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Fungicidal triazolopyrimidines, method for the production thereof and use thereof in controlling noxious fungi and agents containing said compounds |
Triazolopyrimidines of formula (I), wherein the index and substituents have the following meaning: n=0 or a whole number of 1-5; R=halogen, cyano, hydroxy, cyanate, alkyl, alkenyl, alkinyl, halogenalkyl, halogenalkenyl, alkoxy, alkenyloxy, alkinyloxy, halogenalkoxy, cycloalkyl, cycloalkenyl, cycloalkoxy, alkoxycarbonyl, alkenyloxycarbonyl, alkinyloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkoximinoalkyl, alkenyloximinocarbonyl, alkinyloximinoalkyl, alkylcarbonyl, alkenylcarbonyl, alkinylcarbonyl, cycloalkylcarbonyl or a five to ten membered saturated, partially unsaturated or aromatic heterocycle, containing one to four heteroatoms from the group O, N or S; R1=alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, phenyl, naphthyl or a five to ten membered saturated, partially unsaturated or aromatic heterocycle, containing one to four heteroatoms from the group O, N or S, R and/or R1 being able to be substituted according to the description; R2=alkyl, alkenyl or alkinyl which can be substituted by halogen, cyano, nitro, alkoxy or alkoxycarbonyl. The invention also relates to a method for the production of said compounds, agents containing same, and the use thereof in controlling noxious fungi. |
1. A triazolopyrimidine of the formula I in which the index and the substituents are as defined below: n is 0 or an integer from 1 to 5; R is halogen, cyano, hydroxy, cyanato (OCN), C1-C8-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-haloalkyl, C2-C10-haloalkenyl, C1-C6-alkoxy, C2-C11-alkenyloxy, C2-C10-alkynyloxy, C1-C6-haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C3-C6-cycloalkoxy, C1-C8-alkoxycarbonyl, C2-C10-alkenyloxycarbonyl, C2-C10-alkynyloxycarbonyl, aminocarbonyl, C1-C8-alkylaminocarbonyl, di-(C1-C8)alkylaminocarbonyl, C1-C8-alkoximinoalkyl, C2-C10-alkenyloximinocarbonyl, C2-C10-alkynyloximinoalkyl, C1-C8-alkylcarbonyl, C2-C10-alkenylcarbonyl, C2-C10-alkynylcarbonyl, C3-C6-cycloalkylcarbonyl, or a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S; R1 is c2-C10-alkyl, c2-C10-alkenyl, c2-C10-alkynyl, C3-C12-cycloalkyl, c3-C1-1-cycloalkenyl, phenyl or naphthyl, where R and/or R1 may be partially or fully halogenated or may be substituted by one to four identical or different groups Ra: Ra is halogen, cyano, nitro, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkylcarbonyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, C1-C6-alkylamino, di-C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkenyloxy, C3-C6-alkynyloxy, C3-C6-cycloalkyl, C1-C8-alkoximino, C2-C10-alkenyloximino, C2-C10-alkynyloximino, aryl-C1-C8-alkyloximino, C2-C10-alkynyl, c2-C10-alkenyloxycarbonyl, C2-C10-alkynyloxycarbonyl, phenyl, naphthyl, a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S, where these aliphatic, alicyclic or aromatic groups for their part may be partially or fully halogenated or may carry one to three groups Rb: Rb is halogen, cyano, nitro, hydroxyl, mercapto, amino, carboxyl, aminocarbonyl, aminothiocarbonyl, alkyl, haloalkyl, alkenyl, alkenyloxy, alkynyloxy, alkoxy, haloalkoxy, alkylthio, alkylamino, dialkylamino, formyl, alkylcarbonyl, alkylsulfonyl, alkylsulfoxyl, alkoxycarbonyl, alkylcarbonyloxy, alkylaminocaxbonyl, dialkylaminocarbonyl, alkylaminothiocarbonyl, dialkylaminothiocarbonyl, where the alkyl groups in these radicals contain 1 to 6 carbon atoms and the alkenyl or alkynyl groups mentioned in these radicals contain 2 to 8 carbon atoms; and/or one to three of the following radicals: cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, where the cyclic systems contain 3 to 10 ring members; aryl, aryloxy, arylthio, aryl-C1-C6-alkoxy, aryl-C1-C6-alkyl, hetaryl, hetaryloxy, hetarylthio, where the aryl radicals preferably contain 6 to 10 ring members and the hetaryl radicals 5 or 6 ring members, where the cyclic systems may be partially or fully halogenated or substituted by alkyl or haloalkyl groups; and R2 is C1-C4-alkyl, C2-C4-alkenyl or C2-C4-alkynyl, which may be substituted by halogen, cyano, nitro, C1-C2-alkoxy or C1-C4-alkoxycarbonyl. 2. A triazolopyrimidine of the formula I as claims in claim 1, in which the index and the substituents are as defined below: n is 0 or an integer from 1 to 5; R is halogen, cyano, C1-C6-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C1-C6-haloalkyl, C2-C10-haloalkenyl, C1-C6-alkoxy, C2-C10-alkenyloxy, C2-C10-alkynyloxy, C1-C6-haloalkoxy, C3-C6-cycloalkyl, C3-C6-cycloalkenyl, C3-C6-cycloalkoxy or a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S; R1 is C1-C10-alkyl, C2-C10-alkenyl, C2-C10-alkynyl, C3-C10-cycloalkyl, C3-C10-cycloalkenyl, phenyl, naphthyl, or a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S, where R1 may be partially or fully halogenated or may be substituted by one to four identical or different groups Ra: Ra is halogen, cyano, nitro, hydroxyl, C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-alkylcarbonyl, C3-C6-cycloalkyl, C1-C6-alkoxy, C1-C6-haloalkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylthio, C1-C6-alkylamino, di-C1-C6-alkylamino, C2-C6-alkenyl, C2-C6-alkenyloxy, C3-C6-alkynyloxy, C3-C6-cycloalky-1, phenyl, naphthyl, a five- to ten-membered saturated, partially unsaturated or aromatic heterocycle which contains one to four heteroatoms from the group consisting of O, N and S, where these aliphatic, alicyclic or aromatic groups for their part may be partially or fully halogenated or may carry one to three groups Rb, and R2 is C1-C4-alkyl which may be substituted by halogen, cyano, nitro or C1-C2-alkoxy. 3. A triazolopyrimidine of the formula I as claims in claim 1, in which the index and the substituents are as defined below: n is an integer from 1 to 3; R is fluorine, chlorine, bromine, cyano, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkylcarbonyl, C1-C6-alkoximino-C1-C6-alkyl, C2-C6-alkenyloximino-C1-C6-alkyl, C2-C6-alkynyloximino-C1-C6-alkyl; R1 is C3-C8-alkyl, C3-C8-alkenyl, C3-C8-alkynyl, C3-C6-cycloalkyl, C5-C6-cycloalkenyl; Ra is halogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy, C1-C6-alkoxycarbonyl, C1-C6-alkoximino, C2-C6-alkenyloximino, C2-C6-alkynyloximino; Rc is halogen, cyano, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C6-alkoxy; R2 is C1-C4-alkyl which may be substituted by halogen. 4. A process for preparing compounds of the formula I as claimed in claim 1 by reacting 5-aminotriazole of the formula II with dicarbonyl compounds of the formula III 5. A process for preparing compounds of the formula I where n, R and R1 are as defined in claim 1 and RA is hydrogen or C1-C3-alkyl which may be substituted as claimed in claim 1, by reacting halogen compounds of the formula IV in which X is halogen with substituted malonic acid esters of the formula V in which Rx is C1-C4-alkyl, allyl, phenyl or benzyl to give compounds of the formula VI followed by hydrolysis of VI to give the acid VIa and decarboxylation of VIa 6. A dicarbonyl compound of the formula III as set forth in claim 4, where R1 are C1-C10-alkyl, C2-C10-alkyl, C2-C10-alkynyl, C3-C12-cycloalkyl or C3-C10-cycloalkenyl, n, R and R2 are each as defined in claim 1, R and/or R1 may be substituted as set forth in claim 1, and R1 and R2 are not both methyl. 7. A composition suitable for controlling harmful fungi, which composition comprises a solid or liquid carrier and a compound of the formula I as claimed in claim 1. 8. (canceled) 9. A method for controlling harmful fungi, which comprises treating the fungi or the materials, plants, the soil or the seeds to be protected against fungal attack with an effective amount of a compound of the formula I as claimed in claim 1. |
New assays for preimplantation factor and preimplantation factor peptides |
The present invention relates to assay methods used for detecting the presence of PIF, and to PIF peptides identified using this assay. In particular, the present invention relates to flow cytomery assays for detecting PIF. It is based, at least in part, on the observation that flow cytometry using fluorescently labeled antilymphocyte and anti-platelet antibodies demonstrated an increase in rosette formation in the presence of PIF. It is further based on the observation that flow cytometry demonstrated that monoclonal antibody binding to CD2 decreased in the presence of PIF. The present invention further relates to PIF peptides which, when added to Jurkat cell cultures, have been observed to either (I) decrease binding of anti-CD2 antibody to Jurkat cells; (ii) increase expression of CD2 in Jurkat cells; or (iii) decrease Jurkat cell viability. In additional embodiments, the present invention provides for ELISA assays which detect PIF by determining the effect of a test sample on the binding of anti-CD2 antibody to a CD2 substrate. |
1. A method for determining the presence of preimplantation factor in a sample, comprising the step of: detecting whether the sample contains a component which inhibits the binding of an anti-CD2 antibody to CD2 antigen; wherein the ability to inhibit the binding of anti-CD2 antibody to CD2 has a positive correlation with the presence of preimplantation factor. 2. The method of claim 1, where the binding of anti-CD2 antibody to CD2 is detected using flow cytometry. 3. The method of claim 1, where the CD2 antigen is carried by a cell. 4. The method of claim 1, where the CD2 antigen is carried by a Jurkat cell. 5. The method of claim 2, where the CD2 antigen is carried by a cell. 6. The method of claim 2, where the CD2 antigen is carried by a Jurkat cell. 7. The method of claim 1, where the binding of anti-CD2 antibody to CD2 is detected by enzyme-linked immunosorbent assay. 8. An isolated peptide having a sequence Met-Val-Arg-Ile-Lys-Pro-Gly-Ser-Ala. 9. (Cancelled) 10. (Cancelled) 11. (Cancelled) 12. An isolated peptide having a sequence Val-Ile-Ile-Ile-Ala-Gin-Tyr-Mer-Asp. 13. An isolated peptide comprising the peptide of claim 12, which binds to anti-CD2 antibody. 14. An isolated peptide having a sequence Ser-Gln-Ala-Val-Gln-Glu-His-Ala-Ser-Thr. 15. (Cancelled) 16. The method of claim 1, where the anti-CD2 antibody is labeled. 17. The method of claim 2, where the anti-CD2 antibody is labeled. 18. An isolated peptide having a sequence Met-Val-Arg-Ilg-Lys-Pro-Gly-Ser-Ala-Asn-Lys-Phe-Ser. 19. An isolated peptide having a sequence Met-Val-Arg-Ile-Lys-Pro-Gly-Ser-Ala-Asn-Lys-Phe-Ser-Asp. 20. An isolated peptide having a sequence Met-Val-Arg-Ile-Lys-Pro-Gly-Ser-Ala-Asn-Lys-Phe-Ser-Asp-Asp. 21. An isolated peptide comprising the peptide of claim 8, 18, 19 or 20, which binds to anti-CD2 antibody and which is not a circumsporooite protein. 22. An isolated peptide having a sequence Ser-Gly-Ile-Val-Ile-Tyr-Gln-Tyr-Met-Asp-Asp-Arg-Tyr-Val-Gly-Ser-Asp-Leu. 21. An isolated peptide comprising the peptide of claim 20, which binds to anti-CD2 antibody and which is not an HIV protein. 22. An isolated peptide having the sequence Ser-Gln-Ala-Val-Gin-Glu-His-Ala-Ser-Thr-Asn-Xaa-Gly, where Xaa can be any amino acid. 23. An isolated peptide comprising the peptide of claim 14 or 22, which binds to anti-CD2 antibody and which is not a silencing mediator for human retinoid and thyroid hormone. 24. A method for determining the presence of preimplantation factor comprising: withdrawing a sample from a mammal; and determining the presence or absence of a factor which inhibits binding of an anti-CD2 antibody to a CD2 antigen; wherein the presence of such a factor indicates the presence of PIF. 25. An assay for preimplantation factor in mammals comprising: admixing a sample and anti-CD2 antibodies; and determining in the admixture the percentage of antibodies bound to CD2 antigen; whereby a percentage significantly lower than the percentage in non-pregnant mammals indicates the presence of PIF in the sample. |
<SOH> 2. BACKGROUND OF THE INVENTION <EOH>Infertility is a major health care concern affecting millions of couples worldwide. Contributing to this problem, early demise of the human conceptus is a common event. Approximately 73% of natural single conceptions are lost before reaching week 6 of gestation (Boklage C E. Survival probability of human conceptions from fertilization to term. Int J Fertil 1990; 35:75). This is mostly due to early embryonic demise prior to implantation or soon after implantation occurs. Data relating to the low fertility rate observed in older women and its improvement by oocyte donation from young women indicate that oocyte quality is an important factor in achieving a successful pregnancy (Navot D, Bergh P A, Williams M A et al. Poor oocyte quality rather than implantation failure as a cause of age-related decline female fertility. Lancet 1991;337:1375). In vitro fertilization (“IVF”) is a technology which has been developed to address the problem of infertility. However, maintaining embryo viability is even more problematic under the artificial conditions used for culturing embryos in vitro for implantation. In vitro, the embryo development rate is lower than in vivo and only 25-65% of embryos typically develop to the blastocyst stage (Gardner D K, Lane M, KOuridakis K, Schoolvcraft W B. Complex physiologically based serum-free culture media increase mammalian embryo development. In: Gomel V, Leung P C K, eds. In vitro fertilization and assisted reproduction. Procc 10th World Congress, 1997:187). The state of the art is not yet able to identifying embryos likely to implant and survive. Human chorionic gonadotrophin (“hCG”), the currently used marker for fertilization in vivo and early embryo implantation, can only be detected several days after implantation. As a result of the lack of a suitable marker for embryo viability, nowadays many embryos incapable of implanting are being transferred, thus lowering the chance for achieving successful pregnancy. To address the possibility that embryos may not be viable, a greater number of embryos are simultaneously transferred into a potential mother. The transfer of a high number of embryos may lead to multiple pregnancies, which are inherently risky, while transfer of a small number of embryos carries the risk that none would implant, losing a whole IVF cycle. Clearly, there is a need to improve embryo selection and define accurate markers to determine embryo viability. In addition, using non-invasive methods by testing culture media for products specific to viable, implantation-competent embryos would allow selection of those most likely to result in successful pregnancies, without causing embryo damage. Another factor involved in determining whether a pregnancy is successful or not is the interaction between the conceptus and the mother's immune system. Shortly after fertilization a systemic maternal recognition of pregnancy should occur. The mother's immune system modulation triggered by specific early embryo signals could be the key of this process. Once the oocyte is fertilized, the zygote up to hatching blastocyst is surrounded by the zona pellucida, a hard semi permeable membrane. Therefore the embryo-maternal communication must occur simultaneously while the embryo is developing in the oviduct and uterine cavity through compounds that are secreted by the embryo. It has been shown that pregnant sera and viable embryo conditioned culture media can produce an increase in rosette formation by platelets and T lymphocytes in the presence of CD2 antibody. As disclosed in U.S. Pat. No. 5,646,003 by Barnea et al., issued Jul. 8, 1997, and in U.S. Pat. No. 5,981,198 by Barnea et al., granted Nov. 9, 1999, the presence of Preimplantation Factor (“PIF”) can be detected by mixing lymphocytes, platelets, heat inactivated serum from a pregnant subject, guinea pig complement, and T11 (anti-CD2) monoclonal antibody (Dakko, Denmark), where rosette formation between platelets and lymphocytes is increased by PIF in pregnant subjects. PIF has been found to be (i) secreted by viable early human and mouse embryos from the two-cell stage onward; detectable in the peripheral circulation 3-4 days after embryo transfer following IVF; (iii) associated with 73% take home babies vs 3% in early negative PIF results; (iv) detectable 5-6 days after intrauterine insemination; (v) absent in non-pregnant serum, or non-viable embryos; and (vi) present in various pregnant mammals in addition to humans, including mice, horses, cows and pigs. In addition, PIF has been observed to disappear from the circulation two weeks before hCG secretion declines in cases of spontaneous abortion. The monoclonal antibody used in the above-mentioned PIF assay is directed toward the lymphocyte associated antigen referred to as CD2. CD2 is present on about 80-90% of human peripheral blood lymphocytes, greater than 95% of thymocytes, all T lymphocytes that form erythrocyte rosettes and a subset of NK cells. Various roles for CD2 in T cell activation have been proposed, including function as an adhesion molecule which reduces the amount of antigen required for T cell activation and as a costimulatory molecule or direct promoter of T cell activation. Moreover, CD2 has been implicated in the induction of anergy, the modulation of cytokine production and the regulation of positive selection of T-cells. The natural ligand for CD2 is the structurally related IgSF CAMs CD58 (LFA-3), a cell-surface adhesive ligand with broad tissue distribution. In addition, CD2 can interact with CD48, CD59 and CD15 (Lewis x)-associated carbohydrate structure. CD2 binds CD58 with very low affinity and an extremely fast dissociation constant. The lateral redistribution of CD2 and its ligand CD58 also affect cellular adhesion strength. Regulation of CD2 adhesiveness affects the ability of CD2 to enhance antigen responsiveness. CD2-cell lines incapable of avidity regulation exhibit a marked deficiency in an antigen-specific response. Strength of adhesion resulting from increased CD2 avidity contributes directly to T-cell responsiveness independently of CD2-mediated signal transduction. |
<SOH> 3. SUMMARY OF THE INVENTION <EOH>The present invention relates to assay methods used for detecting the presence of PIF, and to PIF peptides identified using this assay. In particular, the present invention relates to flow cytometry assays for detecting PIF. It is based, at least in part, on the observation that flow cytometry using fluorescently labeled anti-lymphocyte and anti-platelet antibodies demonstrated an increase in rosette formation in the presence of PIF. It is further based on the observation that flow cytometry demonstrated that monoclonal antibody binding to CD2 decreased in the presence of PIF. The present invention further relates to PIF peptides which, when added to Jurkat cell cultures, have been observed to either (i) decrease binding of anti-CD2 antibody to Jurkat cells; (ii) increase expression of CD2 in Jurkat cells; or (iii) decrease Jurkat cell viability. In additional embodiments, the present invention provides for ELISA assays which detect PIF by determining the effect of a test sample on the binding of anti-CD2 antibody to a CD2 substrate. |
Wood-gluing and clamping system and products |
The invention relates to a wood-gluing system enabling the continuous production of glued pieces of lumber for panels and the like. The system includes a deck, a horizontal displacement system for advancing lumber across the deck, a braking system, a one-way clamping system and an upstream pressure system. The system may be used in conjunction with finger-jointing processes or with single pieces of lumber and may be used for the production of both furniture grade and construction grade wood products to NLGA and NGRC standards. |
1. An apparatus for applying a consistent clamping pressure between a plurality of boards comprising: a) a deck for supporting a plurality of boards, the deck having an upstream end and downstream end; b) a horizontal displacement system operatively connected to the upstream end for applying a downstream force to the plurality of boards, the horizontal displacement system operable between a disengaged position allowing a new board to be positioned adjacent the upstream end and an engaged position where the plurality of boards is advanced towards the downstream end; c) a braking system operatively connected to the downstream end for retarding advancement of the plurality of boards along the deck when the downstream force is below a threshold pressure and for allowing advancement of the plurality of boards if the downstream force exceeds the threshold pressure, the braking system including an upstream pressure system for applying an upstream pressure to the plurality of boards when the horizontal displacement system is moving from the engaged position to the disengaged position; and, d) a one-way clamping system operatively connected to the deck for preventing upstream movement of the plurality of boards when the horizontal displacement system is moving from the engaged position to the disengaged position. 2. A system as in claim 1 wherein the horizontal displacement system includes a horizontal displacement member actuated by at least one hydraulic cylinder. 3. A system as in claim 1 wherein the braking system includes at least one friction plate adjacent the downstream end of the deck, the at least one friction plate for applying a downward pressure against the plurality of boards. 4. A system as in claim 1 wherein the braking system includes a roller and rotary brake. 5. A system as in claim 1 wherein the at least one friction plate is an upper and lower friction plate and the lower friction plate includes rollers allowing upstream and downstream motion of the lower friction plate. 6. A system as in claim 1 wherein each at least one friction plates includes a rubber tread for rotational movement about each friction plate. 7. A system as in claim 1 wherein the upstream pressure system includes at least one compression spring operatively attached to the braking system for applying the upstream pressure. 8. A system as in claim 1 wherein the upstream pressure system includes at least one hydraulic cylinder operatively attached to the braking system for applying the upstream pressure. 9. A system as in claim 1 wherein the upstream pressure system is either upstream or downstream of the braking system. 10. A system as in claim 1 wherein the one-way clamping system includes a plurality of passive dogs biased against the deck. 11. A system as in claim 1 wherein the one-way clamping system includes at least one mechanically actuated clamp, the mechanically actuated clamp responsive to the position of the horizontal displacement system. 12. A system as in claim 1 wherein the one-way clamping system includes at least one mechanically actuated knife, for retarding upstream movement of the plurality of boards when the at least one knife is engaged with the plurality of boards. 13. A system as in claim 12 wherein the one-way clamping system includes two mechanically actuated knives, for retarding the advancement of a plurality of boards along the deck. 14. A system as in claim 12 wherein the at least one knife is pivotally connected to the one-way clamping system and biased against an upstream backstop. 15. A system as in claim 1 further comprising a panel press system for providing a flattening pressure against a plurality of boards on the deck. 16. A system as in claim 15 wherein the panel press system is adjacent the upstream end of the deck. 17. A system as in claim 16 wherein the panel press system includes a plurality of rails for contacting the upper surface of the plurality of boards and a pressure bar system transverse to the rails for applying a downward force against the plurality of boards. 18. A system as in claim 1 having a longitudinal clamping system operatively connected to the deck upstream of the one-way clamping system, the longitudinal clamping system for applying a longitudinal clamping pressure to a plurality of interlocked and finger-jointed boards. 19. A system as in claim 2 wherein the braking system includes at least one friction plate adjacent the downstream end of the deck, and at least one friction plate for applying a downward pressure to the plurality of boards. 20. A system as in claim 19 wherein the at least one friction plate is an upper and lower friction plate and the lower friction plate includes rollers allowing upstream and downstream motion of the lower friction plate. 21. A system as in claim 19 wherein each at least one friction plates includes a rubber tread fixed to each of the at least one friction plates or rotatably attached to each at least one friction plate for rotational movement about each friction plate. 22. A system as in claim 21 wherein the upstream pressure system includes at least one compression spring operatively attached to the braking system for applying the upstream pressure. 23. A system as in claim 22 wherein the one-way clamping system includes a plurality of passive dogs biased against the deck. 24. A system as in claim 23 wherein the one-way clamping system includes at least one mechanically actuated clamp, the mechanically actuated clamp responsive to the position of the horizontal displacement system. 25. A system as in claim 24 further comprising a panel press system for providing a flattening pressure against a plurality of boards on the deck. 26. A system as in claim 25 wherein the panel press system is adjacent the upstream end of the deck. 27. A system as in claim 26 wherein the panel press system includes a plurality of rails for contacting the upper surface of the plurality of boards and a pressure bar system transverse to the rails for applying a downward force against the plurality of boards. 28. A system as in claim 27 having a longitudinal clamping system operatively connected to the deck upstream of the one-way clamping system, the longitudinal clamping system for applying a longitudinal clamping pressure to a plurality of interlocked and finger-jointed boards. 29. A system for maintaining a high inter-joint pressure across a plurality of glued boards being continuously assembled on a deck, comprising a downstream pressure system, a braking system, an upstream pressure system and a clamping system operatively connected to the deck. 30. A method of maintaining a high inter-joint pressure between a plurality of boards being assembled into a panel or beam comprising the steps of: a) advancing a board across a deck by a horizontal displacement system through a clamping system restricting upstream movement of the board; and b) restricting the downstream movement of the plurality of boards with a braking system having a threshold pressure, the braking system further providing an upstream pressure against the clamping system. 31. A method as in claim 30 wherein the plurality of boards are manufactured from finger-jointed blocks of wood and step a) further comprises applying a longitudinal clamping pressure to the finger-jointed blocks prior to advancement through the clamping system. 32. A structural wood product comprising a plurality of edge-glued boards wherein the structural wood product meets any one of or a combination of NLGA and NGRC standards for No 2 or higher wood grades. 33. A structural wood product as in claim 32 wherein each board comprises a plurality of finger-jointed blocks. 34. A structural wood product as in claim 32 wherein the NLGA and NGRC standards are No 1 or higher. 35. A structural wood product as in claim 32 wherein the dimensions of the structural wood product are 2×6 or 2×8. 36. A structural wood product as in claim 32 wherein the edge-glued boards are cold-pressed and the glue is a polyurethane. 37. A structural wood product as in claim 32 wherein the edge-glued boards include a certified adhesive meeting ASTM 2559. 38. A structural wood product as in claim 32 wherein the edge-glued boards have flat edges. 39. A structural wood product as in claim 32 wherein edge-glued boards are cold clamped. |
<SOH> BACKGROUND OF THE INVENTION <EOH>In the lumber industry, it is well known that wood boards can be edge-glued to create larger panels of wood or face-glued to create beams. It is also known that the scrap wood from various high-end lumber operations such as sawmill operations contain useful quantities of wood fibre which can be salvaged for lower-end lumber operations including the production of finger-jointed wood products. Finger-jointing processes cut usable wood fibre from scrap material and through shaping, gluing and clamping the ends of the scrap material create longer lengths or boards of lumber. The resulting longer boards built up from shorter lengths have advantages over equivalent lengths of solid, single piece lumber including 1) they will often be less expensive, 2) using certain glues, they will often have structural strengths equivalent to or greater than the strengths of an equivalent length of solid, single-piece lumber and, 3) longer, stable and straight boards of lumber (typically up to 62 feet) can be created. As with solid, single-piece boards, finger jointed boards can, depending on certification, be utilized as conventional lumber (ie for framing) or can be edge-glued and/or face-glued to create other lumber products. In particular, edge-glued lumber can be used to create slabs and face-glued lumber can be used to create beams. Over the years, many techniques for finger jointing have evolved and continue to evolve both with respect to materials handling aspects of the process as well as with the gluing technology. For example, and with respect to gluing technology, in high speed operations producing finger jointed lumber, it is desirable that glue set times are fast in order to maintain high throughput levels. However, high-speed gluing requires that a careful balance be maintained between the glue set time and production speed to ensure that the glue sets during the clamping phase of assembly and not too early or too late in the process. In particular, a glue setting too early in the process will prevent proper assembly of the finger-jointed pieces whereas a glue setting too late will require longer clamping times. Furthermore, there remains the problem that faster setting adhesives may set up in the pot or barrel. Past glues have included phenol based glues which through a combination of moisture and heat-activation (microwaves) initiate the glue setting which in combination with the joint structure provide the resulting adhesive and structural strength at the joint. However, heat-activated glues utilizing microwaves require complex tunnels to both emit the microwaves and shield the plant from this radiation. In addition, the technology relating to products manufactured from phenol glues lend themselves to batch processes as opposed to continuous flow production by virtue of glue-setting apparatus. This is particularly true with respect to an edge gluing process. As a result of some of the problems of phenol glues, quick-setting polyurethane glues have been developed and incorporated into high speed finger jointing operations. Polyurethane glues require moisture for setting which may have to be introduced into the process depending on the moisture content of the wood. Thus, the use of polyurethane glues is particularly suited to use with gluing green or wet-wood. Furthermore, polyurethane glues do not require the same specialized clamping and setting equipment as heat activation systems. The equipment presently used in the continuous production of single lengths of lumber initially creates a series of fingers on the ends of each piece of wood. Glue is applied to each finger joint and each piece of wood is moved onto a linear shuttle which accelerates successive pieces of wood against and into a leading piece of wood thereby causing adjacent finger joints on each piece of wood to interlock. At the end of the shuttle run, the assembled pieces are stopped against a first clamping surface, trimmed to length, moved sideways out of the shuttle run whereupon a longitudinal clamping pressure is applied to fully engage the finger joints. The resulting length of lumber is released from the clamp onto a horizontal deck to allow for final curing of the glue. As successive pieces of lumber are created, cut to length, moved sideways, clamped and released onto the horizontal deck, each piece of lumber is horizontally displaced across the deck. At the edge of the deck, each piece is removed for final processing, cleaning and packaging. In the past, individual boards of single-piece or finger-jointed lumber could be subsequently assembled by edge-gluing to create slabs or face-glued to create beams in one or more separate operations to the milling or finger-jointing processes. For example, past edge-gluing processes apply glue to the edges of adjacent boards and clamp and press adjacent boards together while the glue is curing to form a slab. However, such processes are generally non-continuous, slow and/or labour-intensive which results in higher production costs than could be achieved if the slab was created as part of the initial milling or finger-jointing assembly process. Accordingly, there has been a need for an edge or face gluing process and apparatus that provides the continuous assembly of lumber into edge-glued or face-glued slabs at high speed and pressure. Another problem with past wood-gluing equipment is the clamping pressure profile applied to a growing slab. That is, in past systems which may apply a clamping pressure across a growing slab, as each successive board is added to the growing slab, there are substantial changes in the clamping pressure as linear shuttles advance and retreat. Accordingly, there has been a need for a wood-gluing process and apparatus which provides a high, continuous clamping pressure across the width of the slab while additional boards are being prepared and added to the slab. Further still, there is a distinction between panels manufactured for furniture and for construction. In particular, construction grade lumber requires that the strength of any glued joint meets certain design values established for the particular grade whereas furniture grade wood does not require the same joint strength or integrity. For example, in manufacturing construction grade lumber from glued pieces of wood (either finger jointed or edge-glued) using cold-clamping with a polyurethane adhesive, constant high clamping pressures are required to ensure maximum joint strength and proper glue penetration into the wood during the curing cycle. Furthermore, in particular jurisdictions, the use of wood for construction purposes requires that the lumber meet the standards required under jurisdictional building codes such as the Canadian and U.S. building codes. In North America, the Canadian Lumber Standards Accreditation Board (CLSAB) and the American Lumber Standard (ALS) Board of Review, approve and enforce the rules established by the Canadian National Lumber Grades Authority (NLGA) and the National Grading Rules Committee (NGRC) respectively. The Canadian National Lumber Grade Authority (NLGA) conforms to the National Grading Rule (NGRC) in its own rules for dimension lumber, with some exceptions. For example, the NLGA establishes unique design values for fibre of Canadian origin. Certification of product under these rules is required to enable the use of product by the builders as is required by code officials. Structural lumber products range in dimensions of width and thickness from 2″ to 4″ thick by 2″ and wider. The certification grades, from lowest to highest, progress through stud grade, #2, #1 and select structural. Standards for each grade are described in the manuals of the NLGA, and American rules writing agencies conform to the Department of Commerce PS 20-99 (American Softwood Lumber Standard) determine end uses as prescribed by the appropriate building code agency. All rules and standards under the NLGA and NGRC as of the date of this document are incorporated herein by reference. Furthermore, while it is understood that certification standards may change in the future, the current standards (dated 2002) are the standards as referenced in this application. In the past, commercial production of certificated edge-glued structural lumber has not been achieved. Accordingly, there has been a further need for cost effective, high-speed edge-glued and finger-jointed structural lumber products, which meet inter alia North American Building Code requirements. More specifically, edge-glued boards manufactured from either solid lumber or finger-jointed boards have not passed the certification standards for construction grade lumber and, in particular, commercial production of certification standards #2, #1 and select structural have not been achieved. Accordingly, there has been a further need for cost effective, high-speed edge-glued and finger-jointed structural lumber products which meet the certification standards for a range of dimensions. Past edge-gluing systems have not solved the above problems of manufacture, quality or commercial viability. A review of the prior art has revealed U.S. Pat. No. 6,025,053 and U.S. Pat. No. 5,888,620 (Grenier) which disclose a process for adhesively bonding finger jointed lengths of wood in side-by-side relationship to form boards; U.S. Pat. No. 4,314,871 (Weinstock) which discloses a method and apparatus for laminating timber to form laminated beams; U.S. Pat. No. 4,565,597 (Schulte) which discloses a method for producing a veneer web which are bonded side-by-side to form a veneer web; U.S. Pat. No. 5,679,191 (Robinson) which discloses a method and apparatus of fabricating trailer flooring via an edge-gluing process and U.S. Pat. No. 3,927,705 (Cromeens), U.S. Pat. No. 4,128,119 (Maier), U.S. Pat. No. 4,941,521 (Redekop) and U.S. Pat. No. 5,617,910 (Hill) which each disclose finger jointing apparatus per se. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention solves the above problems by providing a high-speed clamping system that maintains high horizontal clamping pressure across the width of a growing slab while exposing the trailing edge of the growing slab for addition of a further board. In addition, the clamping system allows for the horizontal displacement of the growing slab away from a shuttle delivering a further board for ultimate removal from the system. More specifically, and in accordance with the invention, there is provided an apparatus for applying a consistent clamping pressure between a plurality of boards compising: a) a deck for supporting a plurality of boards, the deck having an upstream end and downstream end; b) a horizontal displacement system operatively connected to the upstream end for applying a downstream force to the plurality of boards, the horizontal displacement system operable between a disengaged position allowing a new board to be positioned adjacent the upstream end and an engaged position where the plurality of boards is advanced towards the downstream end; c) a braking system operatively connected to the downstream end for retarding advancement of the plurality of boards along the deck when the downstream force is below a threshold pressure and for allowing advancement of the plurality of boards if the downstream force exceeds the threshold pressure, the braking system including an upstream pressure system for applying a continuous upstream pressure to the plurality of boards when the horizontal displacement system is moving from the engaged position to the disengaged position; and, d) a one-way clamping system operatively connected to the deck for preventing upstream movement of the plurality of boards when the horizontal displacement system is moving from the engaged position to the disengaged position. In another embodiment, a system for maintaining a high inter-joint pressure across a plurality of glued boards being continuously assembled on a deck is provided, comprising a downstream pressure system, a braking system, an upstream pressure system and a clamping system operatively connected to the deck. In a further embodiment, the invention provides a method of maintaining a high inter-joint pressure between a plurality of boards being assembled into a panel or beam comprising the steps of: a) advancing a board across a deck by a horizontal displacement system through a clamping system restricting the upstream movement of the board; and b) restricting the downstream movement of the plurality of boards with a braking system having a threshold pressure, the braking system further providing an upstream pressure against the clamping system. In further embodiments of the invention, a structural wood product is provided comprising a plurality of edge-glued boards wherein the structural wood product meets any one of or a combination of NLGA and NGRC standards for No 2 or higher wood grades and preferably No 1 or select structural standards. In one embodiment each board comprises a plurality of finger-jointed blocks. The dimensions of the structural wood product may be standard lumber dimension products such as 2×6 or 2×8 or custom dimension products Preferably, the structural wood products includes edge-glued boards that are cold-pressed with a polyurethane glue or any certified adhesive meeting ASTM 2559. |
Washing device for motor vehicles |
The invention provides a device (10) for detailing contoured motor vehicle surfaces (11), including a cleaning head comprising a) a first chamber (12) having an opening (14) facing the direction of said motor vehicle surface and provided with a motor-driven application means and a treatment substance inlet leading into said chamber (12); b) at least one vacuum chamber at least partially bounded by barrier walls (28) having peripheries adapted to slidingly engage said motor vehicle surfaces (11) while maintaining a partial vacuum (26) there against to assist sliding adherence of said head to said surface, said vacuum chamber (26) being provided with a suction outlet (32) exiting therefrom; and c) a stationary portion (34) including guide means (36) and drive means for said motor driven application means. |
1. A device for detailing contoured motor vehicle surfaces, including a cleaning head comprising: a) a first chamber having an opening facing the direction of said motor vehicle surface and provided with a motor-driven application means and a treatment substance inlet leading into said chamber; b) at least one vacuum chamber at least partially bounded by barrier walls having peripheries adapted to slidingly engage said motor vehicle surfaces while maintaining a partial vacuum thereagainst to assist sliding adherence of said head to said surface, said vacuum chamber being provided with a suction outlet exiting therefrom; and c) a stationary portion including guide means and drive means for said motor driven application means. 2. A device according to claim 1, comprising a plurality of vacuum chambers. 3. A device according to claim 1, for washing contoured motor vehicle surfaces, including a cleaning head comprising: a) a first chamber having an opening facing the direction of said motor vehicle surface and provided with a motor-driven cleaning brush and a cleaning substance inlet leading into said chamber; b) at least one vacuum chamber at least partially bounded by barrier walls having peripheries adapted to slidingly engage said motor vehicle surfaces while maintaining a partial vacuum thereagainst to assist sliding adherence of said head to said surface, said second chamber being provided with a suction outlet exiting therefrom; and c) a stationary portion including guide means and drive means for said motor driven brush. 4. A device for washing motor vehicle surfaces according to claim 3, wherein said at least one vacuum chamber is concentrically positioned around said first chamber. 5. A device for washing motor vehicle surfaces according to claim 3, wherein said chambers are shaped as truncated cones, the larger diameters forming the open face arranged to contact said vehicle surface. 6. A device for washing motor vehicle surfaces according to claim 1, wherein said at least one vacuum chamber is provided with a brush means for lifting a cleaning substance deposited by said first chamber and entrained dirt from said vehicle surface for removal via said suction outlet. 7. A device for washing motor vehicle surfaces according to claim 1, further comprising means for limiting the volume of cleaning substance delivered to said first chamber to an amount of less than 3 gallons of fluid per automobile. 8. A device for washing motor vehicle surfaces according to claim 1, wherein said treatment substance comprises a mixture of water and a commercial vehicle wash detergent, and further includes means for limiting the volume of cleaning substance delivered to said first chamber to an amount of less than 2 gallons per automobile. 9. A device for washing motor vehicle surfaces according to claim 1, wherein said barrier walls bounding said second chamber are made of an elastomer material. 10. A device for washing motor vehicle surfaces according to claim 1, wherein said barrier walls bounding said second chamber are made of rubber. 11. A device for washing motor vehicle surfaces according to claim 1, wherein said first chamber contains a motor-driven rotary brush for delivery of a cleaning substance and for scrubbing said motor vehicle surface. 12. A device for washing motor vehicle surfaces according to claim 11, wherein said motor-driven rotary brush is linked to a gear drive which in turn drives the outer brushes in an opposing direction. 13. A device for washing motor vehicle surfaces according to claim 1, wherein said barrier walls bounding said second chamber are flexible for following and adhering to projections and recesses of said contoured motor vehicle surfaces. 14. A device for washing motor vehicle surfaces according to claim 3, wherein said cleaning brush of said first chamber is provided with bristles having a coefficient of sliding friction against wet painted metal of less than 0.12 and are driven at a peripheral speed of at least 200 meters/minute. 15. A device for washing motor vehicle surfaces according to claim 1, wherein said device is portable and hand held. 16. A device for washing motor vehicle surfaces according to claim 1, wherein said device is mounted as a head on a commercial automatic vehicle washer. 17. A device for washing motor vehicle surfaces according to claim 3, wherein said cleaning substance comprises a mixture of water and a cleaning fluid. 18. A device for washing motor vehicle surfaces according to claim 1, wherein said treatment substance is a cleaning substance comprises water carrying a foamed cleaner. 19. A device for washing motor vehicle surfaces according to claim 1, wherein said treatment substance is a foam. 20. A device for washing motor vehicle surfaces according to claim 3, wherein vacuum is transferred from a feed hose to one of said chambers and said cleaning substance is transferred to the remaining said chamber by means of a twin-path rotary union. 21. A device for washing motor vehicle surfaces according to claim 15, further including gripping means for two hands of an operator, attached to said stationary portion. 22. A device for washing motor vehicle surfaces according to claim 1, wherein said treatment substance is a wax. 23. A device according to claim 2, wherein said plurality of vacuum chambers are positioned within said first chamber. |
Vinyl phenyl derivatives as glk activators |
The invention relates to novel compounds of Formula (I) or a salt, solvate or prodrug thereof, wherein A, R1, R2, R3, n and m are as described in the specification, useful in the treatment of a disease or condition mediated through glucokinase (GLK), such as type 2 diabetes, The invention also relates to methods for preparing compounds of Formula (I) and their use as medicaments in the treatment of diseases mediated by glucokinase. |
1. A method for the treatment or prevention of a disease or medical condition mediated through GLK, comprising administering a compound of Formula (I) or a salt, solvate or prodrug thereof, wherein A is heteroaryl; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(CH2)1-4OH, CH3-aFa, —OCH3-aFa, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, NO2, NH2, —NH—C1-4alkyl, —N-di-(C1-4alkyl), CN, formyl, phenyl, or heterocyclyl optionally substituted with C1-6alkyl; each R2 is the group Y—X—; R3 is selected from OH, —O—C1-6alkyl, or NHR6, each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2. COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted with halo, CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1-6alkyl, or OH. R6 is selected from hydrogen, C1-6alkyl, —O—C1-6alkyl, —SO2C1-6alkyl or —(CH2)0-3OH: R7 is independently selected from hydrogen, C1-6alkyl or —C2-4alkyl-O—C1-4alkyl; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, —(CH2) 14-, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Y is independently selected from aryl-Z1-, heterocyclyl-Z1-, —CH(OH)CH3-aFa, and each Y is independently optionally substituted with up to three R4 groups; each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2—(CH2)q—; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6)2—(CH2)q—; each a is independently 1, 2, or 3; m is 0, 1, or 2, n is 0, 1, 2, 3, or 4; and n+mr>0; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+q<4. 2. A method of claim 1, wherein the compound is administered together with a pharmaceutically acceptable diluent or carrier. 3. A compound of Formula (Ib) or a salt, solvate, or prodrug thereof, wherein A is heteroaryl; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(CH2)1-4CH3-aFa, —OCH3-aFa, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, NO2, NH2, —NH—C1-4alkyl, —N-di-(C1-4alkyl), CN, formyl, phenyl, or heterocyclyl optionally substituted with C1-6alkyl; each R2 is the group Y—X—, R3 is selected from hydrogen, C1-6alkyl, or NHR6, each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen C1-6alkyl —CH3-aFa, phenyl naphthyl, heterocyclyl or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2, COOH or —C(O)OC1-6alkyl and each phenyl, naphthyl, or heterocyclyl ring R5 is optionally substituted with halo, CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1alkyl, or OH. R6 is selected from hydrogen. C1-6alkyl. OC1-6alkyl. SO2C1-6alkyl, or (CH2)0-3OH; R7 is independently selected from hydrogen, C1-6alkyl, or —C2-4alkyl-O—C1-4alkyl; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, —(CH2)1-4-, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Y is independently selected from aryl-Z1- or heterocyclyl-Z1-, C3-7cycloalkyl-Z1-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)1-4CH3-aFa, or —CH(OH)CH3-aFa, and each Y is independently optionally substituted with up to three R4 groups, each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2—(CH2)q—; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6)2—(CH2)q—; each a is independently 1, 2, or 3; m is 0, 1, or 2; n is, 1, 2, 3, or 4: and n+m>0; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+q<4. with the proviso that: (i) when m is 1 or 2 and n is 0, and R3 is OH or —O—C1-6alkyl, then R1 is other than OH, CN, halo, methyl, amino, or nitro; (ii) when m=0, n=1, X is —O—, —O—C(O)—, —S—, —S(O)—, —S(O2), —N(CH3)—, —N(CH3)—CH2—, or —C(O)—NH—, and R3 is OH or —O—C1-6alkyl, then Y cannot be C1-6alkyl or C1-6alkyl substituted by with C1-6alkyl; (iii) when m is 0 or, R1 is NO2, and R3 is OH or —O—C1-6alkyl, then when n is 2. (R2)n cannot be di-C1-6alkyl-O— or C1-6alkyl-O—C1-6alkenyl-O—, and when n is 3, (R2)n cannot be tri-C1-6alkyl-O—; (iv) when A is pyridyl, m is 01, R1 is halo, n is 1, and R2 is phenyl, phenyl-CH2—O—, or pyridyl-NH—, then R3 cannot be OH or —O—C1-6alkyl; and (v) when A is pyridyl, R3 is OH, m is 0, n is 2, and one of the R2 groups is phenyl-CH2—O—, then the other R2 group must be other than CH3—S— or CH3—SO2—. 4. A compound according to claim 3, wherein m is 0 or 1 and n is 1 or 2. 5. A compound according to claim 4, wherein n+m is 2 and the R1 and/or R2 groups are substituted at the 2- and 5-positions. 6. A compound according to claim 3, wherein each R1 is independently selected from OH, CH3-aFa, OCH3-aFa, halo, C1-6alkyl, NO2 or heterocyclyl optionally substituted with C1-6alkyl. 7. A compound according to claim 3, wherein each R2 is the group Y—X—; each X is independently selected from —O-Z-, —C(O)O-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R6)SO2,Z- —SO2NH-Z-, —(CH2)14—, —CH═CH-Z-, —C≡C-Z-, —N(R6)CO-Z-, —CON(R6)-Z1-, or a direct bond; each Y is independently selected from aryl-Z1-, heterocyclyl-Z1-, C3-7 cycloalkyl-Z1-, C1-6alkyl, C1-6alkoxy, C2-6alkenyl, or —CH(OH)CH3-aFa, and each Y is independently optionally substituted with R4. 8. A compound according to claim 3, wherein each R4 is independently selected from halo, —CH3-aFa, —OCH3-aFa, CN, NO2, C1-6alkyl, C1-6alkoxy, —COOH, —(CH2)1-3COOH, —(CH2)0-3COOH, —C(O)phenyl, —C(O)NH2, —C(O)NH-phenyl, —SO2NH2, —SO2C1-6alkyl, and phenyl optionally substituted b with C1-6alkyl, or —C(O)OC1-6alkyl. 9. A compound of Formula (II) or a salt, solvate, or prodrug thereof. wherein A is heteroaryl; R3 is selected from hydrogen C1-6alkyl, or NHR6 each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl —CH3-aFa, CN, NH2, COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted with halo, CH3-aFa, CN, NO2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1-6alkyl, or OH; R6 is selected from hydrogen, C1-6alkyl, OC1-6alkyl. SO2C1-6alkyl, or (CH2)0-3OH; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-. —SO-Z-, —SO-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, —(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2, —(CH2)q; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6)2—(CH2)q—. 10. A compound of Formula (IIa) or a salt, solvate, or prodrug thereof, wherein Het is a monocyclic heterocyclyl, optionally substituted with between one and three groups selected from R4; A is heteroaryl; R3 is selected from hydrogen, C1-6alkyl, or NHR6; each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6 alkyl —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2, COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted with halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1-6alkyl or OH: R6 is selected from hydrogen, C1-6alkyl, OC1-6alkyl, SO2C1-6alkyl, or (CH2)0-3OH; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2Z-, —SO2N(R7)-Z-, —(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2NCR7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p —C(R7)2—(CH2)q. each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6)2—(CH2)p—. 11. A compound of Formula (IIf) or a salt, solvate, or prodrug thereof. Het is a monocyclic heterocyclyl optionally substituted with between one and three groups selected from R4; C1-6alkyl is optionally substituted with between one and three groups selected from R4, optionally contains a double bond; A is heteroaryl: R3 is selected from hydrogen. C1alkyl, or NHR6: each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2, COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted with halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1-6alkyl, or OH: R6 is selected from hydrogen, C1-6alkyl, —OC1-6alkyl, SO2C1-6alkyl, or (CH2)0-3OH; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, -(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond: each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2—(CH2)q—. 12. A compound according to any one of claims 9 to 11 or a salt, solvate, or prodrug thereof, wherein X is independently selected from: —O-Z-, SO2N(R6)-Z-, or —N(R6)-Z-; Z is a direct bond or —CH2—; Z1 is selected from a direct bond, —CH2——(CH2)2-1 or R3 is selected from hydrogen, C1-6alkyl, or NHR6; and R6 is selected from hydrogen, C1-6alkyl, —O—C1-6alkyl, —SO2C1-6alkyl or —(CH2)0-3OH. 13. A compound according to any one of claims 3, 9, 10, 11, or 12, wherein A is selected from pyridyl, pyrimidinyl, pyrazinyl, furanyl or thiazolyl. 14. A pharmaceutical composition, comprising a compound according to any one of claims 3, 9, 10, 11 or 12, or a salt, solvate, or prodrug thereof, together with a pharmaceutically acceptable diluent or carrier. 15. A pharmaceutical composition comprising, a compound of Formula (1) or a salt, prodrug or solvate thereof, wherein A is heteroaryl; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(Ch2)1-4CH3-aFa, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, NO2, NH2—NH—C1-4alkyl, —N-di-(C1-4alkyl), CN, formyl, phenyl, or heterocyclyl optionally substituted with C1-6alkyl; each R2 is the group Y—X—; R3 is selected from OH, —O—C1-6alky, or NHR6; each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1—; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2, COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted with halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, or OH; R6 is selected from hydrogen, C1-6alkyl, —O—C1-6alkyl, —SO2C1-6alkyl, or —(CH2)0-3OH; R7 is independently selected from hydrogen, C1-6alkyl, or —C2-4alkyl-O—C1-4alkyl; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, —(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Y is independently selected from aryl-Z1-, heterocyclyl-Z1-, C3-7cycloalkyl-Z1-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)1-4CH3-aFa, or —CH(OH)CH3-aFa, and each Y is independently optionally substituted with up to three R4 groups: each Z is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2—(CH2)q—; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R6)2—(CH2)q—; each a is independently 1, 2, or 3; m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and n+m>0; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+<4. with the proviso that (i) when A is pyridyl or thiazolyl, m is 1 or 2, and n is 0, and R3 is OH or —O—C1-6alkyl, then R1 is other than halo, amino, or nitro; (ii) when A is pyridyl, m=0, n=1, X is —N(CH3)— or —N(CH3)—CH2—, and R3 is OH, then Y cannot be methyl; (iii) when A is thiazolyl, m is 0, and R3 is OH, then when n is 2, (R2)n cannot be di-C1-6alkyl-O— or C1-6alkyl-O— C1-6alkenyl-O—, and when n is 3, then (R2)n cannot be tri-C1-6alkyl-O—; (iv) when A is pyridyl, m is 0 or m is 1, R1 is halo, n is 1 and R2 is phenyl-CH2—O—, then R3 cannot be OH; and (v) when A is pyridyl, R3 is OH, m is 0, n is 2, and one of the R2 groups is phenyl-CH2—O—, then the other R2 group must be other than CH3—S— or CH3—SO2—. 16. A process for the preparation of a compound of Formula (I) wherein A is heteroaryl; each R1 is independently selected from OH, —(CH2)1-4OH, —CH3-aFa, —(CH2)1-4CH3-aFa, —OCH3-aFa, halo, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, NO2, NH2—NH—C1-4alkyl, —N-di-C1-4alkyl) CN, formyl, phenyl or heterocyclyl optionally substituted with C1alkyl; each R2 is the group Y—X— R3 is selected from OH, —O—C1-6alkyl or NHR6, each R4 is independently selected from halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, —COOH, —C(O)OC1-6alkyl, OH, or phenyl optionally substituted with C1-6alkyl, —C(O)OC1-6alkyl, or R5—X1-; R5 is selected from hydrogen, C1-6alkyl, —CH3-aFa, phenyl, naphthyl, heterocyclyl, or C3-7cycloalkyl, and is optionally substituted with halo, C1-6alkyl, —CH3-aFa, CN, NO2, NH2, COOH, or —C(O)OC1-6alkyl, and each phenyl, naphthyl, or heterocyclyl ring in R5 is optionally substituted by halo, —CH3-aFa, CN, NO2, NH2, C1-6alkyl, —OC1-6alkyl, COOH, —C(O)OC1-6alkyl, or OH; R6 is selected from hydrogen, C1-6alkyl, —O—C1-6alkyl, —SO2C1-6 alkyl, or —(CH2)0-3OH; R7 is independently selected from hydrogen, C1-6alkyl, or —C4alkyl-O—C1-4alkyl; each X and X1 is a linker independently selected from -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO2-Z-, —N(R7)-Z-, —N(R7)SO2-Z-, —SO2N(R7)-Z-, —(CH2)1-4—, —CH═CH-Z-, —C≡C-Z-, —N(R7)CO-Z-, —CON(R7)-Z-, —C(O)N(R7)S(O)2-Z-, —S(O)2N(R7)C(O)-Z-, —C(O)-Z-, or a direct bond; each Y is independently selected from aryl -Z1-, heterocyclyl-Z1-, C3-7cycloalkyl-Z1-, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, —(CH2)1-4CH3-aFa, or —CH(OH)CH3-aFa, and each Y is independently optionally substituted with up to three R4 groups; each Z is independently a direct bond. C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2-(CH2)q; each Z1 is independently a direct bond, C2-6alkenylene, or a group of the formula —(CH2)p—C(R7)2—(CH2)q; each a is independently 1, 2, or 3: m is 0, 1, or 2; n is 0, 1, 2, 3, or 4; and n+m>0; p is an integer between 0 and 2; g is an integer between 0 and 2; and p+g<4; which comprises (a) reaction of a compound of Formula (IIIa) with a compound of Formula (IIIb) (b) for compounds of Formula (I) wherein R3 is hydrogen, deprotection of a compound of Formula (IIIc), wherein P1 is a protecting group; (c) reaction of a compound of Formula (IIId) with a compound of Formula (IIIe), wherein X′ and X″ comprise groups which, when reacted together form the group X; (d) for a compound of Formula (I), wherein X or X1 is —SO-Z- or —SO2-Z-, oxidation of the corresponding compound of Formula (I), wherein X or X1 respectively is —S-Z-; or (e) for a compound of Formula (I), wherein R3 is NHR6, reaction of a compound of Formula (IIIf) with a compound of Formula (IIIg), and thereafter, if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; iii) forming a salt, prodrug or solvate thereof. 17. A method for the combined treatment or prevention of diabetes and obesity comprising administering a GLK activator. 18. A method of claim 1, wherein the disease or medical condition is a combination of diabetes and obesity. |
<SOH> FIELD OF THE INVENTION <EOH>The present invention relates to compounds which activate glucokinase (GLK), leading to a decreased glucose threshold for insulin secretion. In addition the compounds are predicted to lower blood glucose by increasing hepatic glucose uptake. Such compounds may have utility in the treatment of Type 2 diabetes and obesity. The invention also relates to pharmaceutical compositions comprising a compound of the invention, and use of such a compound in the conditions described above. In the pancreatic β-cell and liver parenchymal cells the main plasma membrane glucose transporter is GLUT2. Under physiological glucose concentrations the rate at which GLUT2 transports glucose across the membrane is not rate limiting to the overall rate of glucose uptake in these cells. The rate of glucose uptake is limited by the rate of phosphorylation of glucose to glucose-6-phosphate (G-6-P) which is catalysed by glucokinase (GLK) [1]. GLK has a high (6-10 mM) Km for glucose and is not inhibited by physiological concentrations of G-6-P [1]. GLK expression is limited to a few tissues and cell types, most notably pancreatic β-cells and liver cells (hepatocytes) [1]. In these cells GLK activity is rate limiting for glucose utilisation and therefore regulates the extent of glucose induced insulin secretion and hepatic glycogen synthesis. These processes are critical in the maintenance of whole body glucose homeostasis and both are dysfunctional in diabetes [2]. In one sub-type of diabetes, Type 2 maturity-onset diabetes of the young (MODY-2), the diabetes is caused by GLK loss of function mutations [3, 4]. Hyperglycaemia in MODY-2 patients results from defective glucose utilisation in both the pancreas and liver [5]. Defective glucose utilisation in the pancreas of MODY-2 patients results in a raised threshold for glucose stimulated insulin secretion. Conversely, rare activating mutations of GLK reduce this threshold resulting in familial hyperinsulinism [6, 7]. In addition to the reduced GLK activity observed in MODY-2 diabetics, hepatic glucokinase activity is also decreased in type 2 diabetics [8]. Importantly, global or liver selective overexpression of GLK prevents or reverses the development of the diabetic phenotype in both dietary and genetic models of the disease [9-12]. Moreover, acute treatment of type 2 diabetics with fructose improves glucose tolerance through stimulation of hepatic glucose utilisation [13]. This effect is believed to be mediated through a fructose induced increase in cytosolic GLK activity in the hepatocyte by the mechanism described below [13]. Hepatic GLK activity is inhibited through association with GLK regulatory protein (GLKRP). The GLK/GLKRP complex is stabilised by fructose-6-phosphate (F6P) binding to the GLKRP and destabilised by displacement of this sugar phosphate by fructose-1-phosphate (F 1 P). F1 P is generated by fructokinase mediated phosphorylation of dietary fructose. Consequently, GLK/GLKRP complex integrity and hepatic GLK activity is regulated in a nutritionally dependent manner as F6P is elevated in the post-absorptive state whereas F 1 P predominates in the post-prandial state. In contrast to the hepatocyte, the pancreatic β-cell expresses GLK in the absence of GLKRP. Therefore, β-cell GLK activity is regulated exclusively by the availability of its substrate, glucose. Small molecules may activate GLK either directly or through destabilising the GLK/GLKRP complex. The former class of compounds are predicted to stimulate glucose utilisation in both the liver and the pancreas whereas the latter are predicted to act exclusively in the liver. However, compounds with either profile are predicted to be of therapeutic benefit in treating Type 2 diabetes as this disease is characterised by defective glucose utilisation in both tissues. In WO0058293 and WO 01/44216 (Roche), a series of benzylcarbamoyl compounds are described as glucokinase activators. The mechanism by which such compounds activate GLK is assessed by measuring the direct effect of such compounds in an assay in which GLK activity is linked to NADH production, which in turn is measured optically—see details of the in vitro assay described in Example A. In WO9622282/93/94/95 and WO9749707/8 are disclosed a number of intermediates used in the preparation of compounds useful as vasopressin agents which are related to those disclosed in the present invention. Related compounds are also disclosed in WO9641795 and JP8143565 (vasopressin antagonism), in JP8301760 (skin damage prevention) and in EP619116 (osetopathy). We present as a feature of the invention the use of a compound of Formula (I) or a salt, pro-drug or solvate thereof, in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through GLK: wherein A is heteroaryl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n+m>0; each R 1 is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , —OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN, formyl, phenyl or heterocyclyl optionally substituted by C 1-6 alkyl; each R 2 is the group Y—X— wherein each X is a linker independently selected from: -Z-, —O-z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 —, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 14-, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —CON(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, —S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- or a direct bond; each Z is independently a direct bond, C 2-6 alkenylene or a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —; each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-4 alkynyl, —(CH 2 ) 1-4 CH 3-a F a or —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted by up to 3 R 4 groups; each R 4 is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH or phenyl optionally substituted by C 1-4 alkyl or —C(O)OC 1-6 alkyl, or R 5 —X 1 —, where X 1 is independently as defined in X above and R 5 is selected from hydrogen, C 1-4 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl or C 3-7 cycloalkyl; and R 5 is optionally substituted by halo, C 1-4 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, wherein each phenyl, naphthyl or heterocyclyl ring in R 5 is optionally substituted by halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-4 alkyl or OH; each Z 1 is independently a direct bond, C 2-6 alkenylene or a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —; R 3 is selected from OH, —O—C 1-6 alkyl or NHR 6 ; R 6 is selected from hydrogen, C 1-6 alkyl, —O—C 1-6 alkyl, —SO 2 C 1-4 alkyl, —(CH 2 ) 0-3 OH; R 7 is independently selected from hydrogen, C 1-4 alkyl or —C 2-4 alkyl-O—C 1-4 alkyl; each a is independently 1, 2 or 3; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+q<4. According to a further feature of the invention there is provided the use of a compound of Formula (Ia) or a salt, pro-drug or solvate thereof, in the preparation of a medicament for use in the treatment or prevention of a disease or medical condition mediated through GLK: wherein m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n+m>0; each R 1 is independently selected from OH, (CH 2 ) 1-4 OH, CH 3-a F a , (CH 2 ) 1-4 CH 3-a F a , OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , CN, phenyl or a heterocyclyl optionally substituted by C 1-6 alkyl; each R 2 is the group Y—X— wherein each X is a linker independently selected from —O(CH 2 ) 0-3 —, —(CH 2 ) 0-3 O—, —C(O)O(CH 2 ) 0-3 —, —S(CH 2 ) 0-3 —, —SO(CH 2 ) 0-3 —, —SO 2 (CH 2 ) 0-3 —, —NHSO 2 , —SO 2 NH—, —(CH 2 ) 1-4 —, —CH═CH(CH 2 ) 0-2 —, —C≡C(CH 2 ) 0-2 —, —NHCO—, —CONH—; each Y is independently selected from phenyl(CH 2 ) 0-2 , naphthyl(CH 2 ) 0-2 , heterocyclyl(CH 2 ) 0-2 , C 3-7 cycloalkyl(CH 2 ) 0-2 , C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted by one or more R 4 groups; each R 4 is independently selected from halo, CH 3-a F a , OCH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, OC 1-6 alkyl, COOH, (CH 2 ) 0-3 COOH, O(CH 2 ) 0-3 COOH, C(O)OC 1-6 alkyl, C 1-6 alkylC(O)OC 1-6 alkyl, CO-phenyl, CONH 2 , CONH-phenyl, SO 2 NH 2 , SO 2 C 1-6 alkyl, OH, or phenyl optionally substituted by one or more R 5 groups where R 5 is selected from hydrogen, C 1-6 alkyl or C(O)OC 1-6 alkyl. each a is independently 1, 2 or 3; R 3 is selected from hydrogen, C 1-6 alkyl or NHR 6 ; R 6 is selected from hydrogen, C 1-6 alkyl, OC 1-6 alkyl, SO 2 C 1-6 alkyl, (CH 2 ) 030 H. According to a further feature of the invention there is provide a compound of Formula (Ib) or a salt, solvate or pro-drug thereof; wherein A is heteroaryl; m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n+m>0; each R 1 is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , —OCH 3-a F a halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN, formyl, phenyl or heterocyclyl optionally substituted by C 1-6 alkyl; each R 2 is the group Y—X— wherein each X is a linker independently selected from: -Z-, —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 7 )-Z-, —N(R 7 )SO 2 -Z-, —SO 2 N(R 7 )-Z-, —(CH 2 ) 1-4 —, —CH═CH-Z-, —C≡C-Z-, —N(R 7 )CO-Z-, —CON(R 7 )-Z-, —C(O)N(R 7 )S(O) 2 -Z-, S(O) 2 N(R 7 )C(O)-Z-, —C(O)-Z- or a direct bond; each Z is independently a direct bond, C 2-6 alkenylene or a group of the formula —(CH 2 ) p —C(R 7 ) 2 —(CH 2 ) q —; each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, —(CH 2 ) 1-4 CH 3 F a or —CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted by up to 3 R 4 groups; each R 4 is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH or phenyl optionally substituted by C 1-6 alkyl or —C(O)OC 1-6 alkyl, or R 5 —X 1 -, where X 1 is independently as defined in X above and R 5 is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a , phenyl, naphthyl, heterocyclyl or C 3-7 cycloalkyl; and R 5 is optionally substituted by halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH, or —C(O)OC 1-6 alkyl, wherein each phenyl, naphthyl or heterocyclyl ring in R 5 is optionally substituted by halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH; each Z 1 is independently a direct bond, C 2-6 alkenylene or a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —; R 3 is selected from OH, —O—C 1-6 alkyl or NHR 6 ; R 6 is selected from hydrogen, C 1-6 alkyl, —O—C 1-4 alkyl, —SO 2 C 1-4 alkyl, —(CH 2 ) 0-3 OH; R 7 is independently selected from hydrogen, C 1-4 alkyl or —C 2-4 alkyl-O—C 4 alkyl; each a is independently 1, 2 or 3; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+q<4. with the proviso that: (i) when m is 1 or 2 and n is 0, R 3 is OH or —O—C 1-4 alkyl, then R 1 is other than OH, CN, halo, methyl, amino or nitro; (ii) when m=0, n=1, X is —O—, —O—C(O)—, —S—, —S(O)—, —S(O 2 ), —N(CH 3 )—, —N(CH 3 )—CH 2 — or —C(O)—NH—, R 3 is OH or —O—C 1-6 alkyl, then Y cannot be C 1-6 alkyl or C 1-4 alkyl substituted by C 1-6 alkyl; (iii) when m is 0 or m is 1 and R 1 is NO 2 , R 3 is OH or —O—C 6 alkyl, then when n is 2 (R 2 ) n cannot be di-C 1-4 alkyl-O— or C 1-6 alkyl-O—C 1-4 alkenyl-O— and when n is 3 (R 2 ) n cannot be tri-Ci alkyl-O—; (iv) when A is pyridyl, m is 0 or m is 1 and R 1 is halo, n is 1 and R 2 is phenyl, phenyl-CH 2 —O— or pyridyl-NH—, then R 3 cannot be OH or —O—C 1-4 alkyl; and (v) when A is pyridyl, R 3 is OH, m is 0, n is 2 and one of the R 2 groups is phenyl-CH 2 —O—, then the other R 2 group must be other than CH 3 —S— or CH 3 —SO 2 —. According to a further feature of the invention there is provided a compound of Formula (Ib) or salt, solvate of pro-drug thereof, wherein A is pyridyl with the proviso that: (i) when m is 1 or 2 and n is 0 then R 1 is other than halo, methyl, amino or nitro; (ii) when m=0, n=1, X is —O—, —S—, —S(O)—, —S(O 2 )—, —N(CH 3 )—, or —N(CH 3 )—CH 2 —, R 3 is OH or —C 1-6 alkyl, then Y cannot be methyl; (iii) when R 3 is OH, m is 0, n is 2 and one of the R 2 groups is phenyl-CH 2 —O—, then the other R 2 group must be other than CH 3 —S— or CH 3 —SO 2 —; and (iv) when m is 0 or m is 1 and R 1 is halo, n is 1 and R 2 is phenyl, phenyl-CH 2 —O— or pyridyl-NH—, then R 3 cannot be OH or —O—C 1-6 alkyl;. According to a further feature of the invention there is provided a compound of Formula (Ic) or a salt, solvate or pro-drug thereof; wherein m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n+m>0; each R 1 is independently selected from OH, (CH 2 ) 1-4 OH, CH 3-a F a , (CH 2 ) 1-4 CH 3-a F a , OCH 3-a F a , halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , CN, phenyl or a heterocyclyl optionally substituted by C 1-6 alkyl; each R 2 is the group Y—X— wherein each X is a linker independently selected from —O(CH 2 ) 0-3 —, —(CH 2 ) 0-3 O—, —C(O)O(CH 2 ) 0-3 —, —S(CH 2 ) 0-3 —, —SO(CH 2 ) 0-3 —, —SO 2 (CH 2 ) 0-3 —, —NHSO 2 , —SO 2 NH—, —(CH 2 ) 1-4 —, —CH═CH(CH 2 ) 0-2 —, —C≡C(CH 2 ) 0-2 —, —NHCO—, —CONH—; each Y is independently selected from phenyl(CH 2 ) 0-2 , naphthyl(CH 2 ) 0-2 , heterocyclyl(CH 2 ) 0-2 , C 3-7 cycloalkyl(CH 2 ) 0-2 , C 1-6 alkyl, OC 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or CH(OH)CH 3-a F a ; wherein each Y is independently optionally substituted by one or more R 4 groups; each R 4 is independently selected from halo, CH 3-a F a , OCH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, OC 1-4 alkyl, COOH, (CH 2 ) 0-3 COOH, O(CH 2 ) 0-3 COOH, C(O)OC 1-6 alkyl, C 1-6 alkylC(O)OC 1-6 alkyl, CO-phenyl, CONH 2 , CONH-phenyl, SO 2 NH 2 , SO 2 C 1-6 alkyl, OH, or phenyl optionally substituted by one or more R 5 groups where R 5 is selected from hydrogen, C 1-6 alkyl or C(O)OC 1-6 alkyl. each a is independently 1, 2 or 3; R 3 is selected from hydrogen, C 1-6 alkyl or NHR 6 ; R 6 is selected from hydrogen, C 1-4 alkyl, OC 1-6 alkyl, SO 2 C 1-6 alkyl, (CH 2 ) 030 H; with the proviso that: (i) when R 3 is H, m is 0, n is 2 and one of the R 2 groups is phenyl-CH 2 —O—, then the other R 2 group must be other than CH 3 —S— or CH 3 —SO 2 —; and (ii) when R 3 is H, m is 1, n is 1 and R 2 is phenyl-CH 2 —O—, then R 1 must be other than halo. Compounds of the invention may form salts which are within the ambit of the invention. Pharmaceutically acceptable salts are preferred although other salts may be useful in, for example, isolating or purifying compounds. The term “aryl” refers to phenyl, naphthyl or a partially saturated bicyclic carbocyclic ring containing between 8 and 12 carbon atoms, preferably between 8 and 10 carbon atoms. Example of partially saturated bicyclic carbocyclic ring include: 1,2,3,4-tetrahydronaphthyl, indanyl, indenyl, 1,2,4a,5,8,8a- hexahydronaphthyyl or 1,3a-dihydropentalene. The term “halo” includes fluoro, chloro, bromo and iodo; preferably chloro, bromo and fluoro; most preferably fluoro. The expression “—CH 3-a F a ” wherein a is an integer between 1 and 3 refers to a methyl group in which 1, 2 or all 3 hydrogen are replaced by a fluorine atom. Examples include: trifluoromethyl, difluoromethyl and fluoromethylene An analogous notation is used with reference to the group —(CH 2 ) 1-4 CH 3-a F a , examples include: 2,2-difluoroethyl and 3,3,3-trifluoropropyl. In this specification the term “alkyl” includes both straight and branched chain alkyl groups. For example, “C 1-4 alkyl” includes propyl, isopropyl and tert-butyl. The term “heteroaryl” refers to a monocylic aromatic heterocyclic ring containing between 5-6 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH 2 — group can optionally be replaced by a —C(O)— and sulphur atoms in a heterocyclic ring may be oxidised to S(O) or S(O) 2 groups. Examples of “heteroaryl” include: thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-oxopyrrolidinyl, 2,5-dioxopyrrolidinyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxo-oxazolidininyl, 5,6-dihydrouracilyl, 1,2,4-oxadiazolyl, 4-oxothiazolidinyl, morpholinyl, furanyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, thienyl, isoxazolyl, tetrahydropyranyl, piperidyl, piperazinyl, thiomorpholinyl, 1,1-dioxothiomorpholinyl, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, isoxazolyl, imidazolyl, pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyranyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl, 4-oxo-pyridinyl, 1,1-dioxotetrahydrothienyl. Preferably “heteroaryl” is selected from: pyridyl, pyrimidinyl, pyrazinyl, furanyl or thiazolyl. The term “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing 3-12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH 2 — group can optionally be replaced by a —C(O)— and sulphur atoms in a heterocyclic ring may be oxidised to S(O) or S(O) 2 groups. Preferably a “heterocyclyl” is a saturated, partially saturated or unsaturated, mono or bicyclic ring (preferably monocyclic) containing 5 or 6 atoms of which 1 to 3 atoms are nitrogen, sulphur or oxygen, which may, unless otherwise specified, be carbon or nitrogen linked, wherein a —CH 2 — group can optionally be replaced by a —C(O)— or sulphur atoms in a heterocyclic ring may be oxidised to S(O) or S(O) 2 groups. Examples and suitable values of the term “heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl, 1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl, 2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl, 1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl, 4-thiazolidonyl, morpholino, furanyl, 2-oxotetrahydrofuranyl, tetrahydrofuranyl, 2,3-dihydrobenzofuranyl, benzothienyl, isoxazolyl, tetrahydropyranyl, piperidyl, 1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino, 1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl, homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl, thiazolyl, thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, pyranyl, indolyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridyl, 4-pyridonyl, quinolyl, tetrahydrothienyl 1,1-dioxide, 2-oxo-pyrrolidinyl and 1-isoquinolonyl. Preferred examples of “heterocyclyl” when referring to a 5/6 and 6/6 bicyclic ring system include benzofuranyl, benzimidazolyl, benzthiophenyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, imidazo[2,1-b][1,3]thiazolyl, chromanyl and naphthyridinyl. Preferably the term “heterocyclyl” refers to 5- or 6-membered monocyclic heterocyclic rings, such as oxazolyl, isoxazolyl, pyrrolidinyl, 2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, morpholino, furanyl, tetrahydrofuranyl, piperidyl, piperazinyl, thiomorpholino, tetrahydropyranyl, homopiperazinyl, thienyl, imidazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, indolyl, thiazolyl, thiadiazolyl, pyrazinyl, pyridazinyl and pyridyl. The term “cycloalkyl” refers to a saturated carbocylic ring containing between 3 to 12 carbon atoms, preferably between 3 and 7 carbon atoms. Examples of C 3-7 cycloalkyl include cycloheptyl, cyclohexyl, cyclopentyl, cyclobutyl or cyclopropyl. Preferably cyclopropyl, cyclopentyl or cyclohexyl. Examples of C 1-6 alkyl include methyl, ethyl, propyl, isopropyl, 1-methyl-propyl, sec-butyl, tert-butyl and 2-ethyl-butyl; examples of C 2-6 alkenyl include: ethenyl, 2-propenyl, 2-butenyl, or 2-methyl-2-butenyl; examples of C 2-6 alkynyl include: ethynyl, 2-propynyl, 2-butynyl, or 2-methyl-2-butynyl, examples of —OC 1-6 alkyl include methoxy, ethoxy, propoxy and tert-butoxy; examples of —C(O)OC 1-6 alkyl include methoxycarbonyl, ethoxycarbonyl and tert-butyloxycarbonyl; examples of —NH—C 1-4 alkyl include: and examples of —N-di-(C 1-4 alkyl): For the avoidance of doubt, in the definition of linker group ‘X’, the right hand side of the group is attached to phenyl ring and the left hand side is bound to ‘Y’. The invention includes the E and Z isomers of compounds of the invention defined above, but the preferred compounds are the E isomers. It is to be understood that, insofar as certain of the compounds of the invention may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the property of stimulating GLK directly or inhibiting the GLK/GLKRP interaction. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Preferred compounds of Formula (I) to (Ic) above or of Formula (II) to (IIf) below are those wherein any one or more of the following apply: (1) m is 0 or 1; n is 1 or 2; preferably n is 2; most preferably m is 0 and n is 2. (2) The R 1 and/or R 2 group(s) are attached at the 2-position and/or the 3-position and/or the 5-position; when n+m is 2, the groups are preferably at the 2- and 5- or 3- and 5-positions, most preferably at the 2- and 5-positions. (3) each R 1 is independently selected from OH, CH 3-a F a (preferably CF 3 ), OCH 3-a F a (preferably OCF 3 ), halo, C 1-6 alkyl (preferably methyl), NO 2 or heterocyclyl optionally substituted by C 1-6 alkyl; preferably R 1 is selected from CH 3-a F a (preferably CF 3 ), OCH 3-a F a (preferably OCF 3 ) or halo; (4) each R 2 is the group Y—X— wherein each X is independently selected from: —O-Z-, —C(O)O-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 6 )SO 2 ,Z- —SO 2 NH-Z-, —(CH 2 ) 14 —, —CH═CH-Z-, —C≡C-Z-, —N(R 6 )CO-Z-, —CON(R 6 )-Z- or a direct bond; Preferably X is independently selected from: —O-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 6 )SO 2 ,Z- —SO 2 NH-Z—(CH 2 ) 14 — or a direct bond Most preferably X is independently selected from: —O—, —S—, —SO—, —SO 2 —, —(CH 2 ) 1-4 — or a direct bond; each Z is independently selected from: a direct bond or —(CH 2 ) 1-2 , or a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —, wherein one R 6 group is hydrogen and the other R 6 group is C 1-4 alkyl; preferably a direct bond, —(CH 2 ) 0-2 — or more preferably a direct bond or —CH 2 —. each Z 1 is independently selected from: a direct bond, C 2-6 alkenylene or a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —, wherein one R 6 group is hydrogen and the other R 6 group is C 1-4 alkyl; preferably a direct bond, —(CH 2 ) 0-2 —, C 2-4 alkenylene or more preferably a direct bond, —(CH 2 ) 0-4 —, 2-propenylene or most preferably CH 2 ) 0-3 —, 2-propenylene or a direct bond. and each Y is independently selected from: aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl or —CH 3-a F a ; preferably each Y is independently selected from: phenyl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl (preferably a branched C 2-6 alkyl chain such as isopropyl or isobutyl), C 2-6 alkenyl or —CH 3-a F a ; most preferably Y is independently selected from: phenyl-Z 1 -, morpholinyl-Z 1 -, pyridyl-Z 1 -, pyrrolidino-Z 1 -, isoxazolyl-Z 1 -, diazolyl-Z 1 -, furanyl-Z 1 -, thienyl-Z 1 -, thiazolyl-Z 1 -, cyclopropy-Z 1 - or cyclohexyl-Z 1 -, wherein each Y is independently optionally substituted by R 4 . (5) each R 2 is the group Y—X—, Z within the definition of X is a direct bond and Z 1 within the definition of Y is a group of the formula (CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —. most preferably R 2 is independently selected from: methoxy, methylthio, methylsulphinyl, methylsulphonyl, ethoxy, iso-propoxy, pentyloxy, phenoxy, benzyloxy, phenylpropoxy, phenylallyloxy, phenylthio, diazolylmethoxy, diazolylethoxy, furanylmethoxy, isoxazolylmethoxy, morpholino, pyridylmethoxy, pyrrolidinylethoxy, thiazolyl, thiazolylmethoxy, thiazolylethoxy, thienylmethoxy, cyclopropylmethoxy or cyclohexylmethoxy, wherein each of these R 2 groups is optionally substituted by R 4 . (6) each R 4 is independently selected from: halo, —CH 3-a F a , —OCH 3-a F a , CN, NO 2 , C 1-6 alkyl, C 1-6 alkoxy, —COOH, —(CH 2 ) 1-3 COOH, —(CH 2 ) 0-3 COOH, —C(O)phenyl, —C(O)NH 2 , —C(O)NH-phenyl, —SO 2 NH 2 , —SO 2 C 1-6 alkyl, phenyl optionally substituted by C 1-6 alkyl or —C(O)OC 1-6 alkyl; More preferably R 4 is independently selected from. chloro, bromo, fluoro, methyl, tert-butyl, isopropyl, methoxy, C 1-4 alkoxycarbonyl, vinyl, CN, OH, trifluoromethyl, —COOH, —CH 2 COOH, NO 2 , methylsulphonyl, —C(O)NH 2 , —C(O)NH-phenyl, —SO 2 NH 2 or benzyloxy, (7) R 3 is selected from hydrogen or C 1-6 alkyl; preferably R 3 is selected from hydrogen or methyl; most preferably R 3 is hydrogen. According to a further feature of the invention there is provided the following preferred groups of compounds of the invention: (I) a compound of Formula (II) wherein: A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (II) a compound of Formula (IIa) wherein: Het is a monocyclic heterocyclyl, optionally substituted with between 1 and 3 groups selected from R 4 and, A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (III) a compound of Formula (IIb) wherein: the C 1-6 alkyl group is optionally substituted with between 1 and 3 groups selected from R 4 , preferably unsubstituted; the C 1-6 alkyl group optionally contains a double bond, preferably the C 1-6 alkyl group does not contains a double bond; and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); with the proviso that: when A is pyridyl, R 3 is OH, phenyl-Z 1 —X— is phenyl-CH 2 —O— wherein the phenyl ring is unsubstituted, then C 1-6 alkyl-X— must be other than CH 3 —S— or CH 3 —SO 2 —; or a salt, solvate or pro-drug thereof. (IV) a compound of Formula (IIc) wherein: the C 3-7 cycloalkyl group is optionally substituted with between 1 and 3 groups selected from R 4 , and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (V) a compound of Formula (IId) wherein: the C 1-6 alkyl groups are independently optionally substituted with between 1 and 3 groups selected from R 4 , preferably one of the C 1-6 alkyl groups is unsubstituted, the C 1-6 alkyl groups independently optionally contain a double bond, preferably only one of the C 1-6 alkyl groups contain a double bond, preferably neither of the C 1-6 alkyl group contains a double bond, and A, X, R 3 and R 4 are as defined above in a compound of Formula (I); with the proviso that A is other than pyridyl, furanyl or thiazolyl; or a salt, solvate or pro-drug thereof. (VI) a compound of Formula (IIe) wherein: the C 3-7 cycloalkyl and C 1-6 groups are independently optionally substituted with between 1 and 3 groups selected from R 4 , preferably the C 1-6 group is unsubstituted; the C 1-6 group optionally contains a double bond, preferably the C 1-6 group does not contains a double bond; and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (VII) a compound of Formula (IIf) wherein: Het is a monocyclic heterocyclyl, the Het and C 1-6 alkyl groups are independently optionally substituted with between 1 and 3 groups selected from R 4 , preferably the C 1-6 alkyl group is unsubstituted; the C 1-6 alkyl group optionally contains a double bond, preferably the C 1-6 alkyl group does not contains a double bond; and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (VIII) a compound of Formula (IIg) wherein: Het is a monocyclic heterocyclyl, the Het and C 3-7 cycloalkyl groups are independently optionally substituted with between 1 and 3 groups selected from R 4 , and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (IX) a compound of Formula (IIh) wherein: Y is aryl-Z 1 -, wherein aryl is preferably a partially saturated bicyclic carbocyclic ring; Y and the C 1-6 alkyl group are independently optionally substituted with between 1 and 3 groups selected from R 4 , preferably the C 1-6 alkyl group is unsubstituted, the C 1-6 alkyl group optionally contains a double bond, preferably the C 1-6 alkyl group does not contains a double bond; and A, X, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. (X) a compound of Formula (IIj) wherein: X is selected from —SO 2 N(R 6 )-Z- or —N(R 6 )SO 2 -Z-, preferably X is —SO 2 N(R 6 )-Z-; Z is as described above, preferably Z is propylene, ethylene or methylene, more preferably Z is methylene; Z a is selected from a direct bond or a group of the formula —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —; preferably Z a is selected from C 1-2 alkylene or a direct bond; preferably Z a is a direct bond; R 6 is selected from: C 1-4 alkyl or hydrogen, preferably methyl or hydrogen; Y is selected from aryl-Z 1 — or heterocyclyl-Z 1 -; Y and the C 1-6 alkyl group are independently optionally substituted with between 1 and 3 groups selected from R 4 , the C 1-6 alkyl group optionally contains a double bond, preferably the C 1-6 alkyl group does not contain a double bond, and A, Z 1 , R 3 and R 4 are as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. A further preferred groups of compounds of the invention in either of groups (I)—(IX) above is wherein: X is independently selected from: —O-Z-, SO 2 N(R 6 )-Z- or —N(R 6 )-Z-; Z is a direct bond or —CH 2 —; Z 1 is selected from a direct bond, —CH 2 —-(CH 2 ) 2 — or and R 3 is as defined above in a compound of Formula (I); or a salt, solvate or pro-drug thereof. In a further embodiment of the invention there is provided a compound as defined in either of groups (I) to (X) above wherein: A is selected from: pyridyl, pyrimidinyl, pyrazinyl, furanyl or thiazolyl; preferably A is linked to the styryl group at the 2-position of A. In a further embodiment of the invention there is provided a compound as defined in either of groups (I) to (X) above wherein the two Y—X— groups are linked to the phenyl ring in a 2, 5 orientation relative to the styryl group. The compounds of the invention may be administered in the form of a pro-drug. A pro-drug is a bioprecursor or pharmaceutically acceptable compound being degradable in the body to produce a compound of the invention (such as an ester or amide of a compound of the invention, particularly an in vivo hydrolysable ester). Various forms of prodrugs are known in the art. For examples of such prodrug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen; c) H. Bundgaard, Chapter 5 “Design and Application of Prodrugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); and f) N. Kakeya, et al., Chem Pharm Bull, 32, 692 (1984). The contents of the above cited documents are incorporated herein by reference. Examples of pro-drugs are as follows. An in-vivo hydrolysable ester of a compound of the invention containing a carboxy or a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C 1 to C 6 alkoxymethyl esters for example methoxymethyl, C 1 to 6 alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters, C 3 to 8 cycloalkoxycarbonyloxyC 1 to 6 alkyl esters for example 1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, for example 5-methyl-1,3-dioxolen-2-onylmethyl; and C 1-6 alkoxycarbonyloxyethyl esters. An in-vivo hydrolysable ester of a compound of the invention containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and 2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl. A suitable pharmaceutically-acceptable salt of a compound of the invention is, for example, an acid-addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic, citric or maleic acid. In addition a suitable pharmaceutically-acceptable salt of a benzoxazinone derivative of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically-acceptable cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. A further feature of the invention is a pharmaceutical composition comprising a compound of Formula (I) to (Ic) or (II) to (IIj) as defined above, or a salt, solvate or prodrug thereof, together with a pharmaceutically-acceptable diluent or carrier. According to another aspect of the invention there is provided a compound of Formula (Ib) or (Ic), or (II) to (IIj) as defined above for use as a medicament; with the proviso that (i) when A is pyridyl or thiazolyl, m is 1 or 2 and n is 0, R 3 is OH or —C 1-6 alkyl, then R 1 is other than halo, amino or nitro; (ii) when A is pyridyl, m=0, n=1, X is —N(CH 3 )— or —N(CH 3 )—CH 2 —, R 3 is OH, then Y cannot be methyl; (iii) when A is thiazolyl, m is 0, R 3 is OH, then when n is 2 (R 2 ) n cannot be di-C 1-6 alkyl-O— or C 1-6 alkyl-O—C 1-6 alkenyl-O— and when n is 3 (R 2 ) n cannot be tri-C 1-6 alkyl-O—; (iv) when A is pyridyl, m is 0 or m is 1 and R 1 is halo, n is 1 and R 2 is phenyl-CH 2 —O—, then R 3 cannot be OH; and (v) when A is pyridyl, R 3 is OH, m is 0, n is 2 and one of the R 2 groups is phenyl-CH 2 —O—, then the other R 2 group must be other than CH 3 —S— or CH 3 —SO 2 —. Further according to the invention there is provided a compound of Formula (Ib) or (Ic), or (II) to (IIj) for use in the preparation of a medicament for treatment of a disease mediated through GLY, in particular type 2 diabetes. The compound is suitably formulated as a pharmaceutical composition for use in this way. According to another aspect of the present invention there is provided a method of treating GLK mediated diseases, especially diabetes, by administering an effective amount of a compound of Formula (Ib) or (Ic), or (II) to (IIj) to a mammal in need of such treatment. Specific disease which may be treated by the compound or composition of the invention include: blood glucose lowering in Diabetes Mellitus type 2 without a serious risk of hypoglycaemia (and potential to treat type 1), dyslipidemea, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance. Specific disease which may be treated by the compound or composition of the invention include: blood glucose lowering in Diabetes Mellitus type 2 (and potential to treat type 1); dyslipidaemia; obesity; insulin resistance; metabolic syndrome X; impaired glucose tolerance; polycystic ovary syndrome. The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents. Suitable pharmaceutically acceptable excipients for a tablet formulation include, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl or propyl p-hydroxybenzoate, and anti-oxidants, such as ascorbic acid. Tablet formulations may be uncoated or coated either to modify their disintegration and the subsequent absorption of the active ingredient within the gastrointestinal tract, or to improve their stability and/or appearance, in either case, using conventional coating agents and procedures well known in the art. Compositions for oral use may be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules in which the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin, or olive oil. Aqueous suspensions generally contain the active ingredient in finely powdered form together with one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents such as lecithin or condensation products of an alkylene oxide with fatty acids (for example polyoxethylene stearate), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives (such as ethyl or propyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid), colouring agents, flavouring agents, and/or sweetening agents (such as sucrose, saccharine or aspartame). Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil (such as arachis oil, olive oil, sesame oil or coconut oil) or in a mineral oil (such as liquid paraffin). The oily suspensions may also contain a thickening agent such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set out above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water generally contain the active ingredient together with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients such as sweetening, flavouring and colouring agents, may also be present. The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, or a mineral oil, such as for example liquid paraffin or a mixture of any of these. Suitable emulsifying agents may be, for example, naturally-occurring gums such as gum acacia or gum tragacanth, naturally-occurring phosphatides such as soya bean, lecithin, an esters or partial esters derived from fatty acids and hexitol anhydrides (for example sorbitan monooleate) and condensation products of the said partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening, flavouring and preservative agents. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol, aspartame or sucrose, and may also contain a demulcent, preservative, flavouring and/or colouring agent. The pharmaceutical compositions may also be in the form of a sterile injectable aqueous or oily suspension, which may be formulated according to known procedures using one or more of the appropriate dispersing or wetting agents and suspending agents, which have been mentioned above. A sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example a solution in 1,3-butanediol. Compositions for administration by inhalation may be in the form of a conventional pressurised aerosol arranged to dispense the active ingredient either as an aerosol containing finely divided solid or liquid droplets. Conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons may be used and the aerosol device is conveniently arranged to dispense a metered quantity of active ingredient. For further information on formulation the reader is referred to Chapter 25.2 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25.3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990. The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula (I), (Ia), (lb) or (Ic) will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a compound of the Formula (I), (Ia), (lb) or (Ic) for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.5 mg to 75 mg per kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.5 mg to 30 mg per kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.5 mg to 25 mg per kg body weight will be used. Oral administration is however preferred. The elevation of GLK activity described herein may be applied as a sole therapy or may involve, in addition to the subject of the present invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets. For example in the treatment of diabetes mellitus chemotherapy may include the following main categories of treatment: 1) Insulin and insulin analogues; 2) Insulin secretagogues including sulphonylureas (for example glibenclamide, glipizide) and prandial glucose regulators (for example repaglinide, nateglinide); 3) Insulin sensitising agents including PPARg agonists (for example pioglitazone and rosiglitazone); 4) Agents that suppress hepatic glucose output (for example metformin). 5) Agents designed to reduce the absorption of glucose from the intestine (for example acarbose); 6) Agents designed to treat the complications of prolonged hyperglycaemia; 7) Anti-obesity agents (for example sibutramine and orlistat); 8) Anti-dyslipidaemia agents such as, HMG-CoA reductase inhibitors (statins, eg pravastatin); PPARα agonists (fibrates, eg gemfibrozil); bile acid sequestrants (cholestyramine); cholesterol absorption inhibitors (plant stanols, synthetic inhibitors); bile acid absorption inhibitors (IBATi) and nicotinic acid and analogues (niacin and slow release formulations); 9) Antihypertensive agents such as, β blockers (eg atenolol, inderal); ACE inhibitors (eg lisinopril); Calcium antagonists (eg. nifedipine); Angiotensin receptor antagonists (eg candesartan), α antagonists and diuretic agents (eg. furosemide, benzthiazide); 10) Haemostasis modulators such as, antithrombotics, activators of fibrinolysis and antiplatelet agents; thrombin antagonists; factor Xa inhibitors; factor VIIa inhibitors); antiplatelet agents (eg. aspirin, clopidogrel); anticoagulants (heparin and Low molecular weight analogues, hirudin) and warfarin; and 11) Anti-inflammatory agents, such as non-steroidal anti-infammatory drugs (eg. aspirin) and steroidal anti-inflammatory agents (eg. cortisone). According to another aspect of the present invention there is provided individual compounds produced as end products in the Examples set out below and salts thereof. A compound of the invention, or a salt, pro-drug or solvate thereof, may be prepared by any process known to be applicable to the preparation of such compounds or structurally related compounds. Such processes are illustrated by the following representative schemes (1 to 4) in which variable groups have any of the meanings defined for Formula (I) unless stated otherwise and A is for example depicted as pyridyl. Functional groups may be protected and deprotected using conventional methods. For examples of protecting groups such as amino and carboxylic acid protecting groups (as well as means of formation and eventual deprotection), see T. W. Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”, Second Edition, John Wiley & Sons, New York, 1991. Note abbreviations used have been listed immediately before the Examples below. During the preparation process, it may be advantageous to use a protecting group for a functional group within the molecule. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Processes for the synthesis of compounds of Formula (I) are provided as a further feature of the invention. Thus, according to a further aspect of the invention there is provided a process for the preparation of a compound of Formula (I) which comprises: (a) reaction of a compound of Formula (IIIa) with a compound of Formula (IIb), (b) for compounds of Formula (I) wherein R 3 is hydrogen, de-protection of a compound of Formula (IIIc), wherein P is a protecting group; (c) reaction of a compound of Formula (IIId) with a compound of Formula (IIIe), wherein X′ and X″ comprises groups which when reacted together form the group X; (d) for a compound of Formula (I) wherein X or X 1 is —SO-Z- or —SO 2 -Z-, oxidation of the corresponding compound of Formula (I) wherein X or X 1 respectively is —S-Z-; or (e) for a compound of Formula (I) wherein R 3 is NHR 6 , reaction of a compound of Formula (IIIf) with a compound of Formula (IIIg), and thereafter, if necessary: i) converting a compound of Formula (I) into another compound of Formula (I); ii) removing any protecting groups; iii) forming a salt, pro-drug or solvate thereof. Specific reaction conditions for the above reactions are as follows: Process a)—as described above in Scheme 1; Process b)—as described above in Scheme 1/2 Process c)—examples of this process are as follows: (i) to form a group when X is —O-Z-, X′ is a group of formula HO-Z- and X″ is a leaving group (alternatively X′ is a group of formula L 2 -Z- wherein L 2 is a leaving group and X″ is a hydroxyl group), compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent, such as DMF or THF, with a base such as sodium hydride or potassium tert-butoxide, at a temperature in the range 0 to 100° C., optionally using metal catalysis such as palladium on carbon or cuprous iodide; (ii) to form a group when X is N(R 6 )-Z-, X′ is a group of formula H—(R 6 )N-Z- and X″ is a leaving group (alternatively X′ is a group of formula L 2 -Z- wherein L 2 is a leaving group and X″ is a group or formula —N(R 6 )—H), compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent such as THF, an alcohol or acetonitrile, using a reducing agent such as sodium cyano borohydride or sodium trisacetoxyborohydride at room temperature; (iii) to form a group when X is —SO 2 N(R 6 )-Z-, X′ is a group of formula H—N(R 6 )-Z- wherein L 2 is a leaving group and X″ is an activated sulphonyl group such as a group of formula —SO 2 —Cl, compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent such as methylene chloride, THF or pyridine, in the presence of a base such as triethylamine or pyridine at room temperature; (iv) to form a group when X is —N(R 6 )SO 2 -Z-, X′ is an activated sulphonyl group such as a group of formula Cl—SO 2 -Z- group and X″ is a group of formula —N(R 6 )-L 2 wherein L 2 is a leaving group, compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent such as methylene chloride, THF or pyridine, in the presence of a base such as triethylamine or pyridine at room temperature; (v) to form a group when X is —C(O)N(R 6 )-Z-, X′ is a group of formula H—N(R 6 )-Z- wherein L 2 is a leaving group and X″ is an activated carbonyl group such as a group of formula —C(O)—Cl, compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent such as THF or methylene chloride, in the presence of a base such as triethylamine or pyridine at room temperature; (vi) to form a group when X is —N(R 6 )C(O)-Z-, X′ is an activated carbonyl group such as a group of formula Cl—C(O)-Z- group and X″ is a group of formula —N(R 6 )-L 2 wherein L 2 is a leaving group, compounds of Formula (IIId) and (IIIe) are reacted together in a suitable solvent such as THF or methylene chloride, in the presence of a base such as triethylamine or pyridine at room temperature; (vii) to form a group when X is —CH═CH-Z-, a Wittag reaction or a Wadsworth-Emmans Homer reaction can be used. For example, X′ terminates in an aldehyde group and Y—X 1 is a phosphine derivative of the formula Y—C—H—P + PH 3 which can be reacted together in a strong base such as sodium hydride or potassium tert-butoxide, in a suitable solvent such as THF at a temperature between room temperature and 100° C. Process d)—the oxidization of a compound of Formula (I) wherein X or X 1 is —S-Z- is well known in the art, for example, reaction with metachloroperbenzoic acid (MCPBA) is the presence of a suitable solvent such as dichloromethane at ambient temperature. If an excess of MCPBA is used a compound of Formula (I) wherein X is —S(O 2 )— is obtained. Process e)—as described above in Scheme 4. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule. Specific examples of protecting groups are given below for the sake of convenience, in which “lower” signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned is of course within the scope of the invention. A carboxy protecting group may be the residue of an ester-forming aliphatic or araliphatic alcohol or of an ester-forming silanol (the said alcohol or silanol preferably containing 1-20 carbon atoms). Examples of carboxy protecting groups include straight or branched chain (C 1-12 )alkyl groups (e.g. isopropyl, t-butyl); lower alkoxy lower alkyl groups (e.g. methoxymethyl, ethoxymethyl, isobutoxymethyl; lower aliphatic acyloxy lower alkyl groups, (e.g. acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl); lower alkoxycarbonyloxy lower alkyl groups (e.g. 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl); aryl lower alkyl groups (e.g. p-methoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, benzhydryl and phthalidyl); tri(lower alkyl)silyl groups (e.g. trimethylsilyl and t-butyldimethylsilyl); tri(lower alkyl)silyl lower alkyl groups (e.g. trimethylsilylethyl); and (2-6C)alkenyl groups (e.g. allyl and vinylethyl). Methods particularly appropriate for the removal of carboxylprotecting groups include for example acid-, metal- or enzymically-catalysed hydrolysis. Examples of hydroxy protecting groups include lower alkenyl groups (e.g. allyl); lower alkanoyl groups (e.g. acetyl); lower alkoxycarbonyl groups (e.g. t-butoxycarbonyl); lower alkenyloxycarbonyl groups (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzoyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl); tri lower alkyl/arylsilyl groups (e.g. trimethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl); aryl lower alkyl groups (e.g. benzyl) groups; and triaryl lower alkyl groups (e.g. triphenylmethyl). Examples of amino protecting groups include formyl, aralkyl groups (e.g. benzyl and substituted benzyl, e.g. 1-methoxybenzyl, nitrobenzyl and 2,4-dimethoxybenzyl, and triphenylmethyl); di-1-anisylmethyl and furylmethyl groups; lower alkoxycarbonyl (e.g. 1-butoxycarbonyl); lower alkenyloxycarbonyl (e.g. allyloxycarbonyl); aryl lower alkoxycarbonyl groups (e.g. benzyloxycarbonyl, p-methoxybenzyloxycarbonyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl; trialkylsilyl (e.g. trimethylsilyl and t-butyldimethylsilyl); alkylidene (e.g. methylidene); benzylidene and substituted benzylidene groups. Methods appropriate for removal of hydroxy and amino protecting groups include, for example, acid-, base, metal- or enzymically-catalysed hydrolysis, or photolytically for groups such as o-nitrobenzyloxycarbonyl, or with fluoride ions for silyl groups. Examples of protecting groups for amide groups include aralkoxymethyl (e.g. benzyloxymethyl and substituted benzyloxymethyl); alkoxymethyl (e.g. methoxymethyl and trimethylsilylethoxymethyl); tri alkyl/arylsilyl (e.g. trimethylsilyl, t-butyldimethylsily, t-butyldiphenylsilyl); tri alkyl/arylsilyloxymethyl (e.g. t-butyldimethylsilyloxymethyl, t-butyldiphenylsilyloxymethyl); 4-alkoxyphenyl (e.g. 4-methoxyphenyl); 2,4-di(alkoxy)phenyl (e.g. 2,4-dimethoxyphenyl); 4-alkoxybenzyl (e.g. 4-methoxybenzyl); 2,4-di(alkoxy)benzyl (e.g. 2,4-di(methoxy)benzyl); and alk-1-enyl (e.g. allyl, but-1-enyl and substituted vinyl e.g. 2-phenylvinyl). Aralkoxymethyl, groups may be introduced onto the amide group by reacting the latter group with the appropriate aralkoxymethyl chloride, and removed by catalytic hydrogenation. Alkoxymethyl, tri alkyl/arylsilyl and tri alkyl/silyloxymethyl groups may be introduced by reacting the amide with the appropriate chloride and removing with acid; or in the case of the silyl containing groups, fluoride ions. The alkoxyphenyl and alkoxybenzyl groups are conveniently introduced by arylation or alkylation with an appropriate halide and removed by oxidation with ceric ammonium nitrate. Finally alk-1-enyl groups may be introduced by reacting the amide with the appropriate aldehyde and removed with acid. The present invention also relates to the use of a GLK activator for the combined treatment of diabetes and obesity. GLK and GLKRP and the K ATP channel are expressed in neurones of the hypothalamus, a region of the brain that is important in the regulation of energy balance and the control of food intake [14-18]. These neurones have been shown to express orectic and anorectic neuropeptides [15, 19, 20] and have been assumed to be the glucose-sensing neurones within the hypothalamus that are either inhibited or excited by changes in ambient glucose concentrations [17, 19, 21, 22]. The ability of these neurones to sense changes in glucose levels is defective in a variety of genetic and experimentally induced models of obesity [23-28]. Intracerebroventricular (icv) infusion of glucose analogues, that are competitive inhibitors of glucokinase, stimulate food intake in lean rats [29, 30]. In contrast, icv infusion of glucose suppresses feeding [31]. Thus, small molecule activators of GLK may decrease food intake and weight gain through central effects on GLK. Therefore, GLK activators may be of therapeutic use in treating eating disorders, including obesity, in addition to diabetes. The hypothalamic effects will be additive or synergistic to the effects of the same compounds acting in the liver and/or pancreas in normalising glucose homeostasis, for the treatment of Type 2 diabetes. Thus the GLK/GLKRP system can be described as a potential “Diabesity” target (of benefit in both Diabetes and Obesity). This according to a second aspect of the invention there is provided the use of a GLK activator in the preparation of a medicament for the combined treatment or prevention of diabetes and obesity. According to a further feature of the second aspect of the invention there is provided a method of combined treatment, in a warm-blooded animal, of diabetes and obesity, comprising administering a therapeutically effective amount of a compound of a GLK activator, or a pharmaceutically-acceptable salt, pro-drug or solvate thereof. According to a further feature of the second aspect of the invention there is provided a pharmaceutical composition comprising a GLK activator, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the combined treatment of diabetes and obesity in a warm-blooded animal. According to a further feature of the second aspect of the invention there is provided the use a GLK activator in the preparation of a medicament for the treatment or prevention of diabetes and obesity, wherein the GLK activator is a compound of Formula (I) above. According to a further feature of the second aspect of the invention there is provided a method of combined treatment, in a warm-blooded animal, of diabetes and obesity, comprising administering a therapeutically effective amount of a compound of a GLK activator, or a pharmaceutically-acceptable salt, pro-drug or solvate thereof, wherein the GLK activator is a compound of Formula (I) above. According to a further feature of the second aspect of the invention there is provided a pharmaceutical composition comprising a GLK activator, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the combined treatment of diabetes and obesity in a warm-blooded animal, wherein the GLK activator is a compound of Formula (I) above. According to a further feature of the second aspect of the invention there is provided the use a GLK activator in the preparation of a medicament for the treatment or prevention of diabetes and obesity, wherein the GLK activator is a compound of Formula (IV) below. wherein m is 0, 1 or 2; n is 0, 1, 2, 3 or 4; and n+m>0; each R 1 is independently selected from OH, —(CH 2 ) 1-4 OH, —CH 3-a F a , —(CH 2 ) 1-4 CH 3-a F a , halo, C 1-6 , C 2-6 alkenyl, C 2-6 alkynyl, NO 2 , NH 2 , —NH—C 1-4 alkyl, —N-di-(C 1-4 alkyl), CN or formyl; each R 2 is the group Y—X— wherein each X is a linker independently selected from: —O-Z-, —O-Z-O-Z-, —C(O)O-Z-, —OC(O)-Z-, —S-Z-, —SO-Z-, —SO 2 -Z-, —N(R 6 )-Z-, —N(R 6 )SO 2 -Z-, —SO 2 N(R 6 )-Z-, —(CH 2 ) 14-, —CH═CH-Z-, —C≡C-Z-, —N(R 6 )CO-Z-, —CON(R 6 )-Z-, —C(O)N(R 6 )S(O) 2 -Z-, —S(O) 2 N(R 6 )C(O)-Z-, —C(O)-Z- or a direct bond; each Z is independently a direct bond or a group of the formula in-line-formulae description="In-line Formulae" end="lead"? —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —; in-line-formulae description="In-line Formulae" end="tail"? each Y is independently selected from aryl-Z 1 -, heterocyclyl-Z 1 -, C 3-7 cycloalkyl-Z 1 -, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or —(CH 2 ) 1-4 CH 3-a F a ; wherein each Y is independently optionally substituted by up to 3 R 4 groups; each R 4 is independently selected from halo, —CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, —COOH, —C(O)OC 1-6 alkyl, OH or phenyl, or R 5 —X 1 —, where X 1 is independently as defined in X above and R 5 is selected from hydrogen, C 1-6 alkyl, —CH 3-a F a phenyl, naphthyl, heterocyclyl or C 3-7 cycloalkyl; and R 5 is optionally substituted by halo, C 1-6 alkyl, —CH 3-a F a , CN, NO 2 , NH 2 , COOH or —C(O)OC 1-6 alkyl, wherein each phenyl, naphthyl or heterocyclyl ring in R 5 is optionally substituted by halo, CH 3-a F a , CN, NO 2 , NH 2 , C 1-6 alkyl, —OC 1-6 alkyl, COOH, —C(O)OC 1-6 alkyl or OH; each Z 1 is independently a direct bond or a group of the formula in-line-formulae description="In-line Formulae" end="lead"? —(CH 2 ) p —C(R 6 ) 2 —(CH 2 ) q —; in-line-formulae description="In-line Formulae" end="tail"? R 3 is selected from hydrogen or C 1-6 alkyl; and R 6 is independently selected from hydrogen, C 1-6 alkyl or —C 2-4 alkyl-O—C 1-4 alkyl; each a is independently 1, 2 or 3; p is an integer between 0 and 2; q is an integer between 0 and 2; and p+q<4. According to a further feature of the second aspect of the invention there is provided a method of combined treatment, in a warm-blooded animal, of diabetes and obesity, comprising administering a therapeutically effective amount of a compound of a GLK activator, or a pharmaceutically-acceptable salt, pro-drug or solvate thereof, wherein the GLK activator is a compound of Formula (IV). According to a further feature of the second aspect of the invention there is provided a pharmaceutical composition comprising a GLK activator, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the combined treatment of diabetes and obesity in a warm-blooded animal, wherein the GLK activator is a compound of Formula (IV). Further examples of GLK activators are contained in International Application numbers: WO 00/58293, WO 01/44216, WO 01/83465, WO 01/83478, WO 01/85706, WO 01/85707, WO 02/08209 and WO 02/14312. The contents of aforesaid International Applications are hereby incorporated by reference. In a further feature of the second aspect of the invention there is provided the use a GLK activator in the preparation of a medicament for the treatment or prevention of diabetes and obesity, wherein the GLK activator is a compound exemplified in aforesaid International Applications or falls within the scope of aforesaid International Applications. According to a further feature of the second aspect of the invention there is provided a method of combined treatment, in a warm-blooded animal, of diabetes and obesity, comprising administering a therapeutically effective amount of a compound of a GLK activator, wherein the GLK activator is a compound exemplified in aforesaid International Applications or falls within the scope of aforesaid International Applications. According to a further feature of the second aspect of the invention there is provided a pharmaceutical composition comprising a GLK activator, or a pharmaceutically acceptable salt, prodrug or solvate thereof, in admixture with a pharmaceutically-acceptable diluent or carrier for the combined treatment of diabetes and obesity in a warm-blooded animal, wherein the GLK activator is a compound exemplified in aforesaid International Applications or falls within the scope of aforesaid International Applications. The identification of compounds that are useful in the combined treatment of diabetes and obesity is the subject of the present invention. These properties may be assessed, for example, by measuring changes in food intake, feeding-related behaviour (eg. feeding, grooming, physical activity, rest) and body weight separately or together with measuring plasma or blood glucose or insulin concentrations with or without an oral glucose load/food in a variety of animal models such as ob/ob mouse, db/db mouse, Fatty Zucker rat, Zucker diabetic rat (ZDF), streptozotocin-treated rats or mice or diet-induced obese mice or rats, as described in Sima & Shafrir, 2001, Animal Models of Diabetes, A Primer (Harwood Academic Publishers, Netherlands) or in animals treated with glucose directly into the brain or in animals rendered diabetic by treatment with streptozotocin and fed a high fat diet (Metabolism 49: 1390-4, 2000). GLK activators may be used in the combined treatment of diabetes and obesity alone or in combination with one or more additional therapies. Such combination therapy may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. Simultaneous treatment may be in a single tablet or in separate tablets. Examples of agents which may be used in combination therapy include those listed in paragraphs 1)-11) above, as drugs which may be used with compounds of Formula (I). The following examples of Compounds of Formula (I)-(Ic) are for illustration purposes and are not intended to limit the scope of this application. Each exemplified compound represents a particular and independent aspect of the invention. In the following non-limiting Examples, unless otherwise stated: (i) evaporations were carried out by rotary evaporation in vacuo and work-up procedures were carried out after removal of residual solids such as drying agents by filtration; (ii) operations were carried out at room temperature, that is in the range 18-25° C. and under an atmosphere of an inert gas such as argon or nitrogen; (iii) yields are given for illustration only and are not necessarily the maximum attainable; (iv) the structures of the end-products of the Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet, quin, quintet; (v) intermediates were not generally fully characterised and purity was assessed by thin layer chromatography (TLC), high-performance liquid chromatography (HPLC), infra-red (IR) or NMR analysis; (vi) chromatography was performed on silica (Merck Silica gel 60, 0.040-0.063 mm, 230-400 mesh); and (vi) Biotage cartridges refer to pre-packed silica cartridges (from 40 g up to 400 g), eluted using a biotage pump and fraction collector system; Biotage UK Ltd, Hertford, Herts, UK. detailed-description description="Detailed Description" end="lead"? |
Kit enabling a prosthetic valve to be placed in a body enabling a prosthetic valve to be put into place in a duct in the body |
The present invention is an assembly comprising a prosthetic valve to be implanted; a radially expandable stent comprising at least one zone intended to be expanded to allow the stent, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize this stent with respect to this wall; and means for mounting the valve with respect to the stent, making it possible to connect the valve to the stent in such a way that the placement of the stent allows the valve to be mounted in the body duct, and expansion means such as a balloon catheter being provided to trigger expansion of the stent at the implantation site. According to the invention, the valve and the stent are designed in such a way that, at the moment when the stent is expanded, the valve is situated outside the zone or zones of the stent that are subjected to said expansion means. The invention thus consists in separating the valve and said zone or zones to be expanded, so that the expansion of the stent can be effected with an expansion force suitable for perfect anchoring of this stent in the wall of the body duct to be fitted with the valve, and without any risk of destruction or damage of the valve. |
1-21. (canceled). 22. A prosthetic valve assembly comprising: an implantable prosthetic valve; a radially expandable stent comprising at least one expandable zone that is configured, in an expanded state, to bear against a wall of the native body lumen in a manner so as to resist migration; and means for mounting the valve on the stent such that, when expanded, the valve is positioned outside of the zone. 23. The assembly of claim 22, further comprising expansion means to expand at least the zone of the stent at the desired implantation site. 24. The assembly of claim 22, where in the stent is mounted within a second zone distinct from the first zone. 25. The assembly of claim 24, wherein the mounting means comprises conduits on a peripheral wall of the valve and arms arranged on the stent, the peripheral wall of the valve configured to engage and slide on the arms. 26. The assembly of claim 22, wherein the mounting means is configured such that the valve is axially movable with respect to the stent between a position of non-implantation outside the first zone to be expanded, and a position of implantation, which it can reach after expansion of the stent, in which it is immobilized axially with respect to the stent. 27. The assembly of claim 26, wherein the mounting means comprises radially positioned fastening members mounted on the valve configured to be inserted into the body wall. 28. The assembly of claim 27, wherein the fastening member are configured to insert into the body upon a pivoting of the valve about its axis. 29. The assembly of claim 27, wherein the fastening member are configured to insert into the body upon a longitudinal movement of the valve with respect to the stent. 30. The assembly of claim 27, wherein the fastening members comprise spikes, hooks or claws. 31. The assembly of claim 26, wherein the mounting means comprises burstable vesicles. 32. The assembly of claim 31, wherein the vesicles are filled with adhesive. 33. The assembly of claim 32, wherein the vesicles are configured to burst when the valve is brought into its position of implantation. 34. The assembly of claim 26, wherein the mounting means comprises at least one band integrated in the peripheral wall of the valve and having a shape memory, so that it keeps the valve pressed against the stent in the position of implantation of this valve. 35. The assembly of claim 34, wherein the band comprises a wire. 36. The assembly of claim 34, wherein the band is circular in shape. 37. The assembly of claim 34, wherein the band is helical in shape. 38. The assembly of claim 26, wherein the mounting means comprises conduits. 39. The assembly of claim 38, further comprising rods configured to engage and slide through the conduits as the valve moves from its position of non-implantation to its position of implantation. 40. The assembly of claim 39, further comprising means to immobilize the conduits with respect to the rods in the position of implantation. 41. The assembly of claim 40, further comprising wires connected to the rods and configured to pass through said conduits to guide said rods in the conduits. 42. The assembly of claim 22, wherein the mounting means is configured such that beyond a threshold of expansion of the stent, said means permits a different amount of expansion of the valve and the stent, whereby the variation in the degree of expansion of the stent does not substantially impact the degree of expansion of the valve. 43. The assembly of claim 22, further comprising means for limiting the expansion of the valve. 44. The assembly of claim 22, wherein the valve comprises a peripheral wall with a tapered diameter in the axial direction and the zone of the stent supporting the valve has a corresponding shape. 45. The assembly of claim 22, wherein the the stent comprises a middle portion having a smaller diameter than at end portions thereof, the valve having a shape corresponding to that zone of the stent in whose area it is intended to be mounted. 46. The assembly of claim 45, wherein the middle portion forms two inverted truncated cones. 47. The assembly of claim 45, wherein the middle portion forms an hourglass shape. 48. The assembly of claim 22, wherein the valve has a peripheral wall and the stent has, in the distal continuation of that zone of the stent intended to receive the valve, a foldable portion movable between an extended position, in which it is situated in the distal continuation of said zone, and a folded position, in which it is placed against the inner face of the peripheral wall of the valve, and traps this peripheral wall between it and said zone of the stent. 49. The assembly of claim 48, further comprising retaining means for keeping this foldable portion in a folded position. 50. The assembly of claim 49, characterized in that said retaining means are formed by a wire (46) made of a material which is rigid but has a degree of elastic flexibility, for example a metal material having an undulated form and extending over the entire circumference of said foldable portion (45). 51. The assembly of claim 22, further comprising a sheath that comprises an impermeable biocompatible material and at least partially covers the stent. 52. The assembly of claim 52, wherein the sheath has lateral openings that are configured to be positioned opposite the coronary ostia when implanted. 53. The assembly of claim 48, further comprising a sheath that comprises an impermeable biocompatible material and at least partially covers the stent. 54. The assembly of claim 53, wherein the foldable portion is formed by a continuation of the sheath forming a sleeve beyond the zone of the stent intended to receive the valve. 55. The assembly of claim 51, further comprising an inflatable peripheral chamber configured to be inflated so as to substantially form a seal between the stent and the wall of the body lumen to be fitted with the valve. 56. The assembly of claim 55, comprising a plurality of inflatable peripheral chambers positioned radially on the portion of the stent intended to bear against the native cardiac valvular ring. 57. The assembly of claim 22, wherein the stent comprises a cylindrical portion that is configured to bear against the native cardiac valvular ring and a distal portion connected to the cylindrical portion. 58. The assembly of claim 22, wherein the the stent comprises a tapered proximal portion whose diameter decreases in the distal direction and is configured to, upon implantation, to bear against the wall of the ventricle or corresponding auricle of the heart. 59. The assembly of claim 58, further comprising a supplementary bearing portion on the stent connected by rods to the distal portion or to the cylindrical portion, the rods configured of sufficient length so that, when implanted, the supplementary bearing portion is positioned beyond the coronary ostia. 60. The assembly of claim 22, further comprising retractable hooks on the stent to minimize migration. 61. The assembly of claim 22, wherein the stent comprises a portion of high radial force. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to an assembly for placing a prosthetic valve in a lumen of the body, especially a heart valve, and in particular an aortic valve. 2. Description of the Related Art Documents WO 91/17720, WO 98/29057 and EP 1 057 460 each describe an assembly, including the prosthetic valve to be implanted; a radially expandable framework, called a stent, which is able, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize this stent with respect to this wall; and means for fixing the valve to the stent. The placement of the stent permits mounting of the valve in the body duct, eliminating the need for an external access route and, thus, a direct surgical intervention. However, major drawbacks of this technique are that it entails a risk of the valve being damaged by the balloon used to expand the stent, and it limits the force of expansion that can be imparted to the stent. This limitation has repercussions on the anchoring of the stent, making a displacement of said assembly possible. This limitation also has repercussions on the leaktightness of the stent in the area of the valvular ring which is particularly affected when calcified zones give the valvular ring an irregular form and/or a certain rigidity. Another drawback of the prior art technique is that of directly joining the commissures of the valvules to the stent. The result of this is that an expansion of the stent, and thus of the valve, different than that intended may cause poor coaptation of the valvules and, consequently, defective functioning of the valve. The stent therefore has to undergo a predetermined expansion, which prevents or complicates adaptation of this stent to the anatomical variations. In the case of implantation of an aortic valve, the prior art technique also has drawbacks in that it necessitates very exact positioning of the stent in the aorta so that the valve is located opposite the natural valvular ring, and it entails a risk of blocking the apertures of the coronary arteries that open out at the coronary ostia. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention aims to overcome these various drawbacks. The assembly of the present invention comprises a prosthetic valve to be implanted; a radially expandable framework, or stent, comprising at least one zone intended to be expanded to allow the stent, in the expanded state, to bear against the wall of the body duct to be fitted with the valve, this bearing making it possible to immobilize the stent with respect to this wall; and means for mounting the valve with respect to the stent, making it possible to connect the valve to the stent in such a way that the placement of the stent allows the valve to be mounted in the body duct, and expansion means such as a balloon catheter being provided to trigger expansion of the stent at the implantation site. According to the invention, the valve and the stent are designed in such a way that, at the moment when the stent is expanded, the valve is situated outside the zone or zones of the stent that are subjected to said expansion means. The invention thus consists in separating the valve and said zone or zones to be expanded, so that the expansion of the stent can be effected with an expansion force suitable for perfect anchoring of this stent in the wall of the body duct to be fitted with the valve, and without any risk of destruction or damage of the valve. According to one possibility, the stent comprises a zone for mounting of the valve, which zone is distinct from the zone or zones of the stent to be expanded, and said mounting means connect the valve to this mounting zone. The expansion of the stent thus triggers the deployment of the valve. According to another possibility, said mounting means are designed in such a way that the valve is axially movable with respect to the stent between apposition of non-implantation, in which it is situated outside the zone or zones of the stent that are to be expanded, and a position of implantation, which it can reach after expansion of the stent in the body duct, in which it is immobilized axially with respect to the stent. The valve can thus form a subassembly separate from the stent prior to placement of this stent in the body duct, and it can be placed in the stent once the latter has been implanted. Alternatively, the valve is connected to the stent before said stent is placed in the body duct to be treated, and consequently it is introduced into this duct with the stent; said mounting means then comprise means of displacement so that, once the stent has been expanded, the valve can be displaced between said position of non-implantation and said position of implantation. Said mounting means can then comprise one or more of the following arrangements: fastening members such as spikes, hooks or claws that are mounted on the valve and are able to be inserted into the wall delimiting said body duct; these fastening members can be oriented radially with respect to the valve so as to be able to be inserted into said wall upon radial deployment of the valve, or they can be oriented tangentially with respect to the valve so as to be able to be inserted into said wall upon a pivoting of the valve about its axis or upon a longitudinal movement with respect to the stent; burstable vesicles that are filled with biological adhesive or other suitable adhesive product and are placed on the outer face of the valve, these vesicles being able to burst when the valve is brought into its position of implantation, in particular by their being crushed between the valve and the stent; at least one circular or helical wire or band integrated in the peripheral wall of the valve and having a shape memory, so that it keeps the valve pressed against the stent in the position of implantation of this valve; conduits formed in, or fixed on, the peripheral wall of the valve, and rods formed on the stent, or vice versa, these rods being able to be engaged and being able to slide through these conduits as the valve moves from its position of non-implantation to its position of implantation, it being possible to provide means such as hooks in order to immobilize these conduits with respect to these rods in said position of implantation; wires can be connected to the ends of said rods and can pass through said conduits in order to easily guide these rods in these conduits. Preferably, the means for mounting the valve with respect to the stent are designed in such a way that, beyond a threshold of expansion of the stent, they permit a different expansion of the valve and of the stent, so that a variation in the degree of expansion of the stent has no effect on the degree of expansion of the valve. The valve is thus not connected directly to the stent and in particular is not connected to the stent in the area of the commissures of its valvules; in the expanded position of the stent, it can have a predetermined diameter appropriate to it, independently of the diameter of the stent. After implantation, the valve thus has a configuration ensuring that it functions properly irrespective of the degree of expansion of the stent, and this expansion of the stent can be adapted to the anatomical variability encountered at the implantation site. The stent and/or the valve can comprise one or more elements limiting the maximum diameter of expansion of the valve, in particular in the area of the commissure points of this valve. These elements can be longitudinal wires belonging to the stent, or a framework element belonging to the valve. Preferably, the valve has a peripheral wall with a diameter not constant in the axial direction, in particular a frustoconical shape whose diameter decreases in the distal direction, and the zone of the stent intended to receive this peripheral wall of the valve has a shape corresponding to that of this peripheral wall. This peripheral wall and this zone of the stent thus define a determined position of mounting of the valve in the stent, and they ensure that the valve is held in position in the stent. The stent advantageously has a middle portion with a smaller diameter than its end portions. It can in particular have the general form of two inverted truncated cones or an hourglass shape. In the case where the assembly according to the invention permits mounting of an aortic valve, the stent is thus at a distance from the wall of the body duct, in particular by means of a conical or hourglass shape, allowing body fluid to pass to the coronary vessels in the area of the coronary ostia. The valve has a shape corresponding to that zone of the stent in whose area it is intended to be mounted. Advantageously, the valve has a peripheral wall; the stent has, in the distal continuation of that zone of the stent intended to receive the valve, a foldable portion; this foldable portion is movable between an extended position, in which it is situated in the distal continuation of said zone, and a folded position, in which it is placed against the inner face of the peripheral wall of the valve and traps this peripheral wall between it and said zone of the stent, and retaining means are provided for keeping this foldable portion in this folded position. The peripheral wall of the valve is thus pressed against the stent, which ensures leaktightness of the valve with respect to the stent. According to a preferred embodiment of the invention in this case, said retaining means are formed by a wire made of a material that is rigid but has a degree of elastic flexibility, for example a metal material having an undulated form and extending over the entire circumference of said foldable portion. Preferably, the stent comprises a sheath made of an impermeable biocompatible material and at least partially covering it. This sheath forms a fixation base for the valve and at the same time a means of sealing between the stent and the wall of the body duct. The sheath can advantageously have lateral openings that can be positioned opposite the coronary ostia at the time of implantation and thus avoid any zone of stagnation or non-circulation of the blood. Advantageously, in the case where the assembly according to the invention comprises said foldable portion, this foldable portion is formed by a continuation of said sheath, forming a sleeve beyond that zone of the stent intended to receive the valve. Perfect leaktightness is thus obtained between the valve and the stent. The stent preferably has, fixed on said sheath, at least one inflatable peripheral chamber that can be inflated in order to form a seal ensuring leaktightness between the stent and the wall of the body duct to be fitted with the valve. This leaktightness is thus guaranteed notwithstanding the possible presence of calcified portions that give a cardiac ring an irregular shape. Advantageously in this case, the stent has two inflatable peripheral chambers placed either side of that portion of the stent intended to bear against a cardiac valvular ring. The stent can have a cylindrical portion that can bear against a cardiac valvular ring, and a distal portion connected to this cylindrical portion. This distal portion at least partially forms said zone intended to receive the peripheral wall of the valve. The advantage is that said wall of impermeable biocompatible material is situated, in the area of this portion, at a distance from the wall of the body duct, that, in the case of implantation of an aortic valve, eliminates the risk of masking the coronary ostia. The stent can also have a frustoconical or widened proximal portion whose diameter decreases in the distal direction and able, in the case of implantation of a heart valve, to bear against the wall of the ventricle or corresponding auricle of the heart. With this proximal portion it is possible to define the position of the stent, and thus subsequently of the valve, with respect to the zone of implantation. It also helps ensure complete immobilization of the stent. The stent can also have a supplementary bearing portion connected by filiform rods to said distal portion or to said cylindrical portion, these filiform rods having lengths such that this supplementary bearing portion is positioned beyond the coronary ostia. According to an additional characteristic, the stent has hooks that are movable between a retracted position, which they occupy before expansion of the stent, and a position of deployment into which they are brought upon deployment of the stent and in which they are inserted into a wall delimiting the body duct. The stent can also have a portion near to the valvular ring, or situated opposite or on this valular ring, and having a high radial force, that is to say a radial force able to erase the local anatomical irregularities, for example calcifications, with a view to reinforcing the leaktightness at the junction between the stent, the sheath and the wall of the treated duct. This portion can be deployed with the aid of an expansion system with a high radial force and low compliance, for example a balloon. The above embodiments and methods of use are explained in more detail below. |
Information security model |
An information security model provides a set of schemas that ensure coverage of all securing components. All points are addressed and evaluated in a net of three-dimensional coorindate knots The model defines the relation between components in the information risk and security space, and provides an information risk and security framework that ensures that all information security components are addressed; enables standardized information security audit; provides information risk compliance numbers; and defines strategic business direction to address information security implementation. The information security model of the present invention standardizes the approach and creates a matrix through which risk compliance factors can be calculated. |
1. A method of increasing security in an organization, comprising the steps of a. defining a plurality of information technology entities; b. defining a plurality of risk and/or security components; c. defining a plurality of security functional components; and d. calculating a level of compliance of the organization's security components relative to a selected level of compliance. 2. A method of increasing security in an organization, comprising the steps of: a. defining a plurality of information technology entities; b. defining a plurality of risk and/or security components; c. defining a plurality of security functional components; and d. calculating a level of risk of the organization's security components relative to a selected level of risk. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The Information Security Model describes business based approach/methodology data structures that are used to analyze and measure risk and security related impacts on business processes in modern enterprise. The objective of the Information Security Model is to define a standardized set of structures that can be used to exchange data between different risk and security management systems. These structures provide the basis for standardized data bindings that allow exact industry information security compliancy level quantifications. The following specification is focused on defining interoperability between systems residing within the same enterprise or organization and their compliancy presentation within the specific industry best practices and industry vertical average. Traditionally, computer security is often something that is not an integral part of business management system. It is in practice more often than not the case that “security” is limited to periodical backups and whatever access controls are present in the operating system. When entering into a society where possession of information and the ability to process are becoming strategic resources that can be vital to the survival of an organization a broad and coordinated view on information security becomes paramount. At the same time as information becomes increasingly important, advances in communication technology make it possible to build software systems that are highly distributed. While providing many new possibilities, there are also many security issues tied to the use distributed systems. The motivation to create information security model is to help business people to understand information risk and security challenges and to enable information security professionals create easy and complete strategy for information protection. This framework is intended to contribute to the knowledge necessary for making the transition to a new view on security that both place security issues as an integral part of the business activities within an organization and that also take into account the problems arising through the use of distributed technology. The aim of the present invention is to provide a way to model an organization that can monitor, measure and define strategic activities that should tale place within the organization. It should also be possible to model how information flows and is processed within the organization. A key goal is to augment risk and security strategy and wordflow models with security concepts and measures using simple, understandable, and straightforward model. |
<SOH> SUMMARY OF THE INVENTION <EOH>This model was developed to provide an information risk and security framework that enforces the following: Ensure that all information security components are addressed Enable standardized information security audit Provide information risk compliance numbers Define strategic business direction to address information security implementation The information security model of the present invention standardizes the approach and creates a matrix through which risk compliance factors can be calculated. The information security model serves as a model, framework and template through which complete standardized and measurable information security and risk analysis are developed. The present invention thus provides a method of increasing security in an organization, comprising the steps of: a. defining a plurality of information technology entities; b. defining a plurality of risk and/or security components; c. defining a plurality of security functional components; and d. calculating a level of compliance of the organization's security components relative to a selected level of compliance. The present invention further provides method of increasing security in an organization, comprising the steps of: a. defining a plurality of information technology entities; b. defining a plurality of risk and/or security components; c. defining a plurality of security functional components; and d. calculating a level of risk of the organization's security components relative to a selected level of risk. |
Novel human cytomegalovirus (hcmv) cytotoxic t cell epitopes, polyepitopes compositions comprising same and diagnostic and prophylactic and therapeutic uses therefor |
The present invention provides CTL epitope peptides and polyepitope peptides from 14 distinct antigens of human cytomegalovirus (HCMV) that are restricted through HLA the most commonly prevalent class I alleles in different ethnic populations of the world. These epitopes provide an important platform for CTL epitope-based vaccines against HCMV. The present invention further provides vaccine composiitons comprising the subject epitope and polyepitope peptides and methods for vaccination of humans and for the adoptive transfer of HCMV-specific T cells to human subjects. The present invention further provides reagents and methods for determining the HCMV status or level of HCMV-specific immunity of a subject. |
1. An isolated peptide comprising a cytotoxic T-lymphocyte (CTL) epitope of an antigen of a cytomegalovirus of humans (HCMV) selected from the group consisting of pp28, pp50, pp65, pp71, pp150, gB, gH, IE-1, IE-2, US2, US3, US6, US11, and UL18 wherein said peptide consists of an amino acid sequence having about 9 to about 20 contiguous amino acids of said antigen and wherein: (i) said CTL epitope of pp65 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 22 (SQEPMSIYVY); SEQ ID NO: 23 (ATVQGQNLKY); SEQ ID NO: 24 (IRETVELRQY); SEQ ID NO: 25 (IGDQYVKVY); SEQ ID NO: 26 (TVQGQNLKY); SEQ ID NO: 27 (YRIQGKLEY); SEQ ID NO: 28 (QVIGDQYVK); SEQ ID NO: 29 (LLLQRGPQY); SEQ ID NO: 30 (RVTGGGAMA); SEQ ID NO: 31 (GVMTRGRLK); SEQ ID NO: 32 (VYALPLKML); SEQ ID NO: 33 (QYDPVAALF); SEQ ID NO: 34 (VYYTSAFVF); SEQ ID NO: 35 (DVPSGKLFM); SEQ ID NO: 36 (DIDLLLQRG); SEQ ID NO: 37 (YVKVYLESF); SEQ ID NO: 38 (TVQGQNLKY); SEQ ID NO: 39 (EPMSIYVYAL); SEQ ID NO: 40 (HVRVSQPSL); SEQ ID NO: 41 (QARLTVSGL); SEQ ID NO: 42 (RRRHRQDAL); SEQ ID NO: 43 (QPKRRRHRQ); SEQ ID NO: 44 (LCPKSIPGL); SEQ ID NO: 47 (SEHPTFTSQY); SEQ ID NO: 48 (CEDVPSGKLF); SEQ ID NO: 49 (NEIHNPAVF); SEQ ID NO: 50 (RETVELRQY); SEQ ID NO: 51 (QEPMSIYVY); SEQ ID NO: 52 (QMWQARLTV); SEQ ID NO: 53 (LMNGQQIFL); SEQ ID NO: 54 (ILARNLVPM); SEQ ID NO: 56 (QEFFWDANDIY); SEQ ID NO: 57 (QEFFWDANDI); SEQ ID NO: 58 (QYRIQGKLE); SEQ ID NO: 59 (RKHRHLPVADAV); SEQ ID NO: 60 (DPVAALFFF); SEQ ID NO: 61 (PGKISHIMLDVA); SEQ ID NO: 62 (TRATKMQVI); SEQ ID NO: 63 (QAIRETVEL); SEQ ID NO: 64 (YHRTWDRHEGA); SEQ ID NO: 65 (FMRPHERNGFTV); SEQ ID NO: 66 (CPSQEPMSIYVY); SEQ ID NO: 67 (LNIPSINVHHYPSAAERKHR); SEQ ID NO: 68 (ATVQGQNLKYQEFFWDANDI); SEQ ID NO: 69 (QEFFWDANDIYRIFAELEGV); SEQ ID NO: 70 (PQYSEHPTFTSQYRIQGKLE); SEQ ID NO: 71 (SQYRIQGKLEYRHTWDRHDE); SEQ ID NO: 72 (VFTWPPWQAGILARNLVPMV); SEQ ID NO: 73 (ILARNLVPMVATVQGQNLKY); SEQ ID NO: 74 (DQYVKVYLESFCEDVPSGKL); SEQ ID NO: 75 (YPSAAERKHRHLPVADAVIH); SEQ ID NO: 76 (QYDPVAALFFFDIDLLLQRG); SEQ ID NO: 77 (IIKPGKISHIMLDVAFTSHE); SEQ ID NO: 78 (AHELVCSMENTRATKMQVIG); SEQ ID NO: 79 (TRATKMQVIGDQYVKVYLES); SEQ ID NO: 80 (MNGQQIFLEVQAIRETVELR); SEQ ID NO: 81 (QAIRETVELRQYDPVAALFF); SEQ ID NO: 82 (LTVSGLAWTRQQNQWKEPDV); SEQ ID NO: 83 (WQPAAQPKRRRHRQDALPGP); SEQ ID NO: 84 (YRHTWDRHDEGAAQGDDDVW); SEQ ID NO: 85 (TSAGRKRKSASSATACTSGV); SEQ ID NO: 86 (HRQDALPGPCIASTPKKHRG); SEQ ID NO: 87 (YYTSAFVFPTKDVALRHVVC); SEQ ID NO: 88 (VTTERKTPRVTGGGAMAGAS); SEQ ID NO: 89 (QPFMRPHERNGFTVLCPKNM); SEQ ID NO: 90 (SICPSQEPMSIYVYALPLKM); SEQ ID NO: 91 (IYVYALPLKMLNIPSINVHH); SEQ ID NO: 92 (QQNQWKEPDVYYTSAFVFPT); SEQ ID NO: 93 (GAAQGDDDVWTSGSDSDEEL); SEQ ID NO: 94 (TGGGAMAGASTSAGRKRKSA); and SEQ ID NO: 95 (KDVALRHVVCAHELVCSMEN; (ii) said CTL epitope of IE-1 consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 96 (SLLSEFCRV); SEQ ID NO: 97 (VLAELVKQI); SEQ ID NO: 98 (ILGADPLRV); SEQ ID NO: 99 (TMYGGISLL); SEQ ID NO: 100 (LLSEFCRVL); SEQ ID NO: 101 (VLEETSVML); SEQ ID NO: 102 (CLQNALDIL); SEQ ID NO: 103 (ILDEERDKV); SEQ ID NO: 104 (IKEHMLKKY); SEQ ID NO: 105 (DEEEAIVAY); SEQ ID NO: 106 (KLGGALQAK); SEQ ID NO: 107 (QYILGADPL); SEQ ID NO: 108 (KYTQTEEKF); SEQ ID NO: 109 (KARAKKDEL); SEQ ID NO: 110 (VMKRRIEEI); SEQ ID NO: 111 (RHRIKEHML); SEQ ID NO: 112 (ELRRKMMYM); SEQ ID NO: 113 (QIKVRVDMV); SEQ ID NO: 114 (ELKRKMMYM); SEQ ID NO: 115 (RRKMMYMCY); SEQ ID NO: 116 (AYAQKIFKIL); SEQ ID NO: 117 (CSPDEIMAYAQKIFKILDEE); SEQ ID NO: 118 (SEPVSEIEEVAPEEEEDGAE); SEQ ID NO: 119 (VLCCYVLEETSVMLAKRPLI); SEQ ID NO: 120 (RRKMMYMCYRNIEFFTKNSA); and SEQ ID NO: 121 (NIEFFTKNSAFPKTTNGCSQ); and (iii) said CTL epitope of pp150 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 122 (GQTEPIAFV); SEQ ID NO: 130 (RPSTPRAAV); SEQ ID NO: 131 (SPWAPTAPL); SEQ ID NO: 132 (KARDHLAVL); SEQ ID NO: 133 (WPRERAWAL); SEQ ID NO: 134 (NVRRSWEEL); SEQ ID NO: 138 (RIEENLEGV); SEQ ID NO: 139 (PLIPTTAVI); SEQ ID NO: 140 (LIEDFDIYV); SEQ ID NO: 141 (KMSVRETLV); SEQ ID NO: 142 (FLGARSPSL); SEQ ID NO: 143 (ALVNAVNKL); SEQ ID NO: 144 (ALVNFLRHL); SEQ ID NO: 145 (NILQKIEKI); SEQ ID NO: 146 (ERAWALKNPHLA); SEQ ID NO: 147 (WPRERAWALKNPHLAYNPFR); SEQ ID NO: 148 (STSQKPVLGKRVATPHASAR); and SEQ ID NO: 149 (HANTALVNAVNKLVYTGRLI). 2-14 (cancelled). 15. An isolated peptide consisting of about 9 to about 20 contiguous amino acids of a pp50 antigen of a cytomegalovirus of humans (HCMV) wherein said peptide comprises a cytotoxic T-lymphocyte (CTL) epitope of said antigen. 16. The isolated peptide of claim 15 wherein said peptide binds to a MHC Class I cell expressing CD8+. 17. The isolated peptide of claim 16 wherein said peptide binds to a CD8+ cell expressing an HLA allele selected from the group consisting of: HLA A1, HLA A2, HLA A3, HLA B27 and HLA B44. 18. An isolated peptide comprising a cytotoxic T-lymphocyte (CTL) epitope of a pp50 antigen of a cytomegalovirus of humans (HCMV) wherein said peptide consists of an amino acid sequence selected from the group consisting of: (i) SEQ ID NO: 163 (LLNCAVTKL); SEQ ID NO: 164 (QLRSVIRAL); SEQ ID NO: 165 (VTEHDTLLY); SEQ ID NO: 166 (RGDPFDKNY); SEQ ID NO: 167 (GLDRNSGNY); SEQ ID NO: 168 (TLLNCAVTK); SEQ ID NO: 169 (TVRSHCVSK); SEQ ID NO: 170 (YEQHKITSY); SEQ ID NO: 171 (TRVKRNVKK); SEQ ID NO: 172 (SEDSVTFEF); and SEQ ID NO: 173 (TRLSEPPTL); (ii) a derivative of (i) and; (iii) a functionally equivalent variant of (i). 19. The isolated peptide according to claim 18 wherein said peptide consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 163 (LLNCAVTKL); SEQ ID NO: 164 (QLRSVIRAL); SEQ ID NO: 165 (VTEHDTLLY); SEQ ID NO: 166 (RGDPFDKNY); SEQ ID NO: 167 (GLDRNSGNY); SEQ ID NO: 168 (TLLNCAVTK); SEQ ID NO: 169 (TVRSHCVSK); SEQ ID NO: 170 (YEQHKITSY); SEQ ID NO: 171 (TRVKRNVKK); SEQ ID NO: 172 (SEDSVTFEF); and SEQ ID NO: 173 (TRLSEPPTL). 20. The isolated peptide according to claim 19 wherein said peptide has an amino acid sequence selected from the group consisting of SEQ ID NO: 163 (LLNCAVTKL); SEQ ID NO: 165 (VTEHDTLLY); SEQ ID NO: 166 (RGDPFDKNY); SEQ ID NO: 167 (GLDRNSGNY); and SEQ ID NO: 170 (YEQHKITSY). 21. The isolated peptide according to claim 20 wherein said peptide has the amino acid sequence set forth in SEQ ID NO: 165 (VTEHDTLLY). 22-100 (cancelled). 101. An isolated polyepitope peptide comprising two or more cytotoxic T-lymphocyte (CTL) epitopes of the same or different antigen of a cytomegalovirus of humans (HCMV), wherein said antigen is selected from the group consisting of pp28, pp50, pp65, pp71, pp150, gB, gH, IE-1, IE-2, US2, US3, US6, US11, and UL18 and wherein said peptide consists of an amino acid sequence having about 9 to about 20 contiguous amino acids of said antigen and wherein: (i) said CTL epitope of pp65 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 22 (SQEPMSIYVY); (ATVQGQNLKY); SEQ ID NO: 23 (IRETVELRQY); SEQ ID NO: 24 (IGDQYVKVY); SEQ ID NO: 25 (TVQGQNLKY); SEQ ID NO: 26 (YRIQGKLEY); SEQ ID NO: 27 (QVIGDQYVK); SEQ ID NO: 28 (LLLQRGPQY); SEQ ID NO: 29 (RVTGGGAMA); SEQ ID NO: 30 (GVMTRGRLK); SEQ ID NO: 31 (VYALPLKML); SEQ ID NO: 32 (QYDPVAALF); SEQ ID NO: 33 (VYYTSAFVF); SEQ ID NO: 34 (DVPSGKLFM); SEQ ID NO: 35 (DIDLLLQRG); SEQ ID NO: 36 (YVKVYLESF); SEQ ID NO: 37 (TVQGQNLKY); SEQ ID NO: 38 (EPMSIYVYAL); SEQ ID NO: 39 (HVRVSQPSL); SEQ ID NO: 40 (QARLTVSGL); SEQ ID NO: 41 (RRRHRQDAL); SEQ ID NO: 42 (QPKRRRHRQ); SEQ ID NO: 43 (LCPKSIPGL); SEQ ID NO: 44 (SEHPTFTSQY); SEQ ID NO: 47 (CEDVPSGKLF); SEQ ID NO: 48 (NEIHNPAVF); SEQ ID NO: 49 (RETVELRQY); SEQ ID NO: 50 (QEPMSIYVY); SEQ ID NO: 51 (QMWQARLTV); SEQ ID NO: 52 (LMNGQQIFL); SEQ ID NO: 53 (ILARNLVPM); SEQ ID NO: 54 (QEFFWDANDIY); SEQ ID NO: 56 (QEFFWDANDI); SEQ ID NO: 57 (QYRIQGKLE); SEQ ID NO: 58 (RKHRHLPVADAV); SEQ ID NO: 59 (DPVAALFFF); SEQ ID NO: 60 (PGKISHIMLDVA); SEQ ID NO: 61 (TRATKMQVI); SEQ ID NO: 62 (QAIRETVEL); SEQ ID NO: 63 (YHRTWDRHEGA); SEQ ID NO: 64 (FMRPHERNGFTV); SEQ ID NO: 65 (CPSQEPMSIYVY); SEQ ID NO: 66 (LNIPSINVHHYPSAAERKHR); SEQ ID NO: 67 (ATVQGQNLKYQEFFWDANDI); SEQ ID NO: 68 (QEFFWDANDIYRIFAELEGV); SEQ ID NO: 69 (PQYSEHPTFTSQYRIQGKLE); SEQ ID NO: 70 (SQYRIQGKLEYRHTWDRHDE); SEQ ID NO: 71 (VFTWPPWQAGILARNLVPMV); SEQ ID NO: 72 (ILARNLVPMVATVQGQNLKY); SEQ ID NO: 73 (DQYVKVYLESFCEDVPSGKL); SEQ ID NO: 74 (YPSAAERKHRHLPVADAVIH); SEQ ID NO: 75 (QYDPVAALFFFDIDLLLQRG); SEQ ID NO: 76 (IIKPGKISHIMLDVAFTSHE); SEQ ID NO: 77 (AHELVCSMENTRATKMQVIG); SEQ ID NO: 78 (TRATKMQVIGDQYVKVYLES); SEQ ID NO: 79 (MNGQQIFLEVQAIRETVELR); SEQ ID NO: 80 (QAIRETVELRQYDPVAALFF); SEQ ID NO: 81 (LTVSGLAWTRQQNQWKEPDV); SEQ ID NO: 82 (WQPAAQPKRRRHRQDALPGP); SEQ ID NO: 83 (YRHTWDRHDEGAAQGDDDVW); SEQ ID NO: 84 (TSAGRKRKSASSATACTSGV); SEQ ID NO: 85 (HRQDALPGPCIASTPKKHRG); SEQ ID NO: 86 (YYTSAFVFPTKDVALRHVVC); SEQ ID NO: 87 (VTTERKTPRVTGGGAMAGAS); SEQ ID NO: 88 (QPFMRPHERNGFTVLCPKNM); SEQ ID NO: 89 (SICPSQEPMSIYVYALPLKM); SEQ ID NO: 90 (IYVYALPLKMLNIPSINVHH); SEQ ID NO: 91 (QQNQWKEPDVYYTSAFVFPT); SEQ ID NO: 92 (GAAQGDDDVWTSGSDSDEEL); SEQ ID NO: 93 (TGGGAMAGASTSAGRKRKSA); SEQ ID NO: 94 and (KDVALRHVVCAHELVCSMEN; SEQ ID NO: 95 (ii) said CTL epitope of IE-1 consists of an amino acid sequence selected from the group consisting of: SEQ ID NO: 96 (SLLSEFCRV); (VLAELVKQI); SEQ ID NO: 97 (ILGADPLRV); SEQ ID NO: 98 (TMYGGISLL); SEQ ID NO: 99 (LLSEFCRVL); SEQ ID NO: 100 (VLEETSVML); SEQ ID NO: 101 (CLQNALDIL); SEQ ID NO: 102 (ILDEERDKV); SEQ ID NO: 103 (IKEHMLKKY); SEQ ID NO: 104 (DEEEAIVAY); SEQ ID NO: 105 (KLGGALQAK); SEQ ID NO: 106 (QYILGADPL); SEQ ID NO: 107 (KYTQTEEKF); SEQ ID NO: 108 (KARAKKDEL); SEQ ID NO: 109 (VMKRRIEEI); SEQ ID NO: 110 (RHRIKEHML); SEQ ID NO: 111 (ELRRKMMYM); SEQ ID NO: 112 (QIKVRVDMV); SEQ ID NO: 113 (ELKRKMMYM); SEQ ID NO: 114 (RRKMMYMCY); SEQ ID NO: 115 (AYAQKIFKIL); SEQ ID NO: 116 (CSPDEIMAYAQKIFKILDEE); SEQ ID NO: 117 (SEPVSEIEEVAPEEEEDGAE); SEQ ID NO: 118 (VLCCYVLEETSVMLAKRPLI); SEQ ID NO: 119 (RRKMMYMCYRNIEFFTKNSA); SEQ ID NO: 120 and (NIEFFTKNSAFPKTTNGCSQ); SEQ ID NO: 121 and (iii) said CTL epitope of pp15 consists of an amino acid sequence selected from the group consisting of SEQ ID NO: 122 (GQTEPIAFV); (RPSTPRAAV); SEQ ID NO: 130 (SPWAPTAPL); SEQ ID NO: 131 (KARDHLAVL); SEQ ID NO: 132 (WPRERAWAL); SEQ ID NO: 133 (NVRRSWEEL); SEQ ID NO: 134 (RIEENLEGV); SEQ ID NO: 138 (PLIPTTAVI); SEQ ID NO: 139 (LIEDFDIYV); SEQ ID NO: 140 (KMSVRETLV ); SEQ ID NO: 141 (FLGARSPSL); SEQ ID NO: 142 (ALVNAVNKL); SEQ ID NO: 143 (ALVNFLRHL); SEQ ID NO: 144 (NILQKIEKI); SEQ ID NO: 145 (ERAWALKNPHLA); SEQ ID NO: 146 (WPRERAWALKNPHLAYNPFR); SEQ ID NO: 147 (STSQKPVLGKRVATPHASAR); SEQ ID NO: 148 and (HANTALVNAVNKLVYTGRLI). SEQ ID NO: 149 102-113 (cancelled). 114. A prophylactic or therapeutic vaccine composition for eliciting a cellular immune response in a human subject against HCMV, said composition comprising an effective amount of the isolated peptide of claim 1 in combination with a pharmaceutically acceptable carrier, excipient, diluent or adjuvant. 115-116 (cancelled). 117. A prophylactic or therapeutic vaccine composition for eliciting a cellular immune response in a human subject against HCMV, said composition comprising: (i) an effective amount of an isolated peptide consisting of about 9 to about 20 contiguous amino acids of a pp50 antigen of a cytomegalovirus of humans (HCMV) wherein said peptide comprises a cytotoxic T-lymphocyte (CTL) epitope of said antigen; and (ii) a pharmaceutically acceptable carrier, excipient, diluent or adjuvant. 118. A prophylactic or therapeutic vaccine composition for eliciting a cellular immune response in a human subject against HCMV, said composition comprising: (i) an effective amount of an isolated peptide consisting of an amino acid sequence selected from the group consisting of: (LLNCAVTKL); SEQ ID NO: 163 (QLRSVIRAL); SEQ ID NO: 164 (VTEHDTLLY); SEQ ID NO: 165 (RGDPFDKNY); SEQ ID NO: 166 (GLDRNSGNY); SEQ ID NO: 167 (TLLNCAVTK); SEQ ID NO: 168 (TVRSHCVSK); SEQ ID NO: 169 (YEQHKITSY); SEQ ID NO: 170 (TRVKRNVKK); SEQ ID NO: 171 (SEDSVTFEF); SEQ ID NO: 172 and (TRLSEPPTL); SEQ ID NO: 173 and (ii) a pharmaceutically acceptable carrier, excipient, diluent or adjuvant. 119-139 (cancelled). 140. A prophylactic or therapeutic vaccine composition for eliciting a cellular immune response in a human subject against HCMV, said composition comprising: (i) an effective amount of the isolated polyepitope peptide of claim 101; and (ii) a pharmaceutically acceptable carrier, excipient, diluent or adjuvant. 141-143 (cancelled). 144. The prophylactic or therapeutic vaccine composition of claim 114 wherein the adjuvant comprises a saponified adjuvant comprising a saponin or a saponin fraction. 145. The prophylactic or therapeutic vaccine composition of claim 140 wherein the adjuvant comprises a saponified adjuvant comprising a saponin or a saponin fraction. 146-148 (cancelled). 149. A method of enhancing the HCMV-specific cell mediated immunity of a human subject comprising administering an effective amount of the isolated peptide of claim 1 sufficient to activate a CTL or a CTL precursor of said subject. 150. A method of enhancing the HCMV-specific cell mediated immunity of a human subject comprising administering an effective amount of the prophylactic or therapeutic vaccine composition of claim 114 sufficient to activate a CTL or a CTL precursor of said subject. 151-157 (cancelled). 158. A method of enhancing the HCMV-specific cell mediated immunity of a human subject comprising administering an effective amount of the isolated polyepitope peptide of claim 101 sufficient to activate a CTL or a CTL precursor of said subject. 159. A method of enhancing the HCMV-specific cell mediated immunity of a human subject comprising administering an effective amount of the prophylactic or therapeutic vaccine composition of claim 140 sufficient to activate a CTL or a CTL precursor of said subject. 160-166 (cancelled). 167. A method of enhancing the HCMV-specific cell mediated immunity of a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the isolated peptide of claim 1 sufficient to confer HCMV reactivity on said T cells. 168. A method of enhancing the HCMV-specific cell mediated immunity of a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the prophylactic or therapeutic vaccine composition of claim 115 sufficient to confer HCMV reactivity on said T cells. 169-173 (cancelled). 174. A method of enhancing the HCMV-specific cell mediated immunity of a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the isolated polyepitope peptide of claim 102 sufficient to confer HCMV reactivity on said T cells. 175. A method of enhancing the HCMV-specific cell mediated immunity of a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the prophylactic or therapeutic vaccine composition of claim 141 sufficient to confer HCMV reactivity on said T cells. 176-180 (cancelled). 181. A method of providing or enhancing immunity against HCMV in an uninfected human subject comprising administering to said subject an effective amount of the isolated peptide of claim 1 sufficient to provide immunological memory against a future infection by HCMV. 182. A method of providing or enhancing immunity against HCMV in an uninfected human subject comprising administering to said subject an effective amount of the prophylactic or therapeutic vaccine of claim 114 sufficient to provide immunological memory against a future infection by HCMV. 183-186 (cancelled). 187. A method of providing or enhancing immunity against HCMV in an uninfected human subject comprising administering to said subject an effective amount of the isolated polyepitope peptide of claim 101 sufficient to provide immunological memory against a future infection by HCMV. 188. A method of providing or enhancing immunity against HCMV in an uninfected human subject comprising administering to said subject an effective amount of the prophylactic or therapeutic vaccine of claim 140 sufficient to provide immunological memory against a future infection by HCMV. 189-192 (cancelled). 193. A method of providing or enhancing immunity against HCMV in an uninfected human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the isolated peptide of claim 1 sufficient to confer HCMV reactivity on said T cells. 194. A method of providing or enhancing immunity against HCMV in an uninfected human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the prophylactic or therapeutic vaccine composition of claim 114 sufficient to confer HCMV reactivity on said T cells. 195-199 (cancelled). 200. A method of providing or enhancing immunity against HCMV in an uninfected human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the isolated polyepitope peptide of claim 101 sufficient to confer HCMV reactivity on said T cells. 201. A method of providing or enhancing immunity against HCMV in an uninfected human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an effective amount of the prophylactic or therapeutic vaccine composition of claim 140 sufficient to confer HCMV reactivity on said T cells. 202-206 (cancelled). 207. A method for determining whether or not a subject has been previously infected with HCMV, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the isolated peptide of claim 1 and determining the activation of a CTL or precursor CTL, wherein said activation of a CTL or precursor CTL indicates that the subject has been previously infected with HCMV. 208-212 (cancelled). 213. A method for determining whether or not a subject has been previously infected with HCMV, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the isolated polyepitope peptide of claim 101 and determining the activation of a CTL or precursor CTL, wherein said activation of a CTL or precursor CTL indicates that the subject has been previously infected with HCMV. 214-218 (cancelled). 219. A method for determining whether or not a subject has been previously infected with HCMV, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the prophylactic or therapeutic vaccine composition of claim 114 and determining the activation of a CTL or precursor CTL, wherein said activation of a CTL or precursor CTL indicates that the subject has been previously infected with HCMV. 220-224 (cancelled). 225. A method for determining whether or not a subject has been previously infected with HCMV, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the prophylactic or therapeutic vaccine composition of claim 140 and determining the activation of a CTL or precursor CTL, wherein said activation of a CTL or precursor CTL indicates that the subject has been previously infected with HCMV. 226-230 (cancelled). 231. A method for determining the level of HCMV-specific cell mediated immunity in a human subject, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the isolated peptide of claim 1 and determining the level of activation of a CTL or precursor CTL, wherein the level of activation of a CTL or precursor CTL is correlated to the level of HCMV-specific cell mediated immunity of the subject. 232-236 (cancelled). 237. A method for determining the level of HCMV-specific cell mediated immunity in a human subject, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the isolated polyepitope peptide of claim 101 and determining the level of activation of a CTL or precursor CTL, wherein the level of activation of a CTL or precursor CTL is correlated to the level of HCMV-specific cell mediated immunity of the subject. 238-242 (cancelled). 243. A method for determining the level of HCMV-specific cell mediated immunity in a human subject, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the prophylactic or therapeutic vaccine of claim 115 and determining the level of activation of a CTL or precursor CTL, wherein the level of activation of a CTL or precursor CTL is correlated to the level of HCMV-specific cell mediated immunity of the subject. 244-248 (cancelled). 249. A method for determining the level of HCMV-specific cell mediated immunity in a human subject, said method comprising contacting ex vivo a T cell obtained from the subject with an antigen presenting cell (APC) primed with the prophylactic or therapeutic vaccine of claim 140 and determining the level of activation of a CTL or precursor CTL, wherein the level of activation of a CTL or precursor CTL is correlated to the level of HCMV-specific cell mediated immunity of the subject. 250-254 (cancelled). 255. A method of producing an HCMV-specific CTL comprising: (i) contacting a T cell with the isolated peptide of claim 1 or an antigen presenting cell (APC) primed with said peptide or an autologous lymphoblastoid cell line (LCL) primed with said peptide; (ii) culturing the T cell; and (iii) selecting T cells that proliferate. 256-261 (cancelled). 262. An HCMV-specific CTL clone produced by the method of claim 255. 263. A method of producing an HCMV-specific CTL comprising: (i) contacting a T cell with the isolated polyepitope peptide of claim 101 or an antigen presenting cell (APC) primed with said peptide or an autologous lymphoblastoid cell line (LCL) primed with said peptide; (ii) culturing the T cell; and (iii) selecting T cells that proliferate. 264-269 (cancelled). 270. An HCMV-specific CTL clone produced by the method of claim 263. |
<SOH> BACKGROUND TO THE INVENTION <EOH>1. General Information This specification contains amino acid sequence information prepared using Patent in Version 3.1, presented herein after the Abstract. Each sequence is identified in the sequence listing by the numeric indicator <210> followed by the sequence identifier (e.g. <210>1, <210>2, etc). The length of each sequence and source organism are indicated by information provided in the numeric indicator fields <211> and <213>, respectively. Sequences referred to in the specification are defined by the term “SEQ ID NO:”, followed by the sequence identifier (eg. SEQ ID NO: 1 refers to the sequence designated as <400>1). As used herein the term “derived from” shall be taken to indicate that a specified integer may be obtained from a particular source albeit not necessarily directly from that source. Unless the context requires otherwise or specifically stated to the contrary, integers, steps, or elements of the invention recited herein as singular integers, steps or elements clearly encompass both singular and plural forms of the recited integers, steps or elements. Throughout this specification, unless the context requires otherwise, the word “comprise”, or variations such as “comprises” or “comprising”, will be understood to imply the inclusion of a stated step or element or integer or group of steps or elements or integers but not the exclusion of any other step or element or integer or group of elements or integers. Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations or any two or more of said steps or features. The present invention is not to be limited in scope by the specific examples described herein. Functionally-equivalent products, compositions and methods are clearly within the scope of the invention, as described herein. All the references cited in this application are specifically incorporated by reference herein. The present invention is performed without undue experimentation using, unless otherwise indicated, conventional techniques of molecular biology, microbiology, virology, recombinant DNA technology, peptide synthesis in solution, solid phase peptide synthesis, and immunology. Such procedures are described, for example, in the following texts that are incorporated by reference: 1. Sambrook, Fritsch & Maniatis, Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratories, New York, Second Edition (1989), whole of Vols I, II, and III; 2. DNA Cloning: A Practical Approach, Vols. I and II (D. N. Glover, ed., 1985), IRL Press, Oxford, whole of text; 3. Oligonucleotide Synthesis: A Practical Approach (M. J. Gait, ed., 1984) IRL Press, Oxford, whole of text, and particularly the papers therein by Gait, pp1-22; Atkinson et al., pp35-81; Sproat et al., pp 83-115; and Wu et al., pp 135-151; 4. Nucleic Acid Hybridization: A Practical Approach (B. D. Hames & S. J. Higgins, eds., 1985) IRL Press, Oxford, whole of text; 5. Animal Cell Culture: Practical Approach, Third Edition (John R. W. Masters, ed., 2000), ISBN 0199637970, whole of text; 6. Immobilized Cells and Enzymes: A Practical Approach (1986) IRL Press, Oxford, whole of text; 7. Perbal, B., A Practical Guide to Molecular Cloning (1984); 8. Methods In Enzymology (S. Colowick and N. Kaplan, eds., Academic Press, Inc.), whole of series; 9. J. F. Ramalho Ortigäo, “The Chemistry of Peptide Synthesis” In: Knowledge database of Access to Virtual Laboratory website (Interactiva, Germany); 10. Sakakibara, D., Teichman, J., Lien, E. Land Fenichel, R. L. (1976). Biochem. Biophys. Res. Commun. 73 336-342 11. Merrifield, R. B. (1963). J. Am. Chem. Soc. 85, 2149-2154. 12. Barany, G. and Merrifield, R. B. (1979) in The Peptides (Gross, E. and Meienhofer, J. eds.), vol. 2, pp. 1-284, Academic Press, New York. 13. Wünsch, E., ed. (1974) Synthese von Peptiden in Houben - Weyls Metoden der Organischen Chemie (Müler, E., ed.), vol. 15, 4th edn., Parts 1 and 2, Thieme, Stuttgart. 14. Bodanszky, M. (1984) Principles of Peptide Synthesis , Springer-Verlag, Heidelberg. 15. Bodanszky, M. & Bodanszky, A. (1984) The Practice of Peptide Synthesis , Springer-Verilag, Heidelberg. 16. Bodanszky, M. (1985) Int. J. Peptide Protein Res. 25, 449-474. 17. Handbook of Experimental Immunology, Vols. I-IV (D. M. Weir and C. C. Blackwell, eds., 1986, Blackwell Scientific Publications). |
<SOH> SUMMARY OF THE INVENTION <EOH>In work leading up to the present invention, the inventors sought to comprehensively map CTL responses to a wide variety of HCMV antigens that are expressed at different stages of infection and play an important role in overall pathogenesis of HCMV-associated diseases, in particular pp28, pp50, pp65, pp150, pp71, gH, gB, IE-1, IE-2, US2, US3, US6, US11, and UL18. A highly efficient and rapid strategy, based on the use of predictive algorithms, ELISPOT and cytotoxicity assays, was employed to comprehensively profile HLA class I-restricted CTL responses against HCMV in a cohort of twenty four healthy virus carriers. Preliminary analysis of these HCMV antigen sequences, using computer based algorithms and peptide stabilization assays, strongly suggested that these antigens contained CTL epitopes. Synthetic peptides were subsequently tested for their ability to induce CTL activity in peripheral blood T cells from seropositive donors, as measured by IFN-γ production in ELISPOT. The present inventors also isolated both polyclonal and cloned CTLs from seropositive donors that showed strong responses in cytotoxicity assays, thereby confirming strong cytolytic activity toward target cells that were sensitized with synthetic peptides, or alternatively, infected with recombinant vaccinia encoding individual HCMV antigens. Using the above approaches, the present inventors identified a large number of novel HCMV CTL epitopes having utility in the formulation of vaccines against HCMV or otherwise modulating HCMV immune control, or as diagnostic reagents for assaying HCMV or the recovery of HCMV-specific T-cell-mediated immunity following transplantation or during pregnancy. The identification of certain previously-described CTL epitopes was also confirmed by the inventors. The present inventors showed that CD8+ CTL responses to HCMV often contained multiple antigen-specific activities that were not merely constrained to pp65, IE-1, or pp150. In fact, more than 40% of the CTL epitopes are located in antigens other than pp65 and IE-1, which were previously considered to be the primary antigens for CTL control. A number of HCMV antigens were identified by the present inventors for the first time as targets for HCMV-specific cellular immunity. Interestingly, these activities also included subdominant T cell responses to HCMV-encoded immunomodulators, such as, for example, US2, US3, and UL18. Clonal analysis revealed novel individual responses to antigens such as, for example, pp28, pp50, pp65, pp150, gB, gH, US2, IE-1 and IE-2. The overall repertoire of HCMV-specific CTL responses from a spectrum of healthy virus carriers is distributed throughout most of the antigens tested. Several HLA-restricting determinants recognized by the novel CTL epitopes have been defined, in addition to new HLA-restricting determinants for certain previously-described HCMV CTL epitopes. The present inventors also designed novel polyepitopes comprising multiple HCMV epitopes for use in vaccine preparations. The present inventors also designed vaccine preparations based upon the novel epitopes and polyepitopes of the invention. Preferably, an effective CTL epitope-based HCMV vaccine that provides widespread protection against HCMV in a human population comprises not only epitopes derived from pp65 and IE-1 proteins, but also other regions of the genome expressed during early, late and latent infection. Accordingly, one aspect of the present invention relates to an immunologically active peptide comprising one or more CTL epitopes of a HCMV antigen or a derivative thereof or a functionally equivalent variant thereof, wherein said peptide is preferably capable of eliciting a cellular immune response to HCMV in a human subject. Preferably, the peptide directs CTLs of a human subject to recognize and lyse human cells infected with HCMV, thereby providing or enhancing cellular immunity against HCMV. Preferably, the immunologically active peptide, in association with an MHC Class I molecule, is recognized by the CTLs of a healthy HCMV seropositive subject, or a subject having a latent or inactive HCMV infection. Preferably, the immunologically active peptide of the invention displays HLA supertype specificity. Such an epitope is clearly preferred for use in vaccine formulations, because it reduces the total number of epitopes required to cover a significant proportion of the population irrespective of ethnicity, thereby minimizing formulation difficulties. Preferably, the immunologically active peptide of the invention additionally comprises one or more CD4+ determinants sufficient to facilitate a T-helper function in the context of an MHC class II molecule on the surface of an antigen presenting cell (APC) of a human subject infected with HCMV. For example, the present inventors provide herein several 20-mer peptides comprising contiguous or overlapping CTL epitopes and T-helper epitope functions as evidenced by their having the ability to bind to both CD4 + and CD8 + cells. Such a peptide has an advantage over a minimal CTL epitope of not necessarily requiring the inclusion of an exogenous T-helper epitope in a vaccine formulation. In a second aspect, the present invention relates to an immunologically active peptide comprising a polyepitope (ie. two or more distinct epitopes) of a HCMV antigen or a derivative thereof or a functionally equivalent variant thereof, wherein said peptide is preferably capable of eliciting a cellular immune response to HCMV in a human subject. Preferably, the polyepitope is not restricted to a single MHC Class I haplotype. Even more preferably, the polyepitope is specific for a sufficient number of MHC Class I molecules to provide coverage for at least about 35% of the general population, preferably at least about 55% of the general population, more preferably at least about 75% of the general population, and still more preferably at least about 95% of the general population, irrespective of racial origin or ethnicity. Those skilled in the art will readily be in a position to determine the number of individual HCMV CTL epitopes required to provide coverage of any given population from the HLA specificity data provided herein. As with single epitopes, the polyepitope of the invention preferably displays HLA supertype specificity and/or preferably comprise one or more CD4+ determinants sufficient to facilitate a T-helper function in a human subject infected with HCMV. Another aspect of the invention relates to a prophylactic or therapeutic vaccine composition for eliciting a cellular immune response in a human subject against HCMV, said composition comprising an immunologically active peptide of the invention (ie. an epitope or polyepitope) in combination with a pharmaceutically acceptable carrier, excipient, diluent and/or an adjuvant. The vaccine composition may comprise more than one epitope or polyepitope. The vaccine composition of the invention may be a subunit vaccine comprising the immunologically active peptide(s) or a derivative thereof or a functionally equivalent variant thereof or alternatively, a nucleic acid-based vaccine that comprises nucleic acid, such as, for example, DNA or RNA, encoding the immunologically active peptide(s) or derivative or variant and cloned into a suitable vector (eg. vaccinia, canarypox, adenovirus, or other eukaryotic virus vector). Alternatively, the peptide or derivative or variant is formulated as a cellular vaccine via the administration of an autologous or allogeneic antigen presenting cell (APC) or a dendritic cell that has been treated in vitro so as to present the peptide on its surface. In a related embodiment the present invention provides for the use of an immunologically active peptide of the invention or a variant or derivative thereof in the preparation of a vaccine composition for use in the prophylactic or therapeutic treatment of HCMV infection in a human subject, including the therapeutic treatment of a latent HCMV infection in a human subject. In a related embodiment the present invention provides for the use of an immunologically active peptide of the invention or a variant or derivative thereof in the preparation of a vaccine composition for use in enhancing the immune function of a human subject before or during or after transplantation, wherein said subject carries a latent HCMV infection or is at risk of being infected with HCMV. Another aspect of the present invention relates to a method of enhancing the immune system of a human subject comprising administering an immunologically active peptide comprising a CTL epitope of a HCMV antigen or a derivative or variant thereof or a vaccine composition comprising said peptide or derivative or variant for a time and under conditions sufficient to activate a CTL and/or a CTL precursor of said subject. In a related embodiment, the invention relates to a method of enhancing the HCMV-specific cell mediated immunity of a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an immunologically active peptide comprising a CTL epitope of a HCMV antigen or a derivative or variant thereof or a vaccine composition comprising said peptide or derivative or variant for a time and under conditions sufficient to confer HCMV activity on said T cells. Another aspect of the invention relates to a method of providing or enhancing immunity against HCMV in an uninfected human subject comprising administering to said subject an immunologically active peptide comprising a CTL epitope of a HCMV antigen or a derivative or variant thereof or a vaccine composition comprising said peptide or derivative or variant for a time and under conditions sufficient to provide immunological memory against a future infection by HCMV. Another aspect of the invention relates to a method of enhancing or conferring immunity against HCMV in an uninfected human subject comprising contacting ex vivo a T cell obtained from a human subject with an immunologically active peptide comprising a CTL epitope of a HCMV antigen or a derivative or variant thereof or a vaccine composition comprising said peptide or derivative or variant for a time and under conditions sufficient to confer HCMV activity on said T cells. As will be apparent from the description herein, the immunologically active peptide of the invention or a derivative or variant thereof, or a vaccine composition comprising said peptide or derivative or variant, is useful for directly stimulating a CTL or a precursor CTL in vitro. Using appropriate assay technology known to the skilled artisan, the peptide of the invention or a derivative or functionally equivalent variant thereof, or a composition comprising said peptide or derivative or variant, is useful for determining the level of HCMV-specific immunity in a human subject who is either suffering from a primary HCMV infection or at risk of HCMV infection or the reactivation of HCMV infection, such as, for example, a transplant patient, HIV-infected individual, a female having reproductive capacity or a pregnant female. In a related embodiment, the peptide or composition of the invention is also useful for distinguishing an individual who is seropositive from an individual who has not been exposed to HCMV (ie. a seronegative individual). Accordingly, another aspect of the invention relates to a diagnostic method for quantitively or qualitatively monitoring HCMV-specific T cell immunity in a human subject, said method comprising contacting ex vivo a T cell obtained from a human subject with an APC primed with an immunologically active peptide comprising a CTL epitope of a HCMV antigen or a derivative or variant thereof or a vaccine composition comprising said peptide or derivative or variant and determining the activation of a CTL or precursor CTL, wherein said activation of a CTL or precursor CTL indicates that the subject has been previously infected with HCMV. Another aspect of the present invention relates to a method of producing an isolated CTL or precursor CTL capable of binding to or lyzing a human cell infected with HCMV said method comprising contacting a T cell with an isolated peptide of the present invention or an APC primed with an isolated peptide of the invention, culturing the T cell and selecting T cells that proliferate. Optionally, the T cell is contacted with peptide in the presence of a cytokine, such as, for example, IL-2. The present invention clearly extends to the T cell clones produced using a novel immunologically active peptide described herein, and to the use of such T cell clones in any diagnostic, prophylactic or therapeutic procedures for monitoring HCMV infection, latency of HCMV infection, the likelihood of HCMV infection in a human subject, such as, for example, before, during or following organ transplantation (eg. BMT), or during pregnancy. |
Methods and apparatus for objective fetal diagnosis |
Fetal diagnostic apparatus (10) which comprises ultrasonic imaging apparatus (12) for producing ultrasonic images, (14) the images comprises a multiplicity of pixels (16); an ultrasonic transducer (18) that can be placed upon a patient, in data communication with the ultrasonic imaging apparatus (12); and a processor (22) in data communication with the ultrasonic imaging apparatus that measures changes in the pixels (16) with respect to time. |
1. Fetal diagnostic apparatus comprising: ultrasonic imaging apparatus for producing ultrasonic images, said images comprising a multiplicity of pixels; an ultrasonic transducer that can be placed upon a patient, in data communication with said ultrasonic imaging apparatus; and a processor in data communication with said ultrasonic imaging apparatus that measures changes in the pixels with respect to time. 2. Apparatus according to claim 1 and further comprising a display in data communication with said processor that displays the changes in the pixels with respect to time. 3. Apparatus according to claim 2 wherein said display comprises a visual display. 4. Apparatus according to claim 2 wherein said display comprises an audible display. 5. A method for diagnosing a fetus inside a pregnant woman, comprising: acquiring fetal ultrasonic images, said images comprising a multiplicity of pixels; measuring changes in the pixels of a representative portion of said fetal ultrasonic images with respect to time, over a predetermined period of time, the changes in the pixels being associated with a pattern of fetal movements; and monitoring changes in the pattern of the fetal movements with respect to time. 6. The method according to claim 5 and further comprising displaying the changes in the patterns of fetal movements with respect to time. 7. The method according to claim 5 and further comprising choosing a particular region of interest of the fetus, and tracking pixel changes only in said particular region of interest. 8. The method according to claim 7 wherein an ultrasonic transducer is used to acquire the fetal ultrasonic images in a viewing window, and wherein the method comprises controlling movement of the viewing window such that said particular region of interest is generally continuously in the viewing window. 9. The method according to claim 5 and further comprising: providing a normal distribution curve of changes associated with patterns of fetal movement of a large representative fetal population; determining in which range of the normal distribution the measured changes of patterns of fetal movements lie; and diagnosing said fetal movements based on the range of the normal distribution in which the measured changes of patterns of fetal movements lie. 10. The method according to claim 5 and further comprising administering about 0.6-1.2 mg of atropine to the pregnant woman, and monitoring fetal heartbeat rate thereafter. 11. The method according to claim 10 wherein if the fetal heartbeat rate accelerates beyond a predetermined threshold, then the fetus is considered to have an increased risk of Down's syndrome. 12. A method for diagnosing a fetus inside a pregnant woman, comprising: administering about 0.6-1.2 mg of atropine to the pregnant woman; and monitoring fetal heartbeat rate thereafter. 13. The method according to claim 12, wherein if the fetal heartbeat rate accelerates beyond a predetermined threshold, then the fetus is considered to have an increased risk of Down's syndrome. 14. A method for diagnosing a fetus inside a pregnant woman for a risk of having Down's syndrome, comprising: administering to the pregnant woman a cholinergic signaling inhibitor; and monitoring fetal heartbeat rate thereafter; whereby if the fetal heartbeat rate accelerates beyond a predetermined threshold, then the fetus is considered to have an increased risk of Down's syndrome. 15. The method according to claim 6 and further comprising administering about 0.6-1.2 mg of atropine to the pregnant woman, and monitoring fetal heartbeat rate thereafter. 16. The method according to claim 7 and further comprising administering about 0.6-1.2 mg of atropine to the pregnant woman, and monitoring fetal heartbeat rate thereafter. 17. The method according to claim 8 and further comprising administering about 0.6-1.2 mg of atropine to the pregnant woman, and monitoring fetal heartbeat rate thereafter. 18. The method according to claim 9 and further comprising administering about 0.6-1.2 mg of atropine to the pregnant woman, and monitoring fetal heartbeat rate thereafter. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Ultrasound has become a commonplace and routine method for non-invasive diagnosis of well-being of a fetus and progress of pregnancy. Ultrasound is used to check and monitor fetal growth, “breathing” (i.e., diaphragm movement) and limb movement, for example. Some of the parameters detectable with ultrasound are quantities that can be measured, categorized and repeated with the same general degree of accuracy. For example, size of a fetal limb can be measured and compared with the size of a “normal” limb, i.e., the limb size of a majority of a representative fetal population. The limb size measured by one practitioner will generally match the size measured by another practitioner, thereby providing an acceptable and repeatable parameter for fetal monitoring and diagnosis. However, fetal movement, such as that of the diaphragm or limbs, remains a subjective, rather than objective, test, and all the more so in borderline cases. Although some practitioners may claim proficiency in interpreting observations of fetal movement, nevertheless it has been found that such interpretations can vary significantly between practitioners, and can be inaccurate and even misleading. In one extreme example, active arm and leg movement can be interpreted by one practitioner as being indicative of a healthy, lively and active fetus. However, it is possible that in reality the active arm and leg movement is due to the umbilical cord wrapped around the neck of the fetus. The fetus is in distress, writhing in pain, and the supposedly healthy limb movement is actually indicative of danger. As another example, it is sometimes difficult for a practitioner to observe several fetal movements at the same time. The practitioner may be concentrating on heart movement, for example, and ignoring hand or feet movement. Clearly the prior art is problematic and an objective, ultrasonic, reproducible and automatic, fetal diagnostic method is needed. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention seeks to provide novel methods and apparatus for objective, reproducible and automatic fetal diagnosis. The present invention exploits the fact that an ultrasonic image comprises a multiplicity of pixels. The invention quantifies fetal movement by measuring changes in the pixels with respect to time. The pixels are taken from a representative area of the ultrasonic image, either the whole image or a “zoom” of a particular region of interest, such as the diaphragm. The apparatus of the invention can conveniently visually and/or audibly display (or plot) the pixel changes, such that any practitioner can easily and objectively judge total or local fetal movement, as desired. The practitioner can study and judge the fetal well-being either during or after the ultrasonic monitoring. Full documentation of the plots and pixel changes is provided for future reference. Moreover, it is herein postulated that despite the wide variety of reasons for fetal movement, which range from healthy reasons to dangerous reasons as mentioned in the background, nonetheless a plot of the changes in the patterns of a representative portion of fetal ultrasonic images with respect to time, generally follows a normal distribution curve of pattern changes associated with fetal movement of a large representative fetal population. The system of the invention acquires data regarding the time change of the patterns of fetal movement over a predetermined period of time, and determines in which range of the normal distribution the data lie. It is postulated that the time change of the patterns associated with abnormal, unhealthy fetal movement (either overactive or underactive movement of a fetus, each being associated with different prenatal problems) lies in the asymptotic regions of the normal distribution, i.e., beyond the 2σ or 3σ limits of the normal distribution. In contrast, the time change of the patterns associated with normal, healthy fetal movement lies within the majority of the area under the normal distribution curve, i.e., within the 2σ or 3σ limits of the normal distribution. Thus, by monitoring the time-dependent change of patterns of fetal movement, one can objectively associate fetal movement with fetal health, condition and state. In addition to the above ultrasonic diagnostic tool, the present invention provides another non-invasive method for indicating a high risk for the fetus having Down's syndrome. The inventor has surprisingly found that administration of a certain range of dosage of atropine to pregnant women, can cause tachycardia in fetuses with Down's syndrome, whereas the same dosage does not generally change heartbeat rate in normal fetuses to the same extent. There is thus provided in accordance with a preferred embodiment of the present invention fetal diagnostic apparatus including ultrasonic imaging apparatus for producing ultrasonic images, the images including a multiplicity of pixels, an ultrasonic transducer that can be placed upon a patient, in data communication with the ultrasonic imaging apparatus, and a processor in data communication with the ultrasonic imaging apparatus that measures changes in the pixels with respect to time. In accordance with a preferred embodiment of the present invention a display is in data communication with the processor, which displays the changes in the pixels with respect to time. The display may be visual or audible. There is also provided in accordance with a preferred embodiment of the present invention a method for diagnosing a fetus inside a pregnant woman, including acquiring fetal ultrasonic images, the images including a multiplicity of pixels, measuring changes in the pixels of a representative portion of the fetal ultrasonic images with respect to time, over a predetermined period of time, the changes in the pixels being associated with a pattern of fetal movements, and monitoring changes in the pattern of the fetal movements with respect to time. The method also preferably includes displaying the changes in the patterns of fetal movements with respect to time. In accordance with a preferred embodiment of the present invention the method further includes choosing a particular region of interest of the fetus, and tracking pixel changes only in the particular region of interest. Further in accordance with a preferred embodiment of the present invention an ultrasonic transducer is used to acquire the fetal ultrasonic images in a viewing window, and movement of the viewing window is controlled such that the particular region of interest is generally continuously in the viewing window. In accordance with a preferred embodiment of the present invention the method further includes providing a normal distribution curve of changes associated with patterns of fetal movement of a large representative fetal population, determining in which range of the normal distribution the measured changes of patterns of fetal movements lie, and diagnosing the fetal movements based on the range of the normal distribution in which the measured changes of patterns of fetal movements lie. Further in accordance with a preferred embodiment of the present invention there is provided a method for diagnosing a fetus inside a pregnant woman for a risk of having Down's syndrome. The method comprises administering to the pregnant woman a cholinergic signaling inhibitor; and monitoring fetal heartbeat rate thereafter; whereby if the fetal heartbeat rate accelerates beyond a predetermined threshold, then the fetus is considered to have an increased risk of Down's syndrome. Further in accordance with a preferred embodiment of the present invention about 0.6-1.2 mg of atropine are administered to the pregnant woman, and the fetal heartbeat rate is monitored thereafter. If the fetal heartbeat rate accelerates beyond a predetermined threshold, then the fetus is considered to have an increased risk of Down's syndrome. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. In case of conflict, the patent specification will control. Implementation of the method and apparatus of the present invention involves performing or completing selected tasks or steps manually, automatically, or a combination thereof. Moreover, according to actual instrumentation and equipment of preferred embodiments of the method and apparatus of the present invention, several selected steps could be implemented by hardware or by software on any operating system of any firmware or a combination thereof. For example, as hardware, selected steps of the invention could be implemented as a chip or a circuit. As software, selected steps of the invention could be implemented as a plurality of software instructions being executed by a computer using any suitable operating system. In any case, selected steps of the method and system of the invention could be described as being performed by a data processor, such as a computing platform for executing a plurality of instructions. The apparatus and method of the present invention are hence readily convertible into a telemedicine operation format. |
Fine particles of antimony tin oxide for sunscreen, dispersion thereof for sunscreen material formation, sunscreen material and transparent base material for sunscreen |
Physical characteristics of ATO fine particles capable of exhibiting such optical properties as a high visible light transmittance, a low solar radiation transmittance, and a low haze value when the ATO fine particles are formed on a transparent substrate or in the substrate are clarified, and the ATO fine particles having the physical characteristics thereof are manufactured. The ATO fine particles having such physical characteristics that a size of a crystallite constituting the ATO fine particles is 4 to 125 nm, and that a specific surface area of the fine particles of 5 to 110 m2/g can exhibit the above-described optical properties, and an example of a method for manufacturing thereof is to parallel-drop an antimony chloride alcoholic solution and an ammonium hydrogen carbonate aqueous solution in a tin chloride aqueous solution, thoroughly wash generated precipitates, dry and calcinate them in an atmosphere, thereby the ATO fine particles are manufactured. |
1. Antimony tin oxide fine particles for sunlight shielding, wherein a size of a crystallite constituting said fine particles is 4 to 125 nm, and a specific surface area of said fine particles is 5 to 110 m2/g. 2. The antimony tin oxide fine particles for sunlight shielding according to claim 1, wherein L* is 45 to 65, a* is −5 to −1, and b* is −11 to −1 in a color of powders containing said antimony tin oxide fine particles according to an L* a* b* color specification system. 3. A disperse liquid for formation of a sunlight shielding solid, said antimony tin oxide fine particles for sunlight shielding according to claim 1 being dispersed in a solvent, wherein a dispersed particle size of said antimony tin oxide fine particles for sunlight shielding in the solvent is 130 nm or less. 4. The disperse liquid for formation of the sunlight shielding solid according to claim 3, wherein an inorganic binder and/or a resin binder is/are contained as a binder. 5. A sunlight shielding solid, wherein the sunlight shielding solid is formed by using the disperse liquid for formation of the sunlight shielding solid according to claim 3. 6. The sunlight shielding solid according to claim 5, wherein a film of a silicon oxide, a zirconium oxide, a titanium oxide, or an aluminum oxide is formed on the sunlight shielding solid. 7. The sunlight shielding solid according to claim 5, wherein a solar radiation transmittance in a wavelength band of 300 to 2100 nm is less than 60% and a haze value is less than 1% when a visual light transmittance is 70% or more. 8. A transparent substrate for sunlight shielding, wherein the sunlight shielding solid according to claim 5 is formed. 9. A disperse liquid for formation of a sunlight shielding solid, said antimony tin oxide fine particles for sunlight shielding according to claim 2 being dispersed in a solvent, wherein a dispersed particle size of said antimony tin oxide fine particles for sunlight shielding in the solvent is 130 nm or less. 10. A sunlight shielding solid, wherein the sunlight shielding solid is formed by using the disperse liquid for formation of the sunlight shielding solid according to claim 4. 11. The sunlight shielding solid according to claim 6, wherein a solar radiation transmittance in a wavelength band of 300 to 2100 nm is less than 60% and a haze value is less than 1% when a visual light transmittance is 70% or more. 12. A transparent substrate for sunlight shielding, wherein the sunlight shielding solid according to claim 6 is formed. 13. A transparent substrate for sunlight shielding, wherein the sunlight shielding solid according to claim 7 is formed. |
<SOH> BACKGROUND ART <EOH>Conventionally, as a method for removing and reducing a thermal ingredient from light of an external light source such as sunlight, a beam of a bulb, or the like, a film containing a material for reflecting an infrared ray which greatly contributes to a thermal effect is formed as a heat wave reflecting transparent substrate on a surface of a transparent substrate such as glass or the like, and the heat wave reflecting transparent substrate is used. A metal oxide such as FeOx, CoOx, CrOx, TiOx, and the like, or a metallic material containing a large amount of free electrons such as Ag, Au, Cu, Ni, Al, and the like is used as the aforementioned material. However, the aforementioned material has such properties to reflect or absorb not only the infrared ray which greatly contributes to the thermal effect but also a visual light at the same time, and therefore, there is a problem about lowering a visible light transmittance. However, since the transparent substrate such as glass or the like used for a window material such as a building material, a vehicle, a telephone booth, or the like requires a high transmittance in a visible light region, a film thickness thereof needs to be extremely thin when the aforementioned material is used. Accordingly, when the aforementioned material is formed on the transparent substrate, generally, a film having a thickness of as thin as approximately 10 nm is formed by physical film-formation methods such as spray baking, a CVD method, a sputtering method, a vacuum deposition method, and the like. However, these film formation-methods require a huge apparatus or a vacuum equipment, and there is a problem of productivity or area enlargement, and a disadvantage of high manufacturing costs of the film. Furthermore, when a sunlight shielding characteristic (a characteristic for shielding a light having a wavelength band of 300 to 2100 nm) of the aforementioned material becomes high, reflectivity of the visual light region tends to be high at the same time, resulting in disfigurement caused by a glaring appearance like a mirror. In order to improve the aforementioned problems, a sunlight shielding solid which exhibits the high visible transmittance and a high sunlight shielding rate is required to be formed on the transparent substrate or in the substrate. Furthermore, properties such as little haze of the film or the like are required for the sunlight shielding solid used for, for example, the window material or the like in addition to the aforementioned optical characteristics and electrical characteristics. The haze of the film is evaluated by a numerical value called a haze value. The haze value is defined as a ratio of a diffuse transmission light to a total transmittance, and the sunlight shielding solid looks hazy to human eyes when the value is high. Accordingly, the window material or the like requiring for transparency is desired to have the low haze value of less than 1%. Here, an antimony tin oxide (hereinafter abbreviated as ATO) is known as one of the materials having a visible light transmittance function and a sunlight shielding function. However, physical characteristics of the ATO which exhibits the excellent visible light transmittance function and sunlight shielding function have never been studied, and for example, each of the ATO described in Patent Document 1, Patent Document 2, Patent Document 3, and Patent Document 4 relates to conductivity. (Patent Document 1) Japanese Patent No.2844011 (Patent Document 2) Japanese Patent Laid-open No. Hei 11-278826 (Patent Document 3) Japanese Patent Laid-open No. Hei 6-183708 (Patent Document 4) Japanese Patent Laid-open No. Hei 5-246710 Here, the present invention clarifies the physical characteristics of the ATO capable of forming the sunlight shielding solid having such optical properties as the high visible light transmittance, a low solar radiation transmittance, and simultaneously the low haze value when the ATO is formed on the transparent substrate or incorporated in the substrate so as to be formed as a board shape, a sheet shape, a film shape or the like; furthermore, an object of the present invention is to provide ATO fine particles having the physical characteristics thereof, a disperse liquid for formation of a sunlight shielding solid which can form the sunlight shielding solid by a simple coating method or incorporating method, and the sunlight shielding solid containing the ATO which has the physical characteristics thereof. |
<SOH> BRIEF DESCRIPTION OF DRAWINGS <EOH>FIG. 1 is a list about optical characteristics of a crystallite size, a specific surface area, a dispersed particle size, a color of particles, and a sunlight shielding solid sample of ATO samples; and FIG. 2 is an example of a manufacturing flow of the ATO samples. detailed-description description="Detailed Description" end="lead"? |
Lifting system |
What is disclosed is a lifting apparatus, in particular a ferry landing stage, comprising a platform that is capable of being taken into a predetermined lift position with the aid of a hydraulic cylinder or of a cable winch. A safety stop by which the platform may be supported independently of the drive mechanism is associated to the drive mechanism. |
1-13. (Cancelled) 14. A lifting apparatus, in particular a ferry landing stage, comprising a platform which may be taken into a predetermined lift position by means of a drive mechanism (8, 10), characterized by a safety stop (20) acting in parallel with the drive mechanism (8, 10) so that the platform may be supported independently of the drive mechanism (8, 10). 15. A safety stop in accordance with claim 14, wherein the drive mechanism has at least one hydraulic cylinder (8, 10) or one cable winch. 16. The lifting apparatus in accordance with claim 14, wherein the safety stop (20) has a stop rod (22, 24) capable of being connected with the platform (2) through clamping means (26, 28). 17. The lifting apparatus in accordance with claim 16, wherein the clamping means (20) include a clamping cylinder (26, 28) through which the stop rod (22, 24) extends, and wherein clamping members (44) are guided in a slidable manner, which clamping members may be taken into clamping engagement with the stop rod (22, 24) and are hydraulically biased into a release position. 18. The lifting apparatus in accordance with claim 17, wherein the clamping members (44) are received in a clamping piston (40) which is slidably accommodated in the clamping cylinder (26, 28), which clamping piston jointly with the clamping cylinder (26, 28) defines a cylinder space (38) that is connected to a pressure medium source (70, 76) and may be subjected to a biasing pressure. 19. The lifting apparatus in accordance with claim 18, wherein the cylinder space (38) may be connected to a tank (T) via a pressure control valve (82). 20. The lifting apparatus in accordance with claim 18, wherein the clamping members (44) are biased into their release positions through at least one actuating piston (56), the actuating piston (56) being guided in the clamping piston (40), and the rear face of the actuating piston being subjectable to an actuation pressure. 21. The lifting apparatus in accordance with claim 19, wherein the pressure control valve (82) is set to a pressure which is 1.1 to 1.3 times the biasing pressure. 22. The lifting apparatus in accordance with claim 20, including a switching valve (66) whereby the actuation pressure or the tank pressure may be applied to the rear face of the actuating piston (54). 23. The lifting apparatus in accordance with claim 14, including a path measuring system (84) whereby position and velocity of the clamping cylinder (26, 28) relative to the stop rod (22, 24) may be detected. 24. The lifting apparatus in accordance with claim 22, wherein the switching valve (66) may be driven in accordance with the signal of a path measuring system (84). 25. The lifting apparatus in accordance with claim 14, wherein the pressure medium source is a pump (76) to which a hydraulic reservoir (70) is associated. 26. The lifting apparatus in accordance with claim 17, wherein a pressure medium tank (T) is integrated into the clamping cylinder (26, 28) or flange-mounted on the latter. |
Method and device for controlling the refractive index in an optical fiber |
PROBLEM TO BE SOLVED: To provide a polarization control element which may be easily produced and miniaturized and has high reliability. SOLUTION: A core region 11 is a region of a circular shape in cross section disposed at the center of an optical fiber 10 and has a refractive index n1. A clad region 12 is a region disposed around this core region 11 and has a refractive index n2 smaller than the refractive index n1 of the core region 11. A pair of conductive parts 13a and 13b are respectively symmetrical with each other with respect to the optical axis center and are disposed within the clad region 12 over a specified range in a longitudinal direction. When current is passed to a pair of the conductive parts 13a and 13b, respectively, a stress is generated therein and a strain is generated in the core region 11 and the clad region 12. The propagation light propagated in the optical fiber 10 is controlled in the polarization state according to this strain. |
1. A method of altering a refractive index of a core of an optical fiber, said fiber having at least one longitudinal electrode arranged within the fiber along said core, comprising the step of: passing an electric current through said electrode in order to induce ohmic heating thereof, said heating resulting in thermal expansion of the electrode subjecting the core of the fiber to stress. 2. A method as claimed in claim 1, wherein the core of the fiber is subjected to asymmetrical stress such that birefringence is induced in the core of the fiber. 3. A method as claimed in claim 2, wherein the electric currents are selectively passed through one or more of a plurality of longitudinal electrodes. 4. A method as claimed in claim 3, wherein current is first switched on to pass through a first electrode and then switched on to pass through a second electrode, said first and second electrodes being orthogonally arranged around the core of the fiber, such as the onset of the first electrode switches the polarization state and the subsequent onset of the second electrode resets the polarization state. 5. A method as claimed in claim 1, wherein current is passed through a confined length of electrode in the fiber, thermal expansion thereby being effected only over said confined length. 6. A method as claimed in claim 3, wherein stress in the core is induced in different directions in different lengths of the fiber. 7. An optical device, comprising: an optical fiber with a core and a cladding, at least one longitudinal electrode formed in the fiber, and driver means for driving an electrical current through said at least one longitudinal electrode, wherein said electrode and said driver means are adapted to induce refractive index changes in a core of the optical fiber by producing thermally induced stress by means of a thermal expansion of the electrode, said thermal expansion being induced by ohmic heating from an electrical current flowing through the electrode. 8. A device as claimed in claim 7, wherein the or each electrode is provided in the cladding of the fiber adjacent the core. 9. A device as claimed in claim 7, wherein the or each longitudinal electrode is provided within a longitudinal hole in the optical fiber, such that said hole is entirely filled with electrode material in the radial direction. 10. A device as claimed in claim 7, wherein the or each electrode comprises a Sn—Bi alloy. 11. A device as claimed in claim 7, wherein the electrode and the driver means are adapted to induce an asymmetrical field or stress in the core of the fiber, thereby inducing birefringence in the core. 12. A device as claimed in claim 7, comprising a plurality of longitudinal electrodes disposed around the core of the fiber, such that current can be passed selectively along one or more of said plurality of electrodes in order to control the stress induced in the core. 13. A device as claimed in claim 12, wherein external wires are attached to the or each electrode for feeding current, said wires defining a length of electrode to be heated. 14. A device as claimed in claim 7, wherein the fiber comprises a scattering center that makes a portion of the fiber leaky, such that some of the light propagating therein can be coupled out and analyzed. 15. A device as claimed in claim 14, wherein the scattering center comprises a local disturbance in the fiber geometry. 16. A device as claimed in claim 14, wherein the scattering center comprises a bend of the fiber. 17. A device as claimed in claim 7, further comprising a fixed polarizer in the fiber, whereby variable optical attenuation can be obtained by controlling the current passed through the electrode. 18. A method for polarization control of the emission from a laser diode, wherein the light from the laser diode is passed through the device of claim 7, and said device is controlled such that the desired polarization is obtained. 19. A method for variable optical attenuation of a light signal propagating in an optical fiber utilizing the device of claim 7, wherein the light is also directed through a polarizer. 20. A device as defined in claim 7 for stabilizing output from a Mach-Zehnder interferometer that is arranged in one arm of said interferometer so that feedback can be provided. 21. A device as defined in claim 7 that is incorporated into one arm of a Mach-Zehnder interferometer for providing an optical switch in which output can be controlled to occur from a selected output. 22. A device as claimed in claim 8, wherein the or each electrode comprises a Sn—Bi alloy. 23. A device as claimed in claim 9, wherein the or each electrode comprises a Sn—Bi alloy. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The constant increase of information transmission capacity by means of optical fibers is mainly driven by the improved performance of new optical components associated with Wavelength Division Multiplexing (WDM) technology. Innovations in this field create new solutions for telecommunications networks, and bring optics closer to the end user. From an initial passive transport role, optical fibers associated with other technologies are now commonly used in connection with active and passive optical components. By controlling the value and the spatial characteristics of the refractive index of optical fibers, a number of important optical functions such as switching and filtering can be provided. Control of the refractive index can be achieved by applying external perturbations such as electric or magnetic fields, light and elastic stress. The Japanese Patent Abstract “Polarization Control Element” (Toshiaki), Application No. 10-238708 discloses an element wherein two conductors are arranged in the cladding of an optical fiber symmetrically with respect to the fiber core. When current is passed through these two conductors simultaneously, an electrostatic effect is obtained that gives a stress or a strain on the fiber core. If current is passed in the same direction through the two conductors, an attracting force is obtained between the conductors; and if current is passed in opposite directions through the two conductors, a repulsive force in obtained. Hence, depending on the direction of the currents passed through the conductors, the action on the fiber core can be either positive or negative. In this way, the refractive index of the fiber core is said to be controlled. However, the above-referenced technique has some serious drawbacks that render actual implementation of the device very impractical, or perhaps even impossible. The force between the two conductors is very weak unless high currents are employed. Moreover, it is necessary to have at least two conductors in the fiber. Ideally, the above mentioned device should have no thermal dissipation and the conductors should have extremely low resistance. Hence, for practical reasons, such device will not gain any commercial success. |
<SOH> SUMMARY OF THE INVENTION <EOH>It is an object of the present invention to provide a device and a method for controlling the refractive index in a core of an optical fiber, for which the above-mentioned drawbacks are eliminated. This object is achieved by means of a method and a device according to the appended claims. According to the present invention, alteration of the refractive index of the fiber core relies not upon any electrostatic effect, but rather on thermal expansion of longitudinal electrodes arranged along said core, which expansion induces mechanical pressure on the core. Via the so-called photo-elastic effect, which will be explained below, the refractive index of the core is then changed accordingly. When light travels in a cylindrical fiber, as opposed to when propagating in free space, its polarization state gets distorted due to random birefringence induced in the fiber by, for example, thermal stress, mechanical stress, and irregularities of the fiber core. Consequently, at any given point along the fiber, light is generally elliptically polarized with varying degrees of ellipticity and orientation. However, many devices in fiber optic systems, for example electro-optic modulators, are polarization sensitive. Therefore, the arbitrarily polarized light needs to be converted into a desired state of polarization. According to the present invention, this conversion of the polarization into a desired state is effected by means of a length of optical fiber having at least one longitudinal electrode through which an electric current is passed, such that ohmic heating is obtained in the electrode. The heating of the electrode leads to expansion that compresses the core of the fiber. Consequently, the refractive index of the core is changed via the photo-elastic effect. The present invention provides a basis for an electrically driven polarization controller, and a method of altering the refractive index in an optical fiber, particularly to control the birefringence thereof. The present invention can be for both polarization dependent adjustment of the refractive index in the core of an optical fiber, as well as for polarization independent adjustment of the same. When a polarization dependent influence on the refractive index is desired, electrodes are disposed such that an asymmetrical stress field is induced in the core. Furthermore, by arranging one electrode within the evanescent field from the core, the device according to the invention can be made lossy for light having a particular polarization direction, effectively providing a polarizer. The present invention can be applied in various situations and applications, as will be appreciated from the following detailed description of preferred embodiments. |
Method and device for treating a fiber mass |
The invention relates to a method and a device for treating a fibre mass, such as for example a nonwoven or a woven. Such fibre masses are conveyed through a pressing mill for treatment where they are pressed in at least one pressing zone by means of a press-roll. By the pressing, a treatment fluid already present in the fibre mass is pressed out of the fibre mass. After the pressing out of the treatment fluid, a second treatment fluid is introduced into the fibre mass. In order to achieve a distribution of the second treatment fluid in the pressed fibre mass as quickly and homogenously as possible, according to the invention it is provided that the treatment fluid is introduced through the pressing surface area into the fibre mass in an expansion region, where the pressing power exerted by the press-roll is reduced in the moving direction of the fibre mass. Here, the pressing surface area is the surface through which the pressing power acts on the fibre mass. |
1. A method for treating a fiber mass, such as a filament composite, a woven or a nonwoven, wherein the fiber mass is conveyed through a pressing mill, in which the fiber mass is pressed in at least one pressing zone through the pressing surface area of at least one press-roll by means of a pressing power acting on the fiber mass and the pressed fiber mass is impregnated with a treatment fluid, the fiber mass in the pressing zone being conveyed through an expansion region where the pressing power is reduced in the passing direction (B) of the fiber mass, wherein the treatment fluid in the expansion region is conducted through the pressing surface area into the fiber mass. 2. The method according to claim 1, wherein the fiber mass is conveyed before the expansion region through a compression region of the pressing zone, in which the pressing power is increased in the passing direction (B) of the fiber mass and an already present treatment fluid is pressed out of the fiber mass (21). 3. The method according to claim 2, wherein the pressed out treatment fluid is let off in the compression region through the pressing surface area. 4. The method according to claim 1, wherein the treatment fluid is pressed into the fiber mass in the compression region. 5. The method according to claim 4, wherein the treatment fluid is conveyed through the pressing surface area into the fiber mass in the compression region. 6. The method according to claim 1, wherein the fiber mass is passed between at least two press-rolls in the pressing zone. 7. The method according to claim 1, wherein the treatment fluid is pressed into the fiber mass under pressure. 8. The method according to claim 1, wherein before the pressing mill the fiber mass is manufactured with a specific weight between 0.1 and 20 kg/m2. 9. The methods according to claim 1, wherein the fiber mass is supplied to the pressing mill in the form of a mat. 10. The method according to claim 1, wherein the fiber mass is successively conveyed through several press-roll arrangements where in each arrangement a first treatment fluid is pressed out of the fiber mass in the compression region and the fiber mass is impregnated with the second treatment fluid in the expansion region. 11. The method according to claim 1, wherein the fiber mass is prepared from a solution containing cellulose, water and tertiary amine oxide. 12. The method according to claim 1, wherein the press-roll is driven with a peripheral speed of at least 0.1 m/min. 13-18. (Canceled) 19. A press-roll arrangement for treating a fiber mass moving relatively to the press-roll arrangement, comprising at least one press-roll having a pressing surface area through which in operation in a pressing zone a pressing power action on the fiber mass is generated, and having at least one impregnation means through which in operation a treatment fluid is supplied to the fiber mass, wherein in operation the pressing zone forms an expansion region, in which the pressing power is reduced in the moving direction (B) of the fiber mass, wherein the press-roll arrangement comprises openings in the expansion region, through which in operation the treatment fluid is conducted through the pressing surface area into the fiber mass. 20. The press-roll arrangement according to claim 19, wherein the impregnation means is at least by sections arranged within the press-roll. 21. The press-roll arrangement according to claim 19, wherein the press-roll form ribs at its surface facing the fiber mass, which at least by sections form the pressing surface area and between which in operation the treatment fluid can be introduced through the pressing surface area into the fiber mass. 22. The press-roll arrangement according to claim 21, wherein the ribs extend essentially transversely to the moving direction of the fiber mass. 23. The press-roll arrangement according to claim 21, wherein the ribs extend essentially in the moving direction (B) of the fiber mass. 24. The press-roll arrangement according to claims 19, wherein in the press-roll nozzles are integrated through which the treatment fluid is directed in operation to the fiber mass. 25. The press-roll arrangement according to claim 24, wherein the nozzles comprise overlapping atomizing cones. 26. The press-roll arrangement according to claim 24, wherein the nozzles are arranged inside the press-roll and the atomising cones are directed through the rips. 27. The press-roll arrangement according to claim 19, wherein the ribs are formed as a weir which acts against a flow of the treatment fluid through the press-roll from the compression region to the expansion region. 28. The press-roll arrangement according to 19, wherein the impregnation means is provided with a regulation means, b which the size of the region of the pressing surface area through which the treatment fluid passes in operation, can be regulated. 29. The press-roll arrangement according to claim 28, wherein the regulation means is designed as a cover body disposed in the press-roll with an opening associated to the region. 30. The press-roll arrangement according to claim 29, wherein a regulation mimicry is provided by which the orientation and/or size of the opening can be regulated. 31. The press-roll arrangement according to claim 19, wherein a suction means is provided through which the treatment fluid is sucked off from the compression region in operation. 32. The press-roll arrangement according to claim 19, wherein the impregnation means comprises a supply line through which the treatment fluid is conducted from outside the press-roll essentially into the expansion region in operation. 33. The press-roll arrangement according to claim 32, wherein the supply line is arranged at least in the pressing zone at least by sections between two ribs essentially extending in the moving direction (B) of the fiber mass. 34. The press-roll arrangement according to claim 19, wherein at most about 95% of the outer peripheral surface is designed as passage surface for the treatment fluid. 35. The press-roll arrangement according to claim 34, wherein at most about 90% of the outer peripheral surface is designed as passage surface for the treatment fluid. 36. The press-roll arrangement according to claim 35, wherein at most about 85% of the outer peripheral surface is designed as passage surface for the treatment fluid. 37. The press-roll arrangement according to wherein at least about 1% to 3% of the outer peripheral surface is designed as passage surface for the treatment fluid. 38. A pressing mill for treating fiber masses with at least two press-roll arrangements consecutive in a conveying direction of the fiber mass, between which at least one treatment field is formed in which a treatment fluid acts on the fiber mass, wherein the press-roll arrangement is designed according to claim 19. 39. The pressing mill according to claim 38, wherein at least one press-roll arrangement is formed as a conveying means by which the fiber mass is transported through the pressing mill. 40. The pressing mill according to claim 38, wherein the pressing mill comprises at least one pair of press-rolls between which in operation the fiber mass is passed. 41. The pressing mill according to claim 38, wherein the fiber mass comprises in operation a weight per surface unit of 0.1 to 20 kg/m2. 42. The pressing mill according to claim 41, wherein the fiber mass comprises in operation a weight per surface unit of 0.1 to 10 kg/m2. 43. The pressing mill according to claim 38, wherein the throughput of the fiber mass per treatment field is approximately 10 to 1500 kg/(m2h). 44. The pressing mill according to claim 43, wherein the throughput of the fiber mass per treatment field is approximately 10 to 1200 kg/(m2h). 45. The press-roll arrangement according to claim 19, wherein the press-roll is driven at a peripheral speed of less than 400 m/min. 46. The press-roll arrangement according to claim 45, wherein the press-roll is driven at a peripheral speed of less than 60 m/min. 47. The press-roll arrangement according to claim 45, wherein the press-roll is driven at a peripheral speed of less than 10 m/min. 48. The press-roll arrangement according to claim 19, wherein with respect to the roll width, between 0.1 and 125 m3/(h m) of the treatment fluid is supplied. 49. The press-roll arrangement according to claim 48, wherein with respect to the roll width between 0.1 and 50 m3/(h m) of the treatment fluid is supplied. 50. The press-roll arrangement according to claim 48, wherein with respect to the roll width between 0.1 and 20 m3/(h m) of the treatment is supplied. |
Device and method for electrically inducing osteogenesis in the spine |
A technique and associated device for stimulating multiple electrodes with multiple electrical signals in multiple regions of the spine without injury to the patient. The electrodes are applied to respective sides of the patient's spine, and a first electrical signal is applied to any electrodes in a treatment area of the lumbar region of the patient's spine, a second electrical signal is applied to any electrodes in a treatment area of the thoracic region of the patient's spine, and a third electrical signal is applied to any electrodes in a treatment area of the cervical region of the patient's spine to induce osteogenesis in at least one of the respective treated area's of the patient's spine. The first, second, and third electrical signals respectively generate different electrode currents in the respective treated areas and are ideally selected to create current densities that are approximately equal in respective treatment areas. The electrodes may include electrode pairs or strip electrodes placed either side of the patient's spine in the respective treatment areas. |
1. A method of electrically inducing osteogenesis in the spine, comprising the steps of: placing electrodes on either side of the patient's spine; and applying at least one of a first electrical signal to any electrodes in a treatment area of the lumbar region of the patient's spine, a second electrical signal to any electrodes in a treatment area of the thoracic region of the patient's spine, and a third electrical signal to any electrodes in a treatment area of the cervical region of the patient's spine effective to induce osteogenesis in at least one of the respective treatment areas of the patient's spine, wherein the first, second, and third electrical signals respectively generate different electrode currents in the respective treatment areas. 2. The method of claim 1, wherein the first, second and third electrical signals are simultaneously applied to the respective electrodes in the respective treatment areas to create current densities that are approximately equal in the respective treatment areas. 3. The method of claim 1, wherein the electrodes are placed on the patient's skin. 4. The method of claim 1, wherein the electrodes comprise respective pairs of electrodes placed in each of said treatment areas in said placing step. 5. The method of claim 1, wherein the electrodes comprise respective strip electrodes each placed in said placing step so as to run vertically along the back on respective sides of the patient's spine. 6. The method of claim 1, wherein a current stimulated by the first electrical signal is greater than the current stimulated by the second electrical signal, and the current stimulated by the second electrical signal is greater than the current stimulated by the third electrical signal. 7. The method of claim 6, wherein the current stimulated by the second electrical signal is approximately {fraction (2/3)} the current stimulated by the first electrical signal, and the current stimulated by the third electrical signal is approximately {fraction (2/3)} the current stimulated by the second electrical signal. 8. The method of claim 7, wherein the electrode current stimulated by the first electrical signal is in the current range of 7-10 mA, the electrode current stimulated by the second electrical signal is in the current range of 4.7-6.7 mA, and the electrode current stimulated by the third electrical signal is in the current range of 3.14.5 mA. 9. A device for electrically inducing osteogenesis in the spine, comprising: a pair of electrodes for application on either side of the patient's spine in each treatment region of the patient's spine; and a power source that selectively applies a first electrical signal to any electrode pair in a treatment area of the lumbar region of the patient's spine, a second electrical signal to any electrode pair in a treatment area of the thoracic region of the patient's spine, and a third electrical signal to any electrode pair in a treatment area of the cervical region of the patient's spine effective to induce osteogenesis in the respective treatment areas of the patient's spine, wherein the first, second, and third electrical signals respectively generate different electrode currents in the respective treatment areas. 10. The device of claim 9, wherein the first, second and third electrical signals are simultaneously applied to the respective electrode pairs in the respective treatment areas by the power source to create current densities that are approximately equal in the respective treatment areas and such that all electrodes on one side of the patient's spine are all positive while all electrodes on another side of the patient's spine are all negative. 11. The device of claim 9, wherein the electrode pairs are adapted to be attached to the patient's skin and to apply the electrode currents to the patient's spine through capacitive coupling. 12. The device of claim 9 wherein a current stimulated by the first electrical signal is greater than the current stimulated by the second electrical signal, and the current stimulated by the second electrical signal is greater than the current stimulated by the third electrical signal. 13. The device of claim 12, wherein the current stimulated by the second electrical signal is approximately {fraction (2/3)} the current stimulated by the first electrical signal, and the current stimulated by the third electrical signal is approximately {fraction (2/3)} the current stimulated by the second electrical signal. 14. The device of claim 13, wherein the electrode current stimulated by the first electrical signal is in the current range of 7-10 mA, the electrode current stimulated by the second electrical signal is in the current range of 4.7-6.7 mA, and the electrode current stimulated by the third electrical signal is in the current range of 3.14.5 mA. 15. The device of claim 9, wherein the power source generates said first, second and third electrical signals and said device further comprises at least one switch that selectively applies said first, second or third electrical signals to respective electrode pairs in accordance with the treatment area of the spine in which the respective electrode pairs are placed. 16. The device of claim 15, further comprising a plug-in port for each electrode pair, each electrode pair controlled by a switch that is adjusted inaccordance with the treatment area to which the electrode pair is to be applied. 17. A device for electrically inducing osteogenesis in the spine, comprising: respective strip electrodes for application on either side of the patient's spine so as to run vertically along the patient's back on respective sides of the patient's spine; and a power source that selectively applies a first electrical signal to the strip electrodes when placed in a treatment area of the lumbar region of the patient's spine, a second electrical signal to the strip electrodes when placed in a treatment area of the thoracic region of the patient's spine, and a third electrical signal to the strip electrodes when placed in a treatment area of the cervical region of the patient's spine effective to induce osteogenesis in the respective treatment areas of the patient's spine, wherein the first, second, and third electrical signals respectively generate different electrode currents in the respective treatment areas. 18. The device of claim 17, wherein the strip electrodes are arranged such that a selected amount of current is delivered to every two-vertebra length of strip electrode. 19. The device of claim 18, wherein the strip electrodes are discontinuous and each two vertebra length of strip electrode receives one of the first, second and third electrical signals from the power source based on whether the two vertebra length is placed in the lumbar, thoracic, or cervical region, respectively, of the patient's spine. 20. The device of claim 17, wherein the strip electrodes are arranged to be used in more that one region of the patient's spine, each of said strip electrodes including a graded conductivity strip that causes voltage drops along the respective electrode strips soas to cause a decrease in voltage as the current moves along strip electrodes from the lumbar to the thoracic and/or from the thoracic to the cervical regions of the patient's spine. 21. The device of claim 17, wherein the electrode strips are adaptedto be attached to the patient's skin and to apply the electrode currents to the patient's spine through capacitive coupling. 22. The device of claim 17, wherein a current stimulated by the first electrical signal is greater than the current stimulated by the second electrical signal, and the current stimulated by the second electrical signal is greater than the current stimulated by the third electrical signal. 23. The device of claim 22, wherein the current stimulated by the second electrical signal is approximately {fraction (2/3)} the current stimulated by the first electrical signal, and the current stimulated by the third electrical signal is approximately {fraction (2/3)} the current stimulated by the second electrical signal. 24. The device of claim 23, wherein the electrode current stimulated by the first electrical signal is in the current range of 7-10 mA, the electrode current stimulated by the second electrical signal is in the current range of 4.7-6.7 mA, and the electrode current stimulated by the third electrical signal is in the current range of 3.14.5 mA. 25. The device of claim 17, wherein a separate pair of strip electrodes is provided for the lumbar, thoracic and cervical regions of the patient's spine, the power source comprising respective ports and at least one switch that selectively applies said first, second or third electrical signals to said respective ports in accordance with the treatment area of the spine in which the respective electrode pairs are placed. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention The present invention relates to a device and method for fusing multiple spine levels and otherwise increasing the stability of the spine through selective application of electrical signals. 2. Description of the Prior Art U.S. Pat. No. 4,535,775 demonstrated that an appropriate capacitively coupled electric signal applied to a single pair of surface electrodes placed on the skin on each side overlying a bone defect, nonunion fracture, delayed union, fresh fracture, or fracture at risk produced an internal electric field in the bone that resulted in healing of the bone. This technology has also been successfully applied to the treatment of fracture nonunions and delayed unions and as an adjunct to the treatment of localized spine fusion (Fusion of 1-2 vertebral levels; for example L 1 -L 2 and L 2 -L 3 ). There continues to be a great need to be able to use electricity in its various forms to fuse multiple spinal levels as in spinal scoliosis, degenerative disk disease at multiple levels, spine instability secondary to trauma of any cause, spinal stenosis, osteoporosis and tumor, including pain symptoms associated with the above. The present invention addresses these needs. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention addresses the above-mentioned needs in the art by determining the proper electric field amplitude and electrode placement for application of electric signals in the human spine to aid in spine fusion at multiple levels. To date, no animal or human data exists for such applications, and in order to obtain such data, a model was developed in the rat and then reconfigured for use in humans. The present invention relates to this model and its application to a human spine for electrically induced osteogenesis. In particular, the present invention relates to a device and method of electrically inducing osteogenesis in the spine by placing electrodes on either side of the patient's spine and applying at least one of a first electrical signal to any electrodes in a treatment area of the lumbar region of the patient's spine, a second electrical signal to any electrodes in a treatment area of the thoracic region of the patient's spine, and a third electrical signal to any electrodes in a treatment area of the cervical region of the patient's spine effective to induce osteogenesis in at least one of the respective treatment areas of the patient's spine. In accordance with the invention, the first, second, and third electrical signals respectively generate different electrode currents in the respective treatment areas and create current densities that are approximately equal in the respective treatment areas when applied simultaneously. The electrodes may comprise respective pairs of electrodes placed in each of the treatment areas or strip electrodes that are applied to a single treatment area or across two or more treatment areas that run vertically along the patient's spine. In a preferred embodiment, the current stimulated by the first electrical signal in the lumbar region is greater than the current stimulated by the second electrical signal in the thoracic region, and the current stimulated by the second electrical signal in the thoracic region is greater than the current stimulated by the third electrical signal in the cervical region. Preferably, the current stimulated by the second electrical signal is approximately {fraction (2/3)} the current stimulated by the first electrical signal, and the current stimulated by the third electrical signal is approximately {fraction (2/3)} the current stimulated by the second electrical signal. For example, the electrode current stimulated by the first electrical signal may be in the current range of 7-10 mA, the electrode current stimulated by the second electrical signal may be in the current range of 4.7-6.7 mA, and the electrode current stimulated by the third electrical signal may be in the current range of 3.1-4.5 mA. The power source of the invention generates the first, second and third electrical signals and further comprises at least one switch that selectively applies the first, second or third electrical signals to respective electrode pairs in accordance with the treatment area of the spine in which the respective electrode pairs are placed. In the case of strip electrodes, the strip electrodes may be discontinuous whereby each two vertebra length of strip electrode receives one of the first, second and third electrical signals from the power source based on whether the two vertebra length is placed in the lumbar, thoracic, or cervical region, respectively, of the patient's spine. In one embodiment of strip electrodes, the strip electrodes are arranged to be used in more that one region of the patient's spine, each of the strip electrodes including a graded conductivity strip that causes voltage drops along the respective electrode strips so as to cause a decrease in voltage as the current moves along strip electrodes from the lumbar to the thoracic and/or from the thoracic to the cervical regions of the patient's spine. |
Field effect transistor and method for the production thereof |
A transistor is provided which advantageously utilizes a part of the area which, in conventional transistors, is provided for the isolation between the transistors. In this case, the channel width can be enlarged in a self-aligned manner without the risk of short circuits. The field-effect transistor according to the invention has the advantage that it is possible to ensure a significant increase in the effective channel width for the forward current ION compared with previously used, conventional transistor structures, without having to accept a reduction of the integration density that can be attained. Thus, by way of example, the forward current ION can be increased by up to 50%, without having to alter the arrangement of the active regions or of the trench isolation. |
1. A field-effect transistor, in particular MIS field-effect transistor, having: a) a source region and a drain region, b) a channel region (8), which is arranged between the source region and the drain region, c) a gate electrode (11), which is arranged above the channel region in a manner electrically insulated from the channel region, d) a trench isolation (3), which laterally bounds the channel region (8), e) at least one partial region (8a, 8b) of the channel region (8) covering a part (6) of the trench isolation (3). 2. The field-effect transistor as claimed in claim 1, wherein the channel region (8) is an epitaxially produced semiconductor region. 3. The field-effect transistor as claimed in claim 1, wherein a groove-shaped recess is formed along the upper edge of the trench isolation. 4. The field-effect transistor as claimed in claim 1, wherein the partial region (8a, 8b) of the channel region (8) which covers a part (6) of the trench isolation (3) occupies more than 10%, preferably more than 20%, of the channel region. 5. The field-effect transistor as claimed in claim 1, wherein the width of the channel region (8) is greater than 1.2 times, preferably greater than 1.4 times, the minimum feature size F which can be fabricated by the lithography used to fabricate the transistor. 6. The field-effect transistor as claimed in claim 1, wherein the surface of the channel region (8) is arranged below the surface (3a) of the trench isolation (3). 7. The field-effect transistor as claimed in claim 1, wherein the surface of the channel region (8) is arranged above the surface (3a) of the trench isolation (3) and the channel region (8) has horizontal and vertical regions (8c, 8d). 8. A method for fabricating a field-effect transistor, in particular a MIS field-effect transistor, having the following steps: a) a semiconductor substrate (1) with at least one active region (2) and an already completed trench isolation (3) is provided, b) a selective epitaxy is carried out, an essentially monocrystalline semiconductor material (7) being formed above the active region (2) and above a part (6) of the trench isolation (3), so that a channel region (8) is produced, c) a gate oxide (10) is produced on the channel region (8) and a gate electrode (11) is produced on the gate oxide (10), and d) source and drain regions are produced. 9. The method as claimed in claim 6, wherein an etching is carried out before the selective epitaxy in step b), at least one part (6) of the trench isolation (3) that adjoins the active region (2) being etched, so that a groove-shaped recess is produced along the upper edge of the trench isolation (3). 10. The method as claimed in claim 7, wherein the part (6) of the trench isolation (3) that adjoins the active region (2) is etched isotropically. 11. The method as claimed in claim 7, wherein in step a), an oxide layer (4) is arranged above the active region (2) and the oxide layer (4) on the active region (2) is removed with the etching of the trench isolation, so that a groove-shaped recess is produced along the upper edge of the trench isolation (3). 12. The method as claimed in claim 9, wherein the etching of the trench isolation (3) is ended with the removal of the oxide layer (4). 13. The method as claimed in claim 9, wherein the etching of the trench isolation (3) is also continued after the removal of the oxide layer (4). 14. The method as claimed in claim 9, wherein the etching of the oxide layer (4) and of the trench isolation (3) is effected selectively with respect to the material of the active region (2). 15. The method as claimed in claim 6, wherein the selective epitaxy in step b) is carried out in such a way that the surface of the channel region (8) is arranged below the surface (3a) of the trench isolation (3). 16. The method as claimed in claim 13, wherein after the selective epitaxy, a thermal treatment is carried out for the planarization of the epitaxial surface. 17. The method as claimed in claim 6, wherein the selective epitaxy in step b) is carried out in such a way that the surface of the channel region (8) is arranged above the surface (3a) of the trench isolation (3) and the channel region (8) is formed with horizontal and vertical regions (8c, 8d). 18. The method as claimed in claim 6, wherein monocrystalline silicon is formed by the selective epitaxy. 19. The method as claimed in claim 7, wherein before the selective epitaxy, at least the active region (2) and the etched part (6) of the trench isolation (3) are measured by means of a scanning force microscope. 20. The method as claimed in claim 7, wherein the etching of the part (6) of the trench isolation (3) that adjoins the active region (2) is effected by a wet-chemical etching. 21. The method as claimed in claim 6, wherein before the production of the gate oxide (10), a sacrificial oxide is applied and removed again. |
Field effect transistor and method for production thereof |
The invention relates to a field effect transistor in which the planar channel region on the upper surface of the elevation is extended in width by means of additional vertical channel regions on the lateral surfaces of the elevation. Said additional vertical channel regions connect directly to the planar channel region (vertical extended channel regions). Said field effect transistor has the advantage that a significant increase in the effective channel width for the current flow ION can be guaranteed relative to conventional transistor structures used up until the present, without having to accept a reduction in the achievable integration density. Said field effect transistor furthermore has a low reverse current IOFF. The above advantages are achieved without the thickness of the gate insulators up to the region of the charge transfer tunnels having to be reduced or a reduced stability. |
1. A field-effect transistor in particular MIS field-effect transistor, having: a) at least one web-type elevation (2), which is arranged on a semiconductor substrate (1) and has an upper surface (2a) and lateral surfaces (2b), b) a first gate oxide layer (4), which is arranged on the upper surface (2a) of the web-type elevation (2), c) a first gate electrode (5), which is arranged on the first gate oxide layer (4), the first gate electrode having an upper surface and lateral surfaces, d) a second gate oxide layer (6), which is arranged at least on a part of the lateral surfaces (2b) of the web-type elevation (2) and the first gate electrode (4), e) a second gate electrode (7), which is arranged on the second gate oxide layer (6) and the upper surface of the first gate electrode (5) and f) source and drain regions, which are arranged on the web-type elevation (2). 2. The field-effect transistor as claimed in claim 1, wherein the second gate oxide layer (6) is made thicker on the lateral surfaces of the first gate electrode (5) than on the lateral surfaces (2b) of the web-type elevation (2). 3. The field-effect transistor as claimed in claim 1, wherein an insulating spacer (14) is arranged on the second gate oxide layer (6) at the level of the first gate electrode (5). 4. A field-effect transistor in particular MIS field-effect transistor, having: a) at least one web-type elevation (2), which is arranged on a semiconductor substrate (1) and has an upper surface (2a) and lateral surfaces (2b), b) a first gate oxide layer (4), which is arranged at least on a part of the lateral surfaces (2b) of the web-type elevation (2), c) a first gate electrode (5), which is arranged on the first gate oxide layer (4), the first gate electrode (5) having an upper surface and lateral surfaces, d) a second gate oxide layer (6), which is arranged on the upper surface (2a) of the web-type elevation (2) and the upper surface of the first gate electrode (5), e) a second gate electrode (7), which is arranged on the second gate oxide layer (6) and the lateral surfaces of the first gate electrode (5), and f) source and drain regions, which are arranged on the web-type elevation (2). 5. The field-effect transistor as claimed in claim 1, wherein the edges (8) of the web-type elevation (2) are rounded between the upper surface (2a) and the lateral surfaces (2b) 6. The field-effect transistor as claimed in claim 5, wherein the radius of curvature of the edges (8) is of the order of magnitude of the layer thickness of the first or second gate oxide layer (4, 6). 7. The field-effect transistor as claimed in claim 1, wherein 20 spacers are arranged between the source region and the gate electrodes and also between the drain region and the gate electrodes. 8. The field-effect transistor as claimed in claim 1, wherein the first gate electrode (5) has a polysilicon layer. 9. The field-effect transistor as claimed in claim 1, wherein the second gate electrode (7) has a polysilicon-metal double layer or a polycide layer. 10. The field-effect transistor as claimed in claim 1, wherein the part of the lateral surfaces (2b) of the web-type elevation (2) which is covered by a gate oxide layer (4, 6) is bounded by a trench isolation (3). 11. The field-effect transistor as claimed in claim 1, wherein the doping profile depth of the source and drain regions is greater than the extent of the part of the lateral surfaces (2b) of the web-type elevation (2) which is covered by a gate oxide layer (4, 6). 12. A method for fabricating a field-effect transistor, in particular a MIS field-effect transistor, having the following steps: a) a semiconductor substrate (1) with a first gate oxide layer (4) applied thereon and a first gate electrode layer (5) applied to the gate oxide layer (4) is provided, b) at least one web-type elevation (2) with an upper surface (2a) and lateral surfaces (2b) is produced, the first gate oxide layer (4) and the first gate electrode layer (5) being arranged on the upper surface (2a), c) a second gate oxide layer (6) is produced at least on a part of the lateral surfaces (2b) of the web-type elevation (2) and the first gate electrode layer (5), d) a second gate electrode layer (7) is applied, so that the second gate electrode layer (7) is arranged on the second gate oxide layer (6) and the upper surface of the first gate electrode layer (5), and e) the first and second gate electrode layers (5, 7) are patterned to form first and second gate electrodes and source and drain regions are produced. 13. The method as claimed in claim 12, wherein the web-type elevation (2) is produced with the patterning of the trenches for a trench isolation (3). 14. The method as claimed in claim 13, wherein the trenches for the trench isolation are filled with oxide (3) and etching-back is carried out, so that a part of the lateral surfaces (2b) of the web-type elevation (2) is uncovered. 15. The method as claimed in claim 14, wherein a CMP step is carried out prior to the etching-back. 16. The method as claimed in claim 12, wherein at least one thermal process is carried out for rounding the edges (8) of the web-type elevation (2) between the upper surface (2a) and the lateral surfaces (2b). 17. The method as claimed in claim 12, wherein the gate oxide layers (4, 6) are in each case produced by a thermal oxidation. 18. The method as claimed in claim 12, wherein the second gate oxide layer (6) is produced by selective oxidation, so that the second gate oxide 5 layer (6) is made thicker on the lateral surfaces of the first gate electrode (5) than on the lateral surfaces (2b) of the web-type elevation (2). 19. The method as claimed in claim 12, wherein an insulating spacer is produced after the production of the first gate electrode layer (5), so that an insulating spacer (14) is arranged on 15 the second gate oxide layer (6) at the level of the first gate electrode (5). |
Electrochemical detection of analytes |
An analyte is determined electrochemically indirectly. In a first step an oxidase and an oxidisable substrate, one of which is the analyte or derived therefrom, interact and generate hydrogen peroxide. In a second step a peroxidase (especially horse-radish peroxidase) reduces the hydrogen peroxide and concomitantly oxidises a mediator, preferably 2,2′-azino-bis(3-ethyl=benzthiazoline-6-sulfonic acid, ABTS) to an oxidised form (ABTSOX). The oxidised mediator is then reduced at an electrode and the consequent current is measured. A preferred sensor format uses a carbon electrode screen-printed onto a substrate and overlaid with one or more layers containing the enzymes and other components. |
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