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Workflow method applicable in a workflow engine |
The Cognitive Process Workflow (CPW) method with its grammar, syntax and semantics is a workflow method applicable to different technical systems. The CPW Process is represented in the form of simple sentence with subject, predicate and object. According to the CPW definition the process in the conventional sense is a Predicate. From now on the conventional process (predicate) is consequently put in the context of responsibility (subject) and process result (object), thus forming a CPW Process. The CPW Method—with CPW Process, CPW Dialog and CPW Workflow as well as CPW Context Diagrams (CPW Subject Context Diagram, CPW Object Context Diagram and CPW Subject Object Context Diagram)—can be applied to business areas of financial services (banking, assurance and financial approval), chemistry, pharmacy, medicine, transport, travel, film industry, politics, psychology, legal practice and areas of CRM Customer Relationship Management, ERP Enterprise Resource Planning, SCM Supply Chain Management, E-Business Integration. |
1. All kinds of applications of the Cognitive Process Workflow (CPW) Method—with the CPW Process, CPW Dialog and CPW Workflow as well as the CPW Context Diagrams (CPW Subject Context Diagram, CPW Object Context Diagram and CPW Subject Object Context Diagram)—in technical systems. There are namely: (a) The application of the CPW Method in a Workflow Engine. (b) The application of the graphical representation of the CPW Method in a technical system. (c) The application of the CPW Method in an application system with integrated database. 2. All kinds of applications of the CPW Method by means of Internet technologies. 3. Grammar, syntax and semantics of the CPW Dialog and CPW Workflow, with which the CPW Processes are represented as simple sentences with subject, predicate and object. 4. According to the concept of the CPW Process the process in the conventional sense is formed as a predicate. From now on the conventional process (predicate) is consequently put in the context of a responsibility (subject) and a process result (object), thus forming a CPW Process. 5. The CPW Process in the form of a simple sentence with subject, predicate and object is represented graphically. Within a represented CPW Process respectively within a sentence the subject, predicate and object each corresponds with a graphic object. Subject, predicate and object—each represented as a single graphic object—are graphically linked to one another so that they form a Simple Sentence. 6. Grammar, syntax and semantics of the CPW Method—with the CPW Process, CPW Dialog and CPW Workflow as well as the CPW Context Diagrams (CPW Subject Context Diagram, CPW Object Context Diagram and CPW Subject Object Context Diagram) 7. The application of the CPW Method to data and information in various business areas, in particular: (a) Financial Services (Banking, Assurance and Financial Approval) (b) Chemistry (c) Pharmacy (d) Medicine (e) Transport (f) Travel (g) Film Industry (h) Politics (i) Psychology (j) Legal Practice, Jurisprudence, Judiciary Thereby the application of the CPW Method can take place In a technical system according to claim 1 and claim 2. 8. The application of the CPW Method to data and information in the business areas of Financial Services (Banking, Assurance and Financial Approval). Thereby the application of the CPW Method can take place in a technical system. 9. The application of the CPW Method to data and information in the business area Chemistry. Thereby the application of the CPW Method can take place in a technical system. 10. The application of the CPW Method to data and information in the business area Pharmacy. Thereby the application of the CPW Method can take place in a technical system. 11. The application of the CPW Method to data and information in the business area Medicine. Thereby the application-of the CPW Method can take place in a technical system. 12. The application of the CPW Method to data and information in the business area Transport. Thereby the application of the CPW Method can take place in a technical system. 13. The application of the CPW Method to data and information in the business area Travel. Thereby the application of the CPW Method can take place in a technical system. 14. The application of the CPW Method to data and information in the business area Film Industry. Thereby the application of the CPW Method can take place in a technical system. 15. The application of the CPW Method to data and Information in the business area Politics. Thereby the application of the CPW Method can take place in a technical system. 16. The application of the CPW Method to data and information in the business area Psychology. Thereby the application of the CPW Method can take place in a technical system. 17. The application of the CPW Method to data and information in the area Legal Practice, Jurisprudence and Judiciary. Thereby the application of the CPW Method can take place in a technical system. 18. The application of the CPW Method to data and information in various areas, in particular: (a) CRM Customer Relationship Management (b) ERP Enterprise Resource Planning (c) SCM Supply Chain Management (d) E-Business Integration Thereby the application of the CPW Method can take place in a technical system. |
Nanoparticulate formulations of fenofibrate |
Nanoparticles and nanoparticle formulations or suspensions are provided which comprise a fibrate and vitamin E TPGS. The nanoparticles may have a mean diameter, measured by photon correlation spectroscopy, in the range of from about 100 nm to about 900 nm. Pharmaceutical formulations and uses of such compositions are also provided. |
1. Nanoparticles comprising a fibrate and vitamin E TPGS, said nanoparticles having a mean diameter, measured by photon correlation spectroscopy, in the range of from about 100 nm to about 900 nm. 2. Nanoparticles comprising a fibrate and vitamin E TPGS according to claim 1, said nanoparticles having a mean diameter, measured by photon correlation spectroscopy, in the range of from about 400 nm to about 600 nm. 3. Nanoparticulate fibrate according to claim 1 in the form of a nanosuspension. 4. Nanosuspension according to claim 3 which is an aqueous nanosuspension. 5. Nanoparticulate fibrate according to claim 3 associated with an additional stabilizer. 6. Nanoparticles according to claim 1 wherein the fibrate is fenofibrate. 7. A pharmaceutical formulation comprising a nanoparticulate fibrate according to claim 1. 8. A nanoparticulate fibrate formulation containing nanodroplets of oil. 9. A nanoparticulate fibrate formulation comprising one part of the active substance as dispersed nanoparticles and one part of the active substance solubilized in oil nanodroplets. 10. A process for preparing nanoparticles comprising a fibrate and vitamin E TPGS, which comprises subjecting a coarse dispersion of a fibrate to cavitation, wherein the vitamin E TPGS is either present in the coarse dispersion or is introduced prior to the cavitation process. 11. A process according to claim 7 which is effected using a high-pressure piston-gap homogeniser. 12. Nanoparticles according to claim 1 for use in medicine. 13. The use of nanoparticles according to claim 1 in the preparation of a medicament for the treatment of atherosclerosis, obesity, myocardial infraction or hypertension. 14. A method for the treatment of hyperlipidaemia, comprising administering to a subject in need thereof a therapeutic amount of a pharmaceutical formulation of a nanoparticlate fibrate according to claim 1. |
Power reduction in microprocessor systems |
A method is provided for reducing the power consumtion of a microprocessor system that comprises of a micro-processor and a memory connected by at least one bus. The method includes: determining the frequency with which each control code occurs, or is likely to occur, adjacent to each of the other control codes in consecutive instructions of a program, and based on the frequencies so determined, assigning a bit pattern to each control code which minimises the average Hamming distance between consecutive instructions when the program is run. |
1-15. (canceled) 16. A method of reducing the power consumption of a microprocessor system which comprises a microprocessor and a memory connected by at least one bus, the microprocessor being arranged to execute a program stored in said memory, wherein said program comprises a series of instructions each represented by a number of bits, said instructions contain a plurality of control codes, each control code represents an action to be carried out by the microprocessor, and each control code is represented by a bit pattern corresponding to that control code, the method comprising: determining the frequency with which each control code occurs, or is likely to occur, adjacent to each of the other control codes in adjacent instructions of said program, and based on the frequencies so determined in the previous step, assigning a bit pattern to each control code which minimizes the average hamming distance between consecutive instructions when the program is run. 17. A method as claimed in claim 16, wherein at least some of said control codes are operation codes, which represent basic actions which the processor should carry out. 18. A method as claimed in claim 16, wherein at least some of said control codes are register specifiers. 19. A method as claimed in claim 16, wherein at least some instructions contain a primary control code which always occupies the same bit position within the instruction. 20. A method as claimed in claim 19, wherein the average hamming distance between instructions is minimized by: determining the hamming distance between each pair of primary control codes, determining the frequency with which each primary control code occurs, or is likely to occur, adjacent to each other primary control code, and assigning bit patterns to said primary control codes so that the sum, over all primary control codes, of the hamming distance between pairs of primary control codes weighted by said frequency for each pair of primary control codes, is minimized. 21. A method as claimed in claim 19, wherein the average hamming distance between pairs of primary control codes is minimized by minimizing the summation of Formula 1 referred to herein. 22. A method as claimed in claim 16, wherein at least some instructions contain a secondary control code which may be positioned coincident with, or at least partially overlap with, another secondary control code, or an immediate value, in an adjacent instruction. 23. A method as claimed in claim 22, wherein minimization of the average hamming distance between consecutive instructions takes into account the hamming distance between secondary control codes in adjacent instructions. 24. A method as claimed in claim 22, wherein minimization of the average hamming distance between consecutive instructions takes into account the hamming distance between secondary control codes and immediate values in adjacent instructions. 25. A method as claimed in claim 24, which further includes the following steps: determining the frequency with which each secondary control code occurs, or is likely to occur, in said program, assigning bit patterns to the secondary control codes in such a way that those secondary control codes which occur more frequently are assigned bit patterns which are closer, in terms of their hamming distance, to zero. 26. A method as claimed in claim 24, wherein minimization of the average hamming distance between consecutive instructions includes assigning bit patterns to secondary control codes so as to minimize the summation given in Formula 2 referred to herein. 27. A method as claimed in claim 16, wherein all control codes referred to in the method are operation codes, and all references to primary and secondary control codes are to primary and secondary operation codes respectively. 28. A method as claimed in claim 16, wherein all control codes referred to in the method are register specifiers, and all references to primary and secondary control codes are to primary and secondary register specifiers respectively, secondary register specifiers being register specifiers which may be positioned adjacent to, or at least overlap with, another secondary register specifier, or an immediate value, in an adjacent instruction. 29. A program for reducing the power consumption of a microprocessor system, wherein bit patterns of control codes used in the program have been optimized in accordance with the steps of any preceding claim. 30. A reduced power microprocessor system comprising a microprocessor and a memory connected by at least one bus, wherein said memory contains a program as claimed in claim 29 for execution by said microprocessor. |
Method and means for detecting internal larval infestation in granular material |
A method for detecting internal larval infestation in granular material comprising the steps of: creating an image of grain kernels in the near Infra-Red region; applying a mask to the image to exclude interference on the outer reaches of the kernel; forming a model kernel by applying a medium filter and slightly enlarging the resulting approximate model; comparing the masked image with a model kernel to obtain a difference image; and applying a threshold to difference image to determine larval infestation. |
1. A method for detecting internal larval infestation in granular material comprising the steps of: creating an image of grain kernels in the near Infra-Red region; applying a mask to the image to exclude interference on the outer reaches of the kernel; forming a model kernel by applying a median filter and slightly enlarging the resulting approximate model; comparing the masked image with the model kernel to obtain a difference image; and applying a threshold to difference image to determine larval infestation. 2. A method according to claim 1, wherein the model application step comprises applying a median filter to the grain image. 3. A method according to claim 1, wherein the grain image is created using a background which is darker than the grain at near Infra-Red wavelengths. 4. Apparatus for detecting internal larval infestation in granular material comprising: means for creating an image of grain kernels in the near Infra-Red region; masking means for masking the image to exclude interference on the outer reaches of the kernel; a comparator for comparing the masked image with a model kernel to obtain a difference image; and thresholding means for applying a threshold to the difference image to determine larval infestation. 5. Apparatus according to claim 4, wherein the masking means is associated with a median filter. 6. Apparatus according to claim 4, wherein the image creating means includes a background which is darker than the grain at near Infra-Red wavelengths. 7. Apparatus according to claim 4, and comprising further thresholding means for applying a further threshold in order to determine whether or not to accept a batch of grain. 8. Apparatus according to claim 7, wherein the further threshold means is arranged to reduce the number of false positives but not to eliminate them. 9. Apparatus according to claim 8, where threshold means is arranged to produce typically two false positives for every one true positive. |
Phenotypic effects of ubiquinone deficiencies and methods of screening thereof |
The present invention relates to a method of screening for a compound allowing survival of clk1 homozygous mutant embryos; a method of screening for a compound suitable for rescue of mutant phenotype of mclk1 homozygous cell line; a method of screening for a compound suitable for partial or complete functional replacement of endogenous ubiquinone; a method for screening a compound capable of inhibiting activity of clk-1 and/or other processes required to make ubiquinone from demethoxyubiquinone; a non-ubiquinone-producer mouse; a DNA construct, which comprises an alteration of mclk1; a non-ubiquinone-producer ES cell line; a coq-3 mutant subject non-ubiquinone producer, a method of screening for a compound suitable for complete or partial functional ubiquinone or demethoxyubiquinone replacement; a method for reducing and/or increasing ubiquinone level in a multicellular subject; a method of screening for a genetic suppressor of clk-1; and a method of screening for a genetic suppressor of coq-3. |
1-25. (Canceled) 26. A mouse comprising a knock-out of a murine clk-1 gene, wherein said mouse exhibits an increased life span relative to a wild-type mouse. 27 (Canceled) 28. A mouse cell comprising a knock-out of a murine clk-1 gene. 29-41. (Canceled) 42. The mouse of claim 26, wherein a plurality of cells of said mouse comprise said knock-out. 43. The mouse of claim 26, wherein all somatic cells of said mouse comprise said knock-out. 44. The mouse of claim 43, wherein the amount of murine clk-1 mRNA is about 50% less relative to a wild-type mouse. 45. The mouse of claim 26, which exhibits altered cellular metabolism, altered development rate, altered behavioral rate, or altered cell cycle. 46. The mouse of claim 45, which exhibits a decrease in cellular metabolism or a decrease in developmental rate, relative to a wild-type mouse. 47. A mouse embryo comprising a plurality of cells which comprise a knock-out of a murine clk-1 gene. 48. The mouse embryo of claim 47, wherein all somatic cells of said mouse embryo comprise a knock-out of a murine clk-1 gene. 49. The mouse embryo of claim 47, wherein said plurality of cells comprise a knock-out of a murine clk-1 gene at both alleles. 50. The mouse embryo of claim 47, wherein all somatic cells of said mouse embryo comprise a knock-out of a murine clk-1 gene at both alleles. 51. The mouse embryo of claim 48, wherein the amount of mouse clk-1 mRNA is about 50% less relative to a wild-type mouse embryo. 52. The mouse embryo of claim 49, which exhibits a decrease in ubiquinone level relative to a wild-type mouse embryo. 53. The mouse embryo of claim 49, which exhibits an increase in demethoxyubiquinone level relative to a wild-type mouse embryo. 54. The mouse cell of claim 28, which is heterozygous in the mouse clk-1 locus. 55. The mouse cell of claim 28, which is homozygous in the mouse clk-1 locus. 56. The mouse cell of claim 54, wherein the amount of mouse clk-1 mRNA is about 50% less relative to a wild-type mouse embryonic stem cell. 57. The mouse cell of claim 28, which exhibits a decrease in ubiquinone level relative to a wild-type mouse embryonic stem cell. 58. The mouse cell of claim 55, which exhibits an increase in demethoxyubiquinone level relative to a wild-type mouse embryo. 59. The mouse cell of claim 54 or 55, wherein the knock-out of the murine clk-1 gene is conditional. 60. The mouse cell of claim 59, wherein the knock-out is mediated by Cre-loxP recombination. 61. The mouse embryo of claim 48 or 49, wherein the knock-out of the murine clk-1 genesis conditional. 62. The mouse embryo of claim 61, wherein the knock-out is mediated by Cre-loxP recombination. 63. The mouse of claim 42 or 43, wherein the knock-out of the murine clk-1 gene is conditional. 64. The mouse of claim 63, wherein the knock-out is mediated by Cre-loxP recombination. 65. The mouse embryo of claim 61, wherein the knock-out of the murine clk-1 gene is tissue-specific or organ-specific. 66- The mouse embryo of claim 62, wherein the knock-out of the murine clk-1 gene is tissue-specific or organ-specific. 67. The mouse embryo of claim 61, wherein the knock-out of the murine clk-1 gene is temporally controlled. 68. The mouse embryo of claim 62, wherein the knock-out of the murine clk-1 gene is temporally controlled. 69. The mouse of claim 63, wherein the knock-out of the murine clk-1 gene is tissue-specific or organ-specific. 70. The mouse of claim 64, wherein the knock-out of the murine clk-1 gene is tissue-specific or organ-specific. 71. The mouse of claim 63, wherein the knock-out of the murine clk-1 gene is temporally controlled. 72. The mouse of claim 64, wherein the knock-out of the murine clk-1 gene is temporally controlled. 73. The mouse cell of claim 28 which is from a cell line. 74. The mouse cell of claim 28 which is an embryonic stem cell. 75. The mouse cell of claim 28 which is derived from liver, heart, kidney, muscle, stomach, or cerebellum tissue. |
<SOH> BACKGROUND OF THE INVENTION <EOH>(a) Field of the Invention This invention relates to the phenotypic effects of ubiquinone deficiencies and methods of screening thereof. (b) Description of Prior Art Ubiquinone (UQ), and its reduced form ubiquinol, is a prenylated benzoquinone/ol lipid and is the major site of production of reactive oxygen species (ROS). It is a co-factor in the mitochondrial respiratory chain where it becomes reduced by the activity of Complex I and Complex II, and oxidized by the activity of Complex III. During these processes, ubisemiquinone species are formed, which are unstable and generate superoxide. Furthermore, ubiquinone/ubiquinol is a redox-active cofactor of other enzyme systems that produce ROS, for example the plasma membrane NAD(P)H oxidoreductases, as well as the lysosomal and peroxisomal electron transport chains. In all these locations ROS can be produced during redox reactions involving ubiquinone/ubiquinol. In addition, ubiquinone is a ubiquitous natural anti-oxidant, whose presence in biological membranes helps to detoxify ROS produced by endogenous processes or by toxicants or radiations. Unfortunately, dietary ubiquinone has very poor penetration into cells, in particular into subcellular organelles. Reactive oxygen species have been implicated in numerous human diseases, including, but not exclusively, diabetes (Nishikawa et al., (2000). Nature, 404, 787-790; Brownlee (2001). Nature 414, 813-820), hypoxia/reoxygenation injury (Li et al., (2002). Am J Physiol Cell Physiol 282, C227-C241; Lesnefsy et al., (2001). J. Mol Cell Cardiol 33, 1065-1089; Cuzzocrea et al., (2001). Pharmacological Reviews 53, 1, 135-159), Parkinson's (Betarbet et al., (2002). Bioessays 24, 308-318), atherosclerosis atherosclerosis (Lusis, (2000). Nature, 407, 233-241), and Alzheimer's disease (Butterfield et al., (2001). Trends in Molecular Medicine, 7, 12, 548-554; Tabner et al., (2002) Free Radical Biology & Medicine, 32, 11, 1076-1083, 2002). The gene clk-1 of the nematode Caenorhabditis elegans affects many physiological rates, including embryonic and post-embryonic development, rhythmic behaviors, reproduction and life span. clk-1 encodes a 187 amino acid protein that localizes to mitochondria, and that is homologous to the yeast protein Coq7p, which has been shown to be required for UQ biosynthesis. clk-1 has also been shown to be necessary for UQ biosynthesis (Jonassen, T. et al., (2001). Proc Natl Acad Sci USA 98, 421-6.; Miyadera, H. et al., (2001). J. Biol Chem 276, 7713-6), as UQ 9 is entirely absent from mitochondria purified from clk-1 mutants (Miyadera, H. et al., (2001). J. Biol Chem 276, 7713-6) (the subscript refers to the length of the isoprenoid side chain). Instead, these mitochondria accumulate demethoxyubiquinone (DMQ 9 ), which is an intermediate in the synthesis of UQ 9 (Miyadera, H. et al., (2001). J. Biol Chem 276, 7713-6). Recent evidence suggests that clk-1 encodes a DMQ hydroxylase (Stenmark, P. et al., (2001). J. Biol Chem 2, 2). In E. coli , DMQ 8 is able to sustain respiration in isolated membranes although at a lower rate than UQ 8 . Similarly, DMQ 9 is capable to convey electron transport in eukaryotic mitochondria, as the function of purified mitochondria (Felkai, S. et al., (1999). Embo J 18, 1783-92) and of mitochondrial enzymes (Miyadera, H. et al., (2001). J Biol Chem 276, 7713-6) from clk-1 mutants appear to be almost intact compared to the wild type. Furthermore, synthetic DMQ 2 can function as a co-factor for electron transport from complex I and, more poorly, from complex II (Miyadera, H. et al., (2001). J Biol Chem 276, 7713-6). Interestingly, only DMQ 9 is present in all three clk-1 alleles irrespective of the severity of their effect on physiological rates, which suggests that the lack of UQ cannot solely account for the Clk-1 phenotype (Miyadera, H. et al., (2001). J Biol Chem 276, 7713-6). Recently, it has been found that clk-1 mutants are unable to grow on a UQ-deficient bacterial strain in spite of the presence and the activity of DMQ 9 (Jonassen, T. et al., (2001). Proc Natl Acad Sci USA 98, 421-6). Although, dietary UQ is generally not capable to reach mitochondria, this has been interpreted to suggest that DMQ 9 is insufficient for normal mitochondrial function, and that dietary bacterial UQ 8 can reach the mitochondria and function there in trace amounts (Jonassen, T. et al., (2001). Proc Natl Acad Sci USA 98, 421-6). It would be highly desirable to be provided with characterization of phenotypic effects of UQ deficiencies and screening methods for compounds that can affect the activity of clk-1 and/or relieve UQ deficiencies in multicellular organisms. |
<SOH> SUMMARY OF THE INVENTION <EOH>In accordance with the present invention there is provided a method of screening for a compound allowing survival of clk1 homozygous mutant vertebrate embryos, which comprises the step of breeding heterozygous clk1 subjects to obtain clk1 homozygous mutant embryos and determining viability of clk1 homozygous embryos; wherein at least one of the heterozygous subject is treated with the compound prior to the breeding; and wherein viable embryos are indicative of a compound allowing survival of clk1 homozygous embryos. The method in accordance with a preferred embodiment of the present invention, wherein the subject is a mouse. The method in accordance with a preferred embodiment of the present invention, wherein the compound is suitable for partial or complete functional replacement of endogenous ubiquinone. The method in accordance with a preferred embodiment of the present invention, wherein the compound is administered by at least one route selected from the group consisting of oral, intra-muscular, intravenous, intraperitoneal, subcutaneous, topical, intradermal, and transdermal route. In accordance with the present invention, there is provided a method of screening for a compound suitable for rescue of mutant phenotype of mclk1 homozygous cell line, which comprises the step of determining a mutant phenotype in a mclk1 knockout cell line, wherein cell line is treated with the compound prior to the determining, and wherein the level of the phenotype is indicative of a compound suitable for rescue. In accordance with the present invention, there is provided a method of screening for a compound suitable for partial or complete functional replacement of endogenous ubiquinone, which comprises the step of determining a mutant phenotype in a mclk1 knock-out homozygous ES cell line; wherein the cell line is treated with the compound prior to the determining; and wherein level of the phenotype is indicative a compound suitable for partial or complete functional replacement of ubiquinone. The method in accordance with a preferred embodiment of the present invention, wherein the phenotype is cellular respiration and/or growth rate. In accordance with the present invention, there is provided a method of screening for a compound suitable for partial or complete functional replacement of ubiquinone in a subject, which comprises the step of assessing at least one phenotype selected from the group consisting of viability, fertility, and total or partial absence of a mutant phenotype of a coq-3 homozygous mutant worm; wherein the worm is treated with the compound prior to the assessing; and wherein at least one phenotype selected from the group consisting of the viability, fertility and total or partial absence of the mutant phenotype is indicative of a compound suitable for partial or complete functional replacement of ubiquinone in the subject. The method in accordance with a preferred embodiment of the present invention, wherein the compound is capable of reaching mitochondria in the subject. In accordance with the present invention, there is provided a method for screening for a compound suitable for partial or complete functional replacement of ubiquinone in a subject, which comprises the step of assessing at least one phenotype selected from the group consisting of viability, fertility and total or partial absence of a Clk-1 phenotype of a clk-1 homozygous mutant worm grown on ubiquinone-depleted substrate; wherein the worm is treated with the compound prior to the assessing; and wherein at least one phenotype selected from the group consisting of the viability, fertility and total or partial absence of said Clk-1 phenotype is indicative of a compound suitable for partial or complete functional replacement of ubiquinone in the subject. The method in accordance with a preferred embodiment of the present invention, wherein the ubiquinone-depleted substrate is a non-ubiquinone producer bacteria. The method in accordance with another embodiment of the present invention, wherein the ubiquinone-depleted substrate is a bacteria producing ubiquinone having side-chains shorter than 8 isoprene units. The method in accordance with another embodiment of the present invention, wherein the compound is capable of reaching at least non-mitochondrial sites of ubiquinone requirement in the subject. The method in accordance with a preferred embodiment of the present invention, wherein the bacteria is selected from the group consisting of RKP1452, AN66, IS-16, DM123, GD1, DC349, JC349, JC7623, JF496, KO229(pSN18), KO229Y37A/Y38A), KO229(R321V), and KO229(Y37A/R321V). The method in accordance with a preferred embodiment of the present invention, wherein the bacteria has a mutation in at least one of genes selected from the group consisting of ubiCA, ubiD, ubiX, ubiB, ubiG, ubiH, ubiE, ubiF, and ispB. The method in accordance with a preferred embodiment of the present invention, wherein the bacteria carries at least one of the plasmids selected from the group consisting of pSNI8, Y37A/Y38A, R321V, Y37A/R321V. The method in accordance with a preferred embodiment of the present invention, wherein the functional replacement of ubiquinone is for a function of ubiquinone as co-factor of CLK-1. In accordance with the present invention, there is provided a method for screening a compound capable of inhibiting activity of clk-1 and/or other processes required to make ubiquinone from demethoxyubiquinone in a subject, which comprises the step of determining at least one phenotype selected from the group consisting of growth, fertility and total or partial absence of a Clk-1 phenotypes of a wild-type worm on a ubiquinone-depleted substrate; wherein the worm is treated with the compound prior to the determining; and wherein at least one phenotype selected from the group consisting of total or partial absence of growth, absence of fertility and total or partial absence of said Clk-1 phenotypes is indicative of a compound capable of inhibiting activity of clk-1 and/or other processes required to make ubiquinone from demethoxyubiquinone in a subject. In accordance with the present invention, there is provided a method of screening for a compound suitable for complete or partial functional ubiquinone replacement, which comprises the step of determining a mutant phenotype of a subject in which mclk1 and/or a known ubiquinone biosynthetic enzyme gene is deleted and/or any other gene which when altered leads to absence or reduction of ubiquinone; wherein the subject is treated with the compound prior to the determining; and wherein level of the phenotype is indicative of a compound suitable for complete or partial functional ubiquinone replacement. The method in accordance with a preferred embodiment of the present invention, wherein the subject is a mouse, ES cell line, or any cell line in which mclk1 is deleted or any gene coding for a known ubiquinone biosynthetic enzyme gene is deleted and/or any other gene which when altered leads to absence or reduction of ubiquinone. In accordance with the present invention, there is provided a mouse which is incapable of producing ubiquinone and comprising a gene knock-out of mclk1; wherein the mouse expresses the phenotype related to an absence of ubiquinone and the presence of demethoxyubiquinone. In accordance with the present invention, there is provided a DNA construct, which comprises an alteration of mclk1; wherein the DNA construct is instrumental in producing a mouse mclk1 knockout strain of the present invention. In accordance with the present invention, there is provided an ES cell line which is incapable of producing ubiquinone and comprising a gene knock-out of mclk1; wherein the ES cell line expresses the phenotype related to an absence of ubiquinone and the presence of demethoxyubiquinone. In accordance with the present invention, there is provided a coq-3 mutant subject which is incapable of producing ubiquinone; wherein mutation is a deletion of coq-3 or a deletion of a ubiquinone biosynthetic enzyme and/or any other gene which when altered leads to absence or reduction of ubiquinone. The mutant in accordance with a preferred embodiment of the present invention, wherein the subject is a worm. The mutant in accordance with a preferred embodiment of the present invention, wherein the mutant is selected from the group of worm identified using PCR primers selected from the group consisting of SHP172, SHP1773, SHP1774, SHP1775, SHP1840 and SHP1865. In accordance with the present invention, there is provided a method of screening for a compound suitable for complete or partial functional ubiquinone or demethoxyubiquinone replacement, which comprises the step of determining a mutant phenotype in a subject in which a ubiquinone biosynthetic enzyme gene and/or any gene whose alteration leads to an absence or reduction of ubiquinone or demethoxyubiquinone is altered; wherein the subject is treated with the compound prior to the determining; and wherein level of phenotype is indicative of a compound suitable for complete or partial functional ubiquinone or demethoxyubiquinone replacement. In accordance with the present invention, there is provided a method for reducing and/or increasing ubiquinone level in a multicellular subject, which comprises the step of targeting coq-3 in the subject. In accordance with the present invention, there is provided a method of screening for a genetic suppressor of clk-1, which comprises the step of determining at least one phenotype selected from the group consisting of viability, fertility and total or partial absence of a Clk-1 mutant phenotype of clk-1 mutant worms grown on ubiquinone-depleted bacteria; wherein the worm carries the genetic suppressor prior to the determining; and wherein at least one phenotype selected from the group consisting of the viability, fertility and total or partial absence of said Clk-1 mutant phenotype is indicative of a genetic suppressor of clk-1. In accordance with the present invention, there is provided a method of screening for a genetic suppressor of coq-3, which comprises the step of determining at least one phenotype selected from the group consisting of viability, fertility and total or partial absence of a mutant phenotype of coq-3 mutant worm; wherein the worm carries the genetic suppressor prior to the determining; and wherein the at least one phenotype selected from the group consisting of viability, fertility and total or partial absence of said mutant phenotype is indicative of a genetic suppressor of coq-3. In accordance with the present invention, there is provided a method of screening for a compound suitable for complete or partial functional ubiquinone replacement, which comprises the step of determining a mutant phenotype of a subject in which mclk1 is deleted only in a subset of cells and/or periods of the life cycle, wherein the subject is treated with the compound prior to the determining; and wherein level of the phenotype is indicative of a compound suitable for complete or partial functional ubiquinone replacement. The method in accordance with a preferred embodiment of the present invention, wherein the compounds are useful in treating a disease selected from the group consisting of reactive oxygen species (ROS) mediated disease, diabetes, hypoxia/reoxygenation injury, Parkinson's disease, artherosclerosis and Alzheimer's disease. In the present application, the term “ubiquinone-depleted substrate” is intended to mean a substrate being not producing ubiquinone or being producing ubiquinone with side-chains too short to be effective. An example of what will be considered ubiquinone with side-chains too short to be effective would be ubiquinone with side-chains shorter than 8 isoprene units. |
Substituted anthranilamides for controlling invertebrate pests |
This invention provides compounds of Formula (I), and N-oxides and salts thereof (I) wherein A, B, R1 through R5, R7 through R9, X and Y are as defined in the disclosure. Also disclosed are methods for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula (I). Also disclosed are compositions for controlling an invertebrate pest comprising the compounds of Formula (I). |
1. A compound of Formula I, and N-oxides and salts thereof, wherein A and B are independently O or S; X is N or CR10; Y is N or CH; R1 is H; R11; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R6, halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, (C1-C4 alkyl)C3-C6 cycloalkylamino and R11; R2 is H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C1-C4 alkoxy, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, (C1-C4 alkyl)C3-C6 cycloalkylamino, C2-C6 alkoxycarbonyl or C2-C6 alkylcarbonyl; R3 is H; R11; or C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of R6, halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C3-C6 trialkylsilyl, R11, a phenyl, a phenoxy and 5- or 6-membered heteroaromatic rings, each phenyl, phenoxy and 5- or 6-membered heteroaromatic ring optionally substituted with from one to three substituents independently selected from W and optionally substituted with one R12; or R2 and R3 can be taken together with the nitrogen to which they are attached to form K; R4 is C1-C4 alkyl C1-C4 haloalkyl, CN, halogen, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl; R5 and R8 are each independently H; C1-C4 alkyl; C1-C4 haloalkyl; halogen; R12; G; J; O-J; O-G; S(O)p-J; S(O)p-G; S(O)p-phenyl optionally substituted with one to three substituents independently selected from W and optionally substituted with one R12; C1-C10 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C4 alkoxy or C1-C4 alkythio, each substituted with one or more substituents selected from the group consisting of G, J, R6, halogen, CN, NO2, NH2, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 trialkylsilyl, a phenyl ring and a phenoxy ring, each phenyl and phenoxy ring optionally substituted with from one to three substituents independently selected from W and optionally substituted with one R12; each G is independently a 5- or 6-membered nonaromatic heterocyclic ring, optionally including one or two ring members selected from the group consisting of C(═O), SO or S(O)2 and optionally substituted with from one to four substituents selected from the group consisting of C1-C2 alkyl halogen, CN, NO2 and C1-C2 alkoxy; or each G is independently C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, (cyano)C3-C7 cycloalkyl, (C1-C4 alkyl)C3-C6 cycloalkyl, (C3-C6 cycloalkyl)C1-C4 alkyl, each cycloalkyl, (alkyl)cycloalkyl and (cycloalkyl)alkyl optionally substituted with one or more halogen; each J is independently a 5- or 6-membered heteroaromatic ring optionally substituted with one to three substituents independently selected from W and optionally substituted with R12; each R6 is independently R19C(=E)-; R19C(=E)L-; R19LC(=E)-; (R19)LC(=E)L-; —O(Q=)P(OR19)2; —SO2LR18; or R19SO2L-; each E is independently O, S, NR15, NOR15, NN(R15)2, N—S═O, N—CN or N—NO2; R7 is H, C1-C4 alkyl, C1-C4 haloalkyl, halogen, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl; R9 is CF3, OCF3, OCHF2, OCH2CF3, S(O)pCF3, S(O)pCHF2 or halogen; R10 is H, C1-C4 alkyl, C1-C4 haloalkyl, halogen, CN or C1-C4 haloalkoxy; each R11 is independently C1-C6 alkylthio; C1-C6 alkylsulfenyl; C1-C6 haloalkythio; C1-C6 haloalkylsulfenyl; phenylthio or phenylsulfenyl each optionally substituted with from one to three substituents independently selected from W; (R16)2NS(O)n—; R13C(═O)—; R14C(═O)L-; R14LC(═O)S—; R13LC(═O)—; R13C(═O)NR13S(O)n—; R14LC(═O)NR13S(O)n— or R14LSO2NR13S(O)n—; each L is independently O, NR18 or S; each R12 is independently B(OR17)2; NH2; SH; thiocyanato; C3-C8 trialkylsilyloxy; C1-C4 alkyldisulfide; SF5; R19C(=E)-; R19C(=E)L-; R19LC(=E)-; (R19)LC(=E)L-; -OP(=Q)(OR19)2; -SO2LR19; R19SO2L-; Q is O or S; each R13 is independently hydrogen; C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R6, halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino and (C1-C4 alkyl)C3-C6 cycloalkylamino; each R14 is C1-C20 alkyl, C2-C20 alkenyl, C2-C20 alkynyl or C3-C6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R6, halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino and (C1-C4 alkyl)C3-C6 cycloalkylamino; or phenyl optionally substituted with from one to three substituents independently selected from W and optionally substituted with R12; each R15 is independently H; C1-C6 haloalkyl; C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of CN, NO2, R6, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyl, C3-C6 trialkylsilyl, and a phenyl ring optionally substituted with one to three substituents independently selected from W and optionally substituted with one R12; or phenyl optionally substituted with one to three substituents independently selected from W and optionally substituted with R12; or N(R15)2 can be taken together to form K; R16 is C1-C12 alkyl or C1-C12 haloalkyl; or N(R16)2 can be taken together to form K; each R17 is independently H or C1-C4 alkyl; or B(OR17)2 can form a ring wherein the two oxygen atoms are linked by a chain of two to three carbons optionally substituted with one or two substituents independently selected from methyl or C2-C6 alkoxycarbonyl; each R18 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; or N(R13)(R18) can be taken together to form K; each R19 is independently H; C1-C6 alkyl optionally substituted with one or more substituents selected from the group consisting of CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl, C1-C4 haloalkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, CO2H, C2-C6 alkoxycarbonyl, C2-C6 alkylcarbonyl, C3-C6 trialkylsilyl, and a phenyl ring optionally substituted with one to three substituents independently selected from W; C1-C6 haloalkyl; C3-C6 cycloalkyl; or phenyl or pyridinyl optionally substituted with from one to three substituents independently selected from W; each K is a ring containing, in addition to the nitrogen atom to which the substituent pair R13 and R18, (R15)2 or (R16)2 is attached, from 2 to 6 atoms of carbon and optionally one additional atom of nitrogen, sulfur or oxygen, said ring optionally substituted with from one to four substituents selected from the group consisting of C1-C2 alkyl, halogen, CN, NO2 and C1-C2 alkoxy; each W is independently C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C1-C4 haloalkyl, C2-C4 haloalkenyl, C2-C4 haloalkynyl, C3-C6 halocycloalkyl, halogen, CN, NO2, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino, C3-C6 cycloalkylamino, (C1-C4 alkyl)C3-C6 cycloalkylamino, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, CO2H, C2-C6 alkylaminocarbonyl, C3-C8 dialkylaminocarbonyl or C3-C6 trialkylsilyl; each n is independently 0 or 1; and each p is independently 0, 1 or 2; provided that when both (a) R5 is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C4 haloalkoxy, C1-C4 haloalkylthio or halogen; and (b) R8 is H, C1-C6 alkyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C4 haloalkoxy, C1-C4 haloalkylthio, halogen, C2-C4 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl or C3-C8 dialkylaminocarbonyl; then both (c) at least one substituent selected from the group consisting of R6, R11 and R12 is present; and (d) when R12 is not present, at least one R6 or R11 is other than C2-C6 alkylcarbonyl, C2-C6 alkoxycarbonyl, C2-C6 alkylaminocarbonyl and C3-C8 dialkylaminocarbonyl. 2. A compound of claim 1 wherein A and B are both O; J is a 5- or 6-membered heteroaromatic ring selected from the group consisting of J-1, J-2, J-3 and J-4, each J ring optionally substituted with from one to three substituents independently selected from W and optionally substituted with R12; Q1 is O, S or N—W; and W1, X1, Y1 and Z1 are independently N or C—W, provided that in J-3 and J-4 at least one of W1, X1, Y1 or Z1 is N. 3. A compound of claim 2 wherein one substituent selected from the group consisting of R6, R11 and R12 is present. 4. A compound of claim 3 with the Formula Is wherein X is N or CR10; Y is N or CH; R1 is H; or R 11; R2 is C1-C6 alkyl; R3 is H; or R 11; R4 is C1-C4 alkyl or halogen; R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or halogen; R7 is C1-C4 haloalkyl or halogen; R8 is H; R9 is CF3, OCF3, OCHF2, OCH2CF3, S(O)pCF3, S(O)pCHF2 or halogen; each R11 is independently C1-C6 alkylthio; C1-C6 haloalkythio; phenylthio optionally substituted with from one to three substituents independently selected from W; SN(R16)2; R14C(═O)L1-; R14L2C(═O)S—; R14L2C(═O)NR13S— or R14SO2NR13S—; L1 is NR13 or S; each L2 is independently O, NR13 or S; each R13 is independently hydrogen; C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino and C3-C6 cycloalkylamino; each R14 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl or C3-C6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of halogen, CN, NO2, hydroxy, C1-C4 alkoxy, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 alkylamino, C2-C8 dialkylamino and C3-C6 cycloalkylamino; or phenyl optionally substituted with one to three substituents independently selected from W; and R16 is C1-C4 alkyl or C1-C4 haloalkyl; or N(R16)2 can be taken together to form a ring containing a nitrogen atom and 2 to 6 atoms of carbon and optionally one additional atom of nitrogen, sulfur or oxygen, said ring optionally substituted with from one to four substituents selected from the group consisting of C1-C2 alkyl, halogen, CN, NO2 and C1-C2 alkoxy; provided that one R11 is present. 5. A compound of claim 4 wherein X is N; Y is N; R4 is CH3, F, Cl or Br; R5 is H, CF3, F, Cl, Br or I; R7 is Cl or Br; and R9 is CF3, OCHF2, OCH2CF3, Cl or Br. 6. A compound of claim 3 wherein R1 is H; R2 is H or C1-C6 alkyl; R3 is C1-C6 alkyl; R5 is C1-C10 alkyl substituted with one substituent selected from the group consisting of CN, NO2, NH2, hydroxy and R6; or R12; R6 is R19C(=E)-; R19C(=E)L-; R19LC(=E)-; or (R19)LC(=E)L-; R12 is NH2; R19C(=E)-; R19C(=E)L-; R19LC(=E)-; or (R19)LC(=E)L-; each E is independently O or NOR15; each L is independently O or NR18; each R15 is independently H or C1-C4 alkyl; and each R18 is independently H, C1-C6 alkyl or C1-C6 haloalkyl. 7. A compound of claim 6 wherein R5 is R12; R12 is NH2, R19C(═O)L- or (R19)LC(═O)L-; each L is independently NR18; and each R18 is independently H, C1-C6 alkyl or C1-C6 haloalkyl. 8. A compound of claim 6 wherein R5 is C1-C10 alkyl substituted with hydroxy; or R12; R12 is R19C(=E)- or R19LC(═O)-; E is O or NOR15; L is O or NR18; R15 is H or C1-C4 alkyl; and R18 is H, C1-C6 alkyl or C1-C6 haloalkyl. 9. A compound of claim 3 wherein R1 is H; R2 is H or C1-C6 alkyl; R3 is C1-C6 alkyl; R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or halogen; R8 is C1-C10 alkyl substituted with one substituent selected from the group consisting of CN, NO2, NH2, hydroxy and R6; or R12; R6 is R19C(=E)-; R19C(=E)L-; R19LC(=E)-; or (R19)LC(=E)L-; R12 is R19C(=E1)-; R19C(=E2)L-; R19LC(=E1)- or (R19)LC(=E2)L-; each E is independently O or NOR15; each E1 is NOR15; each E2 is independently O or NOR15; each L is independently O or NR18; each R15 is independently H or C1-C4 alkyl; each R18 is independently H, C1-C6 alkyl or C1-C6 haloalkyl; and each R19 is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C3-C6 cycloalkyl, or phenyl optionally substituted with from one to three substituents independently selected from W. 10. A compound of claim 9 wherein R8 is C1-C10 alkyl substituted with one substituent selected from the group consisting of NH2, hydroxy and R6; or R12; R6 is R19C(═O)L-; R12 is R19LC(═O)—; and each L is independently NR18. 11. The compound of claim 10 that is 1-[2-(hydroxymethyl)phenyl]-N-[2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-3-(tifluoromethyl)-1H-pyrazole-5-carboxamide. 12. A compound of claim 3 wherein R1 is H; R2 is H or C1-C6 alkyl; R3 is C1-C6 alkyl substituted with one R6; R4 is C1-C4 alkyl or halogen; R5 is H, C1-C4 alkyl, C1-C4 haloalkyl or halogen; R6 is R19C(=E1)-; R19C(=E2)L-; R19LC(=E1)- or (R19)LC(=E2)L-; each E1 is independently S, NR15, NOR15, NN(R15)2; each E2 is independently O, S, NR15, NOR15, NN(R15)2; each L is independently O or NR18; R7 is C1-C4 haloalkyl or halogen; R8 is H; R9 is CF3, OCF3, OCHF2, OCH2CF3, S(O)pCF3, S(O)pCHF2 or halogen; each R15 is independently H; C1-C6 haloalkyl; C1-C6 alkyl optionally substituted with one substituent selected from the group consisting of CN, C1-C4 alkoxy, C1-C4 haloalkoxy, C1-C4 alkylthio, C1-C4 alkylsulfinyl, C1-C4 alkylsulfonyl, C1-C4 haloalkylthio, C1-C4 haloalkylsulfinyl and C1-C4 haloalkylsulfonyl; each R19 is independently H or C1-C6 alkyl; and each p is independently 0, 1 or 2. 13. A compound of claim 12 wherein R3 is C1-C6 alkyl substituted with one R6; R6 is R19C(=E1)-; and E1 is NOR15. 14. A compound of claim 1 wherein R5 is NH2. 15. The compound of claim 14 that is N-[4-Amino-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide. 16. The compound of claim 1 selected from the group consisting of Methyl 4-[[[1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl]carbonyl]amino]-3-methyl-5-[[(1-methylethyl)amino]carbonyl]benzoate, N-[4-Acetyl-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, and N-[4-Benzoylamino-2-methyl-6-[[(1-methylethyl)amino]carbonyl]phenyl]-1-(3-chloro-2-pyridinyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide. 17. A method for controlling an invertebrate pest comprising: contacting the invertebrate pest or its environment with a biologically effective amount of a compound of claim 1, an N-oxide thereof or a suitable salt thereof. 18. The method of claim 17 which comprises applying a composition comprising said compound and a biologically effective amount of at least one additional compound or agent for controlling an invertebrate pest. 19. A composition for controlling an invertebrate pest comprising: a biologically effective amount of a compound of claim 1; and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. 20. The composition of claim 19 which further comprises at least one additional compound or agent for controlling an invertebrate pest. |
<SOH> BACKGROUND OF THE INVENTION <EOH>This invention relates to certain substituted anthranilamides, their N-oxides, salts and compositions suitable for agronomic and nonagronomic uses, including those uses listed below, and a method of their use for controlling invertebrate pests in both agronomic and nonagronomic environments. The control of invertebrate pests is extremely important in achieving high crop efficiency. Damage by invertebrate pests to growing and stored agronomic crops can cause significant reduction in productivity and thereby result in increased costs to the consumer. The control of invertebrate pests in forestry, greenhouse crops, ornamentals, nursery crops, stored food and fiber products, livestock, household, and public and animal health is also important. Many products are commercially available for these purposes, but the need continues for new compounds that are more effective, less costly, less toxic, environmentally safer or have different modes of action. NL 9202078 discloses N-acyl anthranilic acid derivatives of Formula i as insecticides wherein, inter alia, X is a direct bond; Y is H or C 1 -C 6 alkyl; Z is NH 2 , NH(C 1 -C 3 alkyl) or N(C 1 -C 3 alkyl) 2 ; and R 1 through R 9 are independently H, halogen, C 1 -C 6 alkyl, phenyl, hydroxy, C 1 -C 6 alkoxy or C 1 -C 7 acyloxy. |
<SOH> SUMMARY OF THE INVENTION <EOH>This invention pertains to compounds of Formula I, and N-oxides and salts thereof, wherein A and B are independently O or S; X is N or CR 10 ; Y is N or CH; R 1 is H; R 11 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R 6 , halogen, CN, NO 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, (C 1 -C 4 alkyl)C 3 -C 6 cycloalkylamino and R 11 ; R 2 is H, C 1 -C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl C 3 -C 6 cycloalkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, (C 1 -C 4 alkyl)C 3 -C 6 cycloalkylamino, C 2 -C 6 alkoxycarbonyl or C 2 -C 6 alkylcarbonyl; R 3 is H; R 11 ; or C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl C 3 -C 6 cycloalkyl, each optionally substituted with one or more substituents selected from the group consisting of R 6 , halogen, CN, NO 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 3 -C 6 trialkylsilyl R 11 , a phenyl, a phenoxy and 5- or 6-membered heteroaromatic rings, each phenyl, phenoxy and 5- or 6-membered heteroaromatic ring optionally substituted with from one to three substituents independently selected from W and optionally substituted with one R 12 ; or R 2 and R 3 can be taken together with the nitrogen to which they are attached to form K; R 4 is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, CN, halogen, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkylsulfinyl C 1 -C 4 haloalkylsulfonyl; R 5 and R 8 are each independently H; C 1 -C 4 alkyl; C 1 -C 4 haloalkyl; halogen; R 12 ; G; J; O-J; O-G; S(O) p -J; S(O) p -J; S(O) p -phenyl optionally substituted with one to three substituents independently selected from W and optionally substituted with one R 12 ; C 1 -C 10 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 4 alkoxy or C 1 -C 4 alkythio, each substituted with one or more substituents selected from the group consisting of G, J, R 6 , halogen, CN, NO 2 , NH 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkylsulfinyl, C 1 -C 4 haloalkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 trialkylsilyl a phenyl ring and a phenoxy ring, each phenyl and phenoxy ring optionally substituted with from one to three substituents independently selected from W and optionally substituted with one R 12 ; each G is independently a 5- or 6-membered nonaromatic heterocyclic ring, optionally including one or two ring members selected from the group consisting of C(═O), SO or S(O) 2 and optionally substituted with from one to four substituents selected from the group consisting of C 1 -C 2 alkyl, halogen, CN, NO 2 and C 1 -C 2 alkoxy; or each G is independently C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, (cyano)C 3 -C 7 cycloalkyl, (C 1 -C 4 alkyl)C 3 -C 6 cycloalkyl, (C 3 -C 6 cycloalkyl)C 1 -C 4 alkyl, each cycloalkyl, (alkyl)cycloalkyl and (cycloalkyl)alkyl optionally substituted with one or more halogen; each J is independently a 5- or 6-membered heteroaromatic ring optionally substituted with one to three substituents independently selected from W and optionally substituted with R 12 ; each R 6 is independently R 19 C(=E)-; R 19 C(=E)L-; R 19 LC(=E)-; (R 19 )LC(=E)L-; —O(Q=)P(OR 19 ) 2 ; —SO 2 LR 18 ; or R 19 SO 2 L-; each E is independently O, S, NR 15 , NOR 15 , NN(R 15 ) 2 , N—S═O, N—CN or N—NO 2 ; R 7 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl halogen, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkylsulfinyl, C 1 -C 4 haloalkylsulfonyl; R 9 is CF 3 , OCF 3 , OCHF 2 , OCH 2 CF 3 , S(O) p CF 3 , S(O) p CHF 2 or halogen; R 10 is H, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, halogen, CN or C 1 -C 4 haloalkoxy; each R 11 is independently C 1 -C 6 alkylthio; C 1 -C 6 alkylsulfenyl; C 1 -C 6 haloalkythio; C 1 -C 6 haloalkylsulfenyl; phenylthio or phenylsulfenyl each optionally substituted with from one to three substituents independently selected from W; (R 16 ) 2 NS(O) n —; R 13 C(═O)—; R 14 C(═O)L-; R 14 LC(═O)S—; R 13 LC(═O)—; R 13 C(═O)NR 13 S(O) n —; R 14 LC(═O)NR 13 S(O) n — or R 14 LSO 2 NR 13 S(O) n —; each L is independently O, NR 18 or S; each R 12 is independently B(OR 17 ) 2 ; NH 2 ; SH; thiocyanato; C 3 -C 8 trialkylsilyloxy; C 1 -C 4 alkyldisulfide; SF 5 ; R 19 C(=E)-; R 19 C(=E)L-; R 19 LC(=E)-; (R 19 )LC(=E)L-; —OP(=Q)(OR 19 ) 2 ; —SO 2 LR 19 ; R 19 SO 2 L-; Q is O or S; each R 13 is independently hydrogen; C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or C 3 -C 6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R 6 , halogen, CN, NO 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino and (C 1 -C 4 alkyl)C 3 -C 6 cycloalkylamino; each R 14 is C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl or C 3 -C 6 cycloalkyl each optionally substituted with one or more substituents selected from the group consisting of R 6 , halogen, CN, NO 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino and (C 1 -C 4 alkyl)C 3 -C 6 cycloalkylamino; or phenyl optionally substituted with from one to three substituents independently selected from W and optionally substituted with R 12 ; each R 15 is independently H; C 1 -C 6 haloalkyl; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of CN, NO 2 , R 6 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkylsulfinyl, C 1 -C 4 haloalkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylcarbonyl, C 3 -C 6 trialkylsilyl, and a phenyl ring optionally substituted with one to three substituents independently selected from W and optionally substituted with one R 12 ; or phenyl optionally substituted with one to three substituents independently selected from W and optionally substituted with R 12 ; or N(R 15 ) 2 can be taken together to form K; R 16 is C 1 -C 12 alkyl or C 1 -C 12 haloalkyl; or N(R 16 ) 2 can be taken together to form K; each R 17 is independently H or C 1 -C 4 alkyl; or B(OR 17 ) 2 can form a ring wherein the two oxygen atoms are linked by a chain of two to three carbons optionally substituted with one or two substituents independently selected from methyl or C 2 -C 6 alkoxycarbonyl; each R 18 is independently H, C 1 -C 6 alkyl or C 1 -C 6 haloalkyl; or N(R 13 )(R 18 ) can be taken together to form K; each R 19 is independently H; C 1 -C 6 alkyl optionally substituted with one or more substituents selected from the group consisting of CN, NO 2 , hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 haloalkylthio, C 1 -C 4 haloalkylsulfinyl, C 1 -C 4 haloalkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, CO 2 H, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylcarbonyl, C 3 -C 6 trialkylsilyl, and a phenyl ring optionally substituted with one to three substituents independently selected from W; C 1 -C 6 haloalkyl; C 3 -C 6 cycloalkyl; or phenyl or pyridinyl optionally substituted with from one to three substituents independently selected from W; each K is a ring containing, in addition to the nitrogen atom to which the substituent pair R 13 and R 18 , (R 15 ) 2 or (R 16 ) 2 is attached, from 2 to 6 atoms of carbon and optionally one additional atom of nitrogen, sulfur or oxygen, said ring optionally substituted with from one to four substituents selected from the group consisting of C 1 -C 2 alkyl, halogen, CN, NO 2 and C 1 -C 2 alkoxy; each W is independently C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkenyl, C 3 -C 6 cycloalkyl C 1 -C 4 haloalkyl C 2 -C 4 haloalkenyl, C 2 -C 4 haloalkynyl, C 3 -C 6 halocycloalkyl, halogen, CN, NO 2 , C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylamino, C 2 -C 8 dialkylamino, C 3 -C 6 cycloalkylamino, (C 1 -C 4 alkyl)C 3 -C 6 cycloalkylamino, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, CO 2 H, C 2 -C 6 alkylaminocarbonyl, C 3 -C 8 dialkylaminocarbonyl or C 3 -C 6 trialkylsilyl; each n is independently 0 or 1; and each p is independently 0, 1 or 2; provided that when both (a) R 5 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkylthio or halogen; and (b) R 8 is H, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 2 -C 6 haloalkenyl, C 2 -C 6 haloalkynyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkylthio, halogen, C 2 -C 4 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylaminocarbonyl or C 3 -C 8 dialkylaminocarbonyl; then both (c) at least one substituent selected from the group consisting of R 6 , R 11 and R 12 is present; and (d) when R 12 is not present, at least one R 6 or R 11 is other than C 2 -C 6 alkylcarbonyl, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylaminocarbonyl and C 3 -C 8 dialkylaminocarbonyl. This invention also pertains to a method for controlling an invertebrate pest comprising contacting the invertebrate pest or its environment with a biologically effective amount of a compound of Formula I, an N-oxide thereof or a salt thereof (e.g., as a composition described herein). This invention also relates to such a method wherein the invertebrate pest or its environment is contacted with a biologically effective amount of a compound of Formula I, an N-oxide thereof or a salt thereof, or a composition comprising the compound, N-oxide thereof or a salt thereof, and a biologically effective amount of at least one additional compound or agent for controlling an invertebrate pest. This invention also pertains to a composition for controlling an invertebrate pest comprising a biologically effective amount of a compound of Formula I, an N-oxide thereof or a salt thereof and at least one additional component selected from the group consisting of surfactants, solid diluents and liquid diluents. This invention also pertains to a composition comprising a biologically effective amount of a compound of Formula I, an N-oxide thereof or a salt thereof and an effective amount of at least one additional biologically active compound or agent. detailed-description description="Detailed Description" end="lead"? |
Genetically modified cyclic-nucleotide controlled ion channels and the use thereof |
The present invention relates to genetically modified cyclic nucleotide-gated ion channels whose subunits have been altered so as to have higher sensitivity to cAMP and/or higher selectivity for cAMP compared to cGMP in comparison with the wild type according to SEQ ID NO 1 and 2. |
1-35. (canceled) 36. A genetically modified cyclic nucleotide-gated ion channel (CNG channel) composed of subunits which have been modified at the position corresponding to threonine T537 in the bovine α3 subunit so that they have higher sensitivity for cAMP and/or higher selectivity for cAMP than for cGMP in comparison with the wild type according to SEQ ID NO 1 and 2. 37. The genetically modified CNG channel as claimed in claim 36, which comprises subunits of CNG channels from bovine and/or other organisms. 38. The genetically modified CNG channel as claimed in claim 36, which has a homooligomeric composition of identical subunits or a heterooligomeric composition of different subunits. 39. The genetically modified CNG channel as claimed in claim 36, which has at least one further genetic modification. 40. The genetically modified CNG channel as claimed in claim 36, which comprises chimeric subunits. 41. The genetically modified CNG channel as claimed in claim 36, wherein the amino acid corresponding to threonine T537 in the bovine α3 subunit has been replaced by methionine or valine. 42. A method for preparing CNG channels, which comprises replacing in the subunits the amino acid corresponding to threonine T537 in the bovine α3 subunit with a different amino acid other than serine. 43. The method as claimed in claim 42, which comprises replacing the amino acid corresponding to threonine T537 in the bovine α3 subunit with methionine or valine. 44. The use of the CNG channel as claimed in claim 36 for measuring the intracellular cAMP concentration. 45. The use of the CNG channels as claimed in claim 36 for determining the action of ligands, agonists and antagonists on G protein-coupled receptors and of activators and inhibitors on other proteins regulating the intracellular cAMP concentration. 46. A modified nucleic acid, which codes for subunits of the CNG channels as claimed in claim 36. 47. An expression vector, which comprises nucleic acids as claimed in claim 46. 48. A cell line which comprises a CNG channel a modified nucleic acid which codes for a CNG channel or an expression vector which comprises a nucleic acid which codes for a CNG channel as defined in claim 36. 49. The cell line as claimed in claim 48, which is capable of expressing CNG channels. 50. The cell line as claimed in claim 48, which is capable of heterologously coexpressing proteins regulating the intracellular cAMP concentration together with CNG channels. 51. The cell line as claimed in claim 48 which is capable of heterologously coexpressing G protein-coupled receptors, phosphodiesterases, or adenylate cyclases together with a CNG channel. 52. A method for preparing cell lines, which comprises transforming the cell lines with an expression vector as claimed in claim 47. 53. The method as claimed in claim 52, which comprises cloning the genes for the proteins into an expression vector and then transforming the cell lines. 54. The method as claimed in claim 52 which comprises using eukaryotic CHO, COS or SF9 cell lines as a heterologous expression system. 55. The method as claimed in claim 52, which comprises using human embryonic kidney (HEK) 293 cell lines as a heterologous expression system. 56. A method for preparing a cell line as claimed in claim 48 which comprises expressing the proteins stably or transiently. 57. The method for preparing cell lines as claimed in claim 50 which comprises expressing one of the proteins stably and the other protein transiently. 58. The use of a cell line as claimed in claim 48 for determining the intracellular Ca2+ concentration. 59. The use of a cell line as claimed in claim 58, wherein the determination is carried out using fluorescence-optical methods. 60. The use of a cell line as claimed in claim 58 wherein fluorescent Ca2+ indicators are used. 61. The use of a cell line as claimed in claim 58, wherein the determination is carried out using luminescence-optical methods. 62. The use of a cell line as claimed in claim 58 wherein luminescent apoaequorin or isoforms thereof are used. 63. The use of a cell line as claimed in claim 58, wherein the Ca2+ concentration is determined in cuvette measuring devices or Ca2+ imaging apparatuses. 64. The use of a cell line as claimed in claim 58, wherein the Ca2+ concentration is determined in fluorescence or luminescence readers. 65. The use of a cell line as claimed in claim 58, wherein multiwell plates are used. 66. The use of a cell line as claimed in claim 58, wherein adherent cells or cells in suspension are used. 67. The use of a cell line as claimed in claim 58 for characterizing pharmaceutically active compounds or pharmacological substances, which increase or reduce the intracellular cAMP concentration. 68. The use of a cell line as claimed in claim 58 for characterizing GPCRs, adenylate cyclases, phosphodiesterases or other proteins regulating the cellular cAMP concentration. 69. The use of a cell line as claimed in claim 67 wherein high throughput (HTS) or ultra-high throughput (UHTS) is employed. 70. The use of a cell line as claimed in claim 58, wherein the measurements are carried out in real time. |
Method and nucleic acids for the analysis of colon cancer |
The present invention relates to chemically modified genomic sequences, oligonucleotides and/or PNA-oligomers for detecting the cytosine methylation state of genomic DNA, as well as to methods for ascertaining genetic and/or epigenetic parameters of genes for use in the characterisation, grading, staging, and/or diagnosis of colon cancer, or the predisposition to colon cancer. |
1. A method to determine the methylation status of CpG dinucleotides within one or more of the genes estrogen receptor, p21, p27, p 16, progesterone receptor, myoglobin, pcna, cdc2, c-erB2, p53 and CEA comprising contacting the target nucleic acid in a biological sample with at least one reagent or series of reagents wherein said reagent or series of reagents distinguishes between methylated and non methylated CpG dinucleotides within the target nucleic acid and concluding from the methylation status of one or more of said CpG positions on the presence or absence of a colon cell proliferative disorder. 2. A method according to claim 1 comprising the following steps: obtaining a biological sample containing genomic DNA extracting the genomic DNA in the genomic DNA sample, cytosine bases which are unmethylated at the 5-position are converted, by treatment, to uracil or another base which is dissimilar to cytosine in terms of base pairing behavior; fragments of the pretreated genomic DNA are amplified using sets of primer oligonucleotides according to Seq ID 76 to Seq ID 97 and a polymerase, the amplificates carrying a detectable label; detection of the fragments Identification of the methylation status of one or more cytosine positions 3. A method according to claim 2, characterized in that the reagent is a solution of bisulfite, hydrogen sulfite or disulfite. 4. A method as recited in one of claims 2 and 3, characterized in that the amplification is carried out by means of the polymerase chain reaction (PCR). 5. A method as recited in one of the claims 2 to 3, characterized in that more than ten different fragments having a length of 100-2000 base pairs are amplified. 6. A method as recited in one of the claims 2 to 3, characterized in that the amplification of several DNA segments is carried out in one reaction vessel. 7. A method as recited in one of the claims 2 to 3, characterized in that the polymerase is a heat-resistant DNA polymerase. 8. A method as recited in one of the claims 2 to 3, characterized in that the labels of the amplificates are fluorescence labels. 9. A method as recited in one of claims 2 to 3, characterized in that the labels of the amplificates are radionuclides. 10. A method according to one of claims 2 to 3, characterized in that each amplificate is detected by hybridization to an oligonucleotide or peptide nucleic acid (PNA)-oligomer. 11. A method according to claim 10, characterized in that the olignonucleotide or peptide nucleic acid (PNA)-oligomer is taken from the group comprising Seq ID 98 to 523. 12. A method as recited in one of claims 2 to 3, characterized in that the labels of the amplificates are detachable molecule fragments having a typical mass which are detected in a mass spectrometer. 13. A method as recited in one of claims 2 to 3, characterized in that the amplificates or fragments of the amplificates are detected in the mass spectrometer. 14. A method as recited in claim 12, characterized in that the produced fragments have a single positive or negative net charge for better detectability in the mass spectrometer. 15. A method as recited in claim 12, characterized in that detection is carried out and visualized by means of matrix assisted laser desorption/ionization mass spectrometry (MALDI) or using electron spray mass spectrometry (ESI). 16. A method as recited in claim 2, characterized in that the amplification step preferentially amplifies DNA which is of particular interest in healthy and/or diseased colon tissues, based on the specific genomic methylation status of colon tissue, as opposed to background DNA. 17. A method according to claim 1 comprising the following steps; a) obtaining a biological sample containing genomic DNA b) extracting the genomic DNA, c) digesting the target nucleic acids with one or more methylation sensitive restriction enzymes, d) amplification of the DNA digest and e) detection of the amplificates. 18. A method according to claim 17 wherein the target nucleic acids comprise one or more sequences taken from the group according to Seq ID 12 to Seq ID 31 or sequences hybridising thereto and fragments thereof. 19. A method as recited in one of claims 17 or 18, characterized in that the amplification is carried out by means of the polymerase chain reaction (PCR). 20. A method as recited in one of claims 17 to 18, characterized in that the amplification of several DNA segments is carried out in one reaction vessel. 21. A method as recited in one of claims 17 to 18, characterized in that the polymerase is a heat-resistant DNA polymerase. 22. An isolated nucleic acid of the pretreated genomic DNA according to one of the sequences taken from the group comprising Seq. ID No.32 to Seq. ID No.75 and sequences complementary thereto. 23. An oligomer, in particular an oligonucleotide or peptide nucleic acid (PNA)-oligomer, said oligomer comprising at least one base sequence of at least 10 nucleotides which hybridizes to or is identical to a pretreated genomic DNA according to one of the Seq. ID No. 32 to Seq. ID No 75 according to claim 22. 24. An oligomer or peptide nucleic acid (PNA)-oligomer as recited in claim 23, wherein the base sequence includes at least one CpG dinucleotide sequence. 25. An oligomer or peptide nucleic acid (PNA)-oligomer as recited in claim 23, characterized in that the cytosine of the at least one CpG dinucleotide is/are located approximately in the middle third of the oligomer. 26. An oligomer or peptide nucleic acid (PNA)-oligomer, in particular an oligonucleotide, according to one of the sequences taken from the group comprising Seq. ID No.98 to Seq. ID No. 523. 27. A set of oligomers or peptide nucleic acid (PNA)-oligomers, comprising at least two oligomers according to any of claims 22 to 26. 28. A set of oligomers or peptide nucleic acid (PNA)-oligomers as recited in claim 27, comprising oligomers for detecting the corresponding genomic methylation state of all CpG dinucleotides within one of the sequences according to Seq. ID Nos. 32 to 75, and sequences complementary thereto. 29. A set of at least two oligonucleotides or peptide nucleic acid (PNA)-oligomers as recited in claim 23, as primer oligonucleotides for the amplification of DNA sequences of one of Seq. ID 32 to Seq. ID 75 and/or sequences complementary thereto and segments thereof. 30. A set of oligonucleotides or peptide nucleic acid (PNA)-oligomers as recited in one of claims 22 and 23, characterized in that at least one oligonucleotide is bound to a solid phase. 31. Use of a set of oligomers or peptide nucleic acid (PNA)-oligomers according to one of the sequences taken from the group comprising Seq. ID No. 32 to Seq. ID No. 75 and sequences complementary thereto as probes for determining the cytosine methylation state and/or single nucleotide polymorphisms (SNPs) of a corresponding genomic DNA by analysis of a chemically pretreated genomic DNA according to claim 2. 32. Use of a pretreated genomic DNA according to claim 22 for the determination of the methylation status of a corresponding genomic DNA and/or detection of single nucleotide polymorphisms (SNPs). 33. A method for manufacturing an arrangement of different oligomers or peptide nucleic acid (PNA)-oligomers (array) for analyzing diseases associated with the corresponding genomic methylation status of the CpG dinucleotides within one of the Seq. ID 32 to Seq. ID 75 and sequences complementary thereto, wherein at least one oligomer according to any of the claims 22 to 26 is coupled to a solid phase. 34. An arrangement of different oligomers or peptide nucleic acid (PNA)-oligomers (array) obtainable according to claim 33. 35. An array of different oligonucleotide- and/or PNA-oligomer sequences as recited in claim 34, characterized in that these are arranged on a plane solid phase in the form of a rectangular or hexagonal lattice. 36. A DNA/PNA array for the analysis of prostate cell proliferative disorders associated with the methylation state of genes comprising at least one nucleic acid according to claim 22. 37. An array as recited in any of the claims 34 to 36, characterized in that the solid phase surface is composed of silicon, glass, polystyrene, aluminium, steel, iron, copper, nickel, silver, or gold. 38. Use of a method according to claim 1 for the characterisation, classification, diagnosis and differentiation of colon cell proliferative disorders. 39. A kit comprising a bisulfite (=disulfite, hydrogen sulfite) reagent as well as oligonucleotides and/or PNA-oligomers according to claim 22. 40. Use of a pretreated genomic DNA according to claim 22 for the characterisation, classification, diagnosis and differentiation of colon cell proliferative disorders. 41. A kit comprising a bisulfite (=disulfite, hydrogen sulfite) reagent as well as oligonucleotides and/or PNA-oligomers according to claim 26. 42. A DNA/PNA array for the analysis of prostate cell proliferative disorders associated with the methylation state of genes comprising at least one nucleic acid according to claim 26. 43. An array as recited in claim 42, characterized in that the solid phase surface is composed of silicon, glass, polystyrene, aluminium, steel, iron, copper, nickel, silver or gold. |
<SOH> FIELD OF THE INVENTION <EOH>The levels of observation that have been studied by the methodological developments of recent years in molecular biology, are the genes themselves, the translation of these genes into RNA, and the resulting proteins. The question of which gene is switched on at which point in the course of the development of an individual, and how the activation and inhibition of specific genes in specific cells and tissues are controlled is correlatable to the degree and character of the methylation of the genes or of the genome. In this respect, pathogenic conditions may manifest themselves in a changed methylation pattern of individual genes or of the genome. The present invention relates to nucleic acids, oligonucleotides, PNA-oligomers, and to a method for the characterisation, grading, staging, treatment and/or diagnosis of colon cancer, or the predisposition to colon cancer, by analysis of the genetic and/or epigenetic parameters of genomic DNA and, in particular, with the cytosine methylation status thereof. |
Fungicidal and/or bactericidal composition, production process thereof and sterilization method using the composition |
The present invention relates to a fungicidal and/or bactericidal composition comprising a combination of iturin and surfactin which are a cyclic peptide produced by a mircoorganism, preferably a microorganism belonging to the genus Bacillus, with an amphipathic organic material having a hydrocarbon chain, its production process and sterilization method using the same. The fungicidal and/or bactericidal composition of the present invention is highly safe to human body or environment, is free of generation of resistant bacteria even on repeated use and has a wide sterilization spectrum. |
1. A fungicidal and or bactericidal composition comprising iturin, surfactin and an amphipathic organic material having a hydrocarbon chain. 2. The fungicidal and/or bactericidal composition as claimed in claim 1, wherein the composition ratio (by mol) of iturin to surfactin is from 10:1 to 1:10. 3. The fungicidal and/or bactericidal composition as claimed in claim 1 or 2, wherein the ratio by weight of the amphipathic organic material having a hydrocarbon chain to the mixture of iturin and surfactin is from 1 to 1,000 times. 4. The fungicidal and/or bactericidal composition as claimed in any of claims 1 to 3, wherein the iturin is an iturin-base peptide represented by the following formula (1) wherein n represents 0 or 1 and R1 represents a straight or branched alkyl group having 3 to 6 carbon atoms. 5. The fungicidal and/or bactericidal composition as described in any one of claims 1 to 3, wherein the surfactin is a surfactin-base peptide represented by the following formula (2) wherein X, Y and Z, which may be the same or different, each represents an amino acid selected from the group consisting of leucine, isoleucine, valine, glycine, serine, alanine, threonine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine, methionine, phenylalanine, thyrosin, tryptophan, histidine, proline, 4-hydroxyproline and homoserine, and R2 represents a straight or branched alkyl group having 8 to 14 carbon atoms. 6. The fungicidal and/or bactericidal composition as claimed in claim 1 or 3, wherein the amphipathic organic material having a hydrocarbon chain is one or more compound(s) selected from the group consisting of long chain fatty acids, glycerophospholipid, sphingolipid, glyceroglycolipid, sphingoglycolipid, acylglycerol, wax, cholesterol ester, ester compounds of vitamin A or D, compounds having a cyclopentanohydrophenanthrene ring, and these organic compounds having bound thereto a protein. 7. The fungicidal and/or bactericidal composition as claimed in claim 1 or 3, wherein the amphipathic organic material having a hydrocarbon chain is a compound constituting one or more cell membrane(s) selected from those of the group consisting of microorganism, erythrocyte, plant cell and virus each including an amphipathic organic material. 8. The fungicidal and/or bactericidal composition as claimed in claim 1 or 3, wherein the amphipathic organic material having a hydrocarbon chain is one or more member(s) selected from the group consisting of liposome, adjusted cell vesicle and virus envelope each including an amphipathic organic material. 9. The fungicidal and/or bactericidal composition as claimed in any one of claims 1 to 4, wherein the iturin is originated in a microorganism belonging to the genus Bacillus. 10. The fungicidal and/or bactericidal composition as claimed in any one of claims 1 to 3 or 5, wherein the surfactin is originated in a microorganism belonging to the genus Bacillus. 11. The fungicidal and/or bactericidal composition as claimed in claim 9, wherein the microorganism belonging to the genus Bacillus is Bacillus subtilis SD142 (FERM P-13204). 12. The fungicidal and/or bactericidal composition as claimed in claim 10, wherein the microorganism belonging to the genus Bacillus is Bacillus subtilis SD901 strain (FERM P-17989). 13. A sterilization method comprising forming a through hole structure in a cell membrane by the fungicidal and/or bactericidal composition as claimed in any one of claims 1 to 12 and thereby killing the cell. 14. The sterilization method as claimed in claim 13, wherein the through hole structure is formed by using microorganism cell, erythrocyte, plant cell, virus, cell vesicle or liposome each including an amphipathic organic material. 15. The sterilization method as claimed in claim 13 or 14, wherein the fungicidal and/or bactericidal composition is pretreated before forming the through hole structure. 16. The sterilization method as claimed in any one of claims 13 to 15, wherein the objective of sterilization is bacteria and fungi. 17. A process for producing a fungicidal and/or bactericidal composition, comprising mixing surfactin obtained using Bacillus subtilis SD901 (FERM P-17989), iturin and an amphipathic organic material having a hydrocarbon chain. 18. The process for producing a fungicidal and/or bactericidal composition, comprising mixing iturin obtained using Bacillus subtilis SD142 (FERM P-13204), surfactin and an amphipathic organic material having a hydrocarbon chain. |
<SOH> BACKGROUND ART <EOH>For the purpose of preventing various products from contamination by microorganisms, various compounds having fungicidal and/or bactericidal activity have been heretofore found or developed. Fungicidal and/or bactericidal compositions comprising these compounds individually or in combination are used, for example, for preventing food or building material from contamination by miscellaneous microorganisms and also for sterilizing and disinfecting hospital, sanitation such as cookery, or bathroom. Accordingly, the fungicidal and/or bactericidal composition is indispensable for daily life. However, these compounds generally have high toxicity in many cases and the amount used thereof is limited, therefore, sufficiently high fungicidal and/or bactericidal effect cannot be necessarily brought out at present. Paraoxybenzoic acid esters which have heretofore been considered harmless to a human body and used for foods in many cases are recently doubted to be a so-called environmental hormone (endocrine disrupter). Thus, fungicidal and/or bactericidal compositions comprising a conventional compound cannot be always safe. In addition, a fundamental problem is not solved such that even if a compound such as paraoxybenzoic acid ester is added to foods, the microorganism as an objective of prevention immediately becomes resistant to the compound, as a result, the compound abruptly decreases in the fungicidal and/or bactericidal power and finally loses its efficacy. Under these circumstances, iturin which is a constituent element of the present invention has been heretofore reported to have antibacterial and antibiotic activity. For example, R. Maget-Dana et al. ( Toxicology, 87, 151-174 (1994)) presume that iturin interacts with cytoplasm membrane and forms a quaternary structure together with phospholipid or sterol in the cell membrane to form a through hole in the cell membrane, whereby the strong antibiotic activity of iturin to fungus is brought out. Also, C. Latoud et al. ( Can. J. Microbiol, 36; 3849-389 (1990)) have reported that when the binding of iturin to a cell membrane is observed using a yeast ( Saccharomyces cerevisiae ) and a variant strain thereof, the binding depends on the alkyl chain length of sterol in the cell membrane. M. A. Klichi et al. ( Mycopathologia, 127: 123-127 (1994)) have measured the preventive and removal effect of iturin on the contamination by mold generated during storage of various grains in view of strong antibiotic activity of iturin on mold and high safety thereof to animals and reported that when iturin is used in a concentration of 50 to 100 ppm, the generation of mold can be extremely inhibited. L. Thinmon et al. ( Biotechnology and Applied Biochemistry, 16; 144-151 (1992)) have found that the interaction of iturin with erythrocyte membrane is intensified in the presence of surfactin, and presume that a micelle produced by iturin and surfactin participates in this intensification. R. Maget-Dana et al. ( Biochimie, 74; 1047-1051 (1992)) have found that the hemolysis activity of iturin is increased by surfactin, and suggest that this increase is attributable to the interaction between iturin and surfactin. As such, many studies have been made on the antibiotic activity of iturin and it is considered that iturin can first bring out the antibiotic activity when interacted with a cell membrane. Furthermore, it is known that iturin is sometimes increased in the antibiotic activity by forming a complex with surfactin and allowing this complex to act on a cell membrane. The method for applying the antibiotic activity of iturin to the prevention of growth of plant pathogenic fungi is disclosed in JP-A-59-212416 (the term “JP-A” as used herein means an “unexamined published Japanese patent application”), JP-A-61-289005 and JP-A-61-289898. However, the preventive effect is not sufficiently high in the practical level. Only JP-A-6-135811 discloses a method of elevating the antibiotic activity of iturin by using it in combination with surfactin and enhancing the performance of controlling the plant pathogenic fungi in the practical level. On the other hand, with respect to the interacting activity of iturin with surfactin on a cell membrane ingredient, the hemolysis activity of erythrocyte has been heretofore mainly studied. As for the microorganism, studies are limited only to testing of a part of microorganisms such as yeast, and there has been no report on the method of giving a fungicidal and/or bactericidal effect on microorganisms over a wide range as disclosed in the present invention. As for the cell membrane, it is pointed out that the interaction with an organic ingredient in the cell membrane of microorganism as an objective of control by iturin is very important. However, a fungicidal and/or bactericidal composition and sterilization method has not been known yet which surely enables the fungicidal and/or bactericidal activity of iturin completely independent of the cell membrane ingredient, as in the fungicidal and/or bactericidal composition disclosed in the present invention, by previously introducing an amphipathic organic material having a hydrocarbon chain in addition to iturin and surfactin. With respect to microorganisms of producing iturin and surfactin, for example, U.S. Pat. No. 6,103,228 discloses Bacillus subtilis AQ713 strain and a variant strain thereof. Bacillus subtilis SD901 strain (FERM P-17989) disclosed in the present invention produces only surfactin and therefore, this strain itself cannot be expected to have fungicidal and/or bactericidal control. SD142 strain which is a Bacillus subtilis strain disclosed in JP-A-06-135811 was found before the filing of AQ713 (NRRL B-21661) and is a completely different Bacillus subtilis strain from AQ713. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 shows the volume change of liposome vesicle when the bactericidal composition of the present invention (iturin+surfactin+cholesterol) is allowed to act on a liposome prepared from soybean lecithin and the membrane permeability by the through hole formed in the liposome is measured using the stopped flow-light scattering method, compared with the volume change of a liposome alone. detailed-description description="Detailed Description" end="lead"? |
Hollow fiber membrane filters in various containers |
A water filter cooperable with a water container includes both a carbon composite filter (30) and a bundle of micro porous hollow fiber membranes (5) in fluid communication with the carbon composite filter (30). An influent side of the hollow fiber membrane (5) is continuously immersed in water whereby air is prevented from being reintroduced to the hollow fiber membrane (5). |
1. A water filter cooperable with a water container, the water filter comprising: a carbon composite filter; and a bundle of sub-micro porous hollow fiber membranes in fluid communication with said carbon composite filter, wherein the carbon composite filter and the hollow fiber bundle are arranged in the water container such that untreated water is first treated with the carbon composite filter and then directed to the hollow fiber bundle, and wherein an influent side of the hollow fiber bundle is continuously immersed in water whereby air is prevented from being re-introduced to the hollow fiber bundle from outside the water filter between inversions of the water container or when the water container is upright. 2. A water filter according to claim 1, further comprising an outer shroud housing the carbon composite filter and the hollow fiber bundle, the outer shroud having at least one water inlet port for untreated water and being formed of a material substantially impervious to water. 3. A water filter according to claim 2, wherein the shroud is configured to permit substantially total removal of water from the water container while retaining the water within the filtration elements. 4. A water filter according to claim 2, wherein the outer shroud is formed in multiple disassemblable pieces. 5. A water filter according to claim 2, wherein the outer shroud comprises exterior longitudinal grooves, and wherein the outer shroud is covered with a sheet of a plastic material defining water delivery tubes with said grooves, the water delivery tubes maintaining a water level within the outer shroud to preclude water from draining from the water filter and prevent entry of air therein. 6. A water filter according to claim 5, wherein one of the water delivery tubes extends a full length of the water filter and is sealed from water, the one tube serving as an air relief port through the water container. 7. A water filter according to claim 1, wherein the carbon composite filter and the hollow fiber bundle are arranged in a nesting configuration. 8. A water filter according to claim 1, wherein the hollow fiber bundle comprises a pore size between 0.1-0.3 micron. 9. A water filter according to claim 1, wherein the carbon composite filter is a composite monolithic block in a closed end cylinder configuration comprising activated carbon and binder. 10. A water filter according to claim 9, wherein the carbon composite filter further comprises zeolyte, ion exchange materials and polymer extractive material. 11. A water filter according to claim 9, wherein the carbon composite filter has an outer surface area of at least 9 in2. 12. A water filter according to claim 1, wherein the carbon composite filter and the hollow fiber bundle are independently interchangeable. 13. A water filter according to claim 1, wherein the hollow fiber bundle is between 2-3 inches in length and at least 1 inch in diameter containing at least about one square foot of available membrane treatment surface area. 14. A water filter according to claim 1, wherein the carbon composite filter and the hollow fiber bundle are arranged end to end. 15. A water filter according to claim 14, further comprising a single mount coupleable with the water container. 16. A water filter according to claim 1, further comprising a pre-filter disposed upstream of the carbon composite filter. 17. A water filter according to claim 16, wherein the pre-filter comprises woven and non-woven material or screen with a pore size of about 10 microns. 18. A water filter according to claim 17, wherein the pre-filter contains a densified carbon composite filter element with a pore size between about 10-20 microns. 19. A water filter according to claim 1, further comprising a chemical disinfecting automatic injector in fluid communication with the carbon composite filter and the hollow fiber bundle, the chemical disinfecting automatic injector including a chemical reservoir and a release mechanism. 20. A water filter according to claim 19, wherein the chemical disinfecting automatic injector is an independent component capable of being selectively attached and removed. 21. A water filter according to claim 20, wherein the chemical reservoir is refillable. 22. A water filter according to claim 20, wherein the chemical reservoir is permanently sealed. 23. A water filter according to claim 19, wherein the chemical reservoir is sized to contain multiple chemical doses comprising one of chlorine, iodine and derivatives thereof. 24. A water filter according to claim 19, wherein the release mechanism releases a predetermined chemical dosage. 25. A water filter according to claim 24, wherein the predetermined chemical dosage is selectively adjustable. 26. A water filter according to claim 24, wherein the release mechanism is engageable with the water container to effect release of the predetermined chemical dosage. 27. A filtration system for filtering water, the filtration system comprising: a water container; and a water filter cooperable with the water container, the water filter including: a carbon composite filter, and a bundle of micro porous hollow fiber membranes in fluid communication with said carbon composite filter, wherein the carbon composite filter and the hollow fiber bundle are arranged in the water container such that untreated water is first treated with the carbon composite filter and then directed to the hollow fiber bundle, and wherein an influent side of the hollow fiber bundle is continuously immersed in water whereby air is prevented from being re-introduced to the hollow fiber bundle from outside the water filter between inversions of the water container or when the water container is upright. 28. A filtration system according to claim 27, wherein the water container comprises a bottle and a bottle top, and wherein the water filter is operatively connectable between the bottle and the bottle top, and wherein the water filter extends into the bottle. 29. A filtration system according to claim 28, wherein the bottle top comprises a removable valve assembly. 30. A filtration system according to claim 27, wherein the water container comprises a bottle having an air relief valve, permitting water to be pressured into and through both the carbon composite filter and the hollow fiber bundle. 31. A filtration system according to claim 30, which utilizes an umbrella type silicon valve with a cracking pressure of between 0.5 and 3 psig depending upon application and container resilience. 32. A filtration system according to claim 27, wherein the carbon composite filter and the hollow fiber bundle are arranged end to end, and wherein the water filter comprises a single mount coupleable with the water container. 33. A filtration system according to claim 27, wherein the water container comprises a bottle having a neck, and wherein the water filter extends into the bottle entirely below the neck. 34. A filtration system according to claim 27, wherein the water container comprises a bottle and a bottle top, and wherein the water filter is secured to the bottle top via a secure waterproof connection. 35. A filtration system according to claim 27, wherein the water container comprises a durable plastic bottle. 36. A filtration system according to claim 27, wherein the water container comprises a multi-gallon crock-type container, and wherein the water filter is positioned in a bottom of the crock-type container such that water flows through the water filter by means of head pressure or siphon. 37. A filtration system according to claim 36, wherein the crock-type container is self-venting. 38. A filtration system according to claim 27, wherein the water container is a collapsible bottle or bladder comprising a water valve, and wherein the water filter is coupled with the water valve via a drinking tube. 39. A filtration system according to claim 38, wherein an adapter of the drinking tube secures the water filter within a neck of the collapsible bottle or bladder. 40. A filtration system according to claim 27, wherein the water container is a bottle having a 28-35 mm neck bottle cap with an air relief valve, and wherein the carbon composite filter and the hollow fiber bundle are mounted in a single housing. 41. A filtration system according to claim 27, wherein the water filter is mountable inside the water container and further comprises a chemical disinfecting automatic injector in fluid communication with the carbon composite filter and the hollow fiber bundle, the chemical disinfecting automatic injector including a chemical reservoir and a release mechanism, wherein the release mechanism is actuated to discharge a chemical dosage upon insertion of the water filter in the water container. 42. A filtration system according to claim 27, wherein the water container is a canteen. 43. A dual component water filter comprising a hollow fiber membrane bundle and a screen pre-filter, the hollow fiber membrane bundle and the screen pre-filter being contained within a single housing, wherein the housing retains water within the hollow fiber membrane bundle and the screen pre-filter. 44. A dual component water filter according to claim 43, wherein the housing is shrink-wrapped with a plastic film. 45. A dual filter element comprising a sub-micron internal filter nested within a carbon composite outer filter shell, the sub-micron internal filter and the carbon composite outer shell both being of a radial flow design. 46. A dual filter element according to claim 45, further comprising a straw extending substantially 90 degrees to an axis of the filter element. 47. A dual filter element according to claim 46, wherein the straw is bendable at 90 degrees to facilitate placement within a container having an opening diameter that is sufficiently large to permit insertion of the filter element axially. 48. A dual filter element according to claim 46, wherein the filter element is configured for removal from a narrow necked container by means of a lanyard attached to the straw, an end of the filter providing for ease of removal upon stripping the straw from the filter element. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The need to treat water in an economical and convenient manner for biological contamination by people away from home, and as they travel, or simply conducting their daily activities has become more evident. While technology allowing filtration of microorganisms from drinking water in a squeezable “sports” bottle is available, a number of serious inadequacies limit the application of microbial filters in these bottles. For the removal of protozoan cysts from water, an effective pore size between 1 and 3 microns in the filtration medium is recommended, while for retention of bacteria particles an order of magnitude smaller must be excluded. Filtration media possessing the capability to exclude particles in this size range is relatively dense, inhibiting the flow of water through the media as well as the material to be filtered out. The apparent dilemma in designing small filters that are effective at removing bacteria in particular, and cysts is that the pressure drop per unit surface area is large while the available surface area is small. One approach to alleviating this restriction is to loosen the pore sizes of the filter to allow particles to be deposited throughout the depth of a bed of media. As the flow path of the water is designed to be torturous, the hope is that weak surface interactions such as van der Waals forces will trap the particles somewhere along the surfaces of the flow paths before they are flushed from the bed. This technology is less desirable from a reliability standpoint than techniques that mechanically screen the particles from the water. Monolithic filters, such as carbon blocks, employ the depth and tortuous path filtration mechanism for particles. They must use this method because filtering out material onto the surface of such structures would result in low capacities due to the pressure required and the small amount of surface area available. Reducing the pore size in these blocks would grossly enhance fouling, and substantially increase the pressure required to achieve a particular flow rate. Another approach to providing for more surface area within a small volume is to employ hollow fiber membranes as the filtration media for size exclusion. The large surface to volume ratio of the hollow fibers greatly increases the area available for contact with the bulk fluid phase. But even with the application of hollow fiber membrane bundles, the pressure drop across a filter capable of being deployed as a portable bottle filter is substantial. For hollow fiber bundles of the approximate dimensions 7.3 Cm in length and 3 Cm in diameter, such as that produced by Spectrum Laboratories, the flow rate through the bundle under pressures capable of being effectively supplied by hand squeezing is fairly low. At an applied pressure of 10 psig, the initial flow rate through such a bundle is around 12 to 35 ml per second. Any blockage or other restriction to the flow of water through the membrane bundles results in even slower flow rates; possibly low enough to no longer be acceptable in actual usage. An unfortunate problem in the use of hollow fiber membrane bundles in sport bottle applications is that if air accumulates inside the bundle housing between uses, a large percentage of the bottle squeeze must be used to expel air from the filter. Because the air vents by flowing through some of the fiber bundles, while the air is venting the flow of water exiting the filter is lessened. Testing has shown that it may take several minutes of continuous flow to fully purge the filter of air. As the acceptability of the liquid flow rate is already marginal under normal use conditions, any reduction in flow results in a significant decrease in performance. Another problem that may be encountered if air is allowed back into the membrane is with entrapped air causing actual membrane blockage. The hollow fiber bundle referenced by Shimizu in U.S. Pat. No. 5,681,463 suffers from both problems as water will drain from the fiber bundle housing as the bottle is returned to an upright position. |
<SOH> BRIEF SUMMARY OF THE INVENTION <EOH>The present invention eliminates the problem of reintroduction of air into the bundle housing between uses preferably by enclosing the axially joined filter elements (the hollow fiber bundle and carbon elements) within an impervious shroud that maintains the water level in contact with the hollow fibers. Thus, between uses, the water within the hollow fiber housing is not allowed to drain, preventing the accumulation of additional air that must be voided for full efficiency. This same approach has been employed in other designs disclosed in this application to preclude the water from draining from the hollow fiber membrane filter. A second method that may be used when the water intake is at the base of the housing and the filter is positioned at the base of a water bottle or canteen is to employ a one-way valve which will not permit the water to drain back into the bottle or container. In an exemplary embodiment of the invention, a water filter is cooperable with a water container. The water filter includes a carbon composite filter and a bundle of sub-micro porous hollow fiber membranes in fluid communication with the carbon composite filter. The carbon composite filter and the hollow fiber bundle are arranged in the water container such that untreated water is first treated with the carbon composite filter and then directed to the hollow fiber bundle. An influent side of the hollow fiber bundle is continuously immersed in water, whereby air is prevented from being re-introduced to the hollow fiber bundle from outside the water filter between inversions of the water container or when the water container is upright. In another exemplary embodiment of the invention, a filtration system for filtering water includes a water container and the water filter according to the present invention. In still another exemplary embodiment of the invention, a dual component water filter includes a hollow fiber membrane bundle and a screen pre-filter. The hollow fiber membrane bundle and the screen pre-filter are contained within a single housing, wherein the housing retains water within the hollow fiber membrane bundle and the screen pre-filter. |
Cooling device |
A cooling apparatus comprises a pulse tube refrigerator (A) having a pressure source (1), a cold reservoir (6), a condenser (7), a pulse tube (9), a radiator (1), and a phase adjuster (12); and a low-temperature container having a liquid reservoir (21) fixed to a vacuum tank (31) through heat-insulating support members (36) and (37). The condenser (7) is fixed to a cold end (6b) of the cold reservoir (6), and is disposed in a gas phase portion (21a) of the liquid reservoir (21). A hot end of the pulse tube (9) is fixed to the vacuum tank (31) and is disposed in such a manner that a cold end (9b) of the pulse tube (9) is located lower than the hot end and is located in a liquid phase portion (21b) of the liquid reservoir (21). The cold end (9b) of the pulse tube (9) is disposed outside the liquid reservoir (21) but within the vacuum tank (31), and the cold end (9b) of the pulse tube (9) and the condenser (7) communicate with each other through piping (8). |
1. A cooling apparatus comprising a pulse tube refrigerator including a cold reservoir, a condenser, and a pulse tube; and a low-temperature container having a liquid reservoir fixed to a vacuum tank through heat-insulating support members, wherein said condenser is fixed to a cold end of said cold reservoir and is disposed in a gas phase portion of said liquid reservoir; and a cold end of said pulse tube is disposed to be located lower than a hot end of said pulse tube and to be located in a portion corresponding to a liquid phase portion of said liquid reservoir. 2. A cooling apparatus according to claim 1, wherein said pulse tube refrigerator comprises a pressure source, a radiator, and a phase adjuster; a high-temperature-side portion of said pulse tube is fixed to said vacuum tank; a low-temperature-side portion of said pulse tube is disposed within said vacuum tank outside said liquid reservoir; and said cold end of said pulse tube and said condenser is connected together through piping. 3. A cooling apparatus according to claim 2, wherein said cold end of said pulse tube is located in a liquid phase portion of said liquid reservoir. 4. A cooling apparatus according to claim 2, wherein said cold end of said pulse tube is located within said vacuum tank outside said liquid reservoir. 5. A cooling apparatus according to claim 3 or 4, wherein said cold reservoir is disposed to extend vertically in such a manner that said cold reservoir penetrates respective walls of said vacuum tank and said container. 6. A cooling apparatus according to claim 3 or 4, wherein said cold reservoir is disposed to extend horizontally in such a manner that said cold reservoir penetrates respective walls of said vacuum tank and said container. 7. A cooling apparatus according to claim 4, wherein said cold end of said pulse tube is located within said vacuum tank inside a container which forms said liquid reservoir. 8. A cooling apparatus according to claim 4, wherein said cold end of said pulse tube is located within said vacuum tank outside a container which forms said liquid reservoir. |
<SOH> BACKGROUND ART <EOH>A convention cooling apparatus (Japanese Patent Application Laid-Open (kokai) No. 2000-161803) is constructed as shown in FIG. 9 . A superconductive magnet 101 cooled by means of a first refrigerant 103 a such as liquid helium is accommodated within a vessel 102 . The vessel 102 is fixed to a vacuum tank 107 via a large number of heat insulating support members 104 , a shield plate 105 , and a large number of heat insulating support members 106 . Vapor of the first refrigerant 103 a such as liquid helium is condensed to liquid by means of a first cooling unit 110 . A second cooling unit 250 includes a refrigerant circulation circuit 250 A and a pulse tube refrigerator 250 B. The refrigerant circulation circuit 250 A consists of a liquid reservoir 251 fixed to the vacuum chamber 107 through a large number of heat insulating support members 254 and storing a second refrigerant liquid 253 a 1 such as liquid nitrogen; and a conduit 252 receiving the second refrigerant liquid 253 a 1 within the liquid reservoir 251 , being in thermal contact with the shield plate 105 , and returning to a second refrigerant gas phase portion 253 b of the liquid reservoir 251 . The pulse tube refrigerator 250 B consists of a compressor 250 B 1 and a second low-temperature generating section 250 B 2 . High-pressure piping 264 of the second low-temperature generating section 250 B 2 communicates with high-pressure ports of rotary changeover valves 253 a and 253 b connected to a drive section 274 . Low-pressure piping 263 of the second low-temperature generating section 250 B 2 communicates with low-pressure ports of the rotary changeover valves 253 a and 253 b. Communication ports of the rotary changeover valves 253 a and 253 b communicate with a cold reservoir 255 and an atmospheric-temperature-side throttle 260 , respectively. A condenser 256 a is provided on a low-temperature side of the cold reservoir 255 . The condenser 256 a communicates with a condenser 256 b provided on a low-temperature side of a pulse tube 258 via a conduit 257 . An atmospheric-temperature side of the pulse tube 258 communicates with the throttle 260 via a radiator 259 . The high-pressure piping 264 and the low-pressure piping 263 of the second low-temperature generating section 250 B are connected to the compressor 250 B 1 through high-pressure piping 262 and low-pressure piping 261 , respectively. In the above-described cooling apparatus, the pulse tube and the cold reservoir are of substantially the same length. However, when a low temperature to be generated is about 100 K or lower, efficiency lowers unless the length of the pulse tube is at least about three times the length of the cold reservoir. When the length of the pulse tube is set to at least about three times the length of the cold reservoir in order to improve efficiency, a portion of the pulse tube, from the cold end to a point near the midpoint, is immersed in the second refrigerant. As a result, heat is conducted from the pulse tube to refrigerant, accompanied by occurrence of a problem of a lowered rate of condensation of refrigerant vapor. Moreover, when the cold end of the pulse tube is positioned in the second refrigerant gas phase portion, the pulse tube projects from the vacuum tank by a greater amount as compared with the cold reservoir, accompanied by occurrence of a problem of an increased occupation space of the cooling apparatus. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a circuit diagram showing the cooling apparatus of the first embodiment according to the present invention. FIG. 2 is a circuit diagram showing the cooling apparatus of the second embodiment according to the present invention. FIG. 3 is a circuit diagram showing the cooling apparatus of the third embodiment according to the present invention. FIG. 4 is a circuit diagram showing the cooling apparatus of the fourth embodiment according to the present invention. FIG. 5 is a circuit diagram showing the cooling apparatus of the fifth embodiment according to the present invention. FIG. 6 is a circuit diagram showing the cooling apparatus of the sixth embodiment according to the present invention. FIG. 7 is a cross section diagram taken along X-X in FIG. 6 showing the cooling apparatus of the sixth embodiment. FIG. 8 is a circuit diagram showing four concrete examples of the phase adjuster which may be used in the embodiments of the present invention. FIG. 9 is a circuit diagram showing a conventional cooling apparatus. detailed-description description="Detailed Description" end="lead"? |
Pulse tube refrigerating machine |
A pulse tube refrigerating machine, comprising a pulse tube (11) connected to a regenerator (9) and having a hot end part (11a) being heated, in which a cooling device (30), for cooling the hot side tube wall (11cd) of the pulse tube by cooling medium lower in temperature than the hot side tube wall of the pulse tube, cools the hot side tube wall (11cd) of the pulse tube by coolant flowing from the pressure source (1) of the pulse tube refrigerating machine into the regenerator (9). |
1. A pulse tube refrigerator comprising a pulse tube connected to a cold reservoir and having a hot end that generates heat, further comprising: cooling means for cooling a high-temperature-side portion of said wall of said pulse tube by use of cooling medium which is lower in temperature than said high-temperature-side portion of said wall of said pulse tube. 2. A pulse tube refrigerator according to claim 1, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant of said pulse tube refrigerator. 3. A pulse tube refrigerator according to claim 1, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of atmospheric air. 4. A pulse tube refrigerator according to claim 2, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant which flows out of a pressure source and flows into said cold reservoir. 5. A pulse tube refrigerator according to claim 2, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant which flows between a discharge port of a pressure source and a high-pressure inlet port of a changeover valve communicating with said discharge port of said pressure source. 6. A pulse tube refrigerator according to claim 2, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant which flows out of said cold reservoir and flows into a pressure source. 7. A pulse tube refrigerator according to claim 2, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant which flows between a low-pressure outlet port of a changeover valve and a suction port of a pressure source. 8. A pulse tube refrigerator according to claim 2, wherein said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant from a compressor provided separately. 9. A pulse tube refrigerator according to claim 2, wherein said cooling means cools a heat radiating unit disposed at said hot end of said pulse tube, by use of refrigerant which flows between a discharge side of a pressure source and a high-pressure inlet port of a changeover valve communicating with said discharge side of said pressure source. 10. A pulse tube refrigerator according to claim 2, wherein said cooling means cools a heat radiating unit disposed at said hot end of said pulse tube, by use of refrigerant which flows between a suction port of a pressure source and a low-pressure outlet port of a changeover valve communicating with said suction port of said pressure source. 11. A pulse tube refrigerator according to claim 2, wherein a radiator is provided between a suction port of a pressure source and a low-pressure outlet port of a changeover valve communicating with said suction port of said pressure source; said cooling means cools said high-temperature-side portion of said wall of said pulse tube by use of refrigerant flowing out of said low-pressure outlet port of said changeover valve; and said refrigerant used to cool said high-temperature-side portion of said wall of said pulse tube is cooled by use of said radiator. 12. A pulse tube refrigerator according to claim 2, wherein a radiator is provided between a suction port of a pressure source and a low-pressure outlet port of a changeover valve communicating with said suction port of said pressure source; said cooling means cools a heat radiating unit disposed at said hot end of said pulse tube by use of refrigerant flowing out of said low-pressure outlet port of said changeover valve; and said refrigerant used to cool said heat radiating unit is cooled by use of the radiator. 13. A pulse tube refrigerator according to claim 3, wherein said cooling means is constituted by a high-temperature-side portion of said wall of said pulse tube disposed in the atmosphere. 14. A pulse tube refrigerator according to claim 13, wherein fins are provided on an outer circumferential surface of said high-temperature-side portion of said wall of said pulse tube disposed in the atmosphere. 15. A pulse tube refrigerator according to claim 13, wherein air is forcedly supplied to said high-temperature-side portion of said wall of said pulse tube. 16. A pulse tube refrigerator according to claim 13, wherein said high-temperature-side portion of said wall of said pulse tube disposed in the atmosphere is formed of a member having good heat conduction; a low-temperature-side portion of said wall of said pulse tube disposed within a vacuum tank is formed of a member having poor heat conduction; and said high-temperature-side portion and said low-temperature-side portion are joined together. 17. A pulse tube refrigerator according to claim 13, wherein one end of a conducting member is disposed in thermal contact with said high-temperature-side portion of said wall of the pulse tube, and the other end of said conducting member is disposed in thermal contact with a cooling source which is lower in temperature than said high-temperature-side portion of said wall of said pulse tube. 18. A pulse tube refrigerator according to claim 17, wherein said cooling source is formed of a vacuum tank of said refrigerator. 19. A pulse tube refrigerator according to claim 14, wherein air is forcedly supplied to said high-temperature-side portion of said wall of said pulse tube. |
<SOH> BACKGROUND ART <EOH>A conventional pulse tube refrigerator (Japanese Patent Application Laid-Open (kokai) No. 8-271071) is constructed as shown in FIG. 14 . A high-pressure port 108 a of a pressure vibration source 101 is connected to a main changeover valve 111 , and a port 111 h of the main changeover valve 111 communicates with a cold reservoir 103 , a heat absorber 104 , and a pulse tube 105 via a heat radiating unit passage 112 . A hot end 105 c of the pulse tube 105 is connected, through flow-rate adjustment means 122 , to a first heat transfer tube 116 having a tubular shape and a port 106 p of a phase adjustment changeover valve 106 . The phase adjustment changeover valve 106 is connected to the high-pressure port 108 a and a low-pressure port 108 b of the pressure vibration source 101 . In the above conventional pulse tube refrigerator, when refrigerant flows from the phase adjustment changeover valve 106 into the hot end 105 c of the pulse tube 105 via the flow-rate adjustment means 122 , the refrigerant undergoes adiabatic compression, whereby the gas temperature within the pulse tube increases, and the wall temperature of the pulse tube 105 elevates to about 120° C. in a range extending from the hot end 105 c of the pulse tube 105 to a longitudinally central portion of the pulse tube. Accordingly, the above conventional pulse tube refrigerator has a problem in that heat of the hot gas within the pulse tube 105 and heat of the wall of the pulse tube 105 are conducted to a cold end of the pulse tube 105 , to thereby lower refrigeration capacity. Moreover, since a heat radiating unit 102 of a heat exchange unit A is interposed between the main changeover valve 111 and the cold reservoir 103 , the above conventional pulse tube refrigerator has a problem in that the free gas space increases, thereby decreasing the refrigeration capacity of the refrigerator. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a circuit diagram showing the pulse tube refrigerator of the first embodiment according to the present invention. FIG. 2 is a circuit diagram showing the pulse tube refrigerator of the second embodiment according to the present invention. FIG. 3 is a circuit diagram showing the pulse tube refrigerator of the third embodiment according to the present invention. FIG. 4 is a circuit diagram showing the pulse tube refrigerator of the fourth embodiment according to the present invention. FIG. 5 is a circuit diagram showing the pulse tube refrigerator of the fifth embodiment according to the present invention. FIG. 6 is PV diagrams at the low temperature and high-temperature sides, respectively, of the pulse tube according to the embodiment of the present invention. FIG. 7 is a circuit diagram showing the pulse tube refrigerator of the sixth embodiment according to the present invention. FIG. 8 is a circuit diagram showing the pulse tube refrigerator of the seventh embodiment according to the present invention. FIG. 9 is a circuit diagram showing the pulse tube refrigerator of the eighth embodiment according to the present invention. FIG. 10 is a circuit diagram showing the pulse tube refrigerator of the ninth embodiment according to the present invention. FIG. 11 is a circuit diagram showing the pulse tube refrigerator of the tenth embodiment according to the present invention. FIG. 12 is a circuit diagram showing the pulse tube refrigerator of the eleventh embodiment according to the present invention. FIG. 13 is a circuit diagram showing four concrete examples of the phase adjuster of the embodiment according to the present invention. FIG. 14 is a circuit diagram showing a conventional pulse tube refrigerator. detailed-description description="Detailed Description" end="lead"? |
Gel matrix consisting of polyacrylic acid and polyvinyl pyrrolidone |
A self-adhesive polyacrylic acid-based gel matrix. The gel matrix comprises a homopolymer and/or copolymer of vinyl pyrrolidone as crosslinker for the polyacrylic acid. |
1-19. (canceled) 20. A self-adhesive polyacrylic acid-based gel matrix, wherein the gel matrix comprises at least one of a homopolymer and a copolymer of vinyl pyrrolidone as a crosslinker of the polyacrylic acid. 21. The gel matrix of claim 20, wherein the polyacrylic acid comprises an acrylates/alkyl acrylate copolymer. 22. The gel matrix of claim 20, wherein the at least one of a homopolymer and a copolymer of vinyl pyrrolidone is present as a mixture of polymers of different average molecular weights. 23. The gel matrix of claim 20, wherein the at least one of a homopolymer and a copolymer of vinyl pyrrolidone comprises at least one polymer having an average molecular weight in a range of from 2,500 to 700,000 g/mol. 24. The gel matrix of claim 20, wherein the gel matrix comprises from 5% to 55% by weight of at least one of a homopolymer and a copolymer of acrylic acid. 25. The gel matrix of claim 24, wherein the gel matrix comprises up to 30% by weight of the at least one of a homopolymer and a copolymer of acrylic acid. 26. The gel matrix of claim 20, wherein the gel matrix comprises from 0.25% to 60% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone. 27. The gel matrix of claim 26, wherein the gel matrix comprises from 1% to 30% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone. 28. The gel matrix of claim 20, wherein the gel matrix comprises from 5% to 30% by weight of at least one of a homopolymer and a copolymer of acrylic acid, and from 1% to 30% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone. 29. The gel matrix of claim 20, wherein the gel matrix further comprises at least one polyalcohol. 30. The gel matrix of claim 29, wherein the gel matrix comprises at least one of propanediol, polyethylene glycol and glycerol. 31. The gel matrix of claim 29, wherein the at least one polyalcohol is present in a concentration of from 5% to 90% by weight. 32. The gel matrix of claim 31, wherein the concentration is up to 45% by weight. 33. The gel matrix of claim 20, wherein the gel matrix further comprises at least one of a protic solvent, an organic proton donor and a Lewis acid. 34. The gel matrix of claim 33, wherein the gel matrix comprises at least one of water, an alcohol, an amine and a thiol. 35. The gel matrix of claim 33, wherein the gel matrix comprises salicylic acid. 36. The gel matrix of claim 20, wherein the gel matrix is doped with a hydrophilic active ingredient. 37. The gel matrix of claim 20, wherein the gel matrix is doped with a combination of a hydrophobic active ingredient and a solubilizer. 38. The gel matrix of claim 20, wherein the gel matrix is doped with at least one of dexpanthenol, jojoba oil, salicylic acid, benzyl nicotinate, glycol salicylate, menthol, peppermint oil, ibuprofen, tea tree oil, urea, vitamin A palmitate, capsicum extract, clotrimazole and lidocaine HCI. 39. The gel matrix of claim 20, which further comprises at least one of a plasticizer, a solubilizer, a penetration enhancer and a filler. 40. The gel matrix of claim 20, which comprises from 5% to 30% by weight of at least one of a homopolymer and a copolymer of acrylic acid, from 1% to 30% by weight of at least one of a homopolymer and a copolymer of vinyl pyrrolidone and from 5% to 45% by weight of at least one polyalcohol. 41. The gel matrix of claim 40, wherein the polyalcohol comprises at least one of propanediol, polyethylene glycol and glycerol. 42. The gel matrix of claim 41, wherein the gel matrix further comprises at least one of water, an alcohol, an amine and a thiol. 43. The gel matrix of claim 42, wherein the gel matrix is doped with at least one of a hydrophilic active ingredient and a combination of a hydrophobic active ingredient and a solubilizer. 44. The gel matrix of claim 41, wherein the gel matrix is doped with at least one of dexpanthenol,jojoba oil, salicylic acid, benzyl nicotinate, glycol salicylate, menthol, peppermint oil, ibuprofen, tea tree oil, urea, vitamin A palmitate, capsicum extract, clotrimazole and lidocaine HCI. 45. A transdermal system which comprises the gel matrix of claim 20. 46. The transdermal system of claim 45, wherein the transdermal system comprises a patch. 47. The transdermal system of claim 46, wherein the patch comprises a backing for the gel matrix and at least one of a covering film, a covering paper and a release paper. 48. A medical fixing which comprises the gel matrix of claim 20. 49. A wound covering which comprises the gel matrix of claim 20. 50. An orthopedic or phlebologic bandage which comprises the gel matrix of claim 20. 51. A dressing which comprises the gel matrix of claim 20. 52. A method for the cosmetic or medical treatment of skin, wherein the method comprises applying to at least parts of the skin the gel matrix of claim 20. 53. A method of controlling at least one of the viscosity and adhesiveness of a self-adhesive polyacrylic acid-based gel matrix, wherein the method comprises combining the gel matrix with at least one of a homopolymer and a copolymer of vinyl pyrrolidone as a crosslinker for the polyacrylic acid. 54. The method of claim 53, wherein the at least one of the viscosity and adhesiveness are controlled by an amount of the vinyl pyrrolidone polymer. 55. The method of claim 53, wherein the at least one of the viscosity and adhesiveness are controlled by an average molecular weight of the vinyl pyrrolidone polymer. 56. A process for producing a self-adhesive polyacrylic acid-based gel matrix, which process comprises mixing at least one of a homopolymer and a copolymer of acrylic acid with at least one of a homopolymer and a copolymer of vinyl pyrrolidone to crosslink the acrylic acid polymer. 57. The process of claim 56, wherein from 5% to 55% by weight of the at least one of a homopolymer and a copolymer of acrylic acid are employed. 58. The process of claim 57, wherein up to 30% by weight of the at least one of a homopolymer and a copolymer of acrylic acid are employed. 59. The process of claim 56, wherein from 0.25% to 60% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone are employed. 60. The process of claim 58, wherein from 1% to 30% by weight of the at least one of a homopolymer and a copolymer of vinyl pyrrolidone are employed. 61. The process of claim 56, wherein further at least one of a polyalcohol and water is employed. 62. The process of claim 61, wherein the polyalcohol comprises at least one of propanediol, polyethylene glycol and glycerol. 63. The process of claim 61, wherein the at least one of a polyalcohol and water is employed in an amount of from 5% to 90% by weight. 64. The process of claim 63, wherein the amount is up to 45% by weight. 65. The process of claim 56, wherein further at least one of a hydrophilic active ingredient and a combination of a hydrophobic active ingredient and a solubilizer is employed. |
Process for producing photochromic layered product |
A method of producing a laminate comprising preparing a substrate having curved surfaces; applying a photpolymerizable and curable composition containing a photochromic compound and a phosphorus-containing photopolymerization initiator onto the curved surfaces of the base member; and curing the photopolymerizable and curable composition by the irradiation with an active energy ray having a relative intensity profile of 0 to 5% of wavelength components of not shorter than 200 nm but shorter than 300 nm, 25 to 75% of wavelength components of not shorter than 300 nm but shorter than 400 nm and 25 to 75% of wavelength components of not shorter than 400 nm but not longer than 500 nm while maintaining the substrate at not higher than 100° C. This method makes it possible to form a homogeneous and thin film containing a photochromic compound at a high concentration and having a uniform thickness on the substrate having a curved surface, such as a spectacle lens that is generally available, and to impart photochromic properties while maintaining excellent mechanical and optical properties of the substrate. |
1. A method of producing a laminate comprising: preparing a substrate having curved surfaces; applying a photpolymerizable and curable composition containing a photochromic compound and a phosphorus-containing photopolymerization initiator onto the curved surfaces of said base member; and curing said photopolymerizable and curable composition by the irradiation with an active energy ray having a relative intensity profile of 25 to 75% of wavelength components of not shorter than 400 nm but not longer than 500 nm, 25 to 75% of wavelength components of not shorter than 300 nm but shorter than 400 nm, and 0 to 5% of wavelength components of not shorter than 200 nm but shorter than 300 nm while maintaining said substrate at not higher than 100° C. 2. A method of producing a laminate according to claim 1, wherein said photopolymerizable and curable composition comprises (A) a radically polymerizable monomer, (B) a photochromic compound and (C) a photopolymerization initiator component, wherein said photochromic compound (B) is contained in an amount of 0.2 to 20% by weight, and a phosphorus-containing polymerization initiator is contained as the photopolymerization initiator component (C) in an amount of 0.01 to 10 parts by weight per 100 parts by weight of the radically polymerizable monomer (A). 3. A method of producing a laminate according to claim 2, wherein said photopolymerizable and curable composition further contains, as the photopolymerization initiator component (C), photopolymerization initiators other than the phosphorus-containing photopolymerization initiator in an amount of 0.01 to 10 parts by weight per 100 parts by weight of the radically polymerizable monomer (A). 4. A production method according to claim 1, wherein said polymerizable and curable composition is cured in a gaseous atmosphere. 5. A production method according to claim 1, wherein said photopolymerizable and curable composition is irradiated with active energy rays containing ultraviolet rays through a filter that reduces the wavelength components of shorter than 300 nm. 6. A production method according to claim 5, wherein a hard soda glass is used as said filter. 7. A production method according to claim 5, wherein said photopolymerizable and curable composition is irradiated with active energy rays containing ultraviolet rays through said filter and, then, through a heat ray cut filter. 8. A production method according to claim 1, wherein said substrate is a thin substrate having a thickness of not larger than 2 mm at the center of curvature of said curved surface. 9. A production method according to claim 1, wherein a spin-coating method is employed to coat the curved surface of the substrate with the photopolymerizable and curable composition that contains the photochromic compound and the phosphorus-containing photopolymerization initiator, and a liquid pool of said photopolymerizable and curable composition staying on the peripheral edge portion of the substrate is removed during the spin-coating operation. 10. A photopolymerizable and curable composition comprising (A) a radically polymerizable monomer, (B) a photochromic compound and (C) a photopolymerization initiator component, wherein said photochromic compound (B) is contained in an amount of 0.2 to 20% by weight, and the photopolymerization initiator component (C) contained therein comprises a phosphorus-containing polymerization initiator in an amount of 0.01 to 10 parts by weight and photopolymerization initiators other than the phosphorus-containing photopolymerization initiator in an amount of 0.01 to 10 parts by weight per 100 parts by weight of the radically polymerizable monomer (A). 11. A laminate comprising a substrate having curved surfaces, and a high molecular film having a thickness of 1 to 100 μm formed on the curved surfaces of the substrate and containing 0.2 to 20% by weight of a photochromic compound, wherein a difference between a spherical refractive power on the curved surface of the substrate of before said high molecular film layer is laminated and a spherical refractive power on the curved surface on where is formed said high molecular film layer of said laminate is smaller than ±0.5 diopters, and a difference between a maximum film thickness or a minimum film thickness of the region of said high molecular film layer except the peripheral edge portions and an average film thickness is not larger than 7%. 12. A laminate according to claim 11, wherein said substrate is a thin optical member having a thickness of not larger than 2 mm at the center of curvature on the curved surface of said substrate. 13. A laminate according to claim 11, wherein said substrate is a plastic lens. |
<SOH> BACKGROUND ART <EOH>Photochromism is a reversible action of a compound which quickly changes its color when it is irradiated with light containing ultraviolet rays such as sunlight or light of a mercury lamp and resumes its initial color when it is no longer irradiated with light and is placed in a dark place, and has been applied for a variety of uses. For example, photochromism has been applied in a field of spectacle lenses, too, and plastic lenses having photochromic properties are obtained by curing polymerizable monomers to which have been added various photochromic compounds having the above-mentioned properties. As photochromic compounds that can be favorably used for such applications, there have been used fulgimide compounds, spirooxazine compounds and chromene compounds. To produce plastic lenses having photochromic properties, there have been proposed: {circle around (1)} a method (imbibition method) of imbibing the surface of a lens (without photochromic property) with a photochromic compound; {circle around (2)} a method (in mass method) of directly obtaining a photochromic lens by dissolving a photochromic compound in a monomer which is, then, polymerized; and {circle around (3)} a method (coating method) of forming a layer having photochromic properties on the surfaces of a lens. To obtain favorable photochromic properties by the above imbibition method {circle around (1)} or the in mass method {circle around (2)}, however, the substrates of lenses must be so designed that favorable photochromic properties are exhibited, and limitation is imposed on the substrates for lenses that can be used. For example, it is contrived to lower the glass transition temperature (Tg) of the substrate of lenses based on such a design policy that the molecules of the photochromic compound are permitted to easily move even in high molecules, or free spaces in the high molecules are expanded so that the molecules of the photochromic compounds are allowed to easily move. As a monomer for forming a substrate of lenses, for example, U.S. Pat. No. 5,739,243 teaches use of a particular long-chain alkylene glycol dimethacrylate in combination with a polyfunctional methacrylate having three or more radically polymerizable groups. This method makes it possible to obtain a photochromic lens having relatively excellent color density and fading rate. According to this method, however, the glass transition temperature Tg of the substrate is lowered to improve photochromic properties and to improve properties of the substrate for being imbibed with a photochromic compound. As a result, the substrate becomes too soft newly arousing such problems as a decrease in the hardness of the substrate, a decrease in the heat resistance and large optical strain. The above problem can be solved by contriving a monomer and a photochromic material for obtaining a substrate of plastic lenses (see, for example, PCT International Patent Publication 01/05854). So far as the above method {circle around (1)} or {circle around (2)} is employed, however, some limitations are inevitably imposed on the substrate. According to the above coating method {circle around (3)}, on the other hand, it is allowed to impart photochromic properties to the substrate of lenses that has been generally used without any limitation. When the coating method is employed, however, a technology has not yet been established for forming a coating film having a small and homogeneous thickness that will not adversely affect the properties of the substrate, having a sufficiently high surface hardness and, further, having good photochromic properties. For example, WO98/37115 is proposing a method of coating the surfaces of a lens with a coating solution obtained by dissolving a photochromic compound in an urethane oligomer, followed by curing. However, a resin obtained by curing the urethane oligomer has a low crosslinking density causing the photochromic property to vary to a large extent depending upon the temperature and, further, involving such a defect that a photochromic compound elutes into the solution of a hard coating material when the hard coating material is being applied onto the photochromic coating layer. U.S. Pat. No. 5,914,174 proposes a method of obtaining a photochromic lens having a high molecular photochromic film laminated on the convex surfaces of a general lens by dissolving a photochromic compound in a polymerizable composition containing monofunctional, bifunctional and polyfunctional radically polymerizable monomers, flowing the polymerizable composition into a cavity between a plastic lens and a glass mold held by an elastomer gasket or a spacer, and polymerizing the polymerizable composition. According to this method, however, the thickness of the obtained photochromic high molecular film (coating) becomes as large as 200 to 500 μm, and the strength of the high molecular film is reflected on the plastic lens. That is, the strength of the photochromic lens is low as compared to the strengths of general lenses without having a high molecular film. According to this method, further, it is difficult to maintain small and constant the cavity between the plastic lens and the glass mold and is, hence, difficult to form a high molecular film having a small and uniform thickness. This tendency becomes conspicuous particularly when the lens surfaces have a complex shape. Further WO01/02449 proposes a method of obtaining a photochromic lens having a photochromic high molecular film of a thickness of about 20 μm formed on the convex surfaces of a general lens by dissolving 5 to 10 parts by weight of a photochromic compound in a polymerizable composition of a combination of two or more kinds of bifunctional (meth)acrylic monomers, applying the polymerizable composition onto the convex surfaces of the lens by spin-coating, and photopolymerizing the lens that is applied by the substitution in a nitrogen atmosphere. According to this method, the surfaces of the lens are coated with a photochromic film that develops color sufficiently densely maintaining a thickness (about 20 μm) that will not adversely affect the properties of the substrate. However, the above publication is considering none of the uniformity of thickness or homogeneity of the coating film, or the optical properties of the obtained lenses. Generally, a photopolymerization initiator and a photochromic compound are both excited with ultraviolet rays. When light is irradiated under a condition where both of them are existing together, therefore, the photopolymerization initiator is little decomposed and the polymerization takes place difficultly. By using a polymerizable and curable composition containing a photochromic compound and a photopolymerization initiator, therefore, the present inventors have studied the effect of the film-forming conditions upon the coating film. As a result, there were found the following problems involved in the coating method. (i) When an extended period of time is spent by the polymerization, the surface of the substrate on where the film is to be formed loses flatness. When the lens has curved surfaces like spectacle lenses, the coating agent drips making it difficult to obtain a film having a uniform thickness. (ii) When the ultraviolet ray is continuously irradiated for extended periods of time under a condition where the polymerization is not taking place to a sufficient degree, the radical reaction is interrupted being affected by oxygen contained in very small amounts in the atmosphere despite the atmosphere is substituted with nitrogen. In particular, an unpolymerized layer is formed near the surface and a film having a sufficiently large surface hardness is not obtained. (iii) The irradiation with ultraviolet rays for extended periods of time in a state where the polymerization is not taking place to a sufficient degree causes the photochromic compound to be deteriorated due to photo oxidation. (iv) When irradiated with active energy rays containing intense ultraviolet rays to shorten the time of light irradiation while promoting the polymerization, the surface of the lens is heated at high temperatures at the time of curing (e.g., 120° C. or higher, or 200° C. or higher) being affected by the heat from the source of light and by infrared rays. When a substrate of plastic lenses having low heat resistance is used, therefore, the lens itself is thermally deformed. (v) A difference occurs in the contraction due to a difference in the polymerizing rate between the surface of the coating and the interior thereof, making it difficult to obtain a homogeneous high molecular film. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a view illustrating a method of applying a photopolymerizable composition that is suited for forming a photochromic coating of a thickness of, for example, not smaller than 10 μm on the curved surfaces of a substrate in the production method of the present invention; and FIG. 2 is a view illustrating a portion of FIG. 1 on an enlarged scale. detailed-description description="Detailed Description" end="lead"? |
Tibial resection guide |
A tibial resection guide for use in preparing a knee joint for implantation of a prosthesis, includes an alignment rod which can be positioned against the tibia, which can be fastened to the tibia towards its distal end, and which has a proximal slot formed in it extending substantially parallel to the axis of the alignment rod. A cutting block is provided at the proximal end of the alignment rod having a saw guide slot in it to guide a saw during resection of the patient's tibia. A guide pin can be fastened into the tibia, with the slot in the alignment rod being a sliding fit over the guide pin. The cutting block, or the alignment rod towards its proximal end, has fixation holes for receiving fixation pins, to fix the cutting block and the alignment rod against further movement relative to the guide pin. |
2. A tibial resection guide for use in preparing a knee joint for implantation of a prosthesis, which comprises: a. an alignment rod which can be positioned against the tibia, which can be fastened to the tibia towards its distal end, and which has a proximal slot formed in it extending substantially parallel to the axis of the alignment rod, b. a cutting block at the proximal end of the alignment rod having a saw guide slot in it to guide a saw during resection of the patient's tibia, c. a guide pin which can be fastened into the tibia, the slot in the alignment rod being a sliding fit over the guide pin, and the cutting block or the alignment rod towards its proximal end having fixation holes for receiving fixation pins, to fix the cutting block and the alignment rod against further movement relative to the guide pin. 3. A guide as claimed in claim 1, in which the alignment rod is constructed so that its length can be adjusted after it has been fastened to the tibia at or towards its distal end. 4. A guide as claimed in claim 1, which includes distal fixation bracket at or towards distal end of the alignment rod, which can engage the patient's leg to fasten the alignment rod relative to the tibia. 5. A guide as claimed in claim 3, which includes means for adjusting the location of the distal end of the alignment rod relative to the bracket. 6. A guide as claimed in claim 3, in which the bracket includes a member which extends generally perpendicularly to the alignment rod, and which provides a track on which the alignment rod can slide, to provide movement along a pre-determined path of the distal end of the alignment rod relative to the bracket. 7. A guide as claimed in claim 1, which includes a stylus component which can be fitted to the alignment rod at about its proximal end. 8. A guide as claimed in claim 1, in which the fixation holes are provided in the cutting block. |
17Afla,21-dihydroxypregnene esters as antiandrogenic agents |
17α,21-Dihydroxypregna-4,9-diene-3,20-dione and 17α,21-dihydroxypregna-4-ene-3,20-dione 17 and/or 21 esters of having remarkable antiandrogenic activity, and the processes for the preparation thereof. |
1. Compounds of formula (I) wherein: R1 and R2, which can be the same or different, are hydrogen or a C3-C18 acyl group, with the provisos that: at least one of R1 and R2 is different from hydrogen; when R1 is hydrogen, R2 is different from C3-C10 acyl; both R1 and R2 cannot be propionyl. 2. Compounds of formula (II) wherein: R1 and R2, which can be the same or different, are hydrogen or a C3-C18 acyl group, with the proviso that: at least one of R1 and R2 is different from hydrogen; as antiandrogenic drugs. 3. A compound as claimed in claim 2 wherein R1 is hydrogen and R2 is propionyl. 4. A compound as claimed in claim 2 wherein R1 and R2 are butanoyl. 5. A process for the preparation of compounds of formula (I) or (II) in which R1 and R2 are both acyl groups, which process comprises reacting the corresponding compounds, wherein R1 and R2 are hydrogen, with carboxylic acids anhydrides or active esters in inert solvents and at temperatures ranging from −5° C. to the reaction mixture boiling temperature. 6. A process for the preparation of the compounds of formula (I) or (II) in which one of R1 or R2 is hydrogen and the other is acyl, which process comprises: a) reaction of the corresponding compounds, wherein R1 and R2 are hydrogen, with C3-C18 carboxylic acids anhydrides or active esters or with allyloxycarbonyl chloride or isobutene in inert solvents and at temperatures ranging from −5° C. to the boiling temperature, to yield the corresponding compound in which R1 is isobutyl, allyloxycarbonyl or C3-C18 acyl; b) optional reaction of the compound from step a) with C3-C18 carboxylic acids anhydrides or active esters in inert solvents and at temperatures ranging from −5° C. to the reaction mixture boiling temperature; c) optional lysis of the 21-allyloxycarbonyl or 21-isobutyloxy group. 7. The use of the compounds of claim 1 for the preparation of medicaments with antiandrogenic activity, in particular for the topical or systemic treatment of acne, seborrhea, hirsutism, alopecia, mastodynia, prostate hyperplasia and carcinoma, virilization syndromes in the female, early puberty, inhibition of sexual aggressiveness in the male, contraception in the male. 8. Pharmaceutical compositions containing as active ingredient a compound of claim 1 in admixture with an acceptable carrier. |
<SOH> SUMMARY OF THE INVENTION <EOH>It has now been found that some 17α,21-dihydroxypregna-4,9-diene-3,20-dione and 17α,21-dihydroxypregna-4-ene-3,20-dione 17 and/or 21 esters have remarkable antiandrogenic activity. Therefore, according to a first embodiment, the present invention relates to compounds of formula (I) wherein: R 1 and R 2 , which can be the same or different, are hydrogen or a C 3 -C 18 acyl group, with the provisos that: at least one of R 1 and R 2 is different from hydrogen; when R 1 is hydrogen, R 2 is different from butyroyl. According to a second embodiment, the invention relates to compounds of formula (II) wherein: R 1 and R 2 , which can be the same or different, are hydrogen or a C 3 -C 18 acyl group, with the proviso that: at least one of R 1 and R 2 is different from hydrogen; as antiandrogenic drugs. According to a further embodiment, the invention relates to a process for the preparation of compounds of formula (I) or (II) in which R 1 and R 2 are both acyl groups, which process comprises reacting the corresponding compounds, wherein R 1 and R 2 are hydrogen, with carboxylic acids anhydrides or active esters in inert solvents and at temperatures ranging from −5° C. to the reaction mixture boiling temperature. Still a further object of the invention relates to a process for the preparation of compounds of formula (I) or (II) wherein one of R 1 or R 2 is hydrogen and the other is acyl, which process comprises: a. reaction of the corresponding compounds wherein R 1 and R 2 are hydrogen with C 3 -C 18 carboxylic acids anhydrides or active esters or with allyloxycarbonyl chloride or isobutene in inert solvents and at temperatures ranging from −5° C. to the boiling temperature, for obtaining the corresponding compound in which R 1 is isobutyl, allyloxycarbonyl or C 3 -C 18 acyl; b. optional reaction of the compound from step a) with C 3 -C 18 carboxylic acids anhydrides or active esters in inert solvents and at temperatures ranging from −5° C. to the reaction mixture boiling temperature; c. optional lysis of the 21-allyloxycarbonyl or 21-isobutyloxy group. Finally, the invention relates to pharmaceutical compositions with antiandrogenic activity containing as active ingredient the compounds of formula (I) or (II). detailed-description description="Detailed Description" end="lead"? |
Moldings of flurorubbers and process for their production |
Moldings of fluoro rubbers produced by crosslinking a tetrafluoroethylene/propylene copolymer or a tetrafluoroethylene/propylene/vinylidene fluoride copolymer, which have metal contents of 1.5% by mass or below in terms of metal elements and are suitable for use applications necessitating clean environment, for example, manufacturing or carrier equipment for semiconductors, manufacturing equipment, carriers, or storage containers for food, or medical supplies. |
1. A fluoro rubber molded product comprising either of a crosslinked tetrafluoroethylene-propylene copolymer and a crosslinked tetrafluoroethylene-propylene-vinylidene fluoride terpolymer, wherein said cross linked copolymer or terpolymer having a metallic component content of not higher than 1.5% by mass in terms of a quantity based on metallic elements. 2. A fluoro rubber molded product according to claim 1, wherein said crosslinking is performed with peroxide. 3. A fluoro rubber molded product according to claim 2, wherein said crosslinking is further performed by ionizing radiation exposure. 4. A fluoro rubber molded product according to claim 2 wherein 0.1 to 20 parts by mass of triallyl isocyanurate as a crosslinking coagent are mixed with 100 parts by mass of the tetrafluoroethylene-propylene copolymer. 5. A fluoro rubber molded product according to claim 2 wherein the metallic element content is not higher than 5000 ppm. 6. A fluoro rubber molded product according to claim 1 wherein said crosslinking is performed by ionizing radiation exposure. 7. A fluoro rubber molded product according to claim 1 wherein an amount of emission gas is not higher than 3 ppm when said fluoro rubber molded product is held at a temperature of 100° C. for 30 minutes. 8. A method of producing a fluoro rubber molded product comprising: the step of crosslinking either of a tetrafluoroethylene-propylene copolymer and a tetrafluoroethylene-propylene-vinylidene fluoride terpolymer which is prepared as a starting material to have a metallic component content of not higher than 1.5% by mass in terms of a quantity based on metallic elements. 9. A method of producing a fluoro rubber molded product according to claim 8 wherein a mixture containing a starting material and a peroxide crosslinking agent or a mixture containing a starting material, a peroxide crosslinking agent and a crosslinking coagent is heat-molded into a crosslinked body. 10. A method of producing a fluoro rubber molded product according to claim 9 wherein said crosslinked body is further irradiated with an ionizing radiation. 11. A method of producing a fluoro rubber molded product according to claim 9 wherein either of a tetrafluoroethylene-propylene copolymer and a tetrafluoroethylene-propylene-vinylidene fluoride terpolymer prepared to have a metallic component content of not higher than 5000 ppm is used as said starting material. 12. A method of producing a fluoro rubber molded product according to claim 8 wherein said starting material is preformed into a predetermined shape and then a preformed body is irradiated with an ionizing radiation. 13. A method of producing a fluoro rubber molded product according to claim 8 wherein said molded product obtained by crosslinking is further subjected to a cleaning treatment using pure water, a heat treatment at a temperature of not lower than 150° C. or a combination of said cleaning treatment and said heat treatment. 14. A rubber material for use in a semiconductor producing apparatus or a semiconductor conveying apparatus, characterized by comprising a fluoro rubber molded product according to claim 7. 15. A rubber material for use in a food manufacturing apparatus, a food conveyor or a food storage, characterized by comprising a fluoro rubber molded product according to claim 1. 16. A rubber material for use in a medical appliance, characterized by comprising a fluoro rubber molded product according to claim 1. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Technical Field The present invention relates to fluoro rubber molded products and more particularly to fluoro rubber molded products suitable for rubber materials used for applications requiring cleanliness such as low emission gas, low eluted metal, etc. and physical and chemical durability such as plasma resistance, ozone resistance, chemical resistance, heat resistance, etc., for example, in a semiconductor producing apparatus, a semiconductor conveying apparatus, a food manufacturing apparatus, a food conveyor, a food storage and a medical appliance. The invention also relates to a producing method for obtaining these fluoro rubber molded products. 2. Background Art A demand for high cleanliness to prevent contamination of the outside is common to rubber materials used in a semiconductor producing apparatus, a semiconductor conveying apparatus, a food manufacturing apparatus, a food conveyor, a food storage and a medical appliance. Specifically, it is important that components of a rubber material must not be released as gases or particles from the rubber material per se. In a semiconductor producing apparatus or a semiconductor conveying apparatus, physical and chemical durability such as plasma resistance, ozone resistance, chemical resistance, heat resistance, etc. is required in addition to purity because the rubber material comes into contact with various chemicals or gases and also with plasma, ozone, etc. Therefore, fluoro rubber molded products have been heretofore often used. Fluoro rubber as a raw material, however, contains metallic elements derived from metallic salt which is generally used in the fluoro rubber as a polymerization catalyst and an emulsifying agent, and for coagulating the fluoro rubber from raw-material latex. If such fluoro rubber is used as a sealing material in a semiconductor producing apparatus using plasma gases, there is fear that the fluoro rubber may be decomposed due to its contact with plasma or ozone and volatilized so that the metallic element is released as particles to the outside. Therefore, an object of the invention is to solve the aforementioned problem, more particularly, to provide fluoro rubber molded products suitable for rubber materials quite excellent in cleanliness such as low emission gas, low eluted metal, etc. and in physical and chemical durability such as plasma resistance, ozone resistance, chemical resistance, heat resistance, etc. compared with the background art and used in a semiconductor producing apparatus, a semiconductor conveying apparatus, a food manufacturing apparatus, a food conveyor, a food storage and a medical appliance. Another object of the invention is to provide a producing method for obtaining these fluoro rubber molded products. |
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