept at a room temperature. For some monomer materials, the polymerization chamber is heated up to 160° C. during polymerization. FIG. 1 shows an example of a manufacturing method for a semiconductor device which uses poly-paraxylylene for the insulating layer. (Japanese Application Patent Laid-open Publication Nos. Hei 09-317499 and Hei 09-345669) A method of producing a semiconductor device having multiple wiring layers comprises the processes of forming a first aluminum wiring 14 on a semiconductor substrate 13 , forming an organic polymer layer 15 over the semiconductor device having the aluminum wiring 14 thereon by the above method (Process “a”), forming a silicon oxide layer 16 over the organic polymer layer by a chemical vapor-phase growth (Process “b”), grinding the silicon oxide layer 16 by a chemical machine grinding method (Process “c”), forming via-holes in the layer 15 with tungsten 17 , forming a second aluminum wiring on the ground layer 16 (Process “d”), and repeating these processes (a) to (d). Another process to manufacture multi-layer membranes and films of poly-paraxylylene is provided in U.S. Pat. No. 1,151,546 (1985). This process comprises the steps of pyrolyzing cyclic poly-paraxylylene dimer at 450 to 700° C. under a reduced pressure of 1 to 100 mmHg, depositing the product of decomposition on a substrate at about 15 to 25° C., and polymerizing thereof. Reducing the dielectric constant is desirable for the insulating film of semiconductor devices. Insulating materials having specific inductive capacity of 2.5 or less have been wanted. MACROMOLECULES 1999, 32, 7555-7561 discloses an organic polymer film of a low specific inductive capacity of 2.3 and excellent heat resistance prepared by subliming 1,1,2,2,9,9,10,10-octafluoro-2,2-cyclophane at 70 to 100° C. at a vacuum pressure, pyrolyzing thereof at 650° C., and depositing the resulting polymer onto a cool substrate. |
<SOH> SUMMARY OF THE INVENTION <EOH>An object of this invention is to provide an organic polymer film of low dielectric constant and high heating resistance which is applicable as an insulating layer for semiconductor devices. Additional objects include a manufacturing method for such organic polymer films, and a semiconductor device using such films. These and other objects and advantages of the invention are achieved by a porous poly-paraxylylene film prepared by the processes of subliming paraxylylene or its derivative cyclic dimer, pyrolyzing the resulting product at 800 to 950° C., and polymerizing the product obtained by pyrolysis. Said poly-paraxylylene film should preferably contain a porous structure of 10 to 50% by volume. In an embodiment, the invention also provides a method of manufacturing porous poly-paraxylylene films comprising the processes of subliming paraxylylene or its derivative cyclic dimer at 30 to 160° C., pyrolyzing the resulting product at 800 to 950° C., polymerizing the product obtained by pyrolysis at −40 to +25° C., and heat-treating the resulting polymer. It is preferable that each of the sublimation, pyrolysis, and polymerization processes is kept at a vacuum pressure of 0.001 to 0.1 mmHg. Further, it is preferable that the heat-treating process alternately comprises heating to increase the temperature and heating to maintain the temperature in a stepwise manner, that the final heating is made at 390 to 410° C., and that the heat-treating process is kept at a vacuum pressure of 0.001 to 0.1 mmHg. Furthermore, it is preferable that the heat-treating process comprises a first step of heating up to 200° C. at a maximum rate of 4° C./minute, a second step of heating for at least 35 minutes to maintain the temperature at 170 to 220° C., a third step of heating up to 380° C. at a maximum rate of 0.5° C./minute, a fourth step of heating for at least 70 minutes at 350 to 390° C., a fifth step of heating up to 390 to 410° C. at a maximum rate of 0.5° C./minute, and a sixth step of heating for at least 70 minutes at 390 to 410° C. In still another embodiment, the invention provides a porous poly-paraxylylene and its derivative film prepared by the processes of subliming paraxylylene or its derivative cyclic dimer at 30 to 160° C., pyrolyzing the resulting product at 800 to 950° C., polymerizing the product obtained by pyrolysis at −40 to +25° C., and heat-treating the resulting polymer, wherein the polymer is taken out from the polymerization tank and heat-treated by any of methods stated above after said polymerization process. A semiconductor device whose semiconductor elements are electrically connected to thin-film wirings formed on an insulating film, wherein said insulating film is a porous poly-paraxylylene film prepared by the processes of subliming paraxylylene or its derivative cyclic dimer, pyrolyzing the resulting product at 800 to 950° C., and polymerizing the product obtained by pyrolysis. Said insulating film should preferably be fluorinated poly-paraxylylene prepared by subliming a cyclophane compound which contains fluorine atoms, pyrolyzing the sublimed compound into paraxylylene monomer at 800 to 950° C., polymerizing said paraxylylene monomer into poly-paraxylylene precipitate, and heat-treating thereof. It is preferable that the heat-treating process performs heating to alternately increase the temperature and maintain the temperature in a stepwise manner, with the final heating step made at 390 to 410° C. In another embodiment, the invention provides a semiconductor device wherein said insulating film is a poly-paraxylylene film containing a porous structure therein which is prepared by a process of subliming a cyclophane compound at 30 to 160° C. under reduced pressure of 0.001 to 0.1 mmHg, a process of pyrolyzing said product of sublimation into paraxylylene monomer at 800 to 950° C., and a process of polymerizing said paraxylylene monomer on a substrate at −40 to +25° C. In still another embodiment, the invention provides a semiconductor device whose semiconductor elements are electrically connected to thin-film wirings formed on an insulating film, wherein said insulating film is a porous poly-paraxylylene film prepared by the processes of subliming paraxylylene or its derivative cyclic dimer at 30 to 160° C., pyrolyzing the resulting product at 800 to 950° C., polymerizing the product obtained by pyrolysis at −40 to +25° C., and heat-treating the obtained polymer. The poly-paraxylylene film should preferably contain a porous structure of 25 to 50% by volume. In yet another embodiment, the invention provides a multi-layer wiring substrate which laminates wiring layers having a conductive circuit on at least one side of an insulating base with an insulating layer therebetween, wherein at least one of said insulating base or said insulating layer is a poly-paraxylylene film containing a porous structure in said insulating layer, which is prepared by subliming paraxylylene or its derivative cyclic dimer at 30 to 160° C., pyrolyzing the resulting product at 800 to 950° C., polymerizing the product obtained by pyrolysis at −40 to +25° C., and heat-treating the obtained polymer. |
Metrological recording of bearing plays in a highly dynamic mechanical transmission chain |
Method for measuring the bearing play in a highly dynamic mechanical transmission chain between a setting member and a functional member on which it acts, wherein a control unit te actuates the setting member with a square-shaped desired signal of at least half a period and a measuring device is provided with a sensor for sensing the position of the functional element measures its distance from a reference point of the functional element, and the bearing play is determined from the comparison of the actual deflection with the command signal of the setting member. |
1. Method for measuring the bearing play in a highly dynamic mechanical transmission chain comprising a setting member, which acts on a functional element and the interaction of which generates the bearing play to be measured, comprising a control unit to actuate the setting member and an evaluator to gather the measured values, wherein a measuring device is provided with a sensor for sensing the position of the functional element, whereby the sensor measures its distance from a reference point of the functional element, the control unit actuates the setting member by means of a square-shaped desired signal of half a period and the bearing play is determined from the comparison of the actual deflection with the command signal of the setting member. 2. Method for measuring the bearing play in a highly dynamic mechanical transmission chain, as claimed in claim 1, wherein a delay, the maximum deflection or a end value of the response signal form the basis in the comparison of the actual deflection with the command signal. 3. Method for measuring the bearing play in a highly dynamic mechanical transmission chain, as claimed claim 1, wherein the method is applied to the measurement of the bearing play of a control surface of a lifting surface of an airplane as the functional element, and that to setup the measuring device (with respect to the control surface, a support arm is fastened to the lifting surface. 4. Method for measuring the bearing play in a highly dynamic mechanical transmission chain, as claimed claim 2, wherein the method is applied to the measurement of the bearing play of a control surface of a lifting surface of an airplane as the functional element, and that to setup the measuring device with respect to the control surface, a support arm is fastened to the lifting surface. 5. A method for measuring a bearing play in a highly dynamic mechanical transmission chain having a setting member which acts on a functional element, comprising the steps of: actuating the setting member, wherein a control unit commands actuation of the setting member in accordance with a predetermined signal to cause a commanded deflection of the functional element; measuring a deflection of the functional element during the actuation of the setting member, wherein a measuring device provided with a sensor senses a distance between the sensor and a reference point of the functional element; and determining the bearing play between the setting member and the functional element from a comparison of the measured deflection with the commanded deflection. 6. The method of claim 5, wherein the predetermined signal is a square-shaped signal of half a period. 7. The method of claim 6, wherein in the determining step, one of a delay, a maximum deflection or an end value of the measured deflection is compared with the commanded deflection. 8. The method of claim 6, wherein the functional element is a control surface of a lifting surface of an airplane, and a support arm supporting the measuring device is affixed to the lifting surface. 9. The method of claim 7, wherein the functional element is a control surface of a lifting surface of an airplane, and a support arm supporting the measuring device is affixed to the lifting surface. 10. An apparatus for measuring a bearing play in a highly dynamic mechanical transmission chain having a setting member which acts on a functional element, comprising: a control unit, wherein the control unit commands actuation of the setting member with a predetermined signal to cause a commanded deflection of the functional element; a measuring device provided with a sensor which senses a distance between the sensor and a reference point of the functional element, wherein the measuring device measures a deflection of the functional element during actuation of the setting member; and an evaluator which determines the bearing play between the setting member and the functional element from a comparison of the measured deflection with the commanded deflection. 11. The apparatus of claim 10, wherein the predetermined signal is a square-shaped signal of half a period. 12. The apparatus of claim 11, wherein the evaluator determines the bearing play by comparing one of a delay, a maximum deflection or an end value of the measured deflection with the commanded deflection. 13. The apparatus of claim 11, wherein the functional element is a control surface of a lifting surface of an airplane, further comprising: a support arm supporting the measuring device affixed to the lifting surface. 14. The apparatus of claim 12, wherein the functional element is a control surface of a lifting surface of an airplane, further comprising: a support arm supporting the measuring device affixed to the lifting surface. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a method for measuring the bearing play in a highly dynamic mechanical transmission chain with a setting member, which acts on a functional element and the interaction of which generates the bearing play to be measured. In high frequency mechanical transmission chains, the setting members are moved in high frequency in particular to carry out an adjustment. Thus, the resulting bearing play of the transmission elements can increase very rapidly. When the resulting bearing play exceeds a specific size, the case occurs that a commanding transmission chain is moved with a phase delay in a specific direction of the setting member attached thereto. In so doing, the phase delay can amount to −180 degrees, whereby the control or damping effect that is intended by the setting member is not achieved, but rather an opposite effect. In particular, however, there is the danger that before such a phase delay can occur, the structural parts of the mechanical transmission chain have broken down due to the massive follow-up movements. One example, to which the method of the invention can be applied, is the checking of the bearing play in controlled aircrafts, where the bearing play has to be observed and checked at regular intervals. In addition to the frequency of the required checking due to the continuous loads, the high frequency of the required bearing play measurements is also caused by the fact that such a measurement has to be taken for every change in the system lifting surface/control surface. However, the invention does not relate only to the checking of the bearing play in controlled aircrafts. The invention can be applied just as well to the checking of the bearing play in any type of flying devices as well as in general to highly dynamic mechanical transmission chains. Another device or another method from the construction of aircrafts for measuring the bearing play of control surfaces is known from the DE 199 43 481 A1. In this case the actuator is moved into an arrested position by generating a predefined hydraulic pressure, by activating the electricity and by setting a predefined operating state of the automatic pilot. Furthermore, the control surface to be checked is loaded first in a first direction of movement by means of a weight; and in this load state the deflection is measured with a dial gauge. Then in a second step the control surface is loaded in the opposite direction. Then one can conclude the bearing play from the information of the dial gauge. One drawback of this method is that to generate a weight in the opposite directions large gallows must be set up at least for one direction so that the complexity of the devices is not insignificant. Another drawback is that the process of ascending and removal of relatively large weights per measurement must be performed twice and repeated for all control surfaces. In so doing, first of all, the labor cost and secondly the storage cost of the weights and the measurement setups is very high. Since, furthermore, weights of up to 300 kg must be raised in partial weights of 20 kg, the carrying of the weights for the engineer taking the measurements is dangerous. In addition, the process is subject on the whole to risks, since it can never be totally ruled out that one of the control surfaces will not start to move as a consequence of the control movements of the dynamics and thus overthrow the measurement setup with the weights. Another drawback of the method according to the prior art is that each measured value of the dial gauge has to be read and entered manually on a log sheet, since for every work step the indicating dial gauge has to be recorded as a function of the weights to be raised manually. Irrespective of the onerous task of writing down, this method is subject to a high risk of errors. Similarly the manual input of the measured values into a computer constitutes a source of error that cannot be ignored. Therefore, the object of the invention is to provide a device and a method for measuring the bearing play of a highly dynamic mechanical transmission chain, which is simple to set up, safe to use and guarantees a high degree of accuracy. This problem is solved by providing a measuring device with a sensor for sensing the position of a functional element, whereby the sensor measures its distance from a reference point of the functional element, and a control unit which actuates the setting member by means of a square-shaped desired signal of half a period, wherein the bearing play is determined from the comparison of the actual deflection with the command signal of the setting member. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
<SOH> BACKGROUND AND SUMMARY OF THE INVENTION <EOH>The invention relates to a method for measuring the bearing play in a highly dynamic mechanical transmission chain with a setting member, which acts on a functional element and the interaction of which generates the bearing play to be measured. In high frequency mechanical transmission chains, the setting members are moved in high frequency in particular to carry out an adjustment. Thus, the resulting bearing play of the transmission elements can increase very rapidly. When the resulting bearing play exceeds a specific size, the case occurs that a commanding transmission chain is moved with a phase delay in a specific direction of the setting member attached thereto. In so doing, the phase delay can amount to −180 degrees, whereby the control or damping effect that is intended by the setting member is not achieved, but rather an opposite effect. In particular, however, there is the danger that before such a phase delay can occur, the structural parts of the mechanical transmission chain have broken down due to the massive follow-up movements. One example, to which the method of the invention can be applied, is the checking of the bearing play in controlled aircrafts, where the bearing play has to be observed and checked at regular intervals. In addition to the frequency of the required checking due to the continuous loads, the high frequency of the required bearing play measurements is also caused by the fact that such a measurement has to be taken for every change in the system lifting surface/control surface. However, the invention does not relate only to the checking of the bearing play in controlled aircrafts. The invention can be applied just as well to the checking of the bearing play in any type of flying devices as well as in general to highly dynamic mechanical transmission chains. Another device or another method from the construction of aircrafts for measuring the bearing play of control surfaces is known from the DE 199 43 481 A1. In this case the actuator is moved into an arrested position by generating a predefined hydraulic pressure, by activating the electricity and by setting a predefined operating state of the automatic pilot. Furthermore, the control surface to be checked is loaded first in a first direction of movement by means of a weight; and in this load state the deflection is measured with a dial gauge. Then in a second step the control surface is loaded in the opposite direction. Then one can conclude the bearing play from the information of the dial gauge. One drawback of this method is that to generate a weight in the opposite directions large gallows must be set up at least for one direction so that the complexity of the devices is not insignificant. Another drawback is that the process of ascending and removal of relatively large weights per measurement must be performed twice and repeated for all control surfaces. In so doing, first of all, the labor cost and secondly the storage cost of the weights and the measurement setups is very high. Since, furthermore, weights of up to 300 kg must be raised in partial weights of 20 kg, the carrying of the weights for the engineer taking the measurements is dangerous. In addition, the process is subject on the whole to risks, since it can never be totally ruled out that one of the control surfaces will not start to move as a consequence of the control movements of the dynamics and thus overthrow the measurement setup with the weights. Another drawback of the method according to the prior art is that each measured value of the dial gauge has to be read and entered manually on a log sheet, since for every work step the indicating dial gauge has to be recorded as a function of the weights to be raised manually. Irrespective of the onerous task of writing down, this method is subject to a high risk of errors. Similarly the manual input of the measured values into a computer constitutes a source of error that cannot be ignored. Therefore, the object of the invention is to provide a device and a method for measuring the bearing play of a highly dynamic mechanical transmission chain, which is simple to set up, safe to use and guarantees a high degree of accuracy. This problem is solved by providing a measuring device with a sensor for sensing the position of a functional element, whereby the sensor measures its distance from a reference point of the functional element, and a control unit which actuates the setting member by means of a square-shaped desired signal of half a period, wherein the bearing play is determined from the comparison of the actual deflection with the command signal of the setting member. Other objects, advantages and novel features of the present invention will become apparent from the following detailed description of the invention when considered in conjunction with the accompanying drawings. |
Nitrogen atom transfer |
Process and apparatus for addition of nitrogen to an organic molecule under electrochemical conditions. Processes include aziridination of olefins and imination of sulfoxides to form sulfoximines. Nitrene generation in the presence of a carboxylate is described |
1. An electrochemical process for the formation of a compound having formula I, the process comprising step of: contacting a compound having formula II and a compound having formula III, with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula I, wherein: (A) A is selected from the group consisting of C, N and O, and (i) when A is a carbon atom, each of R1, R2, R3, and R4 is hydrogen or an organic group; (ii) when A is a nitrogen atom, each of R1, R2, and R3, is hydrogen or an organic group, and R4 is an electron pair; (iii) when A is an oxygen atom, each of R1 and R2 is hydrogen or an organic group, and each of R3 and R4 is an electron pair; and (iv) R5 is NR6R7 and each of R6 and R7 is an organic group. 2. The process of claim 1, wherein A is a carbon atom. 3. The process of claim 1, wherein A is a nitrogen atom. 4. The process of claim 1, wherein A is an oxygen atom. 5. The process of claim 2, 3, or 4, wherein the group of organic groups from which each of R1, R2, R3, and R4 may be selected is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. 6. The process of claim 5, wherein said group from which each of R1, R2, R3, and R4 may be selected is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 7. The process of claim 6, wherein said group from which each of R1, R2, R3, and R4 may be selected is the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, and preferably wherein each of R1, R2, R3, and R4 includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 8. The process of claim 5, 6 or 7, wherein the substituents are selected from the group of halide, ketone, alcohol and ester. 9. The process of any of claims 2 to 8 wherein, when A is a carbon atom, (i) if R3 and P4 are each hydrogen, then each of R1 and R2 is not hydrogen, or the double bond shown in formula II is conjugated with another olefinic double bond, (ii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R1, then the second carbon atom of the double bond is not in an α-position with respect to a carbonyl group of R3, and (iii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R2, then the second carbon atom of the double bond is not in an α-position with respect to carbonyl group of R4. 10. The process of any of claims 1 to 9, wherein compound II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex-4-en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4-dichlorobutene, 2-(phenyl p-toluenesulfonamidomethyl)acrylic acid methyl ester and any derivative thereof obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any said group can itself be substituted with a said group. 11. The process of claim 10, wherein compound II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex-4-en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4-dichlorobutene, and 2-(phenyl p-toluenesulfonamidomethyl)acrylic acid methyl ester. 12. The process of any of claims 1 to 11, wherein R5 is selected from the group consisting of: wherein each of R8, R9, R10, R11, R12 and R13 is an organic group. 13. The process of claim 12, wherein each of R8, R9, R10, R11, R12 and R13 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. 14. The process of claim 12, wherein each of R8, R9, R10, R11, R12 and R13 is selected from the group consisting of alkyl, aryl, phenyl and substituted alkyl, aryl and phenyl, wherein the substituents are selected from the group of alkyl, aryl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 15. The process of claim 14, wherein each of R8, R9, R10, R11, R12 and R13 includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 16. The process of claim 13, 14, or 15, wherein each of the substituents of said substituted alkyl and aryl groups from which R8, R9, R10, R11, R12 and R13 can be selected is selected from the group consisting of halide, ketone, alcohol and ester. 17. The process of any of claims 1 to 16, wherein the compound having formula III is N-aminophthalmide. 18. The process of any of claims 1 to 17, wherein the compound having formula III has a lower oxidation potential than that of a compound having formula II. 19. The process of any of claims 1 to 17 wherein the compound having formula III is oxidized at a faster rate than a compound having formula II under said conditions of electrolysis. 20. The process of any preceding claim, wherein the solvent of the electrolytic cell is a polar non-protic solvent, and particularly wherein the solvent is selected from the group consisting of dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, nitromethane, chloroform, propylene carbonate, and mixtures thereof. 21. An electrochemical process for the formation of a compound having formula IV, the process comprising step of: contacting a compound having formula V and a compound having formula III, with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula IV, wherein: (i) B is selected from the group consisting of P, S, Se and Te; (ii) each of R14 and R15 is hydrogen or an organic group; and (iii) R5 is NR6R7 and each of R6 and R7 is an organic group. 22. The process of claim 21, wherein B is a phosphorus atom. 23. The process of claim 21, wherein B is a sulfur atom. 24. The process of claim 21, wherein B is an selenium atom. 25. The process of claim 21, wherein B is an tellurium atom. 26. The process of claim 22, 23, 24 or 25 wherein each of R14, and R15 may be selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. 27. The process of claim 26, wherein each of R14, and R15 maybe selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane and preferably wherein each of R14 and R15 includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 28. The process of claim 27, wherein each of R14, and R15 may be selected from the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 29. The process of claim 26, 27 or 28, wherein the substituents are selected from the group of halide, ketone, alcohol and ester. 30. The process of any of claims 21 to 29, wherein compound V is selected from the group consisting of compounds VIII to XV, and any derivative of any of compounds VIII to XV obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any said group can itself include such a substituent. 31. The process of claim 30, wherein compound V is selected from the group consisting of compounds VIII to XV. 32. The process of any of claims 21 to 31, wherein R5 is selected from the group consisting of: wherein each of R8, R9, R10, R11, R12 and R13 is an organic group. 33. The process of claim 32, wherein each of R8, R9, R10, R1, R12 and R13 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. 34. The process of claim 32, wherein each of R8, R9, R10, R11, R12 and R13 is selected from the group consisting of alkyl, aryl, phenyl and substituted alkyl, aryl and phenyl, wherein the substituents are selected from the group of alkyl, aryl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 35. The process of claim 34, wherein each of R8, R9, R10, R11, R12 and R13 includes up to includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 36. The process of claim 33, 34, or 35, wherein each of the substituents of said substituted alkyl and aryl groups from which R8, R9, R10, R1, R12 and R13 can be selected is selected from the group consisting of halide, ketone, alcohol and ester. 37. The process of any of claims 21 to 36, wherein the compound having formula III is N-aminophthalimide. 38. The process of any of claims 21 to 37, wherein the compound having formula III has a lower oxidation potential than that of a compound having formula II. 39. The process of any of claims 21 to 37 wherein the compound having formula III is oxidized at a faster rate than a compound having formula II under said conditions, of electrolysis. 40. The process of any of claims 21 to 39, wherein the solvent of the electrolytic cell is a polar non-protic solvent, and particularly wherein the solvent is selected from the group consisting of dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, nitromethane, chloroform, propylene carbonate, and mixtures thereof. 41. An electrochemical process for the formation of a compound having formula VI, the process comprising step of: contacting a compound having formula VII and a compound having formula III, with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula VI, wherein: (i) when D is a carbon atom, each of R16 and R17 is hydrogen or an organic group; and (ii) when D is a nitrogen atom, R16 is hydrogen or an organic group, and R17 is an electron pair. 42. The process of claim 41, wherein D is a carbon atom. 43. The process of claim 41, wherein D is a nitrogen atom. 44. The process of claim 42 or 45 wherein each of R16, and R17 may be selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane, and preferably wherein each of R16 and R17 includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 45. The process of claim 44, wherein each of R16, and R17 maybe selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 46. The process of claim 45, wherein each of R16, and R17 may be selected from the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 47. The process of claim 44, 45 or 46, wherein the substituents are selected from the group of halide, ketone, alcohol and ester. 48. The process of any of claims 41 to 47, wherein R5 is selected from the group consisting of: wherein each of R8, R9, R10, R11, R12 and R13 is an organic group. 49. The process of claim 48, wherein each of R8, R9, R10, R11, R12 and R13 is selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. 50. The process of claim 48, wherein each of R8, R9, R10, R11, R12 and R13 is selected from the group consisting of alkyl, aryl, phenyl and substituted alkyl, aryl and phenyl, wherein the substituents are selected from the group of alkyl, aryl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. 51. The process of claim 50, wherein each of R8, R9, R10, R11, R12 and R13 includes up to includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. 52. The process of claim 49, 50, or 51, wherein each of the substituents of said substituted alkyl and aryl groups from which R8, R9, R10, R11, R12 and R13 can be selected is selected from the group consisting of halide, ketone, alcohol and ester. 53. The process of any of claims 41 to 52, wherein the compound having formula II is N-aminophthalimide. 54. The process of any of claims 41 to 53, wherein the compound having formula III has a lower oxidation potential than that of a compound having formula II. 55. The process of any of claims 41 to 53 wherein the compound having formula III is oxidized at a faster rate than a compound having formula II under said conditions of electrolysis. 56. The process of any of claims 41 to 55, wherein the solvent of the electrolytic cell is a polar non-protic solvent, and particularly wherein the solven is selected from the group consisting of dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, nitromethane, chloroform, propylene carbonate, and mixtures thereof. 57. An electrochemical process of any preceding claim wherein said contacting step includes contacting said compounds with each other in an anode compartment of said electrolytic cell in an anolyte which comprises a carboxylate ion. 58. The process of claim 57, wherein the anolyte solution is substantially free of a metal catalyst. 59. The process of claim 58, wherein said metal is selected from the group of lead cadmium, cerium, cobalt, chromium, copper, ion, mercury, iridium, manganese, molybdenum, nickel, osmium, palladium, rhenium, rhodium, ruthenium, antimony, thallium, tin and vanadium. 60. The process of any of claims 57 to 59, wherein said anode a platinum electrode. 61. The process of any of claims 57 to 60, wherein an acid form of said carboxylate has a first pKa, and said anolyte solution further comprises an acid having a second pKa wherein said second pKa exceeds the first pKa. 62. The process of claim 61 wherein the carboxylate and the acid having the second pKa are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative. 63. The process of claim 62 wherein the acid form of said carboxylate has the formula RCO2H wherein R is an organic group. 64. The process of claim 62 wherein the acid for of said carboxylate has the formula RCO2H wherein R is an alkyl group or a haloalkyl group. 65. The process of any of claims 61 to 64 wherein the first pKa is in the range of about −2 to about +7. 66. The process of claim 65 wherein the first pKa is in the range of about −1 to about +6. 67. The process of claim 66 wherein the first pKa is in the range of about 0 to about +5. 68. The process of claim 67 wherein the first pKa is about 0.3. 69. The process of claim 67 wherein the first pKa is about 2.8. 70. The process of claim 67 wherein the first pKa is about 4.8. 71. The process of any of claims 57 to 65, wherein said carboxylate is selected from the group acetate, trifluoroacetate, and monochloroacetate. 72. The process of any of claims 61 to 71, wherein said acid is an ammonium acid and said second pKa exceeds the first pKa by at least 2. 73. The process of claim 72, wherein said ammonium acid has the formula R1R2R3NH+ wherein each of R1, R2 and R3 is an organic group or hydrogen. 74. The process of claim 73, wherein each of R1, R2 and R3 of the ammonium acid is an alkyl group or hydrogen. 75. The process of any of claims 61 to 63, wherein said acid having the second pKa is triethylammonium. 76. The process of any of claims 57 to 75, wherein the carboxylate is provided in solution in a stoichiometric amount about equal to that of the hydrazine derivative. 77. The process of any of claims 57 to 76, wherein the anolyte solution further comprises a counterion to the carboxylate, the counterion having the formula R1R2R3 R4 N+ wherein each of R1, R2, R3, and R4 is an organic group. 78. The process of claim 77, wherein each said organic group of the counterion is an alkyl group or a haloalkyl group. 79. The process of claim 78, wherein each said organic group of the counterion is an alkyl group. 80. The process of claim 79, wherein each said organic group of the counterion is an alkyl group selected from the group of methyl, ethyl, propyl, butyl and pentyl. 81. The process of any preceding claim, wherein said contacting step is carried out in an anodic half cell divided from and operatively linked to a cathodic half cell. 82. The process of claim 81, wherein said half cells are linked by an ion permselective diaphragm. 83. The process of claim 82 wherein said diaphragm comprises a synthetic polymer having anions affixed thereto. 84. The process apparatus of claim 83, wherein said anions include perfluorosulfonate groups. 85. The process of claim 84, wherein said diaphragm comprises a Nafion membrane. 86. The process of any preceding claim, wherein compound II, V, or VII, as the case may be, has a more positive potential than the voltage at which the contacting step is conducted. 87. The process of claim 86 wherein compound III has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl, more preferably between about 1 and 2 volts. 88. The process of any preceding claim wherein the mole ratio of the compound having formula Im to the compound having formula II, V, or VU, as the case may be, is from about 1:1 to about 1000:1; more preferably between 500:1 and 1:1; more preferably between about 100: and 1:1; more preferably between about 25:1 and 1:1; more preferably between about 10:1 and 1:1; more preferably between about 5:1 and 1:1, more preferably between about 2:1 and 1:1. 89. The process of any preceding claim wherein the electric potential applied during the contacting step is applied for a period between about 1 minute and 10 hours. 90. In a process of addition of a nitrogen across a multiple bond of an organic molecule wherein a first atom of the multiple bond is a carbon atom, and the second atom is selected from the group of carbon, oxygen and nitrogen, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. 91. The process of claim 90, wherein the nitrogen is generated from a compound having the structure indicated by formula III, as defined in any of claims 1 and 12 to 17. 92. The process of claim 91, wherein the organic molecule has the structure indicated by formula I as defined in any of claims 1 to 11, or formula VII as defined in any of claims 41 to 47. 93. In a process of addition of a nitrogen to a heteroatom of an organic molecule wherein the heteroatom forms a double bond with an oxygen atom and is a P, S, Se or Te atom, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. 94. The process of claim 93, wherein the nitrogen is generated from a compound having the structure indicated by formula HI, as defined in any of claims 1 and 12 to 17. 95. The process of claim 94, wherein the organic molecule has the structure indicated by formula V as defined in any of claims 21 to 29. 96. A product when obtained by a process defined by any preceding claim. 97. A process for electrochemically generating a nitrene, the process comprising the step of: exposing a hydrazine derivative contained in an anolyte solution of an electroytic cell to the anode of the cell in the presence of a carboxylate ion, wherein one of the nitrogens of the hydrazine group is a primary amino group. 98. The process of claim 97, wherein the anolyte solution is substantially free of a metal catalyst. 99. The process of claim 98, wherein said metal is selected from the group of lead cadmium, cerium, cobalt, chromium, copper, ion, mercury, iridium, manganese, molybdenum, nickel, osmium, palladium, rhenium, rhodium, ruthenium, antimony, thallium, tin and vanadium. 100. The process of any of claims 97 to 99, wherein said anode a platinum electrode. 101. The process of any of claims 97 to 100, wherein an acid form of said carboxylate has a first pKa, and said anolyte solution further comprises an acid having a second pKa wherein said second pKa exceeds the first pKa. 102. The process of claim 101 wherein the carboxylate and the acid having the second pKa are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative. 103. The process of claim 102 wherein the acid form of said carboxylate has the formula RCO2H wherein R is an organic group. 104. The process of claim 102 wherein the acid for of said carboxylate has the formula RCO2H wherein R is an alkyl group or a haloalkyl group. 105. The process of any of claims 101 to 104 wherein the first pKa is in the range of about −2 to about +7. 106. The process of claim 105 wherein the first pKa is in the range of about −1 to about +6. 107. The process of claim 106 wherein the first pKa is in the range of about 0 to about +5. 108. The process of claim 107 wherein the first pKa is about 0.3. 109. The process of claim 107 wherein the first pKa is about 2.8. 110. The process of claim 107 wherein the first pKa is about 4.8. 111. The process of any of claims 97 to 105, wherein said carboxylate is selected from the group acetate, trifluoroacetate, and monochloroacetate. 112. The process of any of claims 101 to 111, wherein said acid is an ammonium acid and said second pKa exceeds the first pKa by at least 2. 113. The process of claim 112, wherein said ammonium acid has the formula R1R2R3NH+ wherein each of R1, R2 and R3 is an organic group or hydrogen. 114. The process of claim 113, wherein each of R1, R2 and R3 of the ammonium acid is an alkyl group or hydrogen. 115. The process of any of claims 101 to 103, wherein said acid having the second pKa is triethylammonium. 116. The process of any of claims 97 to 115, wherein the carboxylate is provided in solution in a stoichiometric amount about equal to that of the hydrazine derivative. 117. The process of any of claims 97 to 116, wherein the anolyte solution further comprises a counterion to the carboxylate, the counterion having the formula R1R2R3 R4 N+ wherein each of R1, R2, R3, and R4 is an organic group. 118. The process of claim 117, wherein each said organic group of the counterion is an alkyl group or a haloalkyl group. 119. The process of claim 118, wherein each said organic group of the counterion is an alkyl group. 120. The process of claim 119, wherein each said organic group of the counterion is an alkyl group selected from the group of methyl, ethyl, propyl, butyl and pentyl. 121. The process of any of claims 97 to 120 wherein said hydrazine derivative comprises a molecule having the structure indicated as formula Im as defined in any of claims 1 and 12 to 17. 122. The process of any of claims 97 to 121, wherein the anolyte solution comprises a solvent as defined in claim 20. 123. An apparatus for electrochemical generation of a nitrene, the apparatus comprising: an anodic half cell operatively linked to a cathodic half cell; and an anolyte solution comprising a carboxylate anion and a primary hydrazine derivative. 124. The apparatus of claim 123, wherein said half cells are linked by an ion permselective diaphragm. 125. The apparatus of claim 124, wherein said diaphragm comprises a synthetic polymer having anions affixed thereto. 126. The apparatus of claim 125, wherein said anions include perfluorosulfonate groups. 127. The apparatus of claim 126, wherein said diaphragm comprises a Nafion membrane. 128. The apparatus of any of claims 123 to 127, wherein the hydrazine has a formula im as defined in any of claims 1 and 5 to 17. 129. The apparatus of any of claims 123 to 128, wherein the anolyte solution is substantially free of a metal catalyst. 130. The apparatus of claim 129, wherein said metal is selected from the group of lead cadmium, cerium, cobalt, chromium, copper, ion, mercury, iridium, manganese, molybdenum, nickel, osmium, palladium, rhenium, rhodium, ruthenium, antimony, thallium, tin and vanadium. 131. The apparatus of any of claims 123 to 130, wherein said anode a platinum electrode. 132. The apparatus of any of claims 123 to 131, wherein an acid form of said carboxylate has a first pKa, and said anolyte solution further comprises an acid having a second pKa wherein said second pKa exceeds the first pKa. 133. The apparatus of claim 132 wherein the carboxylate and the acid having the second pKa are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative. 134. The apparatus of claim 133 wherein the acid form of said carboxylate has the formula RCO2H wherein R is an organic group. 135. The apparatus of claim 133 wherein the acid for of said carboxylate has the formula RCO2H wherein R is an alkyl group or a haloalkyl group. 136. The apparatus of any of claims 132 to 135 wherein the first pKa is in the range of about −2 to about +7. 137. The apparatus of claim 136 wherein the first pKa is in the range of about −1 to about +6. 138. The apparatus of claim 137 wherein the first pKa is in the range of about 0 to about +5. 139. The apparatus of claim 138 wherein the first pKa is about 0.3. 140. The apparatus of claim 138 wherein the first pKa is about 2.8. 141. The apparatus of claim 138 wherein the first pKa is about 4.8. 142. The apparatus of any of claims 123 to 136, wherein said carboxylate is selected from the group acetate, trifluoroacetate, and monochloroacetate. 143. The apparatus of any of claims 132 to 142, wherein said acid is an ammonium acid and said second pKa exceeds the first pKa by at least 2. 144. The apparatus of claim 143, wherein said ammonium acid has the formula R1R2R3NH+ wherein each of R1, R2 and R3 is an organic group or hydrogen. 145. The apparatus of claim 144, wherein each of R1, R2 and R3 of the ammonium acid is an alkyl group or hydrogen. 146. The apparatus of any of claims 132 to 134, wherein said acid having the second pKa is triethylammonium. 147. The apparatus of any of claims 123 to 146, wherein the carboxylate is provided in solution in a stoichiometric amount about equal to that of the hydrazine derivative. 148. The apparatus of any of claims 123 to 147, wherein the anolyte solution further comprises a counterion to the carboxylate, the counterion having the formula R1R2R3 R4 N+ wherein each of R1, R2, R3, and R is an organic group. 149. The apparatus of claim 148, wherein each said organic group of the counterion is an alkyl group or a haloalkyl group. 150. The apparatus of claim 149, wherein each said organic group of the counterion is an alkyl group. 151. The apparatus of claim 149, wherein each said organic group of the counterion is an alkyl group selected from the group of methyl, ethyl, propyl, butyl and pentyl. 152. A process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of: providing the olefin; determining the redox potential of the olefin at a predetermined voltage at which the aziridine derivative is oxidized, wherein a said olefin determined to have a less positive potential than the predetermined voltage is eliminated as a candidate for electrochemical aziridination by said hydrazine derivative. 153. A process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of: providing the olefin; determining the redox potential of the olefin at a predetermined voltage at which the aziridine derivative is oxidized, wherein a said olefin determined to have a more positive potential than the predetermined voltage is selected as a candidate for electrochemical aziridination by said hydrazine derivative. 154. The process of claim 152 or 153, wherein said hydrazine derivative has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl. 155. The process of claim 154, wherein said hydrazine derivative has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The reactions of organic compounds can be classified into two broad categories: carbon-carbon bond forming processes and reactions in which carbon atoms change their oxidation states (redox processes). The redox reactions in nature are accomplished by the enzyme molecules. These catalysts contain metal centers that carry out the requisite electron and/or atom transfer reactions. Over the years, remarkable progress has been achieved in design and applications of novel metal-based complexes. The metal center of a synthetic catalyst is surrounded by a small molecule ligand that often resembles and emulates the catalytic reaction site of an enzyme. One of the key roles of the ligand is to modulate reactivity at the metal center. This permits the reactivity of the metal ion in a given oxidation state to be adjusted to control the steric and electronic parameters of a given reaction. This strategy has been shown to adequately address the issues of regio-, chemo-, and stereoselectivity of a number of widely used synthetic transformations. The judicious choice of stoichiometric reductant or oxidant is required in order to render a given reaction catalytic in the metal reagent. Aziridination of olefins is of particular current interest due to the enormous synthetic potential of aziridines. 1 These nitrogen-containing heterocycles have 28 kcal/mol of strai 2 and are amenable to ring-opening reactions with a wide range of nucleophiles. Such transformations lead to molecules with valuable 1,2-heteroatom relationships, commonly found in natural products and in pharmaceuticals. 3 Olefin aziridination reactions are usually accomplished via metal-mediated transfer of a nitrene fragment to the olefin. 4 The corresponding processes can produce a variety of by-products that stem from metal additives and from oxidants. To date, there are no examples of catalytic oxidation systems based on readily available oxidants that convert simple amines or amides into active nitrogen transfer species in the presence of olefins and leave no by-products. A synthetically attractive route is the aziridination of olefins with N-aminophthalimide and lead tetraacetate as oxidant (eq. 1). 5 However, its widespread application is hampered by the use of large amounts of Pb(OAc) 4 , known for its high toxicity. 6 |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention provides an electrochemical process by which a new organic molecule is obtained through the formation of a nitrogen bond. An example is the formation of an aziridine by addition of the nitrogen across a double bond between two carbon atoms, in which two C—N bonds form. Another example is formation of a sulfoxime by addition of the nitrogen to the sulfur atom of a sulfoxide, in which a S═N bond forms. The results of the various addition reactions shown herein can be explained in terms of the formation of a nitrene intermediate formed under the electrochemical conditions of the invention. In one aspect, the invention is an electrochemical process for the formation of a compound having formula I: The process includes a step of contacting a compound having formula II and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula I. “A” shown in these formulae is selected from the group consisting of C, N and O, and (i) when A is a carbon atom, each of R 1 , R 2 , R 3 , and R is hydrogen or an organic group; (ii) when A is a nitrogen atom, each of R 1 , R 2 , and R 3 , is hydrogen or an organic group, and R 4 is an electron pair; (iii) when A is an oxygen atom, each of R 1 and R 2 is hydrogen or an organic group, and each of R 3 and R 4 is an electron pair; and (iv) R 5 is NR 6 R 7 and each of R 6 and R 7 is an organic group. A is preferably a carbon atom, but it can be a nitrogen atom, or an oxygen atom. The group from which each of R 1 , R 2 , R 3 , and R 4 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. In another aspect, the group from which each of R 1 , R 2 , R 3 , and R 4 may be selected is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. In a narrower aspect, the group from which each of R 1 , R 2 , R 3 , and R 4 may be selected can the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. More particularly, the substituents can be selected from the group of halide, ketone, alcohol and ester. In another aspect, “A” of starting compound II is a carbon atom, (i) if R 3 and R 4 are each hydrogen, then each of R 1 and R 2 is not hydrogen, or the double bond shown in formula II is conjugated with another olefinic double bond, (ii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R 1 , then the second carbon atom of the double bond is not in an α-position with respect to a carbonyl group of R 3 , and (iii) if a first carbon atom of the double bond shown in formula II is in an α-position with respect to a carbonyl group of R 2 , then the second carbon atom of the double bond is not in an α-position with respect to carbonyl group of R 4 . In another aspect of a process of the invention, II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex-4-en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4 dichlorobutene, 2-(phenylp-toluenesulfonamidomethyl)acrylic acid methyl ester and any derivative thereof obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any such group can itself be substituted with a said group. In a specific aspect, compound II is selected from the group consisting of cyclohexene, cyclohex-2-enone, 2-methyl-pent-2-ene, 3-bromo-2-methyl-propene, trans-3-phenyl-acrylic acid methyl ester, cyclooctene, 2-methyl-buta-1,3-diene, trans-1,3-diphenylpropenone, trans-hex en-3-one, trans-but-2-enedioic acid dimethyl ester, trans-3-phenyl-prop-2-en-1-ol, trans-4-phenyl-but-3-enoic acid methyl ester, 2-(acetoxy-phenyl-methyl)-acrylic acid methyl ester, 2-(hydroxy-phenyl-methyl)-acrylic acid methyl ester, trans-1,4-dichlorobutene, cis-1,4 dichlorobutene, and 2-(phenyl p-toluenesulfonamidomethyl)acrylic acid methyl ester. In another aspect, the invention is process for the syn-addition of a nitrogen atom across a double bond. The R 5 group of compound III, can be selected from the specific group: wherein each of R 8 , R 9 , R 10 , R 11 , R 12 and R 13 is an organic group. Even more specifically, each of R 8 , R 9 , R 10 , R 11 , R 12 and R 13 can be selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl and substituted alkyl, alkenyl, alkynyl, aryl, phenyl and biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alknyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. In a narrower aspect of the invention, each of R 8 , R 9 , R 10 , R 11 , R 12 and R 13 can be selected from the group consisting of alkyl, aryl, phenyl and substituted alkyl, aryl and phenyl, wherein the substituents are selected from the group of alkyl, aryl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane Each of R 8 , R 9 , R 10 , R 11 , R 12 and R 13 preferably includes up to 20 carbon atoms, more preferably up to 18 carbon atoms, more preferably up to 16 carbon atoms, more preferably up to 14 carbon atoms, or up to 12 carbon atoms, or up to 10 carbon atoms, or up to 8 carbon atoms, or up to 6 carbon atoms. Each of the substituents of the substituted groups from which R 8 , R 9 , R 10 , R 1 1 , R 12 and R 13 can be selected is preferably selected from the group consisting of halide, ketone, alcohol and ester, and more preferably from halide, alcohol and ester. In a specific aspect of the invention, the compound having formula III is N-aminophthalimide. Any of the four C—H bonds of this molecule can be replaced with substituents that would not destroy the primary amino group of this compound to be electrochemically oxidized, i.e., alkyl, aryl, halide, alkyl halide, etc. In another aspect of the invention, the compound having formula Im has a lower oxidation potential than that of a compound having formula II. It is also preferred that the compound having formula III is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis of the invention. The solvent the electrolytic cell can be a polar non-protic solvent, and particularly wherein the solvent can be selected from the group consisting of dichloromethane, acetonitrile, N,N-dimethylformamide, tetrahydrofuran, nitromethane, chloroform, propylene carbonate, and mixtures thereof, or other solvent suitable for conducting an electrochemical process of the invention. In another aspect, the invention is an electrochemical process for the formation of a compound having formula IV, In this aspect, the process includes contacting a compound having formula V and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula IV. In the indicated formulae, (i) B is selected from the group consisting of P, S, Se and Te; (ii) each of R 14 and R 15 is hydrogen or an organic group; and (iii) R 5 is NR 6 R 7 and each of R and R 7 is an organic group. The “B” is most preferably a sulfur atom, but it can be a phosphorus atom, a selenium atom, or a tellurium atom. The group of organic groups from which each of R 14 , and R 15 may be selected can be the group of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, and substituted alkyl, alkenyl, alkynyl, aryl, phenyl and biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. More particularly, the group from which each of R 14 , and R 15 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide; nitro, epoxide, aziridine, sulfone, phosphone, and silane. Even more particularly, the group from which each of R 14 , and R 15 may be selected is the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. More particularly, wherein the substituents are selected from the group of halide, ketone, alcohol and ester, and more particularly, halide, alcohol and ester. The invention includes a process wherein compound V is selected from the group consisting of compounds VIII to XV: and any derivative of any of compounds VII to XV obtained by substitution of a hydrogen of a C—H bond with an alkyl, phenyl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane, wherein any said group can itself include such a substituent. More specifically, compound V can be selected from any of compounds VIII to XV. R 5 can be selected as described above, for reaction of compound V and III. In a particular embodiment, the compound having formula III has a lower oxidation potential than that of a compound having formula II. Further, the compound having formula III is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis. In another aspect, the invention is an electrochemical process for the formation of a compound having formula VI: Here, the process involves contacting a compound having formula VII and a compound having formula III with each other in an electrolytic cell under conditions of electrolysis sufficient to form the compound of formula VI. In this aspect of the invention, (i) when D is a carbon atom, each of R 16 and R 17 is hydrogen or an organic group; and (ii) when D is a nitrogen atom, R 16 is hydrogen or an organic group, and R 17 is an electron pair. In one aspect of this process of the invention, the group from which each of R 16 , and R 17 may be selected can be the group consisting of alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl, etc., and substituted alkyl, alkenyl, alkynyl, aryl, phenyl, biphenyl wherein the substituents are selected from the group of alkyl, alkenyl, alkynyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitrile, nitro, epoxide, imine, aziridine, sulfone, phosphone, and silane. The group from which each of R 16 , and R 17 may be selected, in a narrower aspect of the invention, is the group consisting of alkyl, alkenyl, alkynyl, aryl, and substituted alkyl, alkenyl, alkynyl, aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. The group from which each of R 16 , and R 17 may be selected can also be the group consisting of alkyl and aryl, and substituted alkyl and aryl, wherein the substituents are selected from the group of alkyl, aryl, halide, ketone, aldehyde, alcohol, ether, ester, carboxylic acid, primary amino, secondary amino, tertiary amino, amide, nitro, epoxide, aziridine, sulfone, phosphone, and silane. More preferably, the substituents are selected from the group of halide, ketone, alcohol and ester. Again, wherein R 5 of compound III can be selected as previously described. The compound having formula III preferably has a lower oxidation potential than that of a compound having formula II, and preferably is oxidized at a faster rate than a compound having formula II under the conditions of electrolysis. In one general aspect, the invention involves including a carboxylate anion in the anodic cell in which the hydrazine compound II is oxidized. Preferably, the cell is substantially free, or even completely free, of a toxic metal catalyst. Toxic metal catalysts that are to avoided include of lead cadmium, cerium, cobalt, chromium, copper, ion, mercury, iridium, manganese, molybdenum, nickel, osmium, palladium, rhenium, rhodium, ruthenium, antimony, thallium, tin and vanadium. The anodic electrode is preferably a platinum electrode. In a preferred aspect, the acid form of the carboxylate has a first pK a , and the anolyte solution further includes an acid having a second pK a wherein the second pK a exceeds the first pK a . Preferably, the carboxylate and the acid having the second p& are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative, but more preferably to at least 60% that of the hydrazine derivative, or at least 70% that of the hydrazine derivative, or 80% that of the hydrazine derivative, or 90% that of the hydrazine derivative, or the carboxylate can be present in a stoichiometric amount about equal to that of the hydrazine derivative, or it could be said, in an amount at least as great as that of the hydrazine derivative. Usually, the acid form of the carboxylate has the formula RCO 2 H wherein R is an organic group. According to a preferred aspect, the acid for of the carboxylate has the formula RCO 2 H wherein R is an alkyl group or a haloalkyl group. The first pK a is preferably in the range of about −2 to about +7, more preferably in the range of about −1 to about +6, more preferably in the range of about 0 to about +5. The first pK a can be about 0.3 first pK a , or it can be about 2.8, or the first pK a can be about 4.8. The carboxylate can be one or more of acetate, trifluoroacetate, and monochloroacetate. The acid is preferably an ammonium acid and the second pK a preferably exceeds the first pK a by at least 2. The ammonium acid typically has the wherein each of R 1 , R 2 and R 3 is an organic group or hydrogen. Commonly, each of R 1 , R 2 and R 3 of the ammonium acid is an alkyl group (e.g., methyl, ethyl, propyl, butyl and pentyl) or hydrogen. In a specifically disclosed aspect of the invention, the acid having the second pK a is triethylammonium. In another aspect, the anolyte solution includes a counterion to the carboxylate, the counterion having the formula R 1 R 2 R 3 R 4 N + wherein each of R 1 , R 2 , R 3 , and R 4 is an organic group selected from the group described in connection with R 1 , R 2 and R 3 of R 1 R 2 R 3 NH + . The contacting step is preferably carried out in an anodic half cell divided from and operatively linked to a cathodic half cell. Preferably, the half cells are linked by an ion permselective diaphragm. The diaphragm is preferably made up of a synthetic polymer having anions affixed (usually covalently bonded) thereto. A preferred anion is perfluorosulfonate. A commercially available diaphragm suitable for many aspects of the invention is that sold under the name Nafion. In one aspect of the invention, compound II, V, or VII, as the case may be, has a more positive potential than the voltage at which the contacting step is conducted. Compound III preferably has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl, more preferably between about 1 and 2 volts. Preferably, the mole ratio of the compound having formula III to the compound having formula II, V, or VII, as the case may be, is from about 1:1 to about 1000:1; more preferably between 500:1 and 1:1; more preferably between about 100: and 1:1; more preferably between about 25:1 and 1:1; more preferably between about 10:1 and 1:1; more preferably between about 5:1 and 1:1, more preferably between about 2:1 and 1:1. The process can be carried out such that the electric potential applied during the contacting step is applied for a period between about 1 minute and 10 hours. In another aspect the invention is a process of addition of a nitrogen across a multiple bond of an organic molecule wherein a first atom of the multiple bond is a carbon atom, and the second atom is selected from the group of carbon, oxygen and nitrogen, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. It is preferred here that the nitrogen is generated from a compound having the structure indicated by formula III, as defined above and that the organic molecule has the structure indicated by formula I formula VII. Another process of the invention is addition of a nitrogen to a heteroatom of an organic molecule wherein the heteroatom forms a double bond with an oxygen atom and is a P, S, Se or Te atom, the improvement comprising electrochemically generating the nitrogen for the addition from a primary hydrazine derivative in the presence of a carboxylate anion. Again, the nitrogen is preferably generated from a compound having the structure indicated by formula III, as defined above and the organic molecule has the structure indicated by formula V. Another aspect of the invention is a process for electrochemically generating a nitrene. The process includes exposing a hydrazine derivative contained in an anolyte solution of an electroytic cell to the anode of the cell in the presence of a carboxylate ion, wherein one of the nitrogens of the hydrazine group is a primary amino group. Preferably, the anolyte solution is substantially free of a metal catalyst, particularly a toxic metal catalyst. Preferably, the anode a platinum electrode. Preferably, an acid form of the carboxylate has a first pK a , and the anolyte solution further comprises an acid having a second pK a wherein the second pK a exceeds the first pK a , and the carboxylate and acid (or counterion to the carboxylate) are selected as described above. Preferably, the carboxylate and the acid having the second pK a are solubilized in the solution and the carboxylate is provided in solution in a stoichiometric amount equal to at least half that of the hydrazine derivative, but more preferably to at least 60% that of the hydrazine derivative, or at least 70% that of the hydrazine derivative, or 80% that of the hydrazine derivative, or 90% that of the hydrazine derivative, or the carboxylate can be present in a stoichiometric amount about equal to that of the hydrazine derivative, or it could be said, in an amount at least as great as that of the hydrazine derivative. In this process for generating a nitrene, the hydrazine derivative can be a molecule having the structure indicated as formula III as described above, and the anolyte solution can be a solvent as described above. In another aspect, the invention is an apparatus for electrochemical generation of a nitrene. The apparatus includes an anodic half cell operatively linked to a cathodic half cell, and an anolyte solution comprising a carboxylate anion and a primary hydrazine derivative. Preferably, the half cells are linked by an ion permselective diaphragm. A preferred diaphragm is a synthetic polymer having anions affixed thereto, as by covalent bonding, and the anions can include perfluorosulfonate groups. A commercially available diaphragm suitable for use according to many processes of the invention is a Nafion membrane. The hydrazine of the apparatus includes any of those having formula III, as described above. Preferably, the anolyte solution is substantially free of a metal catalyst Preferably, the anode of the apparatus is a platinum electrode. Preferably, the an acid form of the carboxylate of the apparatus has a first pK a , and the anolyte solution includes an acid having a second pK a wherein the second pK a exceeds the first pK a . The carboxylate and counterion included in the apparatus can be selected and included in the apparatus as described above. An apparatus of the invention can be used for nitrene generation, an aziridination, sulfoximation, or other nitrogen addition to a suitable organic substrate. Another aspect of the invention is a process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of: providing the olefin; determining the redox potential of the olefin at a predetermined voltage at which the aziridine derivative is oxidized, wherein a said olefin determined to have a less positive potential than the predetermined voltage is eliminated as a candidate for electrochemical aziridination by the hydrazine derivative. In another aspect, the invention is a process for screening an olefin for electrochemical aziridination of an olefin with a hydrazine derivative, the process comprising the steps of: providing the olefin; determining the redox potential of the olefin at a predetermined voltage at which the aziridine derivative is oxidized, wherein a said olefin determined to have a more positive potential than the predetermined voltage is selected as a candidate for electrochemical aziridination by the hydrazine derivative. Preferably, the hydrazine derivative has first and second peak potentials, each of which potentials is between about 0 and 3 volts against Ag/AgCl, more preferably between about 1 and 2 volts. |
System for commonly utilizing vehicle |
A system for commonly utilizing a vehicle in which illegal use of the vehicle can be surely prevented. In the system for lending a shared vehicle, which is parked in a parking area and of which the use information concerning lending and returning is managed, to a user after confirming permission to utilize the vehicle based on previously registered personal identification information, the shared vehicle is provided in the control section thereof with a popup key which can control whether a mechanical switch unit for starting the driving of the vehicle can be operated or not, and with an ignition mechanism control mean which permits starting operation of an ignition mechanism when personal cipher information inputted by the user matches personal cipher information imparted to the user in association with the personal identification information and the user sets a destination, and permits returning operation of the ignition mechanism when arrival at the set destination is detected. |
1. A system for commonly utilizing a vehicle in which vehicle use information relating to lending and returning of a vehicle parked in a parking area is managed, and the vehicle is lent to a user by confirming permission to utilize the vehicle based on preregistered personal identification information, wherein the vehicle comprises: a mechanical switch device, which is used to start a driving device of the vehicle, and an ignition mechanism which is capable of controlling an operation of the mechanical switch device; and an ignition mechanism controlling means which permits a starting operation of the driving device using the ignition mechanism when information input by the user matches personal cipher information imparted to the user in association with the personal identification information and the user sets a destination, and which permits a returning operation of the vehicle using the ignition mechanism when arrival at the set destination is detected. 2. A system for commonly utilizing a vehicle according to claim 1, wherein the vehicle further comprising: a use information controlling means which starts measurement of the vehicle use information when the starting operation of the driving device using the ignition mechanism is permitted, and which stops the measurement of the vehicle use information when the returning operation of the vehicle using the ignition mechanism is permitted. |
<SOH> BACKGROUND ART <EOH>Conventionally, a system in which a user approaches a vehicle which is parked in a parking area and makes the vehicle read personal identification information (user ID) recorded in an IC card, etc., to unlock the door so that the user is permitted to enter the inside of the vehicle has been conceived as a system for commonly utilizing a vehicle. However, in such a system for commonly utilizing a vehicle, it is unavoidable to keep the ignition key which is used for starting a driving device of the vehicle (engine, motor, etc.), inside the vehicle since the vehicle is managed and operated in an unwatched parking area in such a system for commonly utilizing a vehicle. Accordingly, there is a danger that the vehicle can be easily stolen if the door lock is broken. In consideration of the above, a device which is capable of preventing theft of the vehicle while keeping the ignition key inside the vehicle has been proposed in, for example, Japanese Unexamined Patent Application, First Publication No. 2000-120308. In the device disclosed in the above patent application, a glove box having a key lock mechanism to store the ignition key in an unusable locked state is provided, and the key lock of the glove box is unlocked when the personal identification information in an IC card matches identification information of a person who made the reservation so that the use of the ignition key becomes possible. Also, a method has been proposed in which a portable ignition key is avoided, and the ignition mechanism is entirely controlled by an electrical controlling means only, and the starting of the driving device of the vehicle is controlled thereby. However, according to the above conventional techniques, although the possibility that the ignition key is stolen may be reduced by combining the door lock mechanism with the key lock mechanism to generate a double lock mechanism, there is a danger that the vehicle may be unlawfully utilized if the vehicle is lawfully lent to a user and the user copies the ignition key since the ignition key is easily removed from the vehicle. Also, if the entire ignition mechanism is controlled only by an electrical controlling means, there are problems in that the vehicle cannot be driven if electric power cannot be supplied to the controlling means for some reasons, and it is troublesome to repair the vehicle. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a block diagram showing a configuration according to an embodiment of the present invention. FIG. 2 is a diagram showing a configuration of a shared vehicle used in an embodiment of the present invention. FIG. 3 is a diagram showing a port for parking the shared vehicle used in an embodiment of the present invention. FIG. 4 is a diagram showing an overall operation of the system for commonly utilizing a vehicle according to an embodiment of the present invention. FIG. 5 is a diagram showing a vehicle lending operation in the system for commonly utilizing a vehicle according to an embodiment of the present invention. FIG. 6 is a diagram showing a process for exiting the vehicle in the system for commonly utilizing a vehicle according to an embodiment of the present invention. detailed-description description="Detailed Description" end="lead"? |
Apparatus for electrophoresis separation on microchannels and for laser-induced fluorescence detection |
An integrated apparatus includes a miniaturized flattened support having a planar surface whereon are formed wells and a microchannel, elements for projecting exciting light locally on an excitation zone of the microchannel along a direction forming an angle (α) greater than 60° with a longitudinal direction of the microchannel, optical collector elements coupled with one free end of the microchannel, optical measurement elements and processing elements, the microchannel having a portion forming a reservoir with internal cross-section flaring from its free end up to the excitation zone, the portion being extended by a conical, ellipsoidal or paraboloidal internal wall, and emerging onto a second microchannel portion with reduced internal cross-section, the latter communication with the wells. |
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