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Stable expression of polymorphous forms of human cytochrome p450 2d6

The present invention relates to a test system containing cell lines expressing human cytochrome P450 2D6 as well as to the use of said test system for the study of pharmacological and toxicological aspects of the hCYP2D6 polymorphism. The present invention further relates to methods for the detection of novel polymorphic forms of human cytochrome P450 2D6 using the test system according to the invention as well as to methods for the simple and exact quantification of the cytochrome P450 content using CO difference spectra.

1. Test system consisting of cells expressing a cytochrome P450 2D6 (hCYP2D6) allele in a heterologous manner wherein at least three P450 2D6 alleles are expressed in said test system. 2. Test system according to claim 1 wherein said at least three P450 2D6 alleles correspond to the most frequent allele types in a population. 3. Test system according to claim 1 wherein said test system expresses at least 5 functional hCYP2D6 alleles in a heterologous manner. 4. Test system according to claim 3 wherein the alleles hCYP2D6*1, *2, *9, *10 and *17 are expressed. 5. Test system according to any one of claims 1 to 4 wherein said cells are Chinese hamster lung fibroblasts or cells derived therefrom. 6. Test system according to claim 5 wherein said cells are V79 cells. 7. Test system according to claim 6 wherein said cells are the cell lines V79MZh2D6*1, V79MZh2D6*2, V79MZh2D6*9, V79MZh2D6*10 and V79MZh2D6*17 deposited on Feb. 15, 2000, at the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH under the accession numbers DSM ACC2446, DSM ACC2447, DSM ACC2448, DSM ACC2449 and DSM ACC2450. 8. Test system according to any of the claims 1 to 7 wherein said cells express cDNA. 9. Kit comprising the test system according to any of the claims 1 to 8. 10. Use of the test system according to any of the claims 1 to 8 for the study of the gene-dependent toxicity of metabolites. 11. Use according to claim 10 wherein said metabolites are drugs. 12. Use of the test system according to any of the claims 1 to 8 for determining a toxic, mutagenic or cancerogenous effect of compounds. 13. Use according to any one of claims 10 to 12 wherein the cells expressing human cytochrome P450 2D6 are contacted with the substance to be tested. 14. Method for screening of substances with respect to their metabolization by human cytochrome P450 2D6 wherein the cells of the test system according to any of the claims 1 to 8 are contacted with a substance and the metabolic product is measured. 15. Method for the detection of novel P450 2D6 alleles wherein said method comprises the heterologous expression of the allele in question in a cell, testing the cells expressing the allele in question with respect to the cytochrome P450 2D6-dependent metabolism of one or more compounds and comparison of the metabolism of the cells to the metabolism of cells of the test system according to any one of claims 1 to 8. 16. Method for the quantification of the cytochrome P450 content wherein said method comprises the solubilization of cytochrome P450 by means of the non-ionic detergent emulgen 913, centrifuging the solubilizate and measurement using CO difference spectra. 17. Method according to claim 16 wherein said method comprises the following steps: (a) preparation of cell homogenate; (b) addition of emulgen 913 to the cell homogenate; (c) removing insoluble material; (d) determination of the reduced spectrum; (e) saturation with carbon monoxide; (f) measurement of the CO/reduced spectrum; (g) evaluation of the cytochrome P450 content by means of the spectra. 18. Method according to claim 16 or 17 wherein emulgen 913 is added in a final concentration of 0.25% (w/v).

Connecting device for fluids

A connection means for two base bodies (3a and 3b) of a subassembly conducting a fluid. On each base body (3a and 3b) holding means are provided, which respectively have at least one holding pin (16) projecting toward the respectively other base body (3a and 3b), such holding pin fitting between two coupling bodies (17 and 18) and being at the same time peripherally acted upon by the working faces (22 and 23) of both coupling bodies (17 and 18). The coupling bodies (17 and 18) are able to be clamped together athwart the connection direction (5) of the two base bodies (3a and 3b) and by virtue of oblique faces are able to exert a connection force (Fv) acting to produce a movement together of the base bodies (3a and 3b).

1. A connection means for two base bodies of a fluid conducting subassembly and more particularly a modularly designed device for treating compressed air, comprising holding means provided on the mutually facing connection faces (9a and 9b) of the base bodies (3a and 3b) to be connected, and furthermore a coupling unit (7) fitting between the base bodies to be connected, said coupling unit (7) having two coupling bodies (17 and 18), said coupling bodies (17 and 18) being able to be clamped athwart the connection direction (5) of the two base bodies (3a and 3b) and thereby by virtue of inclined faces extending obliquely in relation to the connection direction (5) exerting a connection force (Fv) on the holding means, said connection force acting to provide a movement together of the base bodies (3a and 3b), characterized in that the holding means provided on each respective base body (3a and 3b) each possess at least one holding pin (16) extending toward the respectively other base body (3a and 3b), said pin fitting between the two coupling bodies (17 and 18) and simultaneously being acted upon peripherally by working faces (22 and 23) of both coupling bodies (17 and 18). 2. The connection means as set forth in claim 1, characterized in that on the connection faces (9a and 9b) of both base bodies (3a and 3b) respectively two mutually spaced apart holding pins (16) are provided, which respectively are able to cooperate with working faces (22 and 23) of both coupling bodies (17 and 18). 3. The connection means as set forth in claim 2, characterized in that the two holding pins (16) on the associated connection face (9a and 9b) are arranged on mutually diametrally opposite sides of the opening (8a and 8b) of a fluid duct (4a and 4b) opening toward the connection face (9a and 9b). 4. The connection means as set forth in any one of the claims 1 through 3, characterized in that the holding pins (16) are placed within periphery of the associated connection face (9a and 9b) in contact with the coupling unit (7), such holding pins being located preferably near the edge of the respective connection face (9a and 9b). 5. The connection means as set forth in any one of the claims 1 through 4, characterized in that the holding pins (16) are in the form of components separate from the associated base body (3a and 3b), which components are attached to the respective base body (3a and 3b) more particularly in a detachable manner. 6. The connection means as set forth in claim 5, characterized in that the holding pins (16) are screwed to the associated base body (3a and 3b). 7. The connection means as set forth in any one of the claims 1 through 6, characterized in that the holding pins (16) on the base bodies (3a and 3b) to be connected together are coaxially opposite to one another in pairs. 8. The connection means as set forth in any one of the claim 1 through 7, characterized in that for the mutual clamping together of the two coupling bodies (17 and 18) clamping means (25) engaging same are provided which are preferably in the form of clamping means (25) designed in the form of screw connection means. 9. The connection means as set forth in claim 8 in conjunction with claim 7, characterized in that the clamping means (25) are provided with clamping screws (38) one respective clamping screw fitting through an intermediate space (37) present between two holding pins (16) associated with each other in a pair. 10. The connection means as set forth in any one of the claims 1 through 9, characterized in that both the working faces (22 and 23) of the coupling bodies (17 and 18) and also the mating working faces (24) cooperating with the same, of the holding pins (16) are designed in the form of oblique faces. 11. The connection means as set forth in claim 10, characterized in that, as related to the connection direction (5) of the two base bodies (3a and 3b), the working faces (22 and 23), have the same angles (w) of inclination as the mating working faces (24). 12. The connection means as set forth in any one of the claims 1 through 11, characterized in that the mating working faces (22 and 23,) cooperating with the working faces (22 and 23), of the holding pins (16) have a conical form. 13. The connection means as set forth in any one of the claims 1 through 11, characterized in that the mating working faces (22 and 23,) cooperating with the working faces (22 and 23), of the holding pins (16) are provided on a surrounding radial projection (31), which preferably is formed by a head portion (33) of the respective holding pin (16). 14. The connection means as set forth in any one of the claims 1 through 13, characterized in that each holding pin (16) possesses a mating working face (24) facing the connection face (9a and 9b) of the base body (3a and 3b) bearing it and cooperating with the associated working faces (22 and 23) of the coupling bodies (17 and 18), the coupling bodies (17 and 18) fitting, in the clamped together condition thereof, between a respective mating working face (24) and the associated connection face (9a and 9b) and acting on both the mating working face (24) and the connection face (9a and 9b). 15. The connection means as set forth in any one of the claims 1 through 14, characterized in that the coupling bodies (17 and 18) fit round the holding pins (16) like clips in the clamped together state, each coupling body (17 and 18) possessing, for each holding pin (16), a recess partly receiving it. 16. The connection means as set forth in any one of the claim 1 through 15, characterized in that the coupling bodies (17 and 18) engage each other in the direction of the biasing force when in the clamped together state. 17. The connection means as set forth in any one of the claims 1 through 16, characterized in that the coupling unit (7) has a through duct (13) flush with the duct openings (8a and 8b) provided on the connection faces (9a and 9b) in the fitted state, such through duct being completely formed in one of the two coupling bodies. 18. The connection means as set forth in claim 17, characterized in that the through duct (13) provided on the one coupling body (18) is delimited, on the side facing the other body (17), by a wall bulging out toward the other coupling body (17), such wall fitting into a complementary recess in the other coupling body (17). 19. The connection means as set forth in claim 17 or in claim 18, characterized in that an annular seal (15) is fitted between the coupling body (18) having the opening and the two base bodies (3a and 3b) to be connected, said seal being coaxial in relation to the through duct (13).

Process for preparing optically active 2-[6-(hydroxy-methyl)-1,3-dioxan-4-yl] acetic acid derivatives

The present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative, which are of value as pharmaceutical intermediates, can be produced from inexpensive and readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor. The present invention is a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative which comprises reacting an enolate, prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative with (S)-β-hydroxy-γ-butyrolactone at a temperature not lower than −30° C. to give a dihydroxyoxohexanoic acid derivative, treating the same with an acylating agent in the presence of a base to produce a dihydroxyoxohexanoic acid monoacyl derivative, reducing this compound with a microorganism to produce a trihydroxyhexanoic acid monoacyl derivative, treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce an acyloxymethyldioxanylacetic acid derivative, and finally, subjecting this compound to solvolysis in the presence of a base.

1. A production process of a following compound (I); in the formula, R1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R2 and R3 each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, and R2 and R3 may jointly form a ring, which comprises (1) reacting an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative represented by the following formula (II); X1CH2CO2R1 (II) in the formula, R1 is as defined above; and X1 represents a hydrogen or a halogen atom, with (S)-β-hydroxy-γ-butyrolactone represented by the following formula (III); at a temperature not lower than −30° C. to produce a compound represented by the following formula (IV); in the formula, R1 is as defined above, (2) treating this compound with an acylating agent in the presence of a base to produce a compound represented by the following formula (V); in the formula, R1 is as defined above; and R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, (3) reducing this compound with a microorganism to produce a compound represented by the following formula (VI); in the formula, R1 and R4 are as defined above, (4) treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce a compound represented by the following formula (VII); in the formula, R1, R2, R3, and R4 are as defined above, and (5) subjecting this compound to solvolysis in the presence of a base. 2. The production process according to claim 1 wherein X1 of the acetic acid ester derivative (II) is a hydrogen atom and a magnesium amide represented by the following formula (VIII); in the formula, R5 and R6 each independently represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group; and X2 represents a halogen atom, is used as the base in preparing the enolate. 3. The production process according to claim 2 wherein, of the magnesium amide (VIII), each of R5 and R6 is an isopropyl group and X2 is a chlorine atom. 4. The production process according to claim 1 wherein X1 of the acetic acid ester derivative (II) is a halogen atom and magnesium or zinc is used as the 0-valent metal in preparing the enolate. wherein the reaction of the enolate with (S)-β-hydroxy-γ-butyrolactone (III) is carried out in the presence of a polyether. 6. The production process according to claim 5 wherein dimethoxyethane is used as the polyether. 7. The production process according to claim 1 wherein (S)-β-hydroxy-γ-butyrolactone represented by the following formula (III); is treated, in advance, with a Grignard reagent represented by the following formula (IX); R7—Mg—X3 (IX) in the formula, R7 represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and X3 represents a halogen atom, and reacted, at a temperature not lower than −30° C., with the enolate prepared by permitting the base or the 0-valent metal to act on the acetic acid ester derivative represented by the following formula (II); X1CH2CO2R1 (II) in the formula, R1 and X1 are as defined above, to produce the compound represented by the following formula (IV); in the formula, R1 is as defined above. 8. The production process according to claim 7 wherein, of the Grignard reagent (IX), R7 is a tert-butyl group and X3 is a chlorine atom. 9. The production process according to claim 1 wherein (S)-β-hydroxy-butyrolactone (III) is treated with a base and a magnesium compound in advance and reacted, at a temperature not lower than −30° C., with the enolate prepared by permitting the base or the 0-valent metal to act on the acetic acid ester derivative (II) to produce the compound represented by the above formula (IV). 10. The production process according to claim 9 wherein the base is sodium hydride, lithium diisopropylamide, or chloromagnesium diisopropylamide. 11. The production process according to claim 9 wherein the magnesium compound is magnesium chloride or magnesium bromide. 12. The production process according to claim 7 wherein X1 of the acetic acid ester derivative (II) is a hydrogen atom and a lithium amide represented by the following formula (X); in the formula, R8 and R9 each independently represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group, is used as the base in preparing the enolate. 13. The production process according to claim 12 wherein, of the lithium amide (X), each of R0 and R9 is an isopropyl group. 14. The production process according to claim 7 wherein X1 of the acetic acid ester derivative (II) is a halogen atom and magnesium or zinc is used as the 0-valent metal in preparing the enolate. 15. The production process according to claim 1 wherein, in the acylation step, a compound represented by the following formula (XI); or a compound represented by the following formula (XVI); in the above formulas, R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and Q represents a leaving group, is used as the acylating agent. 16. The production process according to claim 15 wherein Q of the acylating agent (XI) is a halogen atom. 17. The production process according to claim 16 wherein the halogen atom is a chlorine atom. 18. The production process according to claim 1 wherein an amine is used as the base in the acylation step. 19. The production process according to claim 18 wherein triethylamine or pyridine is used as the amine. 20. The production process according to claim 1 wherein, in the acylation step, the compound contaminated with an impurity and represented by the following formula (V); in the formula, R1 and R4 are as defined above, is treated with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (V) and the compound represented by the above formula (V) is obtained in a crystal form. 21. The production process according to claim 20 wherein the impurity contaminating the compound represented by the above formula (V) is a compound represented by the following formula (XII); in the formula, R1 and R4 are as defined above. 22. The production process according to claim 20 wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane. 23. The production process according to claim 20 wherein the crystallization is carried out with additional use of an auxiliary solvent, said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (V). 24. The production process according to claim 23 wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization. 25. The production process according to claim 23 wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride. 26. The production process according to claim 1 wherein a culture broth, cells or processed cells of the microorganism is used in the reduction step using the microorganism, said microorganism for use being selected from among microorganisms belonging to the genera Ashbya, Botryoascus, Brettanomyces, Candida, Citeromyces, Clavispora, Cryptococcus, Debaryomyces, Dekkera, Dipodascus, Galactomyces, Geotrichum, Hanseniaspora, Hansenula, Hormoascus, Hyphopichia, Issatchenkia, Kluyveromyces, Komagataella, Lipomyces, Metschnikowia. Nakazawaea, Ogataea, Pachysolen, Pichia, Rhodotorula, Rhodsporidium, Saccharomyces, Saccharomycodes, Saccharomycopsis, Saturnospora, Schizoblastosporion, Schizosaccharomyces, Schwanniomyces, Sporidiobolus, Sporobolomyces, Torulaspora, Torulopsis, Trichosporon, Trigonopsis, Willopsis, Yamadazyma, Zygosaccharomyces, Acidiphilium, Aerobacter, Alcaligenes, Arthrobacter, Aureobacterium, Bacillus, Brevibacterium, Buttiauxella, Cedecea, Cellulomonas. Citrobacter, Clostridium, Comamonas, Corynebacterium, Enterobacter, Erwinia. Escherichia, Flavobacterium, Klebsiella, Luteococcus, Microbacterium, Micrococcus, Ochrobactrum, Proteus, Providencia, Pseudomonas, Rhodococcus, Sarcina, Serratia, Sphingobacterium, Tsukamurella, Absidia, Acremonium, Aegerita, Agrocybe, Amylostereum, Aspergillus, Byssochlamys, Chaetomidium, Chaetosartorya, Cladosporium, Coprinus, Crinipellis, Endophragmia, Flavolus, Fomitopsis, Fusarium, Ganoderma, Glomerella, Laetiporus, Lentinus, Lenzites, Macrophoma, Monascus, Mortierella, Paecilomyces, Penicillium, Phialophora, Pholiota, Pleurotus, Scopulariopsis, Sehizophyllum, Sporotrichum, Zygorhynchus, Microtetraspora, and Streptomyces. 27. The production process according to claim 1 wherein the microorganism for use in the reduction step using the microorganism is selected from the group consisting of Ashbya gossypii, Botryoascus synnaedendrus, Brettanomyces custersianus, Candida arborea, Candida catenulata, Candida fennica, Candida galucla, Candida haemulonii, Candida magnoliae, Candida musae, Candida nitratophila, Candida parapsilosis, Candida pararugosa, Candida stellata, Citeromyces matritensis, Clavispora lusitaniae, Cryptococcus laurentii, Debaryomyces carsonii, Debaryomyces hansenii var. fabryi, Debaryomyces hansenii var. hansenii, Debaryomyces kloeckeri, Debaryomyces marama, Debaryomyces pseudopolymorphus, Debaryomyces robertsiae, Debaryomyces sp., Dekkera anomala, Dipodascus armillariae, Dipodascus ovetensis, Dipodascus tetrasperma, Galactomyces reessii, Geotrichum candidum, Geotrichum fermentans, Geotrichum fragrans, Geotrichum loubieri, Hanseniaspora guilliermondii, Hansenula methanolosa, Hansenula polymorpha. Hormoascus philentomus, Hormoascus platypodis, Hyphopichia burtonii, Issatchenkia orientalis, Issatchenkia terricola, Kluyveromyces lactis, Kluyveromyces marxianus, Kluyveromyces polysporus, Kluyveromyces thermotolerans, Komagataella pastoris, Lipomyces starkeyi, Metschnikowia bicuspidata, Metschnikowia pulcherrima, Nakazawaea holstii, Ogataea minuta var. minuta, Ogataea pini, Ogataea polymorpha, Ogataea wickerhamii, Pachysolen tannophilus, Pichia canadensis, Pichia farinose, Pichia jandinii, Pichia saitoi, Pichia toletana, Pichia triangularis, Pichia wickerhamii, Rhodotorula graminis, Rhodotorula minula, Rhodsporidium dlobovatum, Rhodsporidium toruloides, Saccharomyces bayanus, Saccharomyces pastorianus. Saccharomyces rosei, Saccharomyces sake, Saccharomyces steineri, Saccaromyces unisporus, Saccharomycodes ludwigii, Saccharomycopsis capsularis, Saccharomycopsis malanga, Saturnospora dispora, Schizoblastosporion kobayasii, Schizosaccharomyces pombe, Schwanniomyces occidentalis var. occidentalis, Sporidiobolus johnsonii, Sporobolomyces pararoseus, Sporobolomyces salmonicolor, Torulaspora delbrueckii, Torulopsis methanolevescens, Torulopsis osboenis, Torulopsis sp., Torulopsis uvae, Trichosporon pullulans, Trichosporon sp. Trigonopsis variabilis, Willopsis saturnus var. mrakii, Willopsis saturnus var. saturnus, Yamadazyma farinosa, Yamadazyma haplophila, Zygosaccharomyces naniwensis, Zygosaccharomyces sp., Acidiphilium cryptum, Aerobacter cloacae, Alcaligenes xylosoxidans, Alcaligenes xylosoxidans subsp. denitrificans, Arthrobacter globiformis, Arthrobacter protophormiae, Aureobacterium esteraromaticum, Bacillus badius, Bacillus sphaericus, Brevibacterium ammomiagenes, Buttiauxella agrestis, Cedecea davisiae, Cellulomonas sp., Cellulomonas turbata, Citrobacter freundii, Clostridium cylindrosporum, Comamonas testosteroni, Corynebacterium acectoacidophilum, Corynebacterium ammoniagenes, Corynebacterium glutamicum, Corynebacterium glutamicus, Enterobacter aerogenes, Enterobacter cloacae, Erwinia carotovora subsp. carotovora, Escherichia coli, Flavobacterium flavesceus, Klebsiella planticola, Luteococcus japonicus, Microbacterium arborescens, Micrococcus flavus, Micrococcus luteus, Ochrobactrum sp., Proteus inconstans, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Rhodococcus equi, Sarcina lutea, Serratia plymuthicum, Serratia proteamaculans subsp. proteamaculans, Sphingobacterium spiritivorum, Tsukamurella paurometabolum, Absidia orchidis, Acremonium bacillisporum, Aegerita candida, Agrocybe cylindracea, Amylostereum areolatum, Aspergillus parasiticus, Aspergillus phoenicis, Byssochlamys fulva, Chaetomidium fimeti, Chaetosartorya stromatoides, Cladosporium resinae F. avellaneum, Coprinus cinereus, Coprinus lagopus, Coprinus sp., Crinipellis stipitaria, Endophragmia alternata, Flavolus arcularius, Fomitopsis pubertatis, Fusarium merismoides, Ganoderma lucidum, Glomerella cingulata, Laetiporus sulphureus, Lentinus lepideus, Lenzites betulina, Macrophoma commelinae, Monascus purpureus, Mortierella isabellina, Paecilomyces varioti, Penicillium chermesinum, Penicillium chrysogenum, Penicillium expansum, Penicillium lilacinium, Phialophora fastigiata, Pholiota aurivella, Pholiota limonella, Pleurotus dryinus, Pleurotus ostreatus, Pleurotus porrigens, Scopulariopsis brevicaulis, Sehizophyllum commune, Sporotrichum aurantiacum, Zygorhynchus moelleri, Microtetraspora roseoviolacea, Streptomyces achromogenes subsp. rubradiris, Streptomyces sp. and Streptomyces aureus. 28. The production process according to claim 1 wherein an amine salt composed of an acid and an amine is used as the acid catalyst in the acetal-forming step. 29. The production process according to claim 28 wherein the amine salt is prepared and used in situ. 30. The production process according to claim 28 wherein the acid is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. 31. The production process according to claim 28 wherein the amine is a tertiary amine. 32. The production process according to claim 31 wherein the tertiary amine is triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, or imidazole. 33. The production process according to claim 28 wherein the amine is used in an excess amount relative to the acid. 34. The production process according to claim 1 wherein the acetal-forming reagent is 2,2-dimethoxypropane. 35. The production process according to claim 1 wherein a compound contaminated with an impurity and represented by the following formula (VII); in the formula, R1, R2, R3 and R4 are as defined above, is treated with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (VII) and the compound represented by the above formula (VII) is obtained in a crystal form. 36. The production process according to claim 35 wherein the impurity contaminating the compound represented by the above formula (VII) is at least one compound selected from the group consisting of a compound represented by the following formula (XIII); in the formula, R2, R3 and R4 are as defined above; and R10 represents a lower alkyl group and is different from R1, a diastereomer represented by the following formula (XIV); in the formula, R1, R2, R3, and R4 are as defined above, a compound represented by the following formula (XV); in the formula, R4 is as defined above, and a compound represented by the following formula (VI); in the formula, R1 and R4 are as defined above. 37. The production process according to claim 36 wherein R10 of the compound (XIII) is a methyl group. 38. The production process according to claim 35 wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane. 39. The production process according to claim 35 wherein the crystallization is carried out with additional use of an auxiliary solvent, said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (VII). 40. The production process according to claim 39 wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization. 41. The production process according to claim 39 wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride. 42. The production process according to claim 1 wherein R1 is a tert-butyl group. 43. The production process according to claim 1 wherein each of R2 and R3 is a methyl group. 44. The production process according to claim 1 wherein 14 is a phenyl group. 45. An isolation/purification process which comprises treating a compound contaminated with an impurity and represented by the following formula (V); in the formula, R1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (V) and obtaining the compound represented by the above formula (V) in a crystal form. 46. The isolation/purification process according to claim 45 wherein the impurity contaminating the compound of the above formula (V) is a compound represented by the following formula (XII); in the formula. R1 and R4 are as defined above. 47. The isolation/purification process according to claim 45 wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane 48. The isolation/purification process according to claim 45 wherein the crystallization is carried out with additional use of an auxiliary solvent, said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (V). 49. The isolation/purification process according to claim 48 wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization. 50. The isolation/purification process according to claim 48 wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride. 51. The isolation/purification process according to claim 45 wherein the compound represented by the above formula (V) is used, said compound being produced by treating a compound represented by the following formula (IV); in the formula, R1 is as defined above, with an acylating agent in the presence of a base. 52. The isolation/purification process according to claim 51 wherein a compound represented by the following formula (XI); or a compound represented by the following formula (XVI); in the above formulas, R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and Q represents a leaving group, is used as the acylating agent. 53. The isolation/purification process according to claim 52 wherein Q of the acylating agent (XI) is a halogen atom. 54. The isolation/purification process according to claim 53 wherein the halogen atom is a chlorine atom. 55. The isolation/purification process according to claim 51 wherein an amine is used as the base. 56. The isolation/purification process according to claim 55 wherein triethylamine or pyridine is used as the amine used in the acylation step. 57. The isolation/purification process according to claim 51 wherein the compound represented by the above formula (IV) is used, said compound being produced by reacting an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative represented by the following formula (II); X1CH2CO2R1 (II) in the formula, R1 is an defined above; and X1 represents a hydrogen or a halogen atom, with (S)-γ-hydroxy-γ-butyrolactone represented by the formula (III); at a temperature not lower than −30° C. 58. The isolation/purification process according to claim 57 wherein X1 of the acetic acid ester derivative (IT) is a hydrogen atom and a magnesium amide represented by the following formula (VIII); in the formula, R1 and R6 each independently represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group; and X2 represents a halogen atom, is used as the base in preparing the enolate. 59. The isolation/purification process according to claim 58 wherein, of the magnesium amide (VIII), each of R5 and R6 is an isopropyl group and X2 is a chlorine atom. 60. The isolation/purification process according to claim 57 wherein X1 of the acetic acid ester derivative (II) is a halogen atom and magnesium or zinc is used as the 0-valent metal in preparing the enolate. 61. The isolation/purification process according to claim 57 wherein the reaction of the enolate with (S)-β-hydroxy-γ-butyrolactone (Ill) is carried out in the presence of a polyether. 62. The isolation/purification process according to claim 61 wherein dimethoxyethane is used as the polyether. 63. The isolation/purification process according to claim 51 wherein the compound represented by the above formula (IV) is used, said compound being produced by treating, in advance, (S)-β-hydroxy-γ-butyrolactone (III) with a Grignard reagent represented by the following formula (IX); R7—Mg—X3 (IX) in the formula, R7 represents an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and X3 represents a halogen atom, and reacting, at a temperature not lower than −30° C., with an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative (II). 64. The isolation/purification process according to claim 63 wherein, of the Grignard reagent (IX), R7 is a tert-butyl group and X3 is a chlorine atom. 65. The isolation/purification process according to claim 51 wherein the compound represented by the above formula (IV) is used, said compound being produced by treating, in advance, (S)-β-hydroxy-γ-butyrolactone (III) with a base and a magnesium compound, and reacting, at a temperature not lower than −30° C., with an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative (II). 66. The isolation/purification process according to claim 65 wherein the base is sodium hydride, lithium diisopropylamide, or chloromagnesium diisopropylamide. 67. The isolation/purification process according to claim 65 wherein the magnesium compound is magnesium chloride or magnesium bromide. 68. The isolation/purification process according to claim 63 wherein X1 of the acetic acid ester derivative (II) is a hydrogen atom and a lithium amide represented by the following formula (X); in the formula, R8 and R9 each independently represents an alkyl group of 1 to 12 carbon atoms, tin aryl group of 6 to 12 carbon atoms, an aralkyl group of 7 to 12 carbon atoms, or a silyl group, is used as the base in preparing the enolate. 69. The isolation/purification process according to claim 68 wherein, of the lithium amide (X), each of R8 and R9 represents an isopropyl group. 70. The isolation/purification process according to claim 63 wherein X1 of the acetic acid ester derivative (II) is a halogen atom and magnesium or zinc is used as the 0-valent metal in preparing the enolate. 71. The isolation/purification process according to claim 45 wherein R1 is a tert-butyl group. 72. The isolation/purification process according to claim 45 wherein R1 is a phenyl group. 73. A production process of a compound represented by the following formula (VI); in the formula, R1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, which comprises reducing a compound represented by the following formula (V); in the formula, R1 and R4 are as defined above, with a microorganism. 74. The production process according to claim 73 wherein a culture broth, cells or processed cells of the microorganism is used, said microorganism being selected from among microorganisms belonging to the genera Ashbya, Botryoascus, Brettanomyces, Candida, Citeromyces, Clavispora, Cryptococcus, Debaryomyces, Dekkera, Dipodascus, Galactomyces, Geotrichum, Hanseniaspora, Hansenula, Hormoascus, Hyphopichia, Issatchenkia, Kluyveromyces, Komagataella, Lipomyces, Metschnikowia, Nakazawaea, Ogataea, Pachysolen, Pichia, Rhodotorula, Rhodsporidium, Saccharomyces, Saccharomycodes, Saccharomycopsis, Saturnospora, Schizoblastosporion, Schizosaccharomyces, Schwanniomyces, Sporidiobolus, Sporobolomyces, Torulaspora, Torulopsis, Trichosporon, Trigonopsis, Willopsis, Yamadazyma, Zygosaccharomyces, Acidiphilium, Aerobacter, Alcaligenes, Arthrobacter, Aureobacterium, Bacillus, Brevibacterium, Buttiauxella, Cedecea, Cellulomonas, Citrobacter, Clostridium, Comamonas, Corynebacterium, Enterobacter, Erwinia, Escherichia, Flavobacterium, Klebsiella, Luteococcus, Microbacterium, Micrococcus, Ochrobactrum, Proteus, Providencia, Pseudomonas, Rhodococcus, Sarcina, Serratia, Sphingobacterium, Tsukamurella, Absidia, Acremonium, Aegerita, Agrocybe, Amylostereum, Aspergillus, Byssochlamys, Chaetomidium, Chaetosartorya, Cladosporium, Coprinus, Crinipellis, Endophragmia, Flavolus. Fomitopsis, Fusarium, Ganoderma, Glomerella, Laetiporus, Lentinus, Lenzites, Macrophoma, Monascus, Mortierella, Paecilomyces, Penicillium, Phialophora, Pholiota, Pleurotus, Scopulariopsis, Sehizophyllum, Sporotrichum, Zygorhynchus, Microtetraspora, and Streptomyces. 75. The production process according to claim 73 wherein the microorganism is selected from the group consisting of Ashbya gossypii, Botryoascus synnaedendrus, Brettanomyces custersianus, Candida arborea, Candida catenulata, Candida fennica, Candida galacta, Candida haemulonii, Candida magnoliae, Candida musae, Candida nitratophila, Candida parapsilosis, Candida pararugosa, Candida stellata, Citeromyces matritensis, Clavispora lusitaniae, Cryptococcus laurentii, Debaryomyces carsonii, Debaryomyces hansenii var. fabryi, Debaryomyces hansenii var. hansenii, Debaryomyces kloeckeri, Debaryomyces marama, Debaryomyces pseudopolymorphus, Debaryomyces robertsiae, Debaryomyces sp., Dekkera anomala, Dipodascus armillariae, Dipodascus ovetensis, Dipodascus tetrasperma, Galactomyces reessii, Geotrichum candidum, Geotrichum fermentans, Geotrichum fragrans, Geotrichum loubieri, Hanseniaspora guilliermondii, Hansenula methanolosa, Hansenula polymorpha, Hormoascus philentomus, Hormoascus platypodis, Hyphopichia burtonii, Issatchenkia orientalis, Issatchenkia terricola, Kluyveromyces lactis, Kluyveromyces marxianus, Kluyveromyces polysporus, Kluyveromyces thermotolerans, Komagataella pastoris, Lipomyces starkeyi, Metschnikowia bicuspidata, Metschnikowia pulcherrima, Nakazawaea holstii, Ogataea minuta var. minuta, Ogataea pini, Ogataea polymorpha, Ogataea wickerhamii, Pachysolen tannophilus, Pichia canadensis, Pichia farinose, Pichia jandinii, Pichia saitoi, Pichia toletana, Pichia triangularis, Pichia wickerhamii, Rhodotorula graminis, Rhodotorula minuta, Rhodsporidium diobavatum, Rhodsporidium toruloides, Saccharomyces bayanus, Saccharomyces pastorianus, Saccharomyces rosei. Saccharomyces sake, Saccharomyces steineri, Saccaromyces unisporus, Saccharomycodes ludwigii, Saccharomycopsis capsularis, Saccharomycopsis malanga, Saturnospora dispora, Schizoblastosporion kobayasii, Schizosaccharomyces pombe, Schwanniomyces occidentalis var. occidentalis, Sporidiobolus johnsonii, Sporobolomyces pararoseus, Sporobolomyces salmonicolor, Torulaspora delbrueckii, Torulopsis methanolevescens, Torulopsis osboenis, Torulopsis sp. Torulopsis uvae, Trichosporon pullulans, Trichosporon sp. Trigonopsis variabilis, Willopsis saturnus var. mrakii, Willopsis saturnus var. saturnus, Yamadazyma farinosa, Yamadazyma haplophila, Zygosaccharomyces naniwensis, Zygosaccharomyces sp., Acidiphilium cryptum, Aerobacter cloacae, Alcaligenes xylosoxidans, Alcaligenes xylosoxidans subsp. denitrificans, Arthrobacter globiformis, Arthrobacter protophormiae, Aureobacterium esteraromaticum, Bacillus badius, Bacillus sphaericus, Brevibacterium ammomiagenes, Buttiauxella agrestis, Cedecea davisiae, Cellulomonas sp., Cellulomonas turbata, Citrobacter freundii, Clostridium cylindrosporum, Comamonas testosteroni, Corynebacterium acectoacidophilum, Corynebacterium ammoniagenes, Corynebacterium glutamicum, Corynebacterium glutamicus, Enterobacter aerogenes, Enterobacter cloacae, Erwinia carotovora subsp. carotovora, Escherichia coli, Flavobacterium flavesceus, Klebsiella planticola, Luteococcus japonicus, Microbacterium arborescens, Micrococcus flavus, Micrococcus luteus, Ochrobactrum sp., Proteus inconstans, Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Providencia stuartii, Pseudomonas aeruginosa, Pseudomonas putida, Pseudomonas stutzeri, Rhodococcus equi, Sarcina lutea, Serratia plymuthicum, Serratia proteamaculans subsp. proteamaculans, Sphingobacterium spiritivorum, Tsukamurella paurometabolum, Absidia orchidis, Acremonium bacillisporum, Aegerita candida, Agrocybe cylindracea, Amylostereum areolatum, Aspergillus parasiticus, Aspergillus phoenicis, Byssochlamys fulva, Chaetomidium fimeti, Chaetosartorya stromatoides, Cladosporium resinae F. avellaneum, Coprinus cinereus, Coprinus lagopus, Coprinus sp., Crinipellis stipitaria, Endophragmia alternata, Flavolus arcularius, Fomitopsis pubertatis, Fusarium merismoides, Ganoderma lucidum, Glomerella cingulata, Laetiporus sulphureus, Lentinus lepideus, Lenzites betulina, Macrophoma commelinae, Monascus purpureus, Mortierella isabellina, Paecilomyces varioti, Penicillium chermesinum, Penicillium chrysogenum, Penicillium expansum, Penicillium lilacinium, Phialophora fastigiata, Pholiota aurivella, Pholiota limonella, Pleurotus dryinus, Pleurotus ostreatus, Pleurotus porrigens, Scopulariopsis brevicaulis, Sehizophyllum commune, Sporotrichum aurantiacum, Zygorhynchus moelleri, Microtetraspora roseoviolacea, Streptomyces achromogenes subsp. rubradiris, Streptomyces sp. and Streptomyces aureus. 76. The production process according to claim 73 wherein R1 is a tert-butyl group. 77. The production process according to claim 73 wherein R4 is a phenyl group. 78. A production process of a compound represented by the following formula (VII); in the formula, R1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R2 and R3 each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R2 and R3 may jointly form a ring, which comprises treating a compound represented by the following formula (VI); in the formula, R1 and R4 are as defined above, with an acetal-forming reagent using an amine salt composed of an acid and an amine as a catalyst. 79. The production process according to claim 78 wherein the amine salt is prepared and used in situ. 80. The production process according to claim 78 wherein the acid is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid or trifluoroacetic acid. 81. The production process according to claim 78 wherein the amine is a tertiary amine. 82. The production process according to claim 81 wherein the tertiary amine is triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, or imidazole. 83. The production process according to claim 78 wherein the amine is used in an excess amount relative to the acid. 84. The production process according to claim 78 wherein the acetal-forming reagent is 2,2-dimethoxypropane. 85. The production process according to claim 78 wherein R1 is a tert-butyl group. 86. The production process according to claim 78 wherein R4 is a phenyl group. 87. The production process according to claim 78 wherein each of R2 and R3 is a methyl group. 88. An isolation/purification process which comprises treating a compound represented by the following formula (VI); in the formula, R1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, with an acetal-forming reagent in the presence of an acid catalyst to thereby convert the same to a compound represented by the following formula (VII); in the formula, R1 and R4 are as defined above; R2 mid R3 each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R2 and R3 may jointly form a ring, treating the compound contaminated with an impurity and represented by the above formula (VII) with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (VII) and obtaining the compound represented by the above formula (VII) in a crystal form. 89. The isolation/purification process according to claim 88 wherein the impurity contaminating the compound represented by the above formula (VII) is at least one compound selected from the group consisting of a compound represented by the following formula (XIII); in the formula, R2, R3 and R4 are as defined above; and R10 represents a lower alkyl group and is different from R1, a diastereomer represented by the following formula (XIV); in the formula, R1, R2, R3, and R4 are as defined above, a compound represented by the following formula (XV); in the formula R4 is as defined above, and a compound represented by the following formula (VT); in the formula, R1 and R4 are as defined above. 90. The isolation/purification process according to claim 88 wherein the aliphatic hydrocarbon solvent is pentane, hexane, methylcyclohexane, heptane, octane, or isooctane. 91. The isolation/purification process according to claim 88 wherein the crystallization is carried out with additional use of an auxiliary solvent, said solvent being used for a purpose of improving at least one of a solubility, yield, treatment concentration, effect of purification, and physical properties of obtainable crystals of the compound represented by the above formula (VII). 92. The isolation/purification process according to claim 91 wherein the auxiliary solvent is used in such an amount that the weight ratio of said auxiliary solvent and the aliphatic hydrocarbon solvent (said auxiliary solvent/aliphatic hydrocarbon solvent) is not greater than 1 at completion of the procedure for crystallization. 93. The isolation/purification process according to claim 91 wherein the auxiliary solvent is at least one species selected from the group consisting of toluene, ethyl acetate, methyl tert-butyl ether and methylene chloride. 94. The isolation/purification process according to claim 88 wherein an amine salt composed of an acid and an amine is used as the acid catalyst. 95. The isolation/purification process according to claim 94 wherein the amine salt is prepared and used in situ. 96. The isolation/purification process according to claim 94 wherein the acid is hydrogen chloride, hydrogen bromide, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, or trifluoroacetic acid. 97. The isolation/purification process according to claim 94 wherein the amine is a tertiary amine. 98. The isolation/purification process according to claim 97 wherein the tertiary amine is triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, 2-methylpyridine, 3-methylpyridine, or imidazole. 99. The isolation/purification process according to claim 94 wherein the amine is used in an excess amount relative to the acid. 100. The isolation/purification process according to claim 88 wherein the acetal-forming reagent is 2,2-dimethoxypropane. 101. The isolation/purification process according to claim 88 wherein R1 is a tert-butyl group and R10 is a methyl group. 102. The isolation/purification process according to claim 88 wherein R4 is a phenyl group. 103. The isolation/purification process according to claim 88 wherein each of R2 and R3 is a methyl group.

<SOH> BACKGROUND ART <EOH>The hitherto-known technology for producing 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives includes the following processes. (1) A process starting with 3-hydroxy-γ-butyrolactone to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 3,5-dihydroxyhexanoic ester derivative (JP-A-04-173767). (2) A process starting with 3,4-dihydroxybutyronitrile acetonide to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 3,5-dihydroxyhexanoic ester derivative (JP-A-O 2 -262537). (3) A process starting with a 4-chloroacetoacetic acid ester to synthesize a 3,5,6-trihydroxyhexanoic ester derivative through benzyloxylation, reduction, chain extension and like steps. (JP-A-06-65226). (4) A process starting with a 4-chloro-3-hydroxybutyric ester to synthesize a 3,5,6-trihydroxyhexanoic ester derivative through chain extension, reduction and like steps. (U.S. Pat. No. 5,278,313). (5) A process starting with malic acid to synthesize a 3,5,6-trihydroxyhexanoic ester derivative via a 2,4-dihydroxyadipic acid derivative (JP-A-04-69355). However, these processes involve ultra-low temperature reactions around −80° C. in some stage or other of the respective production processes (1,2,4 and 5) or a high-pressure hydrogenation reaction requiring a pressure of as high as 100 kg/cm 2 (3), thus invariably requiring extraordinary reaction equipment. Moreover, expensive starting materials are used in some or other stages, so that none of the processes are efficient enough for industrial-scale production.

<SOH> SUMMARY OF THE INVENTION <EOH>In the above state of the art, the object of the present invention is to provide a production technology by which an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative represented by the following formula (I), which are of value as pharmaceutical intermediates, can be produced with ease and high efficiency from inexpensive starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor; in the formula, R 1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R 2 and R 3 each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 2 and R 3 may jointly form a ring. Under the circumstances, the inventors of the present invention carried out intensive investigations and, as a consequence, developed an expedient technology for producing optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivatives of the following formula (I) from inexpensive, readily available starting materials without using any extraordinary equipment such as an ultra-low-temperature reactor; in the formula, R 1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; R 2 and R 3 each independently represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 2 and R 3 may jointly form a ring. The present invention, therefore, is directed to a production process of an optically active 2-[6-(hydroxymethyl)-1,3-dioxan-4-yl]acetic acid derivative represented by the general formula (I); in the formula, R 1 , R 2 and R 3 are as defined above, which comprises (1) reacting an enolate prepared by permitting a base or a 0-valent metal to act on an acetic acid ester derivative represented by the following formula (II); in-line-formulae description="In-line Formulae" end="lead"? X 1 CH 2 CO 2 R 1 (II) in-line-formulae description="In-line Formulae" end="tail"? in the formula, R 1 is as defined above; and X 1 represents a hydrogen or a halogen atom, with (S)-β-hydroxy-γ-butyrolactone represented by the following formula (III); at a temperature not lower than −30° C. to produce a compound represented by the following formula (IV); in the formula, R 1 is as defined above, (2) treating this compound with an acylating agent in the presence of a base to produce a compound represented by the following formula (V); in the formula, R 1 is as defined above; and R 4 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms, (3) reducing this compound with a microorganism to produce a compound represented by the following formula (VI); in the formula, R 1 and R 4 are as defined above, (4) treating this compound with an acetal-forming reagent in the presence of an acid catalyst to produce a compound represented by the following formula (VII); in the formula, R 1 , R 2 , R 3 , and R 4 are as defined above, and (5) subjecting this compound to solvolysis in the presence of a base. The present invention is also directed to an isolation/purification process which comprises treating a compound contaminated with an impurity and represented by the following formula (V); in the formula, R 1 represents a hydrogen, an alkyl group of 1 to 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 to 12 carbon atoms; and R 4 represents a hydrogen, an alkyl group of 1 and 12 carbon atoms, an aryl group of 6 to 12 carbon atoms, or an aralkyl group of 7 and 12 carbon atoms, with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (V) and obtaining the compound represented by the above formula (V) in a crystal form. Furthermore, the present invention is directed to a production process of a compound represented by the following formula (VI); in the formula, R 1 and R 4 are as defined above, which comprises reducing a compound represented by the following formula (V); in the formula, R 1 and R 4 are as defined above, with a microorganism. In another aspect, the present invention is directed to a production process of a compound represented by the following formula (VII); in the formula, R 1 , R 2 , R 3 and R 4 are as defined above, which comprises treating a compound represented by the following formula (VI); in the formula, R 1 and R 4 are as defined above, with an acetal-forming reagent using an amine salt composed of an acid and an amine as a catalyst. In still another aspect, the present invention is directed to an isolation/purification process which comprises treating a compound represented by the following formula (VI); in the formula, R 1 and R 4 are as defined above, with an acetal-forming reagent in the presence of an acid catalyst to thereby convert the same to a compound represented by the following formula (VII); in the formula, R 1 , R 2 , R 3 and R 4 are as defined above, treating the compound contaminated with an impurity and represented by the above formula (VII) with an aliphatic hydrocarbon solvent to remove the impurity contaminating the compound represented by the above formula (VII) and obtaining the compound represented by the above formula (VII) in a crystal form.

System and method for creating a searchable word index of a scanned document including multiple interpretations of a word at a given document location

Multiple recognition engines (110) provide different interpretations (116) of a word at a given location within a scanned document (108). A word node corresponding to each unique interpretation is stored within a word index (102), with each word node being linked to word nodes of previously and subsequently recognized words.

1. A method in a computer system for creating a searchable word index of a scanned document, the method comprising: generating a first interpretation of a word at a given location within the scanned document using a first recognition engine; generating a second interpretation of the word using a second recognition engine, wherein the second interpretation is different from the first interpretation; storing a first word node in the searchable word index associating the first interpretation of the word and the location of the word within the scanned document; and storing a second word node in the searchable word index associating the second interpretation of the word and the location of the word within the scanned document. 2. The method of claim 1, wherein the first and second recognition engines employ different optical character recognition (OCR) techniques. 3. The method of claim 1, wherein the location of the word is defined by a bounding rectangle. 4. The method of claim 3, wherein the bounding rectangle is defined by at least two coordinates, each coordinate comprising a percentage of a width and a height of the scanned document. 5. The method of claim 1, further comprising: linking the first and second word nodes to at least one word node of a previously recognized word from the scanned document. 6. The method of claim 1, further comprising: linking the first and second word nodes to at least one word node of a subsequently recognized word from the scanned document. 7. The method of claim 1, further comprising: generating a third interpretation of the word using a third recognition engine; determining whether the third interpretation of the word is contained within a word list; and storing a third word node in the searchable word index when the third interpretation of the word is contained within the dictionary, the third word node associating the third interpretation of the word and the location of the word within the scanned document. 8. The method of claim 7, wherein the word list comprises a dictionary. 9. The method of claim 1, further comprising: generating a third interpretation of the word using a third recognition engine; determining whether the third interpretation of the word contains an improbable character triplet; storing a third word node in the searchable word index when the third interpretation of the word does not contain an improbable character triplet, the third word node associating the third interpretation of the word and the location of the word within the scanned document, 10. The method of claim 9, wherein an improbable character triplet comprises three consecutive characters not found within a word of a dictionary. 11. A system for creating a searchable word index of a scanned document, the system comprising: a first recognition engine configured to generate a first interpretation of a word at a given location within the scanned document; a second recognition engine configured to generate a second interpretation of the word, wherein the second interpretation is different from the first interpretation; an index creation component configured to store first and second word nodes in the searchable word index, the first word node associating the first interpretation of the word and the location of the word within the scanned document and the second word node associating the second interpretation of the word and the location of the word within the scanned document. 12. The system of claim 11, wherein the first and second recognition engines employ different optical character recognition (OCR) techniques. 13. The system of claim 11, wherein the location of the word is defined by a bounding rectangle. 14. The system of claim 13, wherein the bounding rectangle is defined by at least two coordinates, each coordinate comprising a percentage of a width and a height of the scanned document. 15. The system of claim 11, further comprising: a linking component configured to link the first and second word nodes to a word node of a previously recognized word from the scanned document. 16. The system of claim 11, further comprising: a linking component configured to link the first and second word nodes to a word node of a subsequently recognized word from the scanned document. 17. The system of claim 11, further comprising: a third recognition engine configured to generate a third interpretation of the word using a third recognition engine; and a word filter configured to determine whether the third interpretation of the word is contained within a word list; wherein the index creation component is further configured to store a third word node in the searchable word index when the third interpretation of the word is contained within the dictionary, the third word node associating the third interpretation of the word and the location of the word within the scanned document. 18. The system of claim 17, wherein the word list comprises a dictionary. 19. The system of claim 11, further comprising: a third recognition engine configured to generate a third interpretation of the word using a third recognition engine; and a word filter configured to determine whether the third interpretation of the word contains an improbable character triplet; wherein the index creation component is further configured to store a third word node in the searchable word index when the third interpretation of the word does not contain an improbable character triplet, the third word node associating the third interpretation of the word and the location of the word within the scanned document, 20. The system of claim 19, wherein an improbable character triplet comprises at three consecutive characters not found within a word of a dictionary. 21. A computer program product on a computer-readable medium for creating a searchable word index of a scanned document, the computer program product comprising: program code for generating a first interpretation of a word at a given location within the scanned document using a first recognition engine; program code for generating a second interpretation of the word using a second recognition engine, wherein the second interpretation is different from the first interpretation; program code for storing a first word node in the searchable word index associating the first interpretation of the word and the location of the word within the scanned document; and program code for storing a second word node in the searchable word index associating the second interpretation of the word and the location of the word within the scanned document. 22. The computer program product of claim 21, wherein the first and second recognition engines employ different optical character recognition (OCR) techniques. 23. The computer program product of claim 21, wherein the location of the word is defined by a bounding rectangle. 24. The computer program product of claim 23, wherein the bounding rectangle is defined by at least two coordinates, each coordinate comprising a percentage of a width and a height of the scanned document. 25. The computer program product of claim 21, further comprising: program code for linking the first and second word nodes to at least one word node of a previously recognized word from the scanned document. 26. The computer program product of claim 21, further comprising: program code for linking the first and second word nodes to at least one word node of a subsequently recognized word from the scanned document. 27. The computer program product of claim 21, further comprising: program code for generating a third interpretation of the word using a third recognition engine; program code for determining whether the third interpretation of the word is contained within a word list; and program code for storing a third word node in the searchable word index when the third interpretation of the word is contained within the dictionary, the third word node associating the third interpretation of the word and the location of the word within the scanned document. 28. The computer program product of claim 7, wherein the word list comprises a dictionary. 29. The computer program product of claim 21, further comprising: program code for generating a third interpretation of the word using a third recognition engine; program code for determining whether the third interpretation of the word contains an improbable character triplet; and program code for storing a third word node in the searchable word index when the third interpretation of the word does not contain an improbable character triplet, the third word node associating the third interpretation of the word and the location of the word within the scanned document, 30. The computer program product of claim 9, wherein an improbable character triplet comprises three consecutive characters not found within a word of a dictionary.

<SOH> TECHNICAL BACKGROUND <EOH>In the field of optical character recognition (OCR), analog documents (e.g., paper, microfilm, etc.) are digitally scanned, segmented, and converted into text that may be read, searched, and edited by means of a computer. In order to provide for rapid searching, each recognized word is typically stored in a searchable word index with links to the location (e.g., page number and page coordinates) at which the word may be found within the scanned document. In some conventional OCR systems, multiple recognition engines are used to recognize each word in the document. The use of multiple recognition engines generally increases overall recognition accuracy, since the recognition engines typically use different OCR techniques, each having different strengths and weaknesses. When the recognition engines produce differing interpretations of the same image of a word in the scanned document, one interpretation is typically selected as the “correct” interpretation. Often, the OCR system rely on a “voting” (winner takes all) strategy with the majority interpretation being selected as the correct one. Alternatively, or in addition, confidence scores may be used. For example, suppose two recognition engines correctly recognize the word “may” with confidence scores of 80% and 70%, respectively, while another recognition engine interprets the same input data as “way” with a 90% confidence score, while yet another recognition engine recognizes the input data as “uuav” with a 60% confidence score. In such an example, a combination of voting and confidence scores may lead to a selection of “may” as the preferred interpretation. Unfortunately, by selecting a single interpretation and discarding the rest, the objectively correct interpretation is also frequently discarded. Often, image noise and other effects confuse a majority of the recognition engines, with only a minority of the recognition engines arriving at the correct interpretation. In the above example, the correct interpretation could have been “way,” which would have been discarded using standard methods. Accordingly, conventional OCR systems have never been able to approach total accuracy, no matter how many recognition engines are employed. What is needed, then, is a system and method for creating a searchable word index of a scanned document including multiple interpretations of a word at a given location within the document. What is also needed is a system and method for creating a searchable word index that selectively reduces the size of the index by eliminating interpretations that are not found in a dictionary or word list. In addition, what is needed is a system and method for creating a searchable word index that permits rescaling of a scanned document without requiring modification of location data within the word index.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>Non-exhaustive embodiments of the invention are described with reference to the figures, in which: FIG. 1 is a block diagram of a conventional system for creating a searchable word index of a scanned document; FIG. 2 is a block diagram of a system for creating a searchable word index of a scanned document including multiple interpretations for a word at a given location within the document; FIG. 3 is block diagram of linked word nodes; FIG. 4 is a block diagram of a system for creating a searchable word index including a word filter in communication with a dictionary; FIG. 5 is a physical block diagram of a computer system for creating a searchable word index of a scanned document including multiple interpretations for a word at a given location within the document; and FIG. 6 is a flowchart of a method for creating a searchable word index of a scanned document including multiple interpretations for a word at a given location within the document. detailed-description description="Detailed Description" end="lead"?

Terry tile board

The board provides protection against damage on a slate shingle and tile roof. The upper side of board with plywood serves as the solid foundation for standing on as tool is laid upon the roof. The opposite or under side has plywood and foam rubber. This side is placed directly onto the roof. An added feature is the board is good on a steep roof.

1. A tool for protection of roofs, the tool consisting of one piece of plywood, having wood slats and a non-slip surface on one side with other side bearing an adhesive and foam rubber.

Acid-sensitive compounds, preparation and use thereof

Novel acid-sensitive compounds comprising at least one hydrophilic substituent and a cyclic ortho-ester which is acid-sensitive, and their salts. These compounds are useful for forming conjugates (liposomes, complexes, nanoparticles and the like) with biologically active substances and releasing them into cellular tissues or compartments whose pH is acidic, or as nonionic surfactant for stabilizing particles encapsulating a biologically active substance and then destabilizing them in acid medium, or alternatively as a vector covalently linked to a therapeutic molecule so as to release said therapeutic molecule into the cellular tissues or compartments whose pH is acidic.

1. Acid-sensitive compounds characterized in that they comprise a cyclic ortho-ester and at least one hydrophilic substituent chosen from polyalkylene glycols, mono- or polysaccharides, hydrophilic therapeutic molecules, or alternatively radicals of the polyamine type, as well as their salts. 2. Acid-sensitive compounds according to claim 1, characterized in that they have the general formula: in which: g is an integer which may take the values 0, 1, 2, 3 or 4, G represents a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms in the form of a saturated or unsaturated, straight or branched chain, or an aryl radical, G1 and G2 represent: (a) one a hydrophilic substituent chosen from radicals of the polyamine type, and the other a hydrophobic substituent chosen from single- or double-chain alkyls, steroid derivatives or hydrophobic dendrimers, or alternatively (b) one a hydrophobic linear alkyl group comprising 10 to 24 carbon atoms and optionally comprising one or more unsaturations, and the other a group of general formula: in which i is an integer ranging from 1 to 4 and j is an integer ranging from 9 to 23, and the hydrophilic substituent is chosen from radicals of the polyamine type, or alternatively (c) one a hydrophilic substituent chosen from polyalkylene glycols or mono- or polysaccharides and the other a substituent chosen from polyalkylene imines, or alternatively (d) one a hydrophilic substituent chosen from polyalkylene glycols or mono- or polysaccharides and the other a hydrophobic substituent chosen from single- or double-chain alkyls, steroid derivatives, hydrophobic dendrimers, or the covalent conjugates between a single- or double-chain alkyl, a steroid derivative, or a hydrophobic dendrimer and a polyalkylene glycol molecule comprising 1 to 20 monomeric units, or alternatively (e) one a hydrophilic substituent chosen from polyalkylene glycols or mono- or polysaccharides and the other a therapeutic molecule, or alternatively (f) one a therapeutic molecule of a hydrophilic nature and the other a hydrophobic substituent chosen from single- or double-chain alkyls, steroid derivatives or hydrophobic dendrimers, as well as their salts. 3. Acid-sensitive compounds according to claim 2, characterized in that G is chosen from hydrogen, methyl, ethyl or phenyl. 4. Acid-sensitive compounds according to claim 2, characterized in that the single- or double-chain alkyls consist of one or two linear alkyl chains comprising 10 to 24 carbon atoms and optionally comprising one or more unsaturations. 5. Acid-sensitive compounds according to claim 2, characterized in that the steroid derivative is chosen from sterols, steroids and steroid hormones. 6. Acid-sensitive compounds according to claim 2, characterized in that the hydrophobic dendrimer is poly(benzyl ether). 7. Acid-sensitive compounds according to claim 2, characterized in that the polyalkylene glycols are chosen from polyalkylene glycols having an average molecular weight of between 102 and 105 Daltons. 8. Acid-sensitive compounds according to claim 7, characterized in that the polyalkylene glycols are chosen from polyethylene glycols (PEG) having an average molecular weight of between 102 and 105 Daltons. 9. Acid-sensitive compounds according to claim 2, characterized in that the mono- or polysaccharides are chosen from pyranoses, furanoses, dextrans, α-amylose, amylopectin, fructans, mannans, xylans and arabinans. 10. Acid-sensitive compounds according to claim 2, characterized in that the polyalkylene glycol or the mono- or polysaccharide is covalently linked to a targeting element. 11. Acid-sensitive compounds according to claim 10, characterized in that the targeting element is chosen from sugars, peptides, proteins, oligonucleotides, lipids, neuromediators, hormones, vitamins or their derivatives. 12. Acid-sensitive compounds according to claim 2, characterized in that the polyalkyleneimines are chosen from the polymers comprising the monomeric units of general formula: in which R may be a hydrogen atom or a group of formula: and n is an integer of between 2 and 10, p and q are integers chosen such that the sum p+q is such that the average molecular weight of the polymer is between 100 and 107 Da, it being understood that the value of n may vary between the different units —NR—(CH2)n-. 13. Acid-sensitive compounds according to claim 2, characterized in that each of the substituents G1 and G2 is indirectly linked to the cyclic ortho-ester via a “spacer” molecule. 14. Acid-sensitive compounds according to claim 13, characterized in that said “spacer” molecule is chosen from alkyls (1 to 6 carbon atoms), carbonyl, ester, ether, amide, carbamate or thiocarbamate bonds, glycerol, urea, thiourea or a combination of several of these groups. 15. Acid-sensitive compounds according to claim 2, characterized in that the therapeutic molecules are chosen from peptides, oligopeptides, proteins, antigens and their antibodies, enzymes and their inhibitors, hormones, antibiotics, analgesics, bronchodilators, antimicrobials, antihypertensive agents, cardiovascular agents, agents acting on the central nervous system, antihistamines, antidepressants, tranquilizers, anticonvulsants, anti-inflammatory substances, stimulants, antiemetics, diuretics, antispasmodics, antiischemics, agents limiting cell death, or anticancer agents. 16. Compositions characterized in that they comprise at least one acid-sensitive compound as defined in claims 1 to 15. 17. Compositions characterized in that they comprise at least one biologically active substance and an acid-sensitive compound as defined in claim 2 and for which G1 and G2 have the definitions indicated under (a), (b), (c) or (d). 18. Compositions according to claim 17, characterized in that said biologically active substance is either a therapeutic molecule as defined in claim 15, or a nucleic acid. 19. Compositions according to either of claims 16 and 17, characterized in that they comprise, in addition, one or more adjuvants. 20. Compositions according to claim 19, characterized in that said adjuvant is one or more neutral lipids. 21. Compositions according to claim 20, characterized in that said adjuvant is chosen from natural or synthetic, zwitterionic lipids or lipids lacking an ionic charge under physiological conditions. 22. Compositions according to claim 21, characterized in that said adjuvant is chosen from dioleoylphosphatidylethanolamine (DOPE), oleoyl-palmitoylphosphatidylethanolamine (POPE), distearoyl-phosphatidylethanolamine, dipalmitoylphosphatidyl-ethanolamine, dimirystoylphosphatidylethanolamine as well as their derivative which are N-methylated 1 to 3 times, phosphatidylglycerols, diacylglycerols, glycosyldiacylglycerols, cerebrosides (such as in particular galactocerebrosides), sphingolipids (such as in particular sphingomyelins) or alternatively asialogangliosides (such as in particular asialoGM1 and GM2). 23. Compositions according to one of claims 16 to 22, characterized in that they comprise, in addition, a pharmaceutically acceptable vehicle for an injectable formulation. 24. Compositions according to one of claims 16 to 22, characterized in that they comprise, in addition, a pharmaceutically acceptable vehicle for administration to the skin and/or the mucous membranes. 25. Use of an acid-sensitive compound as defined in claims 1 to 15 for the manufacture of a medicament intended for treating diseases. 26. Use of an acid-sensitive compound as defined as in claim 2 and for which G1 and G2 have the definitions indicated under (a), (b), (c) or (d), for the manufacture of a medicament intended for the transfection of nucleic acids. 27. Acid-sensitive compounds as defined in claim 2 and for which G1 and G2 have the definitions indicated under (e) or (f) for use as a medicament.

Jaw orthopedic device

The invention comprises a jaw orthopedic device for the movement and/or correction of teeth in the tooth arch with a synthetic resin element and/or at least one mature element or tooth contacting or tooth movement, whereby the synthetic resin element is comprised of a hard synthetic resin material and the synthetic resin element (1) has at least one soft plastic element (3) integrated therewith for tooth contacting or tooth movement.

1. A jaw orthopedic device for the movement and/or correction of teeth in the tooth arch having a synthetic resin element and/or at least one wire element for tooth contacting or tooth movement, whereby the synthetic resin element is comprised of a hard synthetic resin material, characterized in that the synthetic resin element (1) has at least one soft plastic element (3) integrated therein for tooth contacting or tooth movement. 2. The jaw orthopedic device according to claim 1, characterized in that the hard synthetic resin material for the synthetic resin element (1) is comprised of methylmethacrylate or polymethylmethacrylate. 3. The jaw orthopedic device according to claim 1 or 2, characterized in that the soft plastic element (3) is comprised of a silicone material, e.g. from vinylpolysiloxane. 4. The jaw orthopedic device according to one of claims 1 to 3, characterized in that the soft plastic element (3) matches the contour of at least one tooth (4). 5. The jaw orthopedic device according to one of claims 1 to 4, characterized in that the soft plastic element (3) contacts against at least one additional element (5) of the tooth (4) for extrusion, intrusion or rotation of the tooth (4). 6. The jaw orthopedic device according to one of claims 1 to 5, characterized in that the soft plastic element (3) contacts flat against at least one tooth (4). 7. The jaw orthopedic device according to one of claims 1 to 6, characterized in that the soft plastic element (3) serves for positioning at least one tooth (4). 8. The jaw orthopedic device according to one of claims 1 to 7, characterized in that the synthetic resin element (4) serves to guide or anchor the jaw orthopedic device in the tooth arch. 9. The jaw orthopedic device according to one of claims 1 to 8, characterized in that at least one spring (6) is provided for tooth contacting. 10. The jaw orthopedic device according to one of claims 1 to 9, characterized in that at least one screw (7) is provided for tooth contacting. 11. The jaw orthopedic device according to one of claims 9 or 10 characterized in that the spring (6) directly contacts a tooth (4). 12. The jaw orthopedic device according to one of claims 9 to 11, characterized in that the spring (6) contacts at least one tooth (4) indirectly via the soft plastic element (3). 13. The jaw orthopedic device according to one of claims 10 to 12 characterized in that the screw (7) contacts at least one tooth (4) directly. 14. The jaw orthopedic device according to one of claims 10 to 13, characterized in that the screw (7) contacts at least one tooth (4) indirectly via the soft plastic element (3). 15. The jaw orthopedic device according to one of claims 1 to 14, characterized in that the synthetic resin element (1) of the jaws orthopedic device is composed of locally different hard synthetic resin materials. 16. The jaw orthopedic device according to one of claims 1 to 15, characterized in that a plurality of soft plastic elements (3) of different materials is provided. 17. The jaw orthopedic device according to one of claims 1 to 16, characterized in that at least one wire element (2) is incorporated in or on the soft plastic element (3). 18. The jaw orthopedic device according to one of claims 1 to 17, characterized in that at least one wire element (2) is incorporated on the one hand on the synthetic resin element (3) and on the other hand on the soft plastic element (3).

Device for the dosing of a reducing agent

An apparatus for metering a urea or a urea-water solution for delivery to a catalytic converter assembly for removing nitrogen oxides from the exhaust gases of a Diesel engine, includes a housing block supporting function components communicating via a line, formed by recesses in the housing block, for transporting the reducing agent, and the walls of the line are formed by the housing block. This apparatus assures a simple line layout for reducing agent with a minimum number of sealing points that is accordingly appropriate for large-scale mass production.

1-14. (Canceled) 15. An apparatus for metering a reducing agent, in particular urea or a urea-water solution, comprising a housing block, means (4, 7, 11), secured to the housing block for delivering the reducing agent to a catalytic converter assembly (30) for removing nitrogen oxides from the exhaust gases of a Diesel engine, said means communicating via a line (12; 80, 81, 82, 83), formed by recesses in the housing block (400), for transporting the reducing agent, and the walls of the line (12) being formed by the housing block. 16. The apparatus of claim 15, wherein at least one recess (80) rectilinearly traverses the entire housing block (400). 17. The apparatus of claim 15, further comprising a heating element extending generally parallel to at least one recess, said heating element being secured to the housing block or embedded in the housing block. 18. The apparatus of claim 16, further comprising a heating element extending generally parallel to at least one recess, said heating element being secured to the housing block or embedded in the housing block. 19. The apparatus of claim 15, wherein the recesses are embodied as bores. 20. The apparatus of claim 17, wherein the recesses are embodied as bores. 21. The apparatus of claim 19, wherein the housing block is injection-molded. 22. The apparatus of claim 15, wherein the housing block is of plastic. 23. The apparatus of claim 22, wherein the plastic has a low modulus of elasticity in the range from approximately 1000 N/mm2 to approximately 7000 N/mm2. 24. The apparatus of claim 15, wherein all the ends of the line (12) communicate with the means (4, 7, 11) and further function components (1, 14, 50, 110), so that no separate closure elements are required. 25. The apparatus of claim 21, wherein all the ends of the line (12) communicate with the means (4, 7, 11) and further function components (1, 14, 50, 110), so that no separate closure elements are required. 26. The apparatus of claim 15, wherein one end of the line (12) is closed by a compensation element embodied as a spring-loaded flange (110). 27. The apparatus of claim 24, wherein one end of the line (12) is closed by a compensation element embodied as a spring-loaded flange (110). 28. The apparatus of claim 15, wherein the means or further function components are at least in part secured to the housing and connected to the line (12) with the aid of elastic elements (61, 51) in such a way that the applicable means or function components can execute a compensatory motion if ice forms in the line. 29. The apparatus of claim 26, wherein the means or further function components are at least in part secured to the housing and connected to the line (12) with the aid of elastic elements (61, 51) in such a way that the applicable means or function components can execute a compensatory motion if ice forms in the line. 30. The apparatus of claim 28, wherein said means includes a pump (4), and wherein the elastic element that secures the pump is embodied as an elastic sheet-metal angle piece (61) secured to the housing block. 31. The apparatus of claim 28, wherein the function components include a pressure sensor (50), which is secured resiliently to the housing and closes the line (12) in a tightly displaceable manner. 32. The apparatus of claim 15, wherein means include a pressure regulator (11) that has a diaphragm acting to compensate for pressure in the event of ice formation. 33. The apparatus of claim 15, wherein at least one volumetrically elastic component, in particular an air-filled element (63), is disposed in the line.

Starting device

A starter device for internal combustion engines is proposed that comprises a drive mechanism (16) and a gearing (22) having a variable gear ratio, which said gearing is situated after the drive mechanism (16). The starter device (10) is characterized by the fact that the gear ratio of the gearing (22) is infinitely variable.

1. A starter device for internal combustion engines comprising a drive mechanism (16) and a gearing (22) having a variable gear ratio, which said gearing is situated after the drive (16), wherein the gear ratio is infinitely variable. 2. The starter device according to claim 1, wherein the gearing (22) is self-regulating. 3. The starter device according to claim 1, wherein the gearing (22) is capable of being regulated according to a input torque of the drive mechanism (16). 4. The starter device according to claim 1, wherein the gearing (22) is capable of being regulated according to a drive speed of the drive mechanism (16). 5. The starter device according to claim 1, wherein the gearing (22) is a planetary-gear set with a center gear (34) having at least one planet gear (46) and a internal gear (49), and wherein a radial actuating force acting on the at least one planet gear (46) can be achieved by means of the input torque. 6. The starter device according to claim 1, wherein the gearing (22) is a planetary-gear set with a center gear (34) having at least one planet gear (46) and a internal gear (49), and wherein a radial actuating force acting on the at least one planet gear (46) can be achieved by means of the drive speed.

<SOH> BACKGROUND OF THE INVENTION <EOH>The invention concerns a starter device for internal combustion engines according to the general class in the independent claim. A starter device is made known in DE 199 27 905 A1, which said starter device comprises a gearing between a drive element and a pinion, which said gearing has a variable gear ratio. The gearing is a planetary-gear set, the sun gear of which is capable of being driven by the drive element. The output of the planetary-gear set takes place via the planet gears and, therefore, via the planetary carrier. The planetary-gear set makes two different gear ratios possible: in the case of the first gear ratio at low speeds, gear reduction takes place via the internal ring gear, which is held stationary by means of an overrunning clutch. When the drive mechanism reaches a certain speed, a plurality of centrifugal clutch elements attached to the planetary carrier cause the internal ring gear to be held stationary with the planetary carrier; this causes the planetary-gear set to be shifted from gear reduction to a one-to-one gear ratio. The disadvantage of this embodiment is the fact that the assistance provided to run the internal combustion engine up to speed is adjusted optimally at only two operating points.

<SOH> SUMMARY OF THE DRAWINGS <EOH>Exemplary embodiments of a starter device according to the invention are shown in the drawings. FIG. 1 shows a schematic view of a starter device according to the invention. FIG. 2 shows a spacial sectional detail view of the torque-controlled gearing, FIG. 3 shows a spacial sectional detail view of the speed-controlled gearing, FIG. 4 shows a spacial view of the coupled planet gears. detailed-description description="Detailed Description" end="lead"?

Force -transmision unit comprising speed -dependent hydraulic clutch and centrifugal force compensation

A power transmission unit with a hydraulic coupling dependent on a rotational-speed difference, in which, when a rotational-speed difference occurs between the input member (1) and the output member (6), a hydrostatic displacement machine (20) produces in a pressure space (34) a pressure that acts on a piston (27) acting on a friction clutch (31), has a housing (4). To compensate for the centrifugal force acting on the working fluid in the pressure space (34), at least one centrifugal-force element (11, 12, 13) is provided in the housing, exerting on the piston (27) a force counter to the pressure produced by the centrifugal force in the pressure chamber (34).

1. A power transmission unit with an input member and an output member and a hydraulic coupling dependent on a rotational-speed difference, in which, when a rotational-speed difference occurs between the input member (1; 6) and the output member (6; 1), a hydrostatic displacement machine (20) produces in a pressure space (34) a pressure that acts on a piston (27) acting on a friction clutch (31), the friction clutch having first and second disks connected in terms of drive to the input member and the output member respectively, and one of the members (1; 6) forming a housing (4) that contains the displacement machine, wherein at least one centrifugal-force element (11, 12, 13; 41, 44; 50, 55) is provided in the housing, exerting on the piston (27) a force counter to the pressure produced by the centrifugal force in the pressure chamber (34). 2. The power transmission unit as claimed in claim 1, wherein the at least one centrifugal-force element is a flyweight (11). 3. The power transmission unit as claimed in claim 2, wherein the centrifugal-force element is a two-armed lever (12), one leg of which forms the flyweight (11) and the other lever of which forms a pressure finger (13). 4. The power transmission unit as claimed in claim 1, wherein the centrifugal-force element is an annular space (44; 50) that contains an operating fluid and rotates with the housing (4). 5. The power transmission unit as claimed in claim 4, wherein the rotating annular space (44) is formed by a cylindrical sleeve (41) surrounding the housing (4) and having a wall (42) in the form of a circular ring normal to the axis and by a wall (43), normal to the axis, of the housing (4), and wherein the sleeve (41) is connected to the piston (27) and can be displaced in an axial direction. 6. The power transmission unit as claimed in claim 4, wherein the radially outermost zone of the rotating annular space (50) is connected via a passage (54) to a compensation pressure space (57) on the opposite side of the piston (27) from the pressure space (34). 7. The power transmission unit as claimed in claim 6, wherein the compensation pressure space (57) is formed by an annular cylinder (55) in the housing (4) and by an annular continuation (56) on the opposite side of the piston (27) from the pressure space (34).

Encasing arrangement for a semicoductor component

A semiconductor component package configuration includes a semiconductor chip mounted to a printed circuit board, and a substrate arranged between the semiconductor chip and the printed circuit board. The substrate is for routing the wiring terminals of the semiconductor chip to the printed circuit board. The substrate is connected to the printed circuit board by solder joints. A filler between the semiconductor chip and the substrate mechanically isolates the semiconductor chip and the solder joints. A metal layer, which is connected to solder joints, is applied to the substrate. At least one molded element of heat-dissipating material is applied to the metal layer and is connected in a heat-conducting manner to the metal layer. This provides the package configuration with an improved capability of conducting the lost power that is dissipated from the installed semiconductor chip, and the desired mechanical properties of the package arrangement are retained.

1-13. Cancel 14. A semiconductor component package configuration, comprising: a semiconductor chip having wiring terminals; a printed circuit board having said semiconductor component mounted thereon; a substrate configured between said semiconductor chip and said printed circuit board, said substrate for routing said wiring terminals of said semiconductor chip to said printed circuit board; solder joints connecting said substrate to said printed circuit board; a filler configured between said semiconductor chip and said substrate, said filler for mechanically isolating said semiconductor chip and said soldered joints; a metal layer applied to said substrate, said metal layer being connected to at least one of said solder joints; and at least one molded element of heat-dissipating material applied to said metal layer, said molded element connected in a heat-conducting manner to said metal layer, said molded element not directly contacting said semiconductor chip. 15. The configuration according to claim 14, wherein: said molded element is configured between said substrate and said semiconductor chip and protrudes into said filler; and said molded element is at a distance of about 10-20 μm from said semiconductor chip. 16. The configuration according to claim 15, wherein: said molded element is formed as a cylinder. 17. The configuration according to claim 14, wherein: said molded element is formed from metal. 18. The configuration according to claim 17, wherein: said molded element has been electrodeposited onto said metal layer. 19. The configuration according to claim 17, wherein: said molded element has been applied to said metal layer by a mask etching process. 20. The configuration according to claim 14, wherein: said substrate has a side facing said semiconductor chip; said semiconductor chip has a side; and said molded element is configured on said side of said substrate facing said semiconductor chip and to said side of said semiconductor chip. 21. The configuration according to claim 20, wherein: said molded element is formed as an electrically conductive, metallic frame surrounding said semiconductor chip; and said molded element is connected to ground potential. 22. The configuration according to claim 20, comprising: a heat-conducting adhesive connecting said molded element to said metal layer. 23. The configuration according to claim 20, wherein: said molded element is bonded to said metal layer. 24. The configuration according to claim 20, comprising: an additional, electrically non-conducting, thermally conductive connection configured between said semiconductor chip and said molded element.

Termination device e.g. for a multiconnector

A termination device e.g. for a multiconnector comprises a cover (2) which is rotatably hinged to a housing (1), and which has a hole for receiving a cable containing a plurality of wires (5a-e). When the individual wires are arranged in respective slits in the cover, the housing and the cover may be rorated mutually to a closed position, so that the wires are gradually inserted into respective terminals for providing an electrical connection. This reduces the required closing force, and the cover may therefore be closed by hand without the use of a special tool.

1. A termination device, e.g. for a multiconnector and comprising a plurality of protruding terminals and a cover which, upon closing of the device, is adapted to guide and force a wire associated with each terminal down into the terminal to provide an electrical connection between the wire and the terminal, and wherein the cover is hinged to the device such that the wires may be positioned correctly in an open position, and such that the wires are in place in the respective terminals in a closed position, characterized in that a first number of terminals distributed in directions crosswise of the hinge axis is greater than a second number of terminals distributed in direction parallel to said axis and that the distance from the hinge axis to the terminals varies substantially evenly distributed between a smallest distance and a greatest distance. 2. A device according to claim 1, characterized in that all terminals are mutually differently spaced from the hinge axis. 3. A device according to claims 1-2, characterized in that the terminals are elastically movable transversely to the hinge axis. 4. A device according to claims 1-3, characterized in that the slit between the terminals for receiving a wire is arc-shaped and substantially concentric with the hinge axis. 5. A device according to claims 1-4, characterized in that the cover has grooves for receiving an associated wire and for guiding the wire when the cover is closed. 6. A device according to claim 5, characterized in that the grooves have a width corresponding to the thickness of the wires. 7. A device according to claim 5, characterized in that the grooves close to the hinge axis are wider than the grooves further away from the hinge axis, measured transversely to the hinge axis. 8. A device according to claims 5-7, characterized in that the grooves are open out toward a pair of opposed sides of the cover. 9. A device according to claims 5 8, characterized in that the grooves are positioned at the bottom of the cover, and that the cover has a through hole from top to bottom for receiving a cable which contains said wires. 10. A device according to claims 5-9, characterized in that at least one of the sides of the cover has a hole for receiving a cable which contains said wires.

Compounds and methods for the treatment of pain

2-substituted 7-chloro-4-hydroxy-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione compounds, pharmaceutical compositions and methods for the treatment of pain are disclosed.

1. A compound selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{[4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-[2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(-1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione. 2. A method for treating a subject suffering from pain comprising administering a pain-ameliorating effective amount of a compound selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-hydroxy-5(hydroxymethyl)-2-methyl(4-pyridyl)]methyl-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-(tetrahydrofuran-2-ylmethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[1-(4-methoxycarbonylphenyl)ethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{[4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-[2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(-1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione. 3. A pharmaceutical composition comprising a pain-ameliorating effective amount of a compound selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-hydroxy-5(hydroxymethyl)-2-methyl(4-pyridyl)]methyl-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-(tetrahydrofuran-2-ylmethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[1-(4-methoxycarbonylphenyl)ethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{[4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-[2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(-1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; together with a pharmaceutically-acceptable excipient or diluent;

<SOH> FIELD OF THE INVENTION <EOH>This invention relates to the treatment or prevention of pain or nociception.

<SOH> SUMMARY OF THE INVENTION <EOH>It has now been discovered that certain compounds which exhibit the property of binding to the NMDA receptor glycine site have utility for the amelioration of pain and particularly for the amelioration of neuropathic pain. Therefore, in a first aspect the present invention provides compounds, or pharmaceutically-acceptable salts thereof, selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-[2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(-1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione. In another aspect the invention comprises a pharmaceutical composition comprising a pain-ameliorating effective amount of a compound, or a pharmaceutically-acceptable salt thereof, selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-hydroxy-5(hydroxymethyl)-2-methyl(4-pyridyl)]methyl-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-(tetrahydrofuran-2-ylmethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[1-(4-methoxycarbonylphenyl)eth-1-yl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-[2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(−1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; together with a pharmaceutically-acceptable excipient or diluent; In a further aspect, the invention provides a method for the treatment of pain comprising administering a pain-ameliorating effective amount of a compound selected from: 7-chloro-4-hydroxy-2-(4-[1,3,4]oxadiazol-2-yl-benzyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-(1H-tetrazol-5-yl)-benzyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[3-hydroxy-5(hydroxymethyl)-2-methyl(4-pyridyl)]methyl-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,0-dione; 7-chloro-4-hydroxy-2-(tetrahydrofuran-2-ylmethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[5-(4-methoxyphenyl)-[1,3,4]oxadiazol-2-ylmethyl]-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 7-chloro-4-hydroxy-2-[1-(4-methoxycarbonylphenyl)ethyl)-1,2,5,10-tetrahydropyridazino[4,5-b]quinoline-1,10-dione; 4-[(7-chloro-4-hydroxy-1,10-dioxo-2,5-dihydropyridazino[4,5-b]quinolin-2-yl)methyl]benzaldehyde; N-(1-aza-2-{[4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)(tert-butoxy)carboxamide; 2-({4-2-aza-2-(2-pyridylamino)vinyl]phenyl}methyl)-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione; N-(-1-aza-2-{4-[(7-chloro-4-hydroxy-1,10-dioxo(2,5-dihydropyridazino[4,5-b]quinolin-2-yl))methyl]phenyl}vinyl)benzamide, and 2-{[4-(2-aza-2-{[(2,4,6-trimethylphenyl)sulfonyl]amino}vinyl)phenyl]methyl}-7-chloro-4-hydroxy-2,5-dihydropyridazino[4,5-b]quinoline-1,10-dione. Other aspects of the invention are methods for making the compounds disclosed herein. Yet other aspects of the invention are pharmaceutical compositions which contain a compound disclosed herein; the use of such compounds for the preparation of medicaments and pharmaceutical compositions, and a method comprising binding a compound of the invention to the NMDA receptor glycine site of a warm-blooded animal, such as a human being, so as to beneficially inhibit the activity of the NMDA receptor. detailed-description description="Detailed Description" end="lead"?

Repressible sterility of animals

A construct which allows animals to be bred in captivity but renders them infertile in the wild by allowing reversible control over fertility and reproduction. The construct comprises: a first promoter that is activated in a defined spatial (tissue specific) or temporal manner linked to DNA encoding a transactivating protein; and a second promoter, which is activated by the transacting protein, linked to DNA encoding a blocker molecule which disrupts gametogenesis or embryogenesis. Feeding an animal a molecule that prevents the transactivating protein binding the second promoter controls fertility.

1. A method of controlling fertility in an animal comprising the steps of: 1) stably transforming an animal cell or single celled embryo with a construct comprising: a) a first nucleic acid molecule, which is activated in a defined spatio-temporal pattern, and which is operably linked to b) a second nucleic acid molecule, which encodes a transactivating protein; and c) a third nucleic acid molecule, which is operably linked to a fourth nucleic acid molecule, wherein activation of said first nucleic acid molecule controls the expression of the second nucleic acid molecule, which in turn activates the third nucleic acid molecule, which effects the expression of the fourth nucleic acid molecule which encodes a blocker molecule which disrupts gametogenesis or embryogenesis in the animal; and 2) and growing a whole animal directly from that cell or implanting the cell into a host animal, whereby a whole animal develops from the implanted cell. 2. The method of claim 1, wherein said first or said fourth nucleic acid molecule is transiently activated or transiently affects development in a defined spatio-temporal pattern. 3. The method of claim 1, wherein each of the first, second, third and fourth nucleic acids is genomic DNA, cDNA, RNA, or a hybrid molecule thereof. 4. The method of claim 3, wherein the nucleic acid molecule is a full-length molecule, or a biologically active fragment thereof. 5. The method of claim 1, wherein the first nucleic acid molecule is a DNA molecule encoding a promoter region. 6. The method of claim 5, wherein the promoter is activated only during embryonic development and/or gametogenesis, and is crucial for completion of embryogenic development and/or gametogenesis. 7. The method of claim 5, wherein the promoter comprises the nucleotide sequence of SEQ ID NO:1, SEQ. ID NO:8, or SEQ ID NO:60. 8. The method of claim 1, wherein the second nucleic acid molecule is a cDNA molecule encoding a tetracycline-responsive transcriptional activator protein. 9. The method of claim 8, wherein said tetracycline-responsive transcriptional activator protein comprises the nucleotide sequence of SEQ ID NO:2. 10. The method of claim 1, wherein the third nucleic acid molecule encodes a repressible promoter. 11. The method of claim 10, wherein the promoter consists of a tet-responsive element (TRE) which is coupled to and tightly regulates a minimal promoter region. 12. The method of claim 11, wherein said minimal promoter region is a PminCMV promoter region that comprises the sequence of SEQ ID NO:3. 13. The method of claim 1, wherein the fourth nucleic acid molecule encodes a blocker molecule selected from the group consisting of an antisense RNA, a double-stranded RNA (dsRNA), a sense RNA and a ribozyme. 14. The method of claim 13, wherein the molecule is dsRNA or sense RNA that when mis-expressed disrupts development in a defined spatio-temporal pattern. 15. The method of claim 13, wherein the RNA is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NO:13, SEQ ID NO:62, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID:61. 16. The method of claim 1, wherein said animal cell or said single celled embryo is transformed with said construct by microinjection, transfection or infection, wherein said construct stably integrates into the genome of said cell or said single celled embryo by homologous recombination. 17. A nucleic acid molecule, which encodes a promoter and is transiently activated in a defined spatio-temporal pattern, wherein said nucleic acid molecule comprises the nucleotide sequence of SEQ ID NO:1, SEQ ID NO:8, or SEQ ID NO:60. 18. A nucleic acid molecule, which encodes a promoter having: a) a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:8 and SEQ ID NO:60; b) a biologically active fragment of the sequence in a); c) a nucleic acid molecule which has at least 85% sequence homology to the sequence in a) or b); or d) a nucleic acid molecule which is capable of hybridizing to the sequence in a) or b) under stringent conditions. 19. A nucleic acid molecule that encodes the coding region of a gene including: a) a nucleotide sequence selected from the group consisting of SEQ ID NO:63, SEQ ID NO:23, SEQ ID NO:24 and SEQ ID NO 61; b) a biologically active fragment of any one of the sequences in a); c) a nucleic acid molecule that has at least 85% sequence homology with any one of the sequences disclosed in a) or b); or d) a nucleic acid molecule that specifically hybridizes to any one of the sequences disclosed in a) or b) under stringent conditions. 20. A nucleic acid molecule that encodes a blocker molecule that disrupts gametogenesis or embryogenesis in an animal, wherein the blocker molecule is encoded, or partially encoded, by a sequence selected from the group consisting of SEQ ID NO:13, SEQ ID NO:62, SEQ ID NO:23 and SEQ ID NO:61. 21. The nucleic acid molecule of claim 20, wherein the blocker molecule is selected from the group consisting of an antisense RNA, a dsRNA, a sense RNA and a ribozyme. 22. The nucleic acid molecule of claim 21, wherein the molecule is a dsRNA or a sense RNA that when mis-expressed disrupts development in a defined spatio-temporal pattern. 23. A transgenic non-human animal stably transformed with the nucleic acid molecule of claim 17. 24. The transgenic non-human animal of claim 23, wherein the animal is selected from the group consisting of fish, mammals, amphibians, and molluscs.

<SOH> BACKGROUND OF THE INVENTION <EOH>Feral animals are one of the world's major environmental problems. Goats, cats, rabbits and carp are only the more prominent of hundreds of species traded internationally for recreation or agriculture that have escaped into the wild and formed destructive populations. Terrestrial, freshwater and marine ecosystems are all conspicuously degraded by these species, to the extent that public concern over feral animals has become a major issue for industries seeking to introduce new species in order to compete on world markets. A good recent example is the Pacific oyster. Despite the promise of new jobs in coastal communities and an industry that is worth $50-75 million annually, recent applications to expand the geographic area for Pacific oyster mariculture facilities in Australia and the United States have been rejected indefinitely until the problem of feral oysters can be overcome. Even plans to expand the size of the industry in areas where farming already occurs are being blocked for the same reason, following very public and often acrimonious debate between industry and conservation-minded elements of the community. Attempts to solve the problem using current techniques such as triploidy and sterile hybrids have not been successful. Neither technique can guarantee a zero risk of producing feral populations, and both also suffer major technical difficulties. In the case of oysters, for example, animals sterilised via chemical or genetic manipulation of ploidy do not produce significant amounts of roe, which substantially reduces their market value. Moreover, these animals still produce a small number of viable gametes. So the debate continues to focus on whether degraded beaches are an acceptable price for new industries and jobs. Hundreds of species of exotic animals are shipped internationally each day, mainly for recreational purposes. Inevitably, either accidentally and/or through intentional release, some animals will escape, and establish feral populations. Sterilisation prior to importation of such exotics would prevent the establishment of feral populations and remove the risk of forming new problem pest species. A generic means of sterilisation that prevents development of these feral populations would have huge economic and environmental benefits. More recently, the containment of genetically modified animals has caused concern. For example, Salmon containing genes for enhanced production of growth hormones have been produced in Europe, New Zealand and North America. Concern has been expressed about the impact of these fish as “super-competitors”, should they escape and form feral populations. Similar concerns have been expressed about other genetic improvements that deliberately or accidentally enhance competitiveness. This concern has now grown to a point where there is pressure to ban such modified organisms in toto. However, given their economic significance, it may be preferable to have effective biological controls in place which enable these organisms to be contained within a specific locality. A sterile feral construct inserted into the genetically enhanced stock would prevent development of viable feral populations, as well as preventing integration of enhanced genes into populations of wild con-specifics. Accordingly, some of the major benefits that a sterile feral construct would offer include: 1. Provision of a fail-safe system for preventing the establishment of feral populations of exotic species. This could fundamentally change the risk of importing these species, and would reduce public antagonism to farming of those that have the potential to be environmentally destructive. 2. Protection of investments in breeding stocks, for example those developed by extensive selective breeding programs. Currently, the commercial advantages from improved stock can be lost when live, reproductively capable animals are marketed (eg oysters, prawns, and sheep). Repressible sterility can be used as a “lock and key” process whereby improved stock could only breed when provided the correct combination of repressers (and optionally inducers) in exactly the right sequence. 3. Production of animals for intentional release that are guaranteed to be sterile. Release of such sterile animals has been used as a control mechanism for certain highly fecund pest species, eg. insects. Repressible sterility technology makes it possible to apply similar approaches to other, existing pest species, for which there are currently no “sterile male” equivalents. 4. Provision of an effective containment mechanism for genetically modified organisms. Repressible sterility provides just such a security system for future applications of molecular engineering in animal production, yet enables safe propagation of these individuals using conventional rearing facilities. Linking a genetically engineered process (faster growth, longer spawning seasons, etc.) to a repressible sterility construct ensures that genetic enhancements of exotic or native species do not enter wild populations. One method of containing genetically-modified organisms, namely, plants, is the so-called “terminator gene” or Technology Protection System (TPS). This approach was developed by Delta and Pine Land Company (D&PL), who jointly owns the rights for this invention with USDA-ARS, as disclosed in U.S. Pat. No. 5,723,765, which is incorporated herein by reference. Essentially, the method stops the seeds of certain plants from germinating, and utilizes: 1. A transiently-active promoter operably linked to a first (toxic, hence lethal) gene, but separated by a blocking sequence which prevents the lethal gene expression; 2. A second gene, encoding a recombinase which, upon expression, excises the blocker sequence; and 3. A third gene, encoding a tetracycline-controllable blocker of the recombinase. Unless the seeds of the plants are transformed with all three genes, and receive the tetracycline at a precise point, the recombinase is expressed, resulting in the blocker sequence being excised, and the toxic gene being expressed. While this method may function well in plants, it would not function in many animal species. Few recombinases have been identified that will function in animals (and vertebrates in particular) and those that have been identified (eg., Cre and Flp recombinase) function in only a limited number of species. Moreover, the use of a toxic substance in animals may be unacceptable, particularly for those likely to be consumed. Further, the system requires a number of complex steps, which are not readily achieved, and once the blocker sequence has been excised it is virtually impossible to reverse the control process. Accordingly, there is still a need to provide methods of preventing the escape of exotic and/or genetically modified animals. We have now developed such a method. We have designed certain genetic constructs that allow animals to be bred in captivity, but render them reproductively non-viable or infertile in the wild. Moreover, these constructs provide reversible control over fertility and reproduction, and are applicable to a wide variety of animal species.

<SOH> SUMMARY OF THE INVENTION <EOH>In its most general aspect, the invention disclosed herein provides a nucleic acid construct which may be inserted into the genome of any target organism. The construct can use any promoter/gene combinations, provided that they satisfy the criteria of being activated only during embryonic development and/or gametogenesis, and being crucial for completion of embryogenic development and/or gametogenesis. One type of construct, which is designed to function in a variety of target species, comprises: a) a native promoter of a crucial gene; b) a blocking DNA sequence (blocker) contoured for and designed to abrogate the crucial gene's function or to cause its mis-expression; and c) a genetic switch to regulate controlled expression/repression of the blocker/gene knockout. In captivity, expression of the blocker can be repressed in the presence of a trigger molecule, supplied via the diet or in soluble form, so that fertilisation occurs and embryos complete development. In the wild, where the trigger molecule is unavailable, the blocker remains active and the critical gene is disrupted, leading to early death of invasive progeny. Accordingly, in a first aspect, the present invention provides a construct for disrupting gametogenesis or embryogenesis in animals, comprising: a) a first nucleic acid molecule, which is activated in a defined spatio-temporal pattern, and which is operably linked to b) a second nucleic acid molecule, which encodes a transactivating protein; and c) a third nucleic acid molecule, which is operably linked to a fourth nucleic acid molecule, wherein activation of said first nucleic acid molecule controls the expression of the second nucleic acid molecule, which in turn activates the third nucleic acid molecule, which effects the expression of the fourth nucleic acid molecule which encodes a blocker molecule which disrupts gametogenesis or embryogenesis in the animal. Either or both the first and fourth nucleic acid molecules are transiently activated or transiently affect development in a defined spatio-temporal pattern. Each of the first, second, third and fourth nucleic acids may be genomic DNA, cDNA, RNA, or a hybrid molecule thereof. It will be clearly understood that the term nucleic acid molecule encompasses a full-length molecule, or a biologically active fragment thereof. Preferably the first nucleic acid molecule is a DNA molecule encoding a promoter region. More preferably the promoter is activated only during embryonic development and/or gametogenesis, and is crucial for completion of embryogenic development and/or gametogenesis. Most preferably this DNA molecule has the nucleotide sequence shown in SEQ ID NO:1, SEQ. ID NO:8 SEQ ID NO:60. A sample of SEQ ID NO.1 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09098. A sample of SEQ ID NO.8 DNA was deposited at the Australian Government Analytical Laboratories on ______, and accorded the accession number ______. A sample of SEQ ID NO.60 DNA was deposited at the Australian Government Analytical Laboratories on 23 Dec. 1999, and accorded the accession number NM99/09106. Preferably the second nucleic acid molecule is a cDNA molecule encoding the tetracycline-responsive transcriptional activator protein (tTA), as defined herein, having a nucleotide sequence of SEQ ID NO:2. A sample of SEQ ID NO.2 cDNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09099. Preferably the third nucleic acid molecule is DNA molecule encoding a repressible promoter. More preferably the promoter consists of the tet responsive element (TRE) which is coupled to and tightly regulates a minimal promoter region. Most preferably this comprises the tet responsive element (TRE) and the P minCMV as shown in SEQ ID NO:3. A sample of SEQ ID NO.3 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09100. Preferably the fourth nucleic acid molecule encodes a blocker molecule selected from the group consisting of antisense RNA, double-stranded RNA (dsRNA), sense RNA and ribozyme. More preferably the molecule is dsRNA or sense RNA that when mis-expressed disrupts development in a defined spatio-temporal pattern. Most preferably this RNA molecule is encoded by the nucleotide sequence shown in SEQ ID NO:13, SEQ ID NO:62, SEQ ID NO:23, SEQ ID NO:24, and SEQ ID:61. A sample of SEQ ID NO.13 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09100. A sample of SEQ ID NO:62 DNA was deposited at the Australian Government Analytical Laboratories on ______, and accorded the accession number ______. A sample of SEQ ID NO.23 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number NM99/09101. A sample of SEQ ID NO.24 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number NM99/09102. A sample of SEQ ID NO.61 DNA was deposited at the Australian Government Analytical Laboratories on 23 Dec. 1999, and accorded the accession number NM99/09107. In a second aspect, the present invention provides a nucleic acid molecule, which encodes a promoter and is transiently activated in a defined spatio-temporal pattern. More preferably, the promoter is active only during a narrow window during embryogenesis or larval development. Most preferably the nucleic acid is a promoter having a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:8 and SEQ ID NO:60. In a third aspect, the present invention provides a nucleic acid molecule, which encodes a promoter having: a) a nucleotide sequence as shown in SEQ ID NO:1, SEQ ID NO:8 and SEQ ID NO:60; or b) a biologically active fragment of the sequence in a); or c) a nucleic acid molecule which has at least 75% sequence homology to the sequence in a) or b); or d) a nucleic acid molecule which is capable of hybridizing to the sequence in a) or b) under stringent conditions. In a fourth aspect, the present invention provides a nucleic acid molecule that encodes the coding region of a gene including: a) a nucleotide sequence selected from the group consisting of SEQ ID NO:63, SEQ ID NO:23, SEQ ID NO:24 and SEQ ID NO 61 or b) a biologically active fragment of any one of the sequences in a); or c) a nucleic acid molecule which has at least 75% sequence homology with any one of the sequences disclosed in a) or b); or d) a nucleic acid molecule that is capable of binding to any one of the sequences disclosed in a) or b) under stringent conditions. A sample of SEQ ID NO.63 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09100. A sample of SEQ ID NO.23 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number NM99/09101. A sample of SEQ ID NO.24 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number NM99/09102. A sample of SEQ ID NO.61 DNA was deposited at the Australian Government Analytical Laboratories on 23 Dec. 1999, and accorded the accession number NM99/09107. In a fifth aspect, the present invention provides a nucleic acid molecule which encodes a blocker molecule wherein the blocker molecule is capable of disrupting gametogenesis or embryogenesis in an animal. Preferably the blocker molecule is selected from the group consisting of antisense RNA, dsRNA, sense RNA and ribozyme. More preferably the molecule is dsRNA or sense RNA that when mis-expressed disrupts development in a defined spatio-temporal pattern. Most preferably the blocker molecule is encoded, or partially encoded, by a sequence selected from the group consisting of SEQ ID NO:13, SEQ ID NO:62, SEQ ID NO:23 and SEQ ID NO:61. A sample of SEQ ID NO.13 DNA was deposited at the Australian Government Analytical Laboratories on 22 Dec. 1999, and accorded the accession number MM99/09100. A sample of SEQ. ID NO.62 DNA was deposited at the Australian Government Analytical Laboratories on ______, and accorded the accession number ______. A sample of SEQ ID NO.61 DNA was deposited at the Australian Government Analytical Laboratories on 23 Dec. 1999, and accorded the accession number NM99/09107. In an sixth aspect, the present invention provides a construct for disrupting gametogenesis or embryogenesis in animals, comprising: a) a first nucleic acid molecule, which is transiently activated in a defined spatio-temporal pattern, and which is operably linked to b) a second nucleic acid molecule, which encodes a blocker molecule. wherein activation of said first nucleic acid molecule controls the expression of the second nucleic acid which disrupts gametogenesis or embryogenesis in the animal. In a seventh aspect, the present invention provides a method of preventing embryogenesis in animals comprising the steps of: 1) stably transforming an animal cell with a construct according to the invention; and 2) implanting the cell into a host organism, whereby a whole animal develops from the implanted cell. Preferably, the stable transformation is effected by microinjection, transfection or infection, wherein the construct stably integrates into the genome by homologous recombination. In an eighth aspect, the present invention provides a transgenic animal stably transformed with a construct according to the invention. Preferably the host organism is of the same genus as the transformed cell. More preferably the host organism is any animal, including vertebrates and invertebrates. Most preferably the host organism is selected from the group consisting of fish, mammals, amphibians, and mollusc. Fish include; but are not limited to, zebrafish, European carp, salmon, tilapia and trout. Mammals include; but are, not limited to, cats, dogs, donkeys, camels, rabbits, rats, and mice. Molluscs include; but are not limited to, Pacific oysters, zebra mussels, striped mussels, abalone, pearl oysters, and scallops. Modified and variant forms of the constructs may be produced in vitro, by means of chemical or enzymatic treatment, or in vivo by means of recombinant DNA technology. Such constructs may differ from those disclosed, for example, by virtue of one or more nucleotide substitutions, deletions or insertions, but substantially retain a biological activity of the construct or nucleic acid molecule of this invention.

Image pickup device, and image pickup device assembling method

The invention integrally arranges a lens, an optical filter, a semiconductor imaging device, on-chip components, and a printed circuit board on a three-dimensional circuit board and contrives the lens attachment structure, bonding method, color of an adhesive, masking of the lens, etc. in order to implement a structure that allows high performance, compact, lightweight and rigid design, and mass production, as well as a high-quality picture.

1. Imaging apparatus comprising: a semiconductor imaging device on a surface of the imaging apparatus; and a three-dimensional circuit board above said semiconductor imaging device. 2. Imaging apparatus comprising: a three-dimensional circuit board having a leg and a cylindrical barrel provided on the leg; a semiconductor imaging device attached on back of said leg; and a lens, supported inside said barrel, to impinge a light onto said semiconductor imaging device. 3. Imaging apparatus according to claim 1 or 2, characterized in that said three-dimensional circuit board includes: a barrel of a bottomed cylinder shape supporting said lens; a leg connected to said barrel, inside of which is formed said wiring pattern; and an opening formed at the boundary between said barrel and the leg, that said optical filter is arranged above said opening of said three-dimensional circuit board, and that said semiconductor imaging device and said on-chip components are arranged below said opening. 4. Imaging apparatus according to claim 1 or 2, characterized in that said three-dimensional circuit board comprises a recessed shoulder where a wiring pattern is formed inside said leg and that on said recessed shoulder is arranged a printed circuit board with an LSI and on-chip components joined on one surface or both surfaces. 5. Imaging apparatus according to claim 3, characterized in that said three-dimensional circuit board has a wiring pattern for directly providing an electric connection between said three-dimensional circuit board and another printed circuit board on the bottom of said leg. 6. Imaging apparatus according to claim 5, characterized in that said three-dimensional circuit board has a plurality of adhesive injection grooves for injecting an adhesive on the upper area of the inner circumference of said barrel. 7. Imaging apparatus according to claim 6, characterized in that the inner circumference of said barrel of said three-dimensional circuit board is formed while tapering downward adjacent to said adhesive injection grooves. 8. Imaging apparatus according to claim 6 or 7, characterized in that said adhesive is black. 9. Imaging apparatus according to any one of the claims 6 through 8, characterized in that in the lower area of said barrel of said three-dimensional circuit board is provided an adhesive reservoir. 10. Imaging apparatus according to any one of the claims 1 through 9, characterized in that the sections other than the effective section of the lens on the front of the lens are masked. 11. Imaging apparatus according to any one of the claims 1 through 10, characterized in that the said optical filter is omitted. 12. A imaging apparatus assembling method characterized in that, with respect to a three-dimensional circuit board having a barrel of a bottomed cylinder shape, a leg connected to said barrel inside of which is formed a wiring pattern and an opening formed at the boundary between said barrel and the leg, said method comprises a step of joining a lens with the inner circumference of said barrel, a step of joining a semiconductor imaging device with said wiring pattern so as to block said opening from the back of said leg, and a step of joining on-chip components with said wiring pattern. 13. A imaging apparatus assembling method characterized in that, with respect to a three-dimensional circuit board having a barrel of a bottomed cylinder shape, a leg connected to said barrel, inside of which is formed a wiring pattern and an opening formed at the boundary between said barrel and the leg, said method comprises a step of joining a lens with the inner circumference of said barrel, a step of joining a semiconductor imaging device with said wiring pattern so as to block said opening from the back of said leg, a step of joining on-chip components with said wiring pattern, and a step of joining with said recessed shoulder a printed circuit board with an LSI and on-chip components joined in advance on one surface or both surfaces. 14. A imaging apparatus assembling method characterized in that, with respect to a three-dimensional circuit board having a barrel of a bottomed cylinder shape, a leg connected to said barrel, inside of which is formed a wiring pattern and an opening formed at the boundary between said barrel and the leg, said method comprises a step of joining an optical filter so as to block said opening from said barrel side, a step of joining a lens with the inner circumference of said barrel, a step of joining a semiconductor imaging device with said wiring pattern so as to block said opening from the back of said leg, and a step of joining on-chip components with said wiring pattern. 15. A imaging apparatus assembling method characterized in that, with respect to a three-dimensional circuit board having a barrel of a bottomed cylinder shape, a leg connected to said barrel, inside of which is formed a wiring pattern and an opening formed at the boundary between said barrel and the leg, said method comprises a step of joining an optical filter so as to block said opening from said barrel side, a step of joining a lens with the inner circumference of said barrel, a step of joining a semiconductor imaging device with said wiring pattern so as to block said opening from the back of said leg, a step of joining on-chip components with said wiring pattern, and a step of joining with said recessed shoulder a printed circuit board with an LSI and on-chip components joined in advance on one surface or both surfaces. 16. A imaging apparatus assembling method according to any one of the claims 12 through 15 characterized in that said method comprises a step of joining an assembled three-dimensional circuit board to another printed circuit board via a wiring pattern formed on the bottom of its leg.

<SOH> BACKGROUND OF THE INVENTION <EOH>Conventionally, concerning imaging apparatus of this type, as the semiconductor imaging device to convert a picture shot by lenses to an electric signal has become smaller and high-performance, the camera has become compact and has been used in various applications thus enhancing the society's convenience. Smaller cameras have widely used in the market of a camera as a picture input sensor. The imaging apparatus that uses a conventional. semiconductor device has combined components such as a lens, a semiconductor-imaging device and an LSI into case or a structure respectively. The printed circuit board of the apparatus has a form of a plane on which components necessary for driving the semiconductor-imaging device are mounted. However, in the method for assembling conventional cameras, reduction of the size of the camera is limited as long as the components are connected to each other even when the semiconductor-imaging device is downsized, that is, an expertise is required for assembling or an automatic machine cannot be used for the assembling procedure. The present invention solves the above problems and provides imaging apparatus that allows further downsizing and assembling using an automatic machine and its assembling method.

<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 is a perspective view of imaging apparatus in Embodiment 1 of the invention. FIG. 2 is a sectional view of imaging apparatus in Embodiment 1 of the invention. FIG. 3 is a sectional view of imaging apparatus in Embodiment 2 of the invention. FIG. 4 is a perspective view of the bottom of a three-dimensional circuit board in the embodiments of the invention. FIG. 5 is a schematic view of an optical system in the embodiments of the invention. FIG. 6 is a characteristic diagram showing the sensitivity characteristic of a semiconductor imaging device in the embodiments of the invention. FIG. 7 is a schematic view of another optical system in the embodiments of the invention. FIG. 8 is a perspective view of imaging apparatus showing the adhesive injecting method in the embodiments of the invention. FIG. 9 is a sectional view of imaging apparatus showing the adhesive injecting method in the embodiments of the invention. FIG. 10 is a sectional view of imaging apparatus showing the irregular reflection prevention method in the embodiments of the invention. FIG. 11 is a partial sectional view of imaging apparatus showing the adhesive seeping prevention method in the embodiments of the invention. FIG. 12 is a perspective view of imaging apparatus showing the lens mask in the embodiments of the invention. FIG. 13 is front view of a lens equipped with a lens mask in the embodiments of the invention. FIG. 14 is front view of a lens without a lens mask in the embodiments of the invention. detailed-description description="Detailed Description" end="lead"? In the figures, a numeral 1 represents a three-dimensional circuit board, 1 A a leg, 1 B a barrel, 1 C an opening, 1 D a recessed shoulder, 2 a lens, 3 an optical filter, 4 a semiconductor imaging device, 5 bonding points (adhesive injection grooves), 6 a lens mask, 7 an adhesive reservoir, 8 on-chip components, 9 an adhesive, 10 a printed circuit board, 11 a an LSI, 11 b on-chip components, 12 a dropping pipet, 13 a printed circuit board, 14 solder, 15 a taper, 16 incident lights, 17 an optical axis, 18 a bottom of a three-dimensional circuit board, 19 a side of a three-dimensional circuit board, 22 a pattern, and 23 a video amplifier circuit.

Ultrasonic diagnosing apparatus

An ultrasonic diagnostic apparatus transmits an ultrasonic beam into an object to be examined using a multi-ring arrangement formed with transducer elements arrayed two-dimensionally in concentric rings and receives an echo so as to create a tomogram or a three-dimensional image of the object. To correct for focusing error due to the difference in length of ultrasound propagating paths, the ultrasonic diagnostic apparatus groups the transducer elements so as to form a multi-ring arrangement, transmits/receives ultrasonic beams with a delay to each ring of the multi-ring arrangement and scans the ultrasonic beam so as to create an ultrasonic image, measures delay error due to presence of a sound speed non-uniformity portion of the object and changes either the coupling of the multi-ring or the delay time based on the measurement error.

1. An ultrasonic diagnostic apparatus comprising a probe having two-dimensional array of transducer elements for transmitting and receiving ultrasonic waves to an object to be examined, in which a circular pattern of transducer elements is formed for transmitting and receiving an ultrasound signal by bundling the transducer elements of said two-dimensional array electronically to compose a multi-ring arrangement of transducer elements in concentric rings, and an ultrasound beam is transmitted and received with application of a delay time between each ring of said multi-ring arrangement, wherein said ultrasonic diagnostic apparatus further comprises means for transmitting and receiving an ultrasonic beam that has been corrected using said multi-ring arrangement by measuring a focusing error due to the presence of a sound speed non-uniformity interior of said object and modifying at least one of the manner of bundling of said multi-ring arrangement or the delay time based on the measuring error, and means for imaging the object with an echo signal formed of the corrected ultrasonic beam. 2. An ultrasonic diagnostic apparatus according to claim 1, wherein the multi-ring arrangement of transducer elements formed by bundling transducer elements of the two-dimensional array in said probe in concentric rings is divided into a plural number of sections in a radial shape from the center to the outside of the circular pattern, and a focusing error due to the presence of a sound speed non-uniformity part in the object is measured between each section of the divided circular pattern or each section of the concentric rings, and the ultrasonic beam is corrected by feeding back a measured value to delay circuits in said transmitting and receiving means. 3. An ultrasonic diagnostic apparatus according to claim 1, wherein a bundled arrangement of transducer elements is provided that is different from that of said multi-ring arrangement composed by bundling said transducer elements of said two-dimensional array of said probe in concentric rings, and a focusing error due to the presence of a sound speed non-uniformity part in the object is measured between each circular pattern, and the ultrasonic beam is corrected by feeding back a measured value to delay circuits in said transmission and receiving means and returning the multi-ring arrangement to an initial setting. 4. An ultrasonic diagnostic apparatus comprising: a probe having a two-dimensional array of transducer elements; transducer selection means for electronically bundling transducer elements into a multi-ring arrangement composed of a plural number of rings, means for dividing said multi-ring arrangement into a plural number of sections; means for calculating a focusing error between sections in said multi-ring arrangement; means for feed-back correcting said calculated focusing error relative to a set delay time to produce a corrected focusing error signal; a beam-forming part comprised of delay circuits for applying a delay time to each ring of said multi-ring arrangement of transducer elements in response to a corrected focusing error signal and an adder circuit for adding the outputs of said each delay circuits; and means for imaging an output signal of said beam-forming part. 5. An ultrasonic diagnostic apparatus according to claim 5, wherein means for calculating the focusing error between sections in said multi-ring arrangement includes means for calculating the focusing error between rings in one section. 6. An ultrasonic diagnostic apparatus comprising: transducer selection means for initially forming a multi-ring arrangement of transducer elements composed of a plural number of rings from a two-dimensional array of transducer elements; means for specifying transducer elements having a focusing error in each ring of said multi-ring arrangement; ring correction means for changing a specified transducer element to a different ring from initial ring location to correct the focusing error; a beam-forming part comprised of delay circuits for applying a delay time to the transducer elements of each ring of said multi-ring arrangement and an adder circuit for adding the outputs of each of said delay circuits; and means for imaging an output signal of said beam-forming part. 7. Ultrasonic diagnosing apparatus according to claim 6, wherein means for specifying transducer elements having a focusing error includes means for bundling a group of adjacent transducer elements different from a ring and assigning a transmitter and beam-forming circuit to this bundled transducer group. 8. An ultrasonic diagnostic apparatus comprising: transducer selection means for initially forming a multi-ring arrangement of transducer elements composed of a plural number of rings from a two-dimensional of array transducer elements; means for setting a multi-ring arrangement to calculate a focusing error, separately from said formed multi-ring arrangement; a beam-forming part comprised of delay circuits for applying a delay time to a respective ring of said multi ring arrangement of transducer elements initially formed or the multi-ring arrangement for calculating said focusing error, and an adder circuit

<SOH> BACKGROUND OF THE INVENTION <EOH>An apparatus having a plural number of transducer composed of a two-dimensional transducer array in which sector scanning is performed using an ultrasonic beam (in an arbitrary direction) generated by a transmitting/receiving circular pattern of transducers formed in the two-dimensional transducer array is known. In this ultrasonic diagnostic apparatus, for example, if 64 64 transducers are disposed in the two-dimensional array, then the total number of transducers is 4,096.; and, ultrasonic scanning is performed with a separate delay control provided for each transducer element. In this case, a beam-forming circuit with 4,096 channels is necessary. Realizing a beam-forming circuit having such a large number of multi-channel delay circuits is difficult. So, by thinning out the number of driven elements for forming one ultrasonic beam, the number of delay circuit channels in the beam-forming circuit is reduced. But the S/N of signal acquired by thinning out the driven elements is deteriorated. So, the apparatus is realized by comprising a beam-forming circuit having as many as delay channels possible. For example, there is an apparatus that comprises a beam-forming circuit having a delay circuit of 256 channels for transmitting and 256 channels for receiving. As shown in FIG. 4 , a linear scanning expanded field of view obtained by moving the transmitting/receiving circular pattern of transducer elements 1 , that are arrayed in a two-dimensional X, Y direction, and a scanning method in which a convex scanning is applied to two-dimensions are proposed. In this case, the number of transducer elements 1 is more than in said sector scanning type apparatus. So, for reducing the number of channels in the beam-forming circuit, an apparatus is known that produces an ultrasound transmitting/receiving circular pattern 2 by electronically bundling a plural number of transducer elements 1 in the two-dimensional array into a multi-ring arrangement with concentric rings, so as to give a consistent delay time to the transducer elements composing one ring of said multi-ring arrangement. The apparatus transmits/receives an ultrasonic beam with a delay time between rings, and forms an ultrasonic image by moving said circular pattern 2 in X, Y directions. As shown in FIG. 5 , in said multi-ring arrangement, each ring is formed by the bundling of transducer elements in concentric rings of which the distance L 1 , L 2 . . . , from the single focal spot F is almost the same, and the diameter of the most exterior ring is diameter 2 for ultrasound transmitting/receiving. In this method, the bundling of transducer elements in concentric rings makes it possible to reduce greatly the number of channels in the beam forming circuit, which corresponds to the number of delay circuits, and the S/N of a signal acquired by using all elements in a circular pattern can be improved. When considering the shape of an ultrasonic beam, a focusing calculation for an ultrasonic beam in the object to be examined is traditionally performed under the condition that the speed of sound in an ultrasonic propagation medium is uniform. As shown in FIG. 6 , a traditional apparatus comprises delay circuits 4 , 4 , . . . comprising one per transducer element of the probe 3 having a plural number of transducers and an adder 5 for adding received signals output from these delay circuits 4 , 4 , . . . Although reflected signals from focus point 6 in the object propagate through medium 7 to reach each transducer element, the difference in the path length from the focus point to each transducer element causes a difference in the arrival time of each reflected signal. In this case, the reflected signals reach the transducer elements located in the center of probe 3 early, and, on the other hand, they reach the transducer elements at the ends late. So, the shape of the wave surface 8 in the received signals is not linear. Thus, the signals output from transducer elements in the center part of the probe are delayed with a large amount of delay time in delay circuits 4 corresponding to each received signal, and the signals output from transducer elements at the ends of the probe are delayed with a small amount of delay time. The signals are then output to adder 5 . With these delay operations, the wave surface 9 of the signal output from delay circuits 4 is linear since the signals have the same phase. The received signals having the same phase, such as shown by wave surface 9 in this condition, are added in adder 5 so as to form the combined signal 10 . But actually, as shown in FIG. 7 , a sound speed non-uniformity part 11 typically exists on the path from the focus point 6 in the object to the probe 3 , so that the wave surface of the received signal is disturbed, as shown at 8 ′. In this case, when performing the delay operation, while assuming that the speed of sound is uniform, the wave surface of the received signals output from delay circuits 4 is distorted. as shown at 9 ′, so that they do not have the same phase. Accordingly. the output produced in adder 5 does not increase in intensity as the signals are added, so that its intensity is small, as shown by signal 10 ′. On the Contrary, there is a technology referred to as an adaptive ultrasonic imaging method which operates to correct the delay amount produced in said delay circuits 4 in accordance with the speed of sound in the medium. In the adaptive ultrasonic imaging technology, a mutual correlation method for correcting the delay amount by correction processing of respectively received signals between adjacent channels, and a maximum value brightness method for searching for a brightness maximum while changing the delay amount of the delay circuits are known. FIG. 8 is a block diagram which illustrates the mutual correlation method. In FIG. 8 , a signal received from each transducer element, which is not shown in the figure, is delayed by a predetermined amount by a respective delay circuit 4 , 4 , . . . This delay is possible by use of analog delay circuits or digital delay circuits. In this case, when outputs of adjacent channels in each transducer element, a mutual correlation processing is carried out with correlation device 12 , and the phase difference between the outputs of adjacent channels can be obtained. By detecting the phase difference value, transforming it to focus data in correction processing part 13 , and feeding the transformed data back to focus controlling part 14 , the delay amount produced by the individual delay circuits 4 . FIG. 9 is a block diagram illustrating the maximum value brightness method. In FIG. 9 , a received signal from each transducer element, which is not shown in the figure, is delayed in a respective delay circuit 4 , 4 , . . . by a predetermined amount. The outputs delayed in the respective delay circuits 4 , 4 , . . . are added in adder 5 ., and this output is input to maximum value detecting part 15 . This maximum value detecting part 15 compares the input signal with the last input value, and, in case the input value is smaller than the last detected value, the focus data is slightly changed systematically in focus controlling part 14 . Then, after the phasing of the received echo signal has been changed by this focus data, the output of adder 5 is inputted to the maximum value detecting part 15 , and judged again. After repeating this operation, when the detected value is formed to converge at the maximum value, its data is used as focus data. However, as shown in FIG. 4 and FIG. 5 , in an ultrasonic diagnostic apparatus in which a transmitting/receiving circular pattern 2 is formed by bundling transducer elements of a two-dimensional array into concentric rings to compose a multi-ring arrangement, in case there is a sound speed non-uniformity part 11 on the path from focus point 6 to the probe 3 in the object, since transducer elements 1 in the two-dimensional array are bundled in concentric rings as thus described, it is difficult to detect the phase difference due to said path difference for correcting for the influence of said sound speed non-uniformity part 11 . Therefore, the phase difference of echo signals caused by said path difference, due to the existence of the sound speed non-uniformity part 11 , is not corrected. As a result, the image quality is deteriorated because the ultrasonic beam becomes worse. Thus, it is an object of the present invention to solve the above-mentioned problems by providing an ultrasonic diagnostic apparatus which is able to correct a focusing error by detecting the phase difference of echo signals which occur due to a difference in the ultrasonic propagating path, even when its multi-ring arrangement of transducers is composed by bundling transducers in a two-dimensional array for transducer elements in concentric rings.

<SOH> SUMMARY OF THE INVENTION <EOH>To achieve the foregoing object, an ultrasonic diagnostic apparatus is provided in accordance with the present invention, in which there is a probe comprising a plural number of transducer elements formed as a two-dimensional array for transmitting/receiving an ultrasound to an object to be examined. A circular pattern of transducers for ultrasound transmitting/receiving is formed by bundling said two-dimensional array of transducer elements in concentric rings to form a multi-ring arrangement, and transmitting/receiving of an ultrasound is achieved with the application of a delay between each ring in said multi-ring arrangement, so that an ultrasonic image is formed by scanning said beam. The ultrasonic diagnostic apparatus comprises means for measuring focusing error that is produced due to a sound speed non-uniformity in said object and for transmitting/receiving an ultrasonic beam that has been corrected based on the measured error by changing at least one of the bundling of said multi-ring arrangement of transducers or the delay time, and means for imaging the object by using an echo signal of the corrected ultrasonic beam. In the apparatus of the present invention, the circular pattern formed by said multi-ring arrangement, in which transducer elements in the two-dimensional array are bundled in concentric rings in said probe is divided into a plural number of sections in a radial form from the center to the outside thereof. And, the focusing error due to a sound speed non-uniformity in the object is measured between the ring sectors of each divided section and between each section, and the ultrasonic beam is corrected by feeding this measured value back to the delay circuits. Furthermore, in the apparatus of the present invention, a bundled arrangement of transducer elements form a circular pattern that is different from that of said multi-ring arrangement composed by bundling said transducer elements of a two dimensional array in said probe in concentric rings. And, the focusing error due to a sound speed non-uniformity in the object between each sector is measured, and the ultrasonic beam is corrected by feeding back this measured value to the delay circuits and returning the form of the multi-ring to an initial setting.

TORSION SENSOR

The invention relates to a device for providing an axial force subject to a torque, which device has a first shaft with a friction surface comprising at least a radial directional component; a second shaft which is placed parallel with at least an axial directional component to the first shaft; a friction member arranged with an axial screw thread on the second shaft for friction contact with the friction surface, which friction member displaces axially in the case of rotation relative to the second shaft; and pressing means for urging the friction member in an axial direction.

1. Mechanical transmission, comprising: a frame; a first and second friction device, which device comprises: a first shaft with a friction surface comprising at least a radial directional component; a second shaft which is placed parallel with at least an axial directional component to the first shaft; a friction member arranged with an axial screw thread on the second shaft for friction contact with the friction surface, which friction member is displaced axially in the case of rotation relative to the second shaft; and pressing means for urging the friction member in an axial direction, wherein the first shaft of the first friction device forms an input shaft, which input shaft is arranged rotatably on the frame; wherein the second shaft of the second friction device forms an output shaft, which output shaft is arranged rotatably on the frame parallel to the input shaft and wherein the second shaft of the first friction device and the first shaft of the second friction device are mutually coupled to form a rotatable body, which rotatable body is arranged for at least radial displacement on the frame; a first push belt arranged between the friction surface and the friction member of the first friction device; a second push belt arranged between the friction surface and the friction member of the second friction device; wherein the friction surfaces are rotation-symmetrical, the friction surfaces comprise at least an axial component and comprise at least a radial directional component. 2. Transmission as claimed in claim 1, wherein the pressing means of the first device and of the second device are shared. 3. Transmission as claimed in claim 1, wherein at least one of the input shaft and the output shaft is axially displaceable and wherein bounding means are arranged in order to bound the axial displacement of the friction member associated with the axially displaceable shaft. 4. Transmission as claimed in claim 3, wherein the friction surface arranged on the displaceable shaft comprises a first engaging surface. 5. Transmission as claimed in claim 4, wherein a second engaging surface is arranged on the push belt which engages on the friction surface associated with the displaceable shaft, wherein the first engaging surface lies outside the plane of the friction surface such that only the first engaging surface can co-act with the second engaging surface.