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<SOH> SUMMARY OF THE INVENTION <EOH>Various embodiments of the invention provide purified polypeptides, extracellular messengers, referred to collectively as “EXMES” and individually as “EXMES-1,” “EXMES-2,” “EXMES-3,” “EXMES-4,” “EXMES-5,” “EXMES-6,” “EXMES-7,” “EXMES-8,” “EXMES-9,” “EXMES-10,” “EXMES-11,” “EXMES-12,” “EXMES-13,” “EXMES-14,” “EXMES-15,” “EXMES-16,” “EXMES-17,” “EXMES-18,” “EXMES-19,” “EXMES-20,” “EXMES-21,” and “EXMES-22,” and methods for using these proteins and their encoding polynucleotides for the detection, diagnosis, and treatment of diseases and medical conditions. Embodiments also provide methods for utilizing the purified extracellular messengers and/or their encoding polynucleotides for facilitating the drug discovery process, including determination of efficacy, dosage, toxicity, and pharmacology. Related embodiments provide methods for utilizing the purified extracellular messengers and/or their encoding polynucleotides for investigating the pathogenesis of diseases and medical conditions. An embodiment provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. Another embodiment provides an isolated polypeptide comprising an amino acid sequence of SEQ ID NO:1-22. Still another embodiment provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. In another embodiment, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO:1-22. In an alternative embodiment, the polynucleotide is selected from the group consisting of SEQ ID NO:23-44. Still another embodiment provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. Another embodiment provides a cell transformed with the recombinant polynucleotide. Yet another embodiment provides a transgenic organism comprising the recombinant polynucleotide. Another embodiment provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed. Yet another embodiment provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. Still yet another embodiment provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). In other embodiments, the polynucleotide can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides. Yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex. In a related embodiment, the method can include detecting the amount of the hybridization complex. In still other embodiments, the probe can comprise at least about 20, 30, 40, 60, 80, or 100 contiguous nucleotides. Still yet another embodiment provides a method for detecting a target polynucleotide in a sample, said target polynucleotide being selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d). The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof. In a related embodiment, the method can include detecting the amount of the amplified target polynucleotide or fragment thereof. Another embodiment provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and a pharmaceutically acceptable excipient. In one embodiment, the composition can comprise an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. Other embodiments provide a method of treating a disease or condition associated with decreased or abnormal expression of functional EXMES, comprising administering to a patient in need of such treatment the composition. Yet another embodiment provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. Another embodiment provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with decreased expression of functional EXMES, comprising administering to a patient in need of such treatment the composition. Still yet another embodiment provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample. Another embodiment provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. Yet another embodiment provides a method of treating a disease or condition associated with overexpression of functional EXMES, comprising administering to a patient in need of such treatment the composition. Another embodiment provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide. Yet another embodiment provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical or at least about 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-22. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide. Still yet another embodiment provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound. Another embodiment provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound; b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical or at least about 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:23-44, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide can comprise a fragment of a polynucleotide selected from the group consisting of i)-v) above; c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound. |
Process for the preparation of 7-amino syn 3,5-dihydroxy heptanoic acid derivatives via 6-cyano syn 3,5-dihydroxy hexanoic acid derivatives |
The invention relates to novel synthesis methods for the preparation of the intermediates, which are suitable for the preparation of statin derivatives, especially to novel synthesis methods of the intermediate of formula VI wherein Ra and Rc are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and Rb is a carboxy-protecting group, which methods are carried out by conversion of the intermediate of formula XIX wherein Ra and Rc are each independently of the other hydrogen or a hydroxy-protecting group, and Rb is a carboxy-protective group. |
1. A process for the preparation of the intermediate of formula VI wherein Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and Rb is a carboxy-protecting group, which is suitable for the preparation of statin derivatives, which process is carried out by conversion of the intermediate of formula XIX wherein Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group, and Rb is a carboxy-protecting group; wherein compound of formula XIX is prepared by a process which comprises the preparation of a compound of formula I wherein X is halogen, acyloxy, activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH3)—OCH3, Ra is hydrogen or a hydroxy-protecting group and Rb is a carboxy-protecting group; wherein compound of formula I is prepared by conversion a compound of formula XI wherein Ra is a hydroxy-protecting group and Rb is a carboxy-protecting group, into the corresponding compound of formula I using a reagent that introduces the radical X. 2. A process according to claim 1, wherein the compound of formula XI is prepared by hydrolysing a compound of formula XII wherein Ra is a hydroxy-protecting group, Rb is a carboxy-protecting group and Rd is hydrocarbyl, Rb and Rd preferably being identical, by means of an enantioselective catalyst, with removal of the radical Rd, the corresponding compound of formula XI being obtained directly, the compound of formula XII in turn being obtained by reacting a glutaric acid derivative of formula XIII wherein Rb and Rd are as defined for compounds of formula XII, by introduction of a hydroxy-protecting group using the corresponding reagent suitable for the introduction of the protecting group. 3. A process, especially according to claim 1, comprises the conversion of a compound of formula I wherein X is halogen, acyloxy, activated hydrocarbyloxy, activated hydrocarbylthio or —N(CH3)OCH3, Ra is hydrogen or a hydroxy-protecting group and Rb is a carboxy-protecting group into an amide of formula I* wherein Rc′ is hydrogen or a hydroxy-protecting group, Rb′ is hydrogen or a carboxy-protecting group and R* and R** are each independently of the other hydrogen or an amide-protecting group, preferably alkyl or substituted alkyl; which compound I*, wherein R* and R** are each hydrogen, Rb′ is a carboxy-protecting group and Rc′ is a hydroxy protecting group is dehydrated to form a nitrile of formula XVII wherein Rc′ is a hydroxy-protecting group and Rb′, is a carboxy-protecting group; that compound, after removal of the hydroxy-protecting group Rc′ is converted by means of a compound of formula XX wherein Rb is a carboxy-protecting group, in the presence of a strong base, into a nitrile of formula XVIII wherein Rc′ is hydrogen and Rb is a carboxy-protecting group; the compound of formula XVIII wherein Rc′ is hydrogen is in turn then converted by diastereoselective reduction into a syn-diol compound of formula XIX wherein Ra′ and Rc′ are hydrogen; or, after subsequent introduction of protecting groups, Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group, with the proviso that at least one of the two radicals is such a protecting group, or Ra′ and Rc′ together are a bridging hydroxy-protecting group; and Rb is a carboxy-protecting group; and by reduction of the cyano function in that compound there is obtained an amino compound of formula VI described in claim 1 wherein Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and Rb is a carboxy-protecting group; and in the processes mentioned above, at any stage, even where not explicitly mentioned, if necessary one or more or all of the protecting groups present in the compounds of formulae I*, I, VI, XI to XIII, XVII to XIX in question are removed or one or more or all of the functional groups that are not to participate in a reaction, or that would interfere with the reaction, are converted into protected groups by the introduction of suitable protecting groups (especially hydroxy-protecting groups and/or carboxy-protecting groups), and it being possible for the compounds of formulae I*, I, VI, XI to XII, XVII to XIX, where salt-forming groups are present and the reaction in question is not impaired, also to be in salt form. 4. A process, especially according to any of the preceding claims 1 to 3, wherein a compound of formula XVIII wherein Rc′ is hydrogen and Rb is tert-butyl; is reduced diastereoselectively with hydrogen in the presence of an alkali metal salt or an alkaline-earth metal salt and a heterogeneous platinum catalyst to form a syn-diol compound of formula XIX wherein Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group, and Rb is tert-butyl. 5. A process, especially according to any of the preceding claims 1 to 3, wherein a compound of formula XVIII, as defined above in claim 3, is reduced diastereoselectively with a mixture of triethylborane or diethylborane methoxide with sodium borhydride to form a syn-diol compound of formula XIX as defined above in claim 3. 6. Use of the processes of any of the preceeding claims for the preparation of statin derivaties and their intermediates of formula VI wherein Ra′ and Rc′ are each independently of the other hydrogen or a hydroxy-protecting group or together are a bridging hydroxy-protecting group, and Rb is a carboxy-protecting group. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Statins are a class of pharmaceuticals that inhibit the enzyme hydroxymethylglutaryl CoA reductase (HMG-CoA-R) and are therefore widely used as hypolipidaemic agents and agents that lower the level of cholesterol in the blood (hypocholesterollipidaemic agents). All synthetically prepared HMG-CoA-R inhibitors have, as common structural features, an aromatic base structure and the so-called statin side chain, as symbolised by the following formula: (wherein Aryl denotes aromatic, heterocyclic or aromatic-heterocyclic, unsubstituted or substituted, mono-, di- or poly-cyclic ring systems). Such a structural unit can be found in a whole range of pharmaceutically active agents, such as cerivastatin (Bayer AG), fluvastatin (Novartis), itavastatin (NK-104; Kowa Company Ltd.), BMY 22089 (Bristol-Myers Squibb), rosuvastatin (S-4522, AstraZeneca/Shionogi), glenvastin (Hoechst(Aventis) and atorvastatin (Warner-Lambert/Gödecke-Parke Davies/Pfizer). The aim of the present invention is to provide new efficient methods of synthesising some known statin derivatives and to provide new intermediate compounds. |
<SOH> SUMMARY OF THE INVENTION <EOH>The invention relates to novel preparation processes for the preparation of 3,5-dihydroxy-heptanoic acid derivatives and to novel intermediates and processes for their preparation. The dihydroxyheptanoic acid derivatives and the intermediates are suitable for advantageous syntheses of statins. |
Macromolecular imaging agents for liver imaging |
Macromolecular imaging agents comprising a polyalkylenimine dendrimer conjugated to a metal chelate are disclosed. In particular embodiment, the imaging agent is a diaminobutane-core polypropylenimine dendrimer having surface amino groups conjugated to gadolinium metal chelates. Administration of this gadolinium conjugate to a subject permits visualization of liver micrometastases as small as about 0.3 mm in a magnetic resonance image of the subject's liver. |
1. A macromolecular imaging agent, comprising: a polyalkylenimine dendrimer; and a metal chelate conjugated to the dendrimer. 2. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer. 3. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a DAB dendrimer. 4. The imaging agent of claim 3 where the DAB dendrimer comprises a DAB-Am dendrimer. 5. The imaging agent of claim 4 where the DAB-Am dendrimer comprises a polypropylenimine tetrahexacontaamine dendrimer. 6. The imaging agent of claim 5 where the metal chelate comprises a 1B4M metal chelate. 7. The imaging agent of claim 6 where the 1B4M metal chelate comprises a gadolinium chelate. 8. The imaging agent of claim 1 where the polyalkylenimine dendrimer comprises a polybutylenimine dendrimer. 9. The imaging agent of claim 1 where the metal chelate comprises a gadolinium metal chelate. 10. The imaging agent of claim 9 where the gadolinium chelate comprises a GdDPTA chelate. 11. The imaging agent of claim 1 where the dendrimer comprises a DAB-Am dendrimer and the metal chelate comprises a gadolinium chelate. 12. A method for making a macromolecular imaging agent, comprising: reacting a reactive group of a bifunctional chelating agent with a surface group of a polyalkylenimine dendrimer; and reacting a metal ion with a metal chelating group of the bifunctional chelating agent. 13. The method of claim 12 where the surface group of the dendrimer comprises an amino group and the reactive group is capable of reacting with the amino group. 14. The method of claim 13 where the reactive group comprises an isothiocyanate group. 15. The method of claim 12 where the metal chelating group is selected from consisting of DOTA, DTPA, DOTA derivatives, DTPA derivatives, and combinations thereof. 16. The method of claim 12 where the metal comprises a paramagnetic ion. 17. The method of claim 16 where the paramagnetic ion comprises Gd(III). 18. The method of claim 12 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer. 19. The method of claim 18 where the polypropylenimine dendrimer comprises a DAB dendrimer. 20. The method of claim 19 where the DAB dendrimer comprises a DAB-Am dendrimer. 21. The method of claim 12 where the bifunctional chelating agent comprises 1B4M, the reactive group comprises an isothiocyanate group and the metal ion comprises Gd(III). 22. A method for imaging the liver of a subject, comprising: administering to the subject an image-enhancing amount of a polyalkylenimine dendrimer conjugated to a metal chelate; and measuring the MRI signal intensity of two or more regions of the subject's liver to detect differences in a signal intensity between the regions. 23. The method of claim 22 where the image enhancing amount of the dendrimer conjugate comprises between about 0.001 mg/kg and about 0.10 mg/kg of the subject's weight. 24. The method according to claim 22 where the polyalkylenimine dendrimer comprises a polypropylenimine dendrimer. 25. The method according to claim 22 where the metal chelate comprises a gadolinium chelate. 26. The method according to claim 22 where the dendrimer conjugated to a metal chelate comprises a DAB dendrimer conjugated to a gadolinium metal chelate. 27. The method according to claim 26 where the DAB dendrimer comprises DAB-Am64 and the gadolinium metal chelate comprises Gd-1B4M. 28. The method according to claim 22 where the polyalkylenimine dendrimer conjugated to a metal chelate comprises DAB-Am64-(1B4M-Gd)64. 29. The method according to claim 22 where the polyalkylenimine dendrimer conjugated to a metal chelate comprises DAB-Am32-(1B4M-Gd)32. 30. A method for imaging the liver of a subject, comprising; administering to a subject an image-enhancing amount of a DAB dendrimer conjugated to a gadolinium chelate; and examining the subject's liver by magnetic resonance imaging to obtain a T1-weighted image. 31. The method of claim 30 further comprising detecting a liver micrometastesis by detecting a dark image of the liver micrometastasis against a bright image of normal liver parenchyma in the T1-weighted image. 32. The method of claim 30 where the DAB dendrimer conjugated to a gadolinium chelate comprises DAB-Am64-(1B4M-Gd)64. 33. The method of claim 30 where the DAB dendrimer conjugated to a gadolinium chelate comprises DAB-Am32-(1B4M-Gd)32. 34. A method for detecting changes in the size of a liver tumor during a period of time, comprising: administering to a subject an image-enhancing amount of a polyalkylenimine dendrimer conjugated to a gadolinium chelate; obtaining a T1-weighted magnetic resonance image of the subject's liver; detecting a liver tumor in the magnetic resonance image by a contrast between the tumor and surrounding normal liver parenchyma; and repeating the steps of administering, obtaining, and detecting two or more times during a period of time to detect changes in the size of the liver tumor. 35. The method of claim 34 where the polyalkylenimine dendrimer conjugated to a gadolinium chelate comprises a polypropylenimine dendrimer conjugated to a gadolinium chelate. 36. The method of claim 35 where the polypropylenimine dendrimer conjugated to a gadolinium chelate comprises a DAB dendrimer conjugated to a gadolinium chelate. 37. The method of claim 36 where the DAB dendrimer conjugated to a gadolinium chelate comprises a DAB-Am64 dendrimer conjugated to a gadolinium chelate. 38. The method of claim 37 where the gadolinium chelate comprises a 1B4M chelate. 39. The method of claim 36 where the DAB dendrimer conjugated to a gadolinium chelate comprises a DAB-Am32 dendrimer conjugated to a gadolinium chelate. 40. The method of claim 39 where the gadolinium chelate comprises a 1B4M chelate. |
<SOH> BACKGROUND <EOH>MRI is a technique that allows whole body in vivo imaging in three dimensions at high resolution. In MRI, a static magnetic field is applied to the object of interest while simultaneously or subsequently applying pulses of radio frequency (RF) to change the distribution of the magnetic moments of protons in the object. The change in distribution of the magnetic moments of protons in the object from their equilibrium (normal) distribution to a non-equilibrium distribution and their subsequent return to the normal distribution constitute the MRI signal. Magnetic resonance (MR) contrast agents assist this return to a normal distribution by shortening T 1 and/or T 2 relaxation times. The longitudinal relaxation time T 1 is defined as the time constant of the exponential recovery of proton spins to their equilibrium distribution along an applied magnetic field after a disturbance. The transverse relaxation time T 2 is the time constant that describes the exponential loss of magnetization in a plane transverse to the direction of the applied magnetic field, following a RF pulse that rotates the aligned magnetization into the transverse plane. Signal intensity in biological MRI depends largely on the local value of the longitudinal relaxation rate (1/T 1 ), and the transverse rate (1/T 2 ) of water protons. Signals tend to increase with increasing 1/T 1 and decrease with increasing 1/T 2 . MRI pulse sequences that emphasize changes in 1/T 1 are referred to as T 1 -weighted and those that emphasize changes in 1/T 2 are referred to as T 2 -weighted. Contrast agents increase 1/T 1 and 1/T 2 , depending on the nature of the agent and the strength of the applied field. Agents such as gadolinium(III) that increase both 1/T 1 and 1/T 2 to a similar extent are best visualized using T 1 -weighted images, since the relative change in 1/T 1 in tissue is much greater than the change in 1/T 2 . Iron particles, in contrast, provide larger changes in 1/T 2 and are best visualized in a T 2 -weighted image. The longitudinal and transverse relaxivity values, r 1 and r 2 , refer to the increase in 1/T 1 and 1/T 2 , respectively, per millimolar concentration of a contrast agent (r 1 and r 2 have units of mM −1 s −1 ). For gadolinium based contrast agents relaxivity is typically expressed on the basis of gadolinium atom concentration. MRI contrast agents that accumulate in particular regions within a subject organism provide image contrast of the accumulation region with surrounding tissue. Superparamagnetic iron oxides (SPIO) were the first clinically approved liver-specific contrast agents among a variety of cell/organ specific MR contrast agents. SPIO agents [e.g., AMI-25 (Advanced Magnetics, Cambridge, Mass.), SH U 555A (Schering, Berlin, Germany)] efficiently accumulate in the liver (approximately 80% of injected dose) and the spleen (5-10% of injected dose) within minutes of their administration. Following sequestration by phagocytic cells, the agents significantly decrease T 2 -weighted signal in the liver, resulting in the visualization of the hypointense/dark liver on the T 2 -weighted image. Certain simple gadolinium (Gd(III)) chelates are subject to hepatocellular uptake and excretion into the bile ducts, gall bladder, and intestines, and enable visualization of a hyperintense/bright liver in the T1-weighted image. Examples of this type of MRI contrast agent, include MultiHance™ ([Gd(BOPTA)(H 2 O)] 2− ), which is approved for use in Europe, and a related chelate, Eovist™ ([Gd(EOB-DTPA)(H 2 O)] 2− ), which is currently in Phase III clinical trials. Eovist™ is excreted to a greater extent via the liver than MultiHance™ (roughly 50% vs. 2-4%, respectively), resulting in significantly greater liver enhancement for Eovist™. Advances in MRI have tended to favor T 1 agents and thus gadolinium based contrast agents, such as small gadolinium chelates. Faster scans with higher resolution require more rapid RF pulsing that can lead to loss of the MRI signal through saturation effects. T 1 agents relieve saturation and restore signal by stimulating relaxation of nuclear spins between RF pulses. However, most metal chelates, because of their small size, tend to be cleared rapidly from blood. Metal chelates also are typically hydrophillic, giving rise to limited cell penetration (but good tolerability). Conjugation of metal chelates to macromolecules to form macromolecular imaging agents is one approach to altering the pharmacological properties (e.g. blood retention, tissue perfusion, and excretion) of metal chelates and to altering their biophysical properties (e.g. relaxivity). For example, higher molecular weight macromolecular imaging agents tend to be retained in the vascular space by virtue of molecular size and thus are useful for blood pool imaging in a technique called magnetic resonance angiography (MRA). Macromolecular imaging agents having multiple metal chelates per macromolecule can provide high relaxivities per metal atom and facilitate simultaneous delivery of many image-enhancing chelates to a particular tissue, especially if cell specific proteins, such as receptors, target the macromolecular imaging agent. (See, for example, Weiner et al., Invest. Radiol., 32: 748-54, 1997. Macromolecular imaging agents have been prepared by conjugation of functionalized chelates to biological molecules, polymers, and dendrimers. Ogan et al., Invest. Radiol., 22: 665-71, 1987, conjugated albumin with diethylenetriaminepentaacetic acid (DTPA) to provide a MRI contrast agent. Gadolinium chelates conjugated with poly-lysine are another example of a macromolecular imaging agent. See, for example, Vexler et al., J. Magn. Reson. Imaging, 4: 381-8, 1994. Weiner et al., Magn. Reson. Med., 31: 1-8, 1994, describe macromolecular imaging agents formed from polyamidoamine dendrimers. Dendrimers are a recently synthesized class of highly branched, often spherical, polymers that exhibit greater monodispersity (i.e. a smaller range of molecular weights, sizes, and shapes) than linear polymers of similar size. Dendrimers are three-dimensional oligomeric structures prepared by reiterative reaction sequences starting from a core molecule having multiple reactive functional groups. When monomer units, also with multiple reactive functional groups, are added to the core, the number of reactive functional groups comprising the outer bounds of the dendrimer increases. The number of reactive groups on the dendrimer will increase geometrically each time the growing dendrimer is reacted exhaustively with more monomers. Each successive reaction of a dendrimer with additional monomers to form a new layer of monomer units around the core is termed a “generation.” The number of reactive functional groups on a dendrimer's outer surface depends on the structure of the core, the structure of the monomers added to the core, and the “generation” of the dendrimer. Based on size alone, macromolecular imaging agents formed from dendrimers might be expected to exhibit definite and predictable pharmacological properties due to their monodisperse nature. To the contrary, the pharmacological behavior of dendrimer-based macromolecular chelates has proven unpredictable. For example, Kobayashi et al. (Kobayashi et al., Bioconjugate Chem., 12: 100-107, 2001) found that two, generation 6 polyamidoamine (PAMAM) dendrimer-based macromolecular imaging agents of presumably similar size, but differing molecular weights and core molecule identities, exhibited different pharmacological properties. |
<SOH> SUMMARY <EOH>In one aspect, macromolecular imaging agents are disclosed. The disclosed imaging agents are polyalkylenimine dendrimers conjugated to metal chelates. For example, the imaging agent may be a polypropylenimine or a polybutylenimine dendrimer conjugated to a gadolinium chelate. In another aspect, a method is provided for making a macromolecular imaging agent by reacting a bifunctional chelating agent with a surface group of a polyalkylenimine dendrimer and adding a metal to the bifunctional chelating agent. The disclosed macromolecular imaging agents are useful entities in medical diagnosis and therapy, due in part to their unique localization in the body. They have in vivo applications related to their unexpectedly specific and rapid biodistribution that preferentially localizes these agents in the parenchyma of the liver. If, for example, the macromolecular imaging agent comprises gadolinium ions, it provides better MRI resolution of liver tissue structure than provided by known liver-specific MRI contrast agents. As such, the macromolecular imaging agent is suitable for a range of uses including detection of liver micrometastic tumors (for example, tumors between about 0.3 and 0.7 mm in size). Detection of liver tumors of such small size enables earlier diagnoses and thus improved chances for successful treatment of liver cancers. Moreover, in view of their enhanced relaxivity, the MRI contrast agents according to the invention can be administered at reduced dosages relative to current monomeric MRI contrast agents such as GdDTPA and GdDOTA, providing a significantly improved safety margin in their use. Therefore, in another aspect, methods for imaging a subject are provided. For example, an image-enhancing amount of a polyalkylenimine dendrimer conjugated to a metal chelate may be administered to a subject. Once the dendrimer conjugate is administered, the MRI signal intensity may measured for different regions of the subject's liver to detect differences in signal intensity between those regions. Certain differences in signal intensity are indicative of the presence of a tumor, for example a micrometastesis of the liver. The foregoing and other objects, features, and advantages of the invention will become more apparent from the following detailed description of several embodiments, which proceeds with reference to the accompanying figures. |
Prescription compliance device and metod of using device |
A prescription compliance device which aids patients in complying with instructions given by a physician for taking prescription medication. The device reminds a patient when the next dose of medication is to be taken and indicates whether a specified dose has been taken. The device includes a microcontroller, a display, a program memory for storing pre-programmed medication-taking regimens for single and multiple medications, a real time clock, a selector for selecting one of the regimens and for programming the device as to the time and day on which a first dose of medication is to be taken, a display which alternately displays the current time and a time at which a next dose of medication is to be taken and an alarm which alerts the patient at times when a dose of medication is to de taken. The selector includes an event switch which is activated by the patient after taking a dose of medication so as to record the taking of medication and to cause the microcontroller to effect the display of the next time at which a dose of medication is to be taken. A memory may also be included to record the times at which a patient takes doses of medication. The device also includes a remote programming feature via a wireless link. |
1. A prescription compliance device comprising: microcontroller; a program memory storing data representing a plurality of pre-programmed commonly prescribed medication-taking regimens; a selector selecting one of said regimens and programming said device in accordance therewith; and a display, said selector including an event switch which is activated in conjunction with a patient taking a dose of a medication corresponding to a respective medication-taking regimen to record the taking of said medication, said event switch causing said microcontroller to effect the display of the time at which a next dose of medication is scheduled to be taken, in accordance with the regimen selected by said selector, wherein the microcontroller recalculates the time the next dose is to be taken based on a last time the dose of medication was taken in conjunction with a time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 2. The device according to claim 1, wherein at least one of the medication-taking regimens includes at least one of an early take window and late take window respectively allowing the patient to take the next dose of medication within medically acceptable times before and after the next dose of medication is to be taken. 3. The device according to claim 1, wherein the microcontroller recalculates the early take window and late take window based on the last time the dose of medication was taken in conjunction with the time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 4. The device according to claim 1, wherein the prescription compliance device is integrated with a cell phone or personal digital assistant (PDA). 5. The device according to claim 1, further comprising: a transmitter/receiver; and an external transmitter/receiver configured to be connected to an input device, said external transmitter/receiver communicating with said transmitter/receiver via a wireless link to select one of said regimens and program said device in accordance therewith from remote locations. 6. The device according to claim 5, wherein the time the next dose of medication may be adjusted via the remote location. 7. The device according to claim 5, wherein said input device is a personal computer. 8. The device according to claim 5, wherein said wireless link is an infrared link. 9. The device according to claim 1, further comprising: a trip function configured to indicate how much medication is needed to be taken between a start date and an end date and whether any medications need to be renewed before the end date. 10. The device according to claim 1, further comprising: a skip function configured to allow the patient to skip taking the next dose of medication. 11. The device according to claim 1, wherein the device is programmed to alert the patient to perform a task different than taking the next dose of medication. 12. The device according to claim 1, further comprising: a log database configured to record medications taken or skipped and related information input by the patient. 13. The device according to claim 1, wherein at least one of the plurality of pre-programmed medication-taking regimens causes calculation of acceptable times during which said patient is scheduled to take said medication, and wherein the calculated times are based on the following factors: 1) a preferred time of day at which the patient is to take a first dose of the medication; 2) a regimen specific predetermined interval of time between doses of the medication; and 3) a regimen specific predetermined time range during which it is medically acceptable for the patient to take the medication. 14. The device according to claim 11, further comprising: a log data base configured to record information entered by the patient corresponding to the additional task performed. 15. The device according to claim 1, further comprising an alarm circuit alerting said patient at times when said patient is scheduled to take a dose of medication. 16. The device according to claim 1, wherein said event switch is activated to scan through regimen and programming options, and wherein said selector further includes: a reset button rendering said device on and off; and a selection button selecting an appropriate regimen and programming options. 17. The device according to claim 16, wherein each of said regimens dictates the times at which said medication is to be taken daily or events during which said medication is to be taken, and wherein said programming options include: a time of day at which the first dose of medication is to be taken or designation of default times in accordance with a selected regimen. 18. A device according to claim 17, wherein said programming options further include: said patient's specified times for said events; and a number of doses in a prescription. 19. A device according to claim 1, wherein said display comprises: a first display area displaying a name of the medication; a second display area displaying a day of the week on which a next dose of said medication is to be taken; a third display area displaying the time or event during which the next dose of said medication is to be taken; a fourth display area displaying AM or PM designations for the time at which a next dose of said medication is to be taken; and a fifth display area displaying an icon indicating the nature of the information currently displayed in said first through fourth display areas. 20. The device according to claim 19, wherein said third display area further displays the current time. 21. The device according to claim 20, wherein said third display area further displays the number of doses remaining in a prescription. 22. The device according to claim 1, wherein said display is a liquid crystal display. 23. The device according to claim 1, wherein said microcontroller causes said display to display a low battery indication when a measured voltage is below a predetermined low voltage value. 24. The device according to claim 15, wherein said alarm circuit alerts said patient by emitting an audible signal. 25. The device according to claim 15, wherein said alarm circuit alerts said patient by emitting a visible signal. 26. The device according to claim 5, further comprising a non-volatile memory recording times at which said patient takes doses of medication when said event switch is activated, contents of said memory being accessible via said wireless link. 27. The device according to claim 26, wherein said non-volatile memory comprises an electrically erasable programmable read only memory (EEPROM). 28. The device according to claim 1, wherein a plurality of medications using at least one of the plurality of preprogrammed medication-taking regimens. 29. The device according to claim 28, wherein said event switch is further activated to view prescription information based on said pre-programmed medication-taking regimens. 30. The device according to claim 28, further comprising an alarm circuit alerting said patient at times when said patient is scheduled to take at least one of said plurality of medications. 31. The device according to claim 28, wherein prescription compliance information is generated based on said plurality of pre-programmed medication-taking regimens and said prescription compliance information is recorded. 32. The device according to claim 28, wherein at least one of said plurality of pre-programmed medication-taking regimens calculates times when said patient is scheduled to take at least one of said plurality of medication based on predetermined time intervals and a time a first dose of said medication is to be taken. 33. The device according to claim 1, further comprising an alarm circuit providing at least one of an audio, visual, voice and vibration indication. 34. The device according to claim 1, further comprising: a transmitter/receiver; and an external transmitter/receiver configured to be connected to a secondary device, said transmitter/receiver communication with said external transmitter/receiver via a wireless link to activate said secondary device to perform at least one of generating an alarm, dispensing said medication, and transmitting prescription information based on said pre-programmed medication-taking regimens to at least a third device. 35. The device according to claim 1, wherein said display comprises: a first display area which alternately displays alerts, alarms and notifications, menu selections and secondary information; a second display area which alternately displays the name of the medication, the name of the regimen and secondary information; a third display area which alternately displays the day of the week and time, and secondary information; a fourth display area which provides a special alert message and secondary information, wherein the secondary information includes at least one of the calendar date, the patient name, the patient phone number, an icon indicating the nature of the information currently displayed in the other display areas, AM, PM designations, historical data stored in the memory, codes describing displayed information, and advice on how medication is to be taken. 36. A prescription compliance device comprising: control means; program memory means for storing data representing a plurality of pre-programmed commonly prescribed medication-taking regimens; select means for selecting one of said regimens and programming said device in accordance therewith; and display means, said select means including an event switch which is activated in conjunction with a patient taking a dose of a medication corresponding to a respective medication-taking regimen for recording the taking of said medication, said event switch causing said control means to effect the display of the time at which a next dose of medication is scheduled to be taken, in accordance with the regimen selected by said select means, wherein the control means recalculates the time the next dose is to be taken based on a last time the dose of medication was taken in conjunction with a time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 37. The device according to claim 36, wherein at least one of the medication-taking regimens includes at least one of an early take window and late take window respectively allowing the patient to take the next dose of medication within medically acceptable times before and after the next dose of medication is to be taken. 38. The device according to claim 36, wherein the microcontroller recalculates the early take window and late take window based on the last time the dose of medication was taken in conjunction with the time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 39. The device according to claim 36, wherein the prescription compliance device is integrated with a cell phone or personal digital assistant (PDA). 40. The device according to claim 36, further comprising: transmitter/receiver means; and external transmitter/receiver means connected to an input device, said external transmitter/receiver communicating with said transmitter/receiver via a wireless link to select one of said regimens and program said device in accordance therewith from remote locations. 41. The device according to claim 40, wherein the time the next dose of medication may be adjusted via the remote location. 42. The device according to claim 40, wherein said input device is a personal computer. 43. The device according to claim 40, wherein said wireless link is an infrared link. 44. The device according to claim 36, further comprising: trip means for indicating how much medication is needed to be taken between a start date and an end date and whether any medications need to be renewed before the end date. 45. The device according to claim 36, further comprising: skip means for allowing the patient to skip taking the next dose of medication. 46. The device according to claim 36, wherein the device is programmed to instruct the patient to perform a task in addition to taking the next dose of medication. 47. The device according to claim 36, further comprising: log means for recording medications taken or skipped and related information input by the patient. 48. The device according to claim 36, wherein at least one of the plurality of pre-programmed medication-taking regimens causes calculation of acceptable times during which said patient is scheduled to take said medication, and wherein the calculated times are based on the following factors: 1) a preferred time of day at which the patient is to take a first dose of the medication; 2) a regimen specific predetermined interval of time between doses of the medication; and 3) a regimen specific predetermined time range during which it is medically acceptable for the patient to take the medication. 49. The device according to claim 46, further comprising: log means for recording information entered by the patient corresponding to the additional task performed. 50. The device according to claim 40, wherein said wireless link is an infrared link. 51. The device according to claim 40, wherein said input device is a personal computer. 52. The device according to claim 40, further comprising non-volatile memory means for recording times at which said patient takes doses of said medication when said event switch is activated, contents of said memory means being accessible via said wireless link. 53. The device according to claim 52, wherein said non-volatile memory means comprises an electrically erasable programmable read only memory (EEPROM). 54. The device according to claim 36, wherein said event switch is activated to scan through regimen and programming options, and wherein said select means further includes: a reset button for rendering said device on and off; and a function button for selecting an appropriate regimen and programming options. 55. The device according to claim 54, wherein each of said regimens dictates the times at which said medication is to be taken daily or events during which said medication is to be taken, and wherein said programming options include: a time of day at which the first dose of medication is to be taken or designation of default times in accordance with a selected regimen. 56. A device according to claim 55, wherein said programming options further include: said patient's specified times for said events; and a number of doses in a prescription. 57. A device according to claim 36, wherein said display means comprises: a first display area displaying a name of the medication; a second display area displaying a day of the week on which a next dose of said medication is to be taken; a third display area displaying the time or event during which the next dose of said medication is to be taken; a fourth display area displaying the time at which a next dose of said medication is to be taken; and a fifth display area displaying an icon indicating the nature of the information currently displayed in said first through fourth display areas. 58. The device according to claim 57, wherein said third display area further displays the current time. 59. The device according to claim 58, wherein said third display area further displays the number of doses remaining in a prescription. 60. The device according to claim 36, wherein said display means comprises a liquid crystal display. 61. The device according to claim 36, further comprising alarm means for alerting said patient at times when said patient is scheduled to take a dose of said medication. 62. The device according to claim 36, wherein said control means causes said display means to display a low battery indication when a measured voltage is below a predetermined low voltage value. 63. The device according to claim 61, wherein said alarm means alerts said patient by emitting an audible signal. 64. The device according to claim 61, wherein said alarm means alerts said patient by emitting a visible signal. 65. The device according to claim 36, wherein said display means comprises: a first display area which alternately displays alerts, alarms and notifications, menu selections and secondary information; a second display area which alternately displays the name of the medication, the name of the regimen and secondary information; a third display area which alternately displays the day of the week and time, and secondary information; a fourth display area which provides a special alert message and secondary information, wherein the secondary information includes at least one of the calendar date, the patient name, the patient phone number, an icon indicating the nature of the information currently displayed in the other display areas, AM, PM designations, historical data stored in the memory, codes describing displayed information, and advice on how medication is to be taken. 66. A method of operating a prescription compliance device, comprising the steps of: (a) switching said device to a setup state; (b) programming the current time into said device; (c) selecting one of a plurality of pre-programmed commonly prescribed medication-taking regimens; (d) programming a time of day a first dose of medication is to be taken in accordance with the selected regimen; (e) switching said device from a setup state to an operation state; (f) indicating to said device that a dose of medication has been taken; and (g) recalculating the time the next dose is to be taken based on a last time the dose of medication was taken in conjunction with a time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 67. The method according to claim 66, wherein at least one of the medication-taking regimens includes at least one of an early take window and late take window respectively allowing the patient to take the next dose of medication within medically acceptable times before and after the next dose of medication is to be taken. 68. The method according to claim 66, wherein said step (g) recalculates the early take window and late take window based on the last time the dose of medication was taken in conjunction with the time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 69. The method according to claim 66, wherein the prescription compliance device is integrated with a cell phone or personal digital assistant (PDA). 70. The method according to claim 66, further comprising the step of: communicating with a transmitter/receiver of the device via a wireless link to select one of said regimens and program said device in accordance therewith from remote locations. 71. The method according to claim 70, wherein the time the next dose of medication may be adjusted via the remote location. 72. The method according to claim 70, wherein said input device is a personal computer. 73. The method according to claim 70, wherein said wireless link is an infrared link. 74. The method according to claim 66, further comprising the step of: indicating how much medication is needed to be taken between a start date and an end date and whether any medications need to be renewed before the end date. 75. The method according to claim 66, further comprising the step of: allowing the patient to skip taking the next dose of medication. 76. The method according to claim 66, further comprising the step of: instructing the patient to perform a task in addition to taking the next dose of medication. 77. The method according to claim 66, further comprising the step of: recording medications taken or skipped and related information input by the patient. 78. The method according to claim 66, wherein at least one of the plurality of pre-programmed medication-taking regimens causes calculation of acceptable times during which said patient is scheduled to take said medication, and wherein the calculated times are based on the following factors: 1) a preferred time of day at which the patient is to take a first dose of the medication; 2) a regimen specific predetermined interval of time between doses of the medication; and 3) a regimen specific predetermined time range during which it is medically acceptable for the patient to take the medication. 79. The method according to claim 66, further comprising the steps of: (h) programming a day of the week on which said first dose of medication is to be taken; (i) programming a number of doses in a prescription; and (j) switching said device from an operation state to an off state after said prescription has been nearly exhausted. 80. The method according to claim 66, wherein said step (b) is executed by activating an event switch to scan through times as displayed on a display, and activating a selection button to select the current time when displayed. 81. The method according to claim 66, wherein said step (c) is executed by activating an event switch to scan through said pre-programmed regimens as displayed on a display, and activating a selection button to select an appropriate regimen when displayed. 82. The method according to claim 66, wherein said step (d) is executed by activating an event switch to scan through times or events as displayed on a display, and activating a selection button to select an appropriate time or event when displayed, or activating an event switch to designate pre-programmed default times in accordance with a selected regimen. 83. The method according to claim 79, wherein said step (h) is executed by activating an event switch to scan through days of the week as displayed on a display, and activating a function button to select an appropriate day when displayed. 84. The method according to claim 79, wherein said step (i) is executed by activating an event switch to scan through numbers as displayed on a display, and activating a selection button to select an appropriate number when displayed. 85. The method according to claim 66, wherein said step (e) is executed by activating an event switch after one of said regimens has been selected and said device has been programmed. 86. The method according to claim 66, wherein said step (f) is executed by activating an event switch after a dose of medication has been taken so as to cause said device to display a time at which a next dose of said medication is to be taken. 87. The method according to claim 79, wherein said steps (a)-(j) are executed by activating an input device which communicates with said prescription compliance device. 88. The method according to claim 87, wherein said input device communicates with said prescription compliance device via a wireless link. 89. The method according to claim 88, wherein said wireless link is an infrared link. 90. The method according to claim 88, further comprising the step of recording times at which doses of medication are taken when said event switch is activated. 91. The method according to claim 90, further comprising the step of accessing the recorded times via said wireless link. 92. A computer program product for operating a prescription compliance device, comprising the steps of: (a) a first computer code configured to switch said device to a setup state; (b) a second computer code configured to program the current time into said device; (c) a third computer code configured to select one of a plurality of pre-programmed commonly prescribed medication-taking regimens; (d) a fourth computer code configured to program a time of day a first dose of medication is to be taken in accordance with the selected regimen; (e) a fifth computer code configured to switch said device from a setup state to an operation state; (f) a sixth computer code configured to indicate to said device that a dose of medication has been taken; and (g) a seventh computer code configured to recalculate the time the next dose is to be taken based on a last time the dose of medication was taken in conjunction with a time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 93. The computer program product according to claim 92, wherein at least one of the medication-taking regimens includes at least one of an early take window and late take window respectively allowing the patient to take the next dose of medication within medically acceptable times before and after the next dose of medication is to be taken. 94. The computer program product according to claim 92, wherein said seventh computer code recalculates the early take window and late take window based on the last time the dose of medication was taken in conjunction with the time change of the prescription compliance device to ensure a medically acceptable minimum time interval is maintained between doses of the medication. 95. The computer program product according to claim 92, wherein the prescription compliance device is integrated with a cell phone or personal digital assistant (PDA). 96. The computer program product according to claim 92, further comprising: an eighth computer code configured to communicate with a transmitter/receiver of the device via a wireless link to select one of said regimens and program said device in accordance therewith from remote locations. 97. The computer program product according to claim 96, wherein the time the next dose of medication may be adjusted via the remote location. 98. The computer program product according to claim 96, wherein said input device is a personal computer. 99. The computer program product according to claim 96, wherein said wireless link is an infrared link. 100. The computer program product according to claim 92, further comprising: an eighth computer code configured to indicate how much medication is needed to be taken between a start date and an end date and whether any medications need to be renewed before the end date. 101. The computer program product according to claim 92, further comprising: an eighth computer code configured to allow the patient to skip taking the next dose of medication. 102. The computer program product according to claim 92, further comprising: an eighth computer code configured to indicate the patient to perform a task in addition to taking the next dose of medication. 103. The computer program product according to claim 92, further comprising: an eighth computer code configured to record medications taken or skipped and related information input by the patient. 104. The computer program product according to claim 92, wherein at least one of the plurality of pre-programmed medication-taking regimens causes calculation of acceptable times during which said patient is scheduled to take said medication, and wherein the calculated times are based on the following factors: 1) a preferred time of day at which the patient is to take a first dose of the medication; 2) a regimen specific predetermined interval of time between doses of the medication; and 3) a regimen specific predetermined time range during which it is medically acceptable for the patient to take the medication. 105. The computer program product according to claim 92, further comprising: (h) an eighth computer code configured to program a day of the week on which said first dose of medication is to be taken; (i) a ninth computer code configured to program a number of doses in a prescription; and (j) a tenth computer code configured to switch said device from an operation state to an off state after said prescription has been nearly exhausted. 106. The computer program product according to claim 92, wherein said second computer code is executed by activating an event switch to scan through times as displayed on a display, and activating a selection button to select the current time when displayed. 107. The computer program product according to claim 92, wherein said third computer code is executed by activating an event switch to scan through said pre-programmed regimens as displayed on a display, and activating a selection button to select an appropriate regimen when displayed. 108. The computer program product according to claim 92, wherein said fourth computer code is executed by activating an event switch to scan through times or events as displayed on a display, and activating a selection button to select an appropriate time or event when displayed, or activating an event switch to designate pre-programmed default times in accordance with a selected regimen. 109. The computer program product according to claim 105, wherein said eighth computer code is executed by activating an event switch to scan through days of the week as displayed on a display, and activating a function button to select an appropriate day when displayed. 110. The computer program product according to claim 105, wherein said ninth computer code is executed by activating an event switch to scan through numbers as displayed on a display, and activating a selection button to select an appropriate number when displayed. 111. The computer program product according to claim 92, wherein said fifth computer code is executed by activating an event switch after one of said regimens has been selected and said device has been programmed. 112. The computer program product according to claim 92, wherein said sixth computer code is executed by activating an event switch after a dose of medication has been taken so as to cause said device to display a time at which a next dose of said medication is to be taken. 113. The computer program product according to claim 105, wherein said first to tenth computer codes are executed by activating an input device which communicates with said prescription compliance device. 114. The computer program product according to claim 113, wherein said input device communicates with said prescription compliance device via a wireless link. 115. The method according to claim 114, wherein said wireless link is an infrared link. 116. The method according to claim 114, further comprising the step of recording times at which doses of medication are taken when said event switch is activated. 117. The method according to claim 116, further comprising an eleventh computer code configured to access the recorded times via said wireless link. |
<SOH> BACKGROUND OF THE INVENTION <EOH>1. Field of the Invention This invention relates to an apparatus which aids patients in complying with instructions given by a physician for taking prescription medication, and more particularly, to a device which is programmable in accordance with the physician's instructions or desired regimen. 2. Discussion of the Background Art A variety of devices have been proposed for recording intervals at which patients, especially those under the care of an attendant, take medication at periodic intervals prescribed by a physician. If the patient or his medical care provider ignores the proper instructions and repeats the dose too frequently or fails to administer or take medication at the proper time, the concentration of medication in the patient's body may become too high or too low. In order to ensure that medications are taken at the proper time, a variety of devices, such as the one disclosed in U.S. Pat. No. 4,361,408, have been devised to generate audible and/or visible prompting or alarm signals that remind a patient or his caretaker to administer the correct dosages at the correct time. Such devices have been complex and costly, inconvenient to program, and have not been flexible enough in establishing varying time intervals at which the medication needs to be administered. |
<SOH> SUMMARY OF THE INVENTION <EOH>Accordingly, one object of this invention is to provide a low cost, easy to use prescription compliance device that has the flexibility of operating in accordance with various different medication-taking intervals. Another object of this invention is to provide a prescription compliance device which is easily programmable either by activating a programmer on the device itself or by remotely programming the device via a wireless link. Multiple programming regimens which correspond to different medication-taking intervals and medication-types may also be programmed into the device. Yet another object of this invention is to provide a prescription compliance device which records the event of taking a dose of medication and displays the time at which the next dose of medication is to be taken. A still further object of this invention is to provide a prescription compliance device having a timer which measures the time that has elapsed since the patient last took a dose of the medication and an alarm which is activated at times when the patient is to take the next dose of medication. A further object of this invention is to provide a prescription compliance device that maintains a count of the number of doses remaining in a patient's prescription and displays the count so that a patient will know when to have the prescription refilled. Another object of this invention is to provide a prescription compliance device that alerts a patient when the patient has missed a scheduled dose of medication or has taken a dose of medication at a non-scheduled time. Yet another object of this invention is to provide a prescription compliance device which records the times at which a patient takes each dose of medication in a format that can be easily accessed. Another object of the invention is to provide a prescription compliance device which aids in the management of a multitude of medications. These and other objects are accomplished by a prescription compliance device which includes a microcontroller, a program memory which stores data representing a plurality of pre-programmed medication-taking regimens for single and multiple medications, an oscillator which controls timing functions of the device, a selector selecting one of the regimens and programming the device in accordance with the selected regimen, a display which alternately displays the current time, the time at which a next dose of medication is to be taken in accordance with the regimen selected by the selector, and the number of doses remaining in a prescription, and an alarm which alerts the patient at times when the patient is scheduled to take a dose of medication. The device may also include a memory which records the times at which a patient takes each dose of medication in a format that can be easily accessed. The selector includes an event switch which is activated by the patient after taking a dose of medication to record the taking of the medication, the event switch causing the microcontroller to effect the display of the next time at which a dose of the medication is scheduled to be taken, in accordance with the regimen selected by the selector. The event switch and a function button are provided for programming the regimens by which the medication is to be taken, the day of the week on which the first dose is to be taken, the time at which the first dose is to be taken or the designation of meals during which the first dose is to be taken, and the number of doses in a patient's prescription. Programming may be done either directly by using the function button and the event switch or remotely via a wireless link. To program from a remote location, the device is provided with a wireless transmitter/receiver and an external wireless transmitter/receiver configured to be connected to an input device. The external wireless transmitter/receiver communicates with the wireless transmitter/receiver via a wireless link to select one of the regimens and to program the device in accordance with the selected regimen. The display includes a first display area which alternately displays the alerts, alarms and notifications, menu selections and other information, a second display area which alternately displays the name of the medication the name of the regimen or other information, a third display area which alternately displays the day of the week and time in addition to other information, a fourth display area which provides special alert message in addition to other information. Further, for each of the above listed display areas, other information may include the calendar date, the patient name, the patient phone number, and icon indicating the nature of the information currently displayed in the other display areas, AM, PM designations, historical data stored in the device memory, codes describing displayed information, advise on how medications is to be taken, etc. |
6-Phenyldihydropyrrolopyrimidinedione derivatives |
6-phenylpyrrolopyrimidinedione derivatives of the formula (I), and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4 and R5 are organic residues, L1 is a spacer group and R6 is C(O) NR10R11, —S(O)2NR10R11, ?—ON═CR12R13, or a heterocyclyl, aryl? or heteroaryl group, where R10, R11, R12 and R13 are organic residues, have therapeutic potential as A2 adenosine receptor inhibitors. |
1. A 6-phenylpyrrolopyrimidinedione derivative of the formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1 and R2 are the same or different and each represents hydrogen, a group of formula —(CH2)n—R7, or an alkyl group which is unsubstituted or substituted by one or more substituents selected from hydroxy, alkoxy, alkylthio, amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy and dialkoxyphosphoryloxy groups, wherein n is an integer of from 0 to 4 and R7 represents a cycloalkyl group, a phenyl group or a cyclic group which is a 3- to 7-membered, aromatic or non-aromatic ring, which contains from 1 to 4 heteroatoms selected from N, O and S and which is optionally fused to an aromatic or heteroaromatic ring, the phenyl group being unsubstituted or substituted by one or more substituents selected from halogen, alkyl, aryl, heteroaryl, heterocyclyl, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, mono- or di-alkylamino, nitro, cyano, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydrophosphoryloxy, dialkoxyphosphoryloxy and haloalkyl groups and the cyclic group being unsubstituted or substituted by one or more substituents selected from halogen, hydroxy, alkoxy, phenyl, alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino, hydroxycarbonyl, and alkyl groups, the alkyl substituents being unsubstituted or substituted by one or more further substituents selected from halogen, hydroxy, alkoxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono- and di-alkylamino and hydroxycarbonyl groups; R3 represents hydrogen, halogen, or a nitro, alkoxycarbonyl or alkyl group, the alkyl group being unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, alkoxy, alkylthio, amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl and alkylcarbamoyl groups; R4 and R5 are the same or different and each represents hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylthio, dialkylaminoalkoxy, amino, mono- or dialkylamino, nitro, cyano or haloalkyl, or R4 and R5, together with the atoms to which they are attached, form a 5 to 7 membered ring containing from 0 to 4 heteroatoms selected from N, O and S; L1 is a direct bond or is —O—, —S—, —N(Z)-, —O(CH2)m—, —O(CR8R9)m—, —S(CR8R9)m—, —CH═CH—, —(CH2)m—, —(CR8R9)m, —(CH2)mO—, —(CR8R9)mO—, —O(CH2)mO—, —O(CR8R9)m N(Z)- or —N(Z)(CR1R9)m— wherein m is an integer of from 1 to 6 and each of Z, R8 and R9 are the same or different and each represent a group selected from hydrogen, C1-C6 alkyl, cycloalkyl, cycloalkyl-C1-C6 alkyl, heterocyclyl, heterocyclyl-C1-C6 alkyl, aryl, aryl-C1-C6 alkyl, heteroaryl, heteroaryl-C1-C6 alkyl, hydroxy, C1-C6 alkoxy, halogen, cyano, C1-C6 alkoxycarbonyl, carbamoyl and haloalkyl, the alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl moieties being unsubstituted or substituted with one to four substituents independently selected from R1, or Z is as defined above and R8 and R9, together with the atom to which they are attached, form a 4 to 8 membered ring; and R6 represents —C(O)NR10R11, —S(O)2NR10R11, —ON═CR2R3, or a heterocyclyl, aryl or heteroaryl group, the heterocyclyl, aryl and heteroaryl groups being unsubstituted or substituted with substituents R14 to R7, wherein: R10 and R11 are either (a) the same or different, each independently representing hydrogen, an alkyl group, a cycloalkyl group or a phenyl group, wherein (i) the alkyl group is unsubstituted or substituted by one or more substituents selected from hydroxy, halogen, alkoxy, alkylthio, amino and mono- and di-alkylamino groups, (ii) the cycloalkyl group is optionally fused to an aromatic ring and (iii) the cycloalkyl group and the phenyl group are unsubstituted or substituted by one or more substituents selected from (1) groups of formula —(CH2)nR7, —O—(CH2)nR7, —S—(CH2)nR7, —COR and —CONHR, wherein R is alkyl or —(CH2)nR7 and n and R7 are as defined above, (2) groups of formula —(CH2), —S(O)2NR′R″ wherein n is as defined above and R′ and R″ are the same or different and are each selected from hydrogen and alkyl or form, together with the nitrogen atom to which they are attached, a 4- to 7-membered heterocyclic ring containing 1, 2 or 3 heteroatoms selected from N, O, and S, (3) groups of formula —(CH2)n—CO2R′″ wherein n is as defined above and R′″ is hydrogen or alkyl, (4) groups of formula —N+ R″″3 wherein each R″″ is the same or different and is an alkyl group, and (5) halogen atoms and alkyl, hydroxy, alkylenedioxy, alkoxy, alkylthio, amino, mono- and di-alkylamino, nitro, cyano, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy or haloalkyl groups, the alkyl substituents being unsubstituted or substituted by one or more further substituents selected from cyano, nitro, amino, hydroxy and halogen, or (b) are taken together with the atom to which they are attached to form, a 3- to 7-membered ring comprising up to 4 heteroatoms selected from N, O and S, which ring is (i) optionally fused to an aromatic ring or to a heteroaromatic ring which is in turn optionally fused to an aromatic ring and is (ii) unsubstituted or substituted by one or more substituents independently selected from halogen atoms, groups of formula —X—R7 and —CO2—X—R7 wherein X is a direct bond, a C1-C4 alkylene group or a carbonyl group and R7 is as defined above, and hydroxy, cyano, nitro, oxoalkyl, carbamoyl, hydroxycarbonyl, alkoxycarbonyl, amino, mono- and di-alkylamino, divalent alkylene and alkyl groups, the alkyl substituents being unsubstituted or substituted by one or more further substituents selected from hydroxy, alkoxy, hydroxyalkoxy, amino and mono- and di-alkylamino groups, and the moiety X being unsubstituted or substituted by one or two further substituents selected from phenyl, alkyl, hydroxy and thio groups and groups of formula —CO2R′ and —CONR′R″ wherein R′ and R″ are the same or different and are hydrogen or alkyl, or (c) are defined so that R10 represents hydrogen or an alkyl group and R11 represents a group of formula —X—R7 wherein X and R7 are as defined above; R12 and R13 are defined as R10 and R11 above, except that either or both of R12 and R13 can be an amino, alkylamino or dialkylamino group; and R14 to R17 are the same or different and each independently represents hydrogen, a halogen atom, a group of formula —(CH2)n—R7, wherein n and R7 are as defined above or an alkyl group, the alkyl group being unsubstituted or substituted by one or more substituents selected from hydroxy, alkoxy, alkylthio, amino, mono- or di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy and haloalkyl groups, or R14 and R15 are as defined above and R16 and R17, together with the atoms to which they are attached, form a 4 to 8 membered aromatic or non-aromatic ring which contains from 0 to 4 heteroatoms selected from N, O and S, and which is unsubstituted or substituted by one or more substituents selected from halogen atoms and alkyl, hydroxy, phenyl, alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino and hydroxycarbonyl groups, the alkyl substituents being unsubstituted or substituted by one or more further substituents selected from halogen atoms and hydroxy, alkoxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono- or di-alkylamino and hydroxycarbonyl groups. 2. A compound according to claim 1, wherein R1 and R2 are the same or different and each independently represent hydrogen, a C1-C4 alkyl group which is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkoxy and C1-C4 alkylthio substituents, a group of formula —(CH2)n—(C3-C6 cycloalkyl) or a group of formula —(CH2)n-(morpholino) wherein n is as defined above in claim 1. 3. A compound according to claim 1, wherein R3 represents hydrogen, halogen or C1-C4 haloalkyl. 4. A compound according to claim 1, wherein R4 and R5 are the same or different and each represent hydrogen, C1-C6 alkyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, amino or C1-C6 alkylamino. 5. A compound according to claim 1, wherein Z, R8 and R9 are hydrogen, C1-C6 alkyl, or phenyl. 6. A compound according to claim 1, wherein L1 is —O(CH2)m—, —O(CR8R9)m—, CH═CH, (CH2)m—, —(CR8R9)m—, —(CH2)mO—, —(CR8R9)mO—, —O(CH2)mO— or —(CR8R9)m N(Z)-, wherein m is from 1 to 4 and R8, R9 and Z are as defined in claim 1. 7. A compound according to claim 1, wherein R12 and R13 are the same or different and each represent amino, mono- or di-(C1-C4 alkyl)amino or phenyl, the phenyl group being unsubstituted or substituted by one or two substituents selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, hydroxy, amino mono-(C1-C4 alkyl)amino and C1-C4 haloalkyl. 8. A compound according to claim 1, wherein R7 is: a C3-C6 cycloalkyl group; or a phenyl group which is unsubstituted or substituted with 1, 2 or 3 substituents selected from halogen, C1-C4 alkyl, aryl, heteroaryl, hydroxy, C1-C4 alkylenedioxy, C1-C4 alkoxy, C1-C4 alkylthio, amino, mono- and di-(C1-C4 alkyl)amino, nitro, cyano, hydroxycarbonyl, (C1-C4 alkoxy)carbonyl, (C2-C7 acyl)amino, carbamoyl, (C1-C4 alkyl)carbamoyl, dihydrophosphoryloxy, di-(C1-C4 alkoxy)phosphoryloxy and C1-C4 haloalkyl groups; or a cyclic group which is a 3- to 7-membered aromatic or non-aromatic ring containing from 1 to 4 heteroatoms selected from N, O and S and which is optionally fused to an aromatic ring, which group is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, hydroxy, C1-C4 alkoxy, phenyl, C1-C4 alkoxycarbonyl, amino, mono-(C1-C4 alkyl)amino, di-(C1-C4 alkyl)amino, hydroxycarbonyl and C1-C4 alkyl groups, the alkyl substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, C2-C7 acylamino, carbamoyl, C1-C4 alkylcarbamoyl, dihydroxyphosphoryloxy, di-(C I—C4 alkoxy)phosphoryloxy, hydroxy-(C1-C4 alkoxy)-, phenyl, C1-C4 alkoxycarbonyl, amino, mono- and di-(C1-C4 alkyl)amino and hydroxycarbonyl groups. 9. A compound according to claim 8, wherein the cyclic group is a 5- or 6-membered aromatic or non-aromatic ring containing 1 or 2 heteroatoms selected from N, O and S. 10. A compound according to claim 9, wherein the substituents on the cyclic group are selected from halogen, hydroxy, phenyl, C1-C4 alkoxy, amino, mono- and di-(C1-C4 alkyl)amino, C1-C4 alkyl, C1-C4 haloalkyl, hydroxy-(C1-C4 alkyl)- and phenyl-(C1-C4 alkyl)-. 11. A compound according to claim 8, wherein, R7 is a phenyl group, which is unsubstituted or substituted by 1 or 2 substituents selected from halogen, C1-C4 alkyl, phenyl, hydroxy, C1-C4 alkoxy, C1-C4 alkylthio, amino, mono- and di-(C1-C4 alkyl)amino and C1-C4 haloalkyl groups. 12. A compound according to claim 1, wherein, when the moiety X is substituted, R7 is a phenyl group as defined in claim 1. 13. A compound according to claim 1, wherein, when R10 and R11 are defined according to option (a), they are the same or different and each represent hydrogen, a C1-C6 alkyl group, a phenyl group or a C5-C6 cycloalkyl group optionally fused to a phenyl ring, the alkyl group being unsubstituted or substituted by 1 or 2 substituents selected from hydroxy, halogen and amino groups and the phenyl and cycloalkyl groups being unsubstituted or substituted by 1, 2 or 3 substituents selected from (1) groups of formula —(CH2)nR7, —O—(CH2)n—R7, —COR and —CONHR wherein R is C1-C4 alkyl or —(CH2)nR7, n is 0, 1 or 2 and R7 is as defined in claim 1, (2) groups of formula —(CH2)n—S(O)2—NR′R″, wherein n is 0 or 1 and R′ and R″ are the same or different and are hydrogen or C1-C4 alkyl or, together with the N atom to which they are attached, form a pyrrolidinyl or piperidyl ring, (3) groups of formula —(CH2)n—CO2R′″ wherein n is 1 or 2 and R′″ is hydrogen or C1-C4 alkyl, (4) groups of formula —N+R″″3 wherein each R″″ is the same or different and is a C1-C4 alkyl group, and (5) halogen atoms and C1-C4 alkyl, hydroxy, C1-C4 alkoxy, amino, mono- and di-(C1-C4 alkyl)amino, nitro, cyano, hydroxycarbonyl, C1-C4 alkoxycarbonyl, (C3 to C5 acyl)amino, carbamoyl and C1-C4 haloalkyl groups, the alkyl substituents being unsubstituted or substituted by a further substituent selected from cyano, nitro, amino, hydroxy and halogen. 14. A compound according to claim 1, wherein when R10 and R11 are defined according to option (b), they form, together with the nitrogen atom to which they are attached to form, an aromatic or non-aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms selected from N, O and S, which ring is optionally fused to a phenyl ring or to an indole group, and is unsubstituted or substituted by 1, 2 or 3 substituents independently selected from halogen atoms, groups of formula —X—R7 and —CO2—X—R7 wherein X and R7 are as defined in claim 1 and hydroxy, cyano, nitro, C1-C4 alkoxycarbonyl, amino, C1-C2 divalent alkylene and C1-C4 alkyl groups. 15. A compound according to claim 1, wherein when R10 and R11 are as defined in option (c), R10 is hydrogen or a C1-C4 alkyl group and R11 is a group of formula —X—R7 wherein: X is a direct bond, a C1-C4 alkylene group or a carbonyl group, wherein the C1-C4 alkylene group is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, hydroxy, —CO2H and —CO2—(C1-C4 alkyl) groups; and R7 is a cyclopentyl, cyclohexyl, benzimidazolyl, benzothiazolyl, thiadiazolyl, thienyl, pyrimidinyl, pyrazinyl, isoxaolyl, pyrazolyl, furanyl, pyridyl, pyrimidinyl, phenyl or piperidinyl group, the pyridyl, pyrimidinyl, piperidinyl, thiadiazolyl and furanyl groups being unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms and hydroxy, C1-C4 alkoxy, phenyl-(C1-C4 alkyl)- and C1-C4 alkyl groups and the phenyl, benzothiazolyl and benzimidazolyl groups being unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms and hydroxy, C1-C4 alkoxy and C1-C4 alkyl groups, provided that when X is substituted, R7 is an unsubstituted phenyl group. 16. A compound according to claim 1, wherein R14 to R17 are the same or different and each independently represent hydrogen, a halogen atom, a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms selected from N, O and S, a C1-C4 alkyl group or a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms, C1-C4 alkyl groups and C1-C4 haloalkyl groups, or R14 and R15 are as defined above and R16 and R17, together with the atoms to which they are attached, form a 5- or 6-membered aromatic or non-aromatic ring which contains 0, 1 or 2 heteroatoms selected from N, O and S and which is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, phenyl and phenyl-(C1-C4 alkyl)-groups. 17. A compound according to claim 1, wherein R6 represents —C(O)NR10R11, wherein R10 and R11 are as defined in claim 1, —ON═CR12R13, wherein R12 and R13 are as defined in claim 1, a phenyl group or a 5- or 6-membered heteroaryl or heterocyclyl group, which group contains 1, 2 or 3 heteroatoms selected from N, O and S, wherein the phenyl, heteroaryl or heterocyclyl group is unsubstituted or substituted with substituents R14 to R17, as defined in claim 1. 18. A compound according to claim 17, wherein the heteroaryl or heterocyclyl group is a 6-membered heteroaryl group having 1 or 2 heteroatoms selected from N, O and S, or a group of formula (H) wherein X represents O, S or N, and the moiety represents —N═C(R18)—, —C(R18)═N—, —C(R18)═C(R19)—, or —CH(R18)—CH(R19)—, wherein R18 and R19 are the same or different and each represent hydrogen, a group of formula —(CH2)n—R7, wherein n and R7 are as defined in claim 1, or an alkyl group, the alkyl group being unsubstituted or substituted by one or more substituents selected from hydroxy, alkoxy, alkylthio, amino, mono- and di-alkylamino, hydroxycarbonyl, alkoxycarbonyl, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy and haloalkyl groups, or R18 and R19, together with the atoms to which they are attached, form a 4- to 8-membered aromatic or non-aromatic ring, which contains from 0 to 4 heteroatoms selected from N, O and S and which is unsubstituted or substituted by one or more substituents selected from halogen atoms and alkyl, hydroxy, phenyl, alkoxycarbonyl, amino, mono-alkylamino, di-alkylamino and hydroxycarbonyl groups, the alkyl substituents being unsubstituted or substituted by one or more further substituents selected from halogen atoms and hydroxy, alkoxy, alkylthio, acylamino, carbamoyl, alkylcarbamoyl, dihydroxyphosphoryloxy, dialkoxyphosphoryloxy, hydroxyalkoxy, phenyl, alkoxycarbonyl, amino, mono- and di-alkylamino and hydroxycarbonyl groups. 19. A compound according to claim 18, wherein R18 and R19 are the same or different and each independently represent hydrogen, a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms selected from N, O and S, a C1-C4 alkyl group or a phenyl group which is unsubstituted or substituted by 1 or 2 substituents selected from halogen atoms, C1-C4 alkyl groups and C1-C4 haloalkyl groups, or R18 and R19, together with the atoms to which they are attached, form a 5- or 6-membered aromatic or non-aromatic ring which contains 0, 1 or 2 heteroatoms selected from N, O and S and which is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4 alkyl, phenyl and phenyl-(C1-C4 alkyl)-substituents. 20. A compound according to claim 17, wherein R6 represents —C(O)NR10R11, wherein R10 and R11 are as defined in claim 1, —ON═CR12R13 wherein R12 and R13 are as defined in claim 1, a phenyl group optionally substituted by a halogen atom or a 5- or 6-membered heteroaryl or heterocyclyl group which is optionally fused to a phenyl ring and which is unsubstituted or substituted by 1 or 2 substituents selected from phenyl, pyridyl, phenyl-(C1-C4 alkyl)-, C1-C4 alkyl and piperidylidene substituents, the phenyl substituents being unsubstituted or substituted by 1 or 2 further substituents selected from halogen atoms and C1-C4 alkyl groups and the piperidylidene substituents being unsubstituted or substituted by 1 or 2 further substituents selected from phenyl, phenyl-(C1-C4 alkyl)- and C1-C4 alkyl groups. 21. (canceled) 22. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. 23. A method of reducing or preventing mast cell degranulation in a subject in need of such treatment, which method comprises administering to the said subject an effective amount of a compound according to claim 1. 24. A method according to claim 23, wherein the subject is suffering from or susceptible to a disorder which is asthma, bronchoconstriction, allergic potentiation, inflammation or reperfusion injury, myocardial ischemia, inflammation, a diarrheal disease, brain arteriole diameter constriction, Parkinson's disease, non insulin dependent diabetes mellitus, release of allergic mediators or an autoimmune disease. 25. A method according to claim 24, wherein the autoimmune disease is Addison's disease, autoimmune hemolytic anemia, Crohn's disease, Goodpasture's syndrome, Grave's disease, Hashimoto's thyroiditis, idiopathic thrombocytopinic purpura, insulin-dependent diabetes mellitus, multiple sclerosis, myasthenia gravis, pemphigus vulgaris, pernicious anemia, poststreptococcal glomerulonephritis, psoriasis, rheumatoid arthritis, scleroderma, Sjogren's syndrome, spontaneous infertility, and systemic lupus erythematosus. 26. A method according to claim 25, wherein the said allergic potentiation is an allergic reaction. 27. A method according to claim 26, wherein the allergic reaction is rhinitis, a poison ivy induced allergic response or urticaria. 28. A method according to claim 24, wherein the reperfusion injury is myocardial reperfusion injury and/or the inflammation is inflammatory bowel disease. 29 and 30. (canceled) |
Synthesis of oligomeric epicatechin and catechin-derived procyanidins |
Various processes are disclosed for preparing procyanidin oligomers having (4,8)-interflavan linkages. In an improved process, a tetra-O-protected-epicatechin or catechin monomer or oligomer is coupled with a protected, C-4 alkoxy-activated-epicatechin or -catechin monomer in the presence of an acidic clay instead of a Lewis acid. In a second process, a 5,7,3′,4′-tetra-O-protected or preferably penta-O-protected-epicatechin or -catechin monomer or oligomer is reacted with a tetra-O-protected or preferably penta-O-protected-epicatechin or -catechin monomer having a thio activating group at the C-4 position; the coupling is carried out in the presence of silver tetrafluoroborate. In third process, two molecules of a penta-O-protected-epicatechin or -catechin monomer activated with a 2-(benzothiazolyl)thio group at the C-4 position are self-condensed in the presence of silver tetrafluoroborate. An improved two-step process for preparing a C-4 alkoxy activated tetra-O-benzyl-protected, 8-bromo-blocked-epicatechin or -catechin monomer is also provided. The use of naturally-derived and synthetically-prepared procyanidin (4β,8)4-pentamers to treat cancer is also disclosed. |
1. A process for preparing a mixture of a 5,7,3′,4′-tetra-O-protected procyanidin (4,8)-dimer and other (4,8) oligomers comprising the step of coupling a 5,7,3′,4′-tetra-O-protected-epicatechin or -catechin monomer with a 5,7,3′,4′-tetra-O-protected-4-alkoxy-epicatechin or -catechin monomer in the presence of an acidic clay. 2. The process of claim 1, wherein the procyanidin dimer is selected from the group consisting of epicatechin-(4β,8)-epicatechin, epicatechin-(4β,8)-catechin, catechin-(4α,8)-catechin, catechin-(4β,8)-catechin, catechin-(4α,8)-epicatechin, and catechin-(4β,8)-epicatechin. 3. A process for preparing a mixture of 5,7,3′,4′-tetra-O-protected procyanidin (4,8)-oligomers comprising the step of coupling a 5,7,3′,4′-tetra-O-protected-epicatechin or -catechin (4,8)-dimer or higher oligomer with a 5,7,3′,4′-tetra-O-protected-4-alkoxy-epicatechin or -catechin monomer in the presence of an acidic clay. 4. The process of claim 1 or 3, wherein the protecting groups are groups which do not deactivate the A ring of the protected monomer, dimer, or oligomer; wherein the 4-alkoxy group is a C2-C6 alkoxy group having a terminal hydroxy group; and wherein the acidic clay is a montmorillonite clay. 5. The process of claim 4, wherein the protecting group are benzyl groups; wherein the C2-C6 alkoxy group having the terminal hydroxyl group is a 2-hydroxyethoxy group and wherein the montmorillonite clay is a Bentonite clay. 6. The process of claim 1, wherein the monomers are 5,7,3′,4′-tetra-O-benzylepicatechin and 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin and the mixture comprises 5,7,3′,4′-tetra-O-benzyl epicatechin (4β,8)-dimer and 5,7,3′,4′-tetra-O-epicatechin (4β,8)2-trimer. 7. The process of claim 3, wherein the dimer is 5,7,3′,4′-tetra-O-benzylepicatechin (4β,8)-dimer, the monomer is 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin, and the mixture comprises 5,7,3′,4′-tetra-O-benzyl epicatechin, (4β,8)2-trimer and (4β,8)3-tetramer. 8. The process of claim 1 or 3, further comprising the steps of separating the protected monomer(s) and protected dimer or higher oligomer by column chromatography and replacing the protecting groups on the dimer or oligomer with hydrogen. 9. A process for preparing a mixture of tetra-O-protected or penta-O-protected (4β,8)-procyandins comprising reacting a protected monomer selected from the group consisting of a tetra-O-protected-epicatechin or -catechin monomer and a penta-O-protected-epicatechin or -catechin monomer with a C-4 thio activated, protected monomer selected from the group consisting of a 4-thio-tetra-O-protected-epicatechin or -catechin monomer and a 4-thio-penta-O-protected-epicatechin -catechin monomer in the presence of silver tetrafluoroborate or an acidic clay. 10. The process of claim 9, wherein the tetra-O-protected-epicatechin monomer is 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin; wherein the penta-O-protected-epicatechin or -catechin monomer is 3-O-acetyl-5,7,3′,4′-tetra-O-benzyl-epicatechin; wherein the 4-thio-tetra-O-protected-epicatechin or -catechin monomer is 4-benzythio- or 4-2-(benzothiazolyl) thio-epicatechin or -catechin; and wherein the 4-thio-penta-O-protected-epicatechin or -catechin monomer is 3-O-acetyl-4-benzylthio-epicatechin or -catechin or 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin. 11. The process of claim 9, wherein the protected monomer is the 3,5,7,3′,4′-penta-O-benzyl-epicatechin and wherein the activated, protected monomer is the 3-O-acetyl-4-(2-benzothiazolyl)thio-3,5,7,3′,4′-penta-O-benzyl-epicatechin. 12. The process of claim 9, further comprising the steps of isolating the protected oligomers by reverse phase high pressure liquid chromatography and removing the acetyl and/or benzyl protecting groups. 13. 4-[(2-Benzothiazolyl)thio]-5,7,3′,4′-tetra-O-benzylepicatechin or 4-[(2-benzothiazolyl)thio]-5,7,3′,4′-tetra-O-benzylcatechin. 14. A process for preparing the compounds of claim 13 comprising reacting 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin or 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)catechin with an organoaluminum thiolate generated from 2-mercaotivenzothiazole and trimethylaluminum. 15. 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3′,4′-tetra-O-benzylepicatechin or 3-O-acetyl-4-[(2-benzothiazolyl)thio]-5,7,3′,4′-tetra-O-benzylcatechin. 16. A process for preparing the compounds of claim 15 comprising reacting 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin or 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)catechin with an organoaluminum thiolate generated from 2-mercaptobenzothiazole and trimethylaluminum. 17. A process for preparing a procyanidin (4,8) dimer digallate comprising the steps of: (a) coupling a 5,7,3′,4′-tetra-O-protected-epicatechin or -catechin monomer with an activated 5,7,3′,4′-tetra-O-protected-4-alkoxy-epicatechin or -catechin monomer in the presence of an acidic clay; (b) separating the protected (4,8) procyanidin dimer from the other protected (4,8) procyanidin oligomers by column chromatography; and (c) esterifying the protected (4,8) procyanidin dimer with a hydroxyl-protected gallic acid or activated gallic acid. 18. The process of claim 17, wherein the protected monomer is 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin; wherein the activated monomer is 5,7,3′,4′-tetra-O-benzyl-4-(2-hydroxyethoxy)-epicatechin or -catechin; wherein the acidic clay is a montmorillomite clay; and wherein the hydroxyl-protected activated gallic acid is tri-O-galloyl chloride. 19. The process of claim 17, wherein the procyanidin dimer digallate is selected from the group consisting of epicatechin-(4β,8)-epicatechin digallate, epicatechin-(4β,8)-catechin digallate, catechin (4α,8)-catechin digallate, catechin-(4β,8)-catechin digallate, catechin (4α,8)-epicatechin digallate, and catechin (4β,8)-epicatechin digallate. 20. A process for preparing a C-4-alkoxy-5,7,3′,4′-tetra-O-benzyl-8-bromo-epicatechin or -catechin comprising the steps of activating the C-4 position of 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin by introducing an alkoxy group and blocking the C-8 position by introducing a bromo group. 21. The process of claim 20, wherein the 4-alkoxy group is 2-hydroxyethoxy, wherein the activating step is carried out before the blocking step; and wherein the blocking step is carried out with N-bromosuccinimide in methylene chloride at −40° C. 22. The process of claim 20, wherein the 4-alkoxy group is 2-hydroxyethoxy; wherein the blocking step is carried out before the activating step; and wherein the blocking step is carried out with N-bromosuccinimide in methylene chloride at −40° C. 23. A method of treating breast cancer in a mammal in need of such treatment, which treatment inhibits cancer cell growth through cell cycle arrest in the Go/G1 phase and comprises administering to the mammal epicatechin(4β,8)4-pentamer. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Condensed tannins (proanthocyanidins) are widespread in the plant kingdom, form part of the human diet, and display multiple biological activities that render them significant to health. Procyanidins have attracted a great deal of recent attention in the fields of nutrition, medicine and health due to their wide range of potentially significant biological activities. There is a growing body of evidence suggesting that these compounds act as potent antioxidants in vitro, ex vivo and in vivo and may thus alter the pathophysiology of imbalances or perturbations of free radical and/or oxidatively driven processes in many diseases or directly interfere with many cellular processes. See Nijveldt, R. J. et al., Am. J. Clin. Nutr. 2001, 74, 418. Initial observations also have shown that procyanidin-rich fractions extracted from defatted cocoa beans elicited in vitro growth inhibition in several human cancer cell lines. See U.S. Pat. No. 5,554.645 issued Sep. 10, 1996 to L. J. Romanczyk, Jr. et al., the disclosure of which is incorporated by reference. Isolation, separation, purification, and identification methods have been established for the recovery of a range of procyanidin oligomers for comparative in vitro and in vivo assessment of biological activities, and currently some oligomers can be synthesized using time-consuming methods. For instance, previous attempts to couple monomeric units in free phenolic form using mineral acid as the catalyst in aqueous media have met with limited success. The yields were low, the reactions proceeded with poor selectivity, and the oligomers were difficult to isolate. See Steynberg, P. J., et al., Tetrahedron, 1998, 54, 8153-8158. An overview of the shortcomings is set out below. The benzylated monomer was prepared from the free monomer using benzyl bromide in combination with potassium carbonate (K 2 CO 3 ) and dimethyl formamide (DMF). See Kawamoto, H. et al., Mokuzai Gakkashi, 1991, 37, 741-747. The yield, however, was only about 40%. In addition, competing C-benzylation leads to a mixture of products, which make isolation of the benzyl-protected target monomer more difficult. Also, partial racemization of (+)-catechin at both the C-2 and C-3 positions was observed (see Pierre, M.-C. et al., Tetrahedron Letters, 1997, 38, 5639-5642). Two primary methods for oxidative functionalization are taught in the literature. See Betts, M. J. et al., J Chem. Soc., C, 1969, 1178 and Steenkamp, J. A., et al., Tetrahedron Lett., 1985 , 3045 -3048. In the older method, protected (+)-catechin was treated with lead tetraacetate (LTA) in benzene to produce the 4β-acetoxy derivative which was then successfully hydrolyzed to the 3,4-diol. Flavan-3,4-diols are incipient electrophiles in the biomimetic synthesis of procyanidins. The major drawback in the oxidative functionalization of the prochiral benzylic position was a low yield (30-36%) of the acetate during the lead tetraacetate (LTA) oxidation. The more recent method of oxidatively functionalizing the C-4 position relies on the use of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). In this method, the protected monomer was treated with DDQ in methanol. This allows introduction of a methoxyl group at the C-4 position in a stereoselective manner. The yield was about 40-50% There are a number of reports on the coupling reaction between monomers and their 3,4-diols in aqueous acid. These methods are unsatisfactory because of low yields, lack of selectivity, and difficulty in the purification from aqueous media. See Kawamoto, H. et al., J. Wood Chem. Technol., 1989, 9, 35-52 who report the titanium tetrachloride (TiCl 4 ) mediated coupling between 4-hydroxy-tetra-O-benzyl-(+)-catechin and 5 equivalents (eq.) of tetra-O-benzyl-(+)-catechin to produce a 3:2 mixture of 4α,8 and 4β,8 catechin dimers. This coupling leads to the 4β,8-dimer together with higher oligomers in yields that decrease with the increasing molecular mass of the oligomer. Using a 2,3-cis-3,4-trans-flavan-3,4-diol, procyanidins B 2 and B 5 derivatives were synthesized. The diol was prepared by the acyloxylation of the C-4 benzylic function of a (−)-epicatechin tetramethyl ether with lead tetraacetate in a benzene solution. This oxidative functionalization of the C-4 position of the methyl-protected epicatechin monomer was improved by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) in methanol to introduce a methoxyl group at the C-4 position. The protected C-4 methoxy monomer was used in the synthesis of 4,8-linked linear procyanidin oligomers up to the trimers. See Steenkamp et al., Tetrahedron. Lett. 1985, 26, 3045-3048. Procyanidin oligomers were prepared using a protected epicatechin or catechin monomer having, as a C-4 substituent, a C 2 -C 6 alkoxy group having a terminal hydroxy group such as a 2-hydroxyethoxy group. The protecting groups used are those that do not deactivate the A ring of the monomer, e.g., benzyl protecting groups. See Kozikowski, A. P. et al. J. Org. Chem. 2000, 65, 5371-5381 and U.S. Pat. No. 6,207,842 (issued Mar. 27, 2001 to Romanczyk, L. J. et al.). The C-4 derivatized, protected monomer was coupled with a protected catechin monomer or protected epicatechin monomer to form a protected 4,8-dimer which was then deprotected or used for further coupling with another protected, C-4 derivatized epicatechin monomer to form protected higher 4,8-oligomers. If a 4,6-linkage was desired, the C-8 position of the protected catechin or epicatechin monomer was blocked with a halogen group prior to coupling with the C-4 derivatized, protected epicatechin monomer or oligomer. Higher oligomers having both 4,8- and 4,6-linkages were also prepared. The protected dimers or oligomers were deprotected, and if necessary, deblocked. The coupling was carried out in the presence of a protic acid or a Lewis acid such as titanium tetrachloride (TiCl 4 ). The stereochemical nature of the interflavan bond was confirmed by the synthesis of a specifically protected derivative and its subsequent degradation reference. Unfortunately, titanium tetrachloride-mediated further chain extension of the epicatechin dimer leads to the formation of regioisomers. This is a serious drawback, not only in terms of yield, but also purity. Even though the 4β,8-trimers and 4β,8-tetramers were isolated in pure form, the same cannot automatically be expected for the larger oligomers, for which the number of possible isomers, and thus contaminants, grows rapidly. One potential way of dealing with this problem is to carefully purify the chain-extended oligomer after each step in order to ensure that all chain-extended oligomers are at least derived from a single isomer of the starting oligomer. However, upon the titanium tetrachloride-mediated chain extension of the protected trimer (2 eq.) with the C-4 derivatized, protected monomer, not only were the protected tetramer, pentamer, and small amounts of higher oligomers formed, but the protected trimer was degraded to the monomer and dimer, which then participated in the chain-extension reaction, giving rise to regioisomeric oligomers such as small amounts of the protected 4β,6:4β,8-trimer. While the reaction conditions (methylene chloride/tetrahydrofuran (9:11), 0° C., 15 min, then room temperature, 140 min) were not optimized, the observation of this deleterious aide reaction warranted a search for a better synthetic approach. Thus, there is a need for improved methods for synthesizing epicatechin oligomers, particularly the higher oligomers, and a process for using protected larger epicatechin oligomers as building blocks for chain extension to even larger oligomers. |
<SOH> SUMMARY OF THE INVENTION <EOH>In one embodiment, bis(5,7,3′,4′-tetra-O-protected) -epicatechin or -catechin (4,8)-dimer and higher (4,8)-oligomers are prepared by coupling a (5,7,3′,4′-tetra-O-protected)-epicatechin or -catechin monomer with a 5,7,3′,4′-tetra-O-protected-4-(alkoxy)-epicatechin or -catechin monomer in the presence of an acidic clay. The protecting groups used should not deactivate the A ring of the protected monomers or the A ring of the upper unit (i.e., mer) of the protected oligomers. The preferred protecting groups are benzyl groups. A suitable 4-alkoxyl group is a C 2 -C 6 alkoxyl group having a terminal hydroxyl group, preferably 2-hydroxyethoxy. When the monomers are benzyl-protected, the protected epicatechin (4β,8)-dimer is produced in significantly increased yields. Under the same conditions, the benzyl-protected epicatechin (4,8)-trimer, -tetramer, and -pentamer are obtained regioselectively from the next lower 5,7,3′,4′-tetra-O-benzyl)epicatechin and/or catechin (4,8)-oligomer. The preferred acidic clay is a montmorillonite clay. The protected monomers and protected oligomers are separated by column chromatography, and then the protecting groups are replaced with hydrogen. A process is also provided for chain extending a tetra-O-benzyl-protected-epicatechin or -catechin monomers or oligomers with a tetra-O-benzyl-protected -epicatechin or -catechin monomer having a thiol C-4 activating group. The C-4 activated monomer is prepared by reacting a C-4 activated, tetra-O-protected-epicatechin or -catechin monomer (e.g. 5,7,3′, 4′-tetra-O-benzyl-4-(2-hydroxyethoxy)epicatechin with a thiol derivatizing reagent such an organoaluminum thiolate generated from 2-mercaptobenzothiazole or other heterocyclic thiol, e.g., 2-pyridinethiol, 4-pyridinethiol, or 4-phenyl-1H-tetrazole-5-thiol. Preferably, to avoid the undesired intervention of the C-3 hydroxyl group, this group is protected in both the electrophilic and nucleophilic reaction partners by acetylation. The acetylation is carried out after the tetra-O-benzyl protected monomer is activated by introduction of the 4-thio group. The chain extension is carried out in the presence of dimethy(methythio)sulfonium tetrafluoroborate or preferably silver tetrafluoraborate. Preferably, the silver tetrafluoroborate is dried before the reaction. More preferably the drying is vacuum drying carried out immediately before the reaction. The resulting mixture comprises protected trimers through protected octamers. The protected oligomers are isolated by reverse phase high pressure liquid chromatography. If present, the acetyl protecting group(s) are removed, preferably with aqueous tetra-n-butyl ammonium hydroxide. The benzyl protecting groups are removed by hydrogenolysis, preferably after removal of the acetyl protecting group(s) if such groups are present. With epicatechin, the yields are near-quantitative. The oligomers are characterized as their peracetates. In another embodiment, chain extension by cross-coupling of two 5,7,3′,4′-tetra-O-benzyl-protected-epicatechin or -catechin(4β,8)-oligomers each having a C-4 thio activating group (e.g., C-4-(2-benzlothiazolyl)thio) is carried out in the presence of silver tetrafluoroborate. An improved process is also provided for preparing a 5,7,3′,4′-tetra-O-benzyl-4-alkoxy-8-bromo-epicatechin or -catechin monomer. In the prior art four step process for preparing the C-8 blocked, C-4 alkoxy monomers the yield was about 51%. The steps included (i) the C-4 activation of 5,7,3′,4′-tetra-O-benzyl-epicatechin by reaction with ethylene glycol in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ) (63% yield), (ii) protection of the 3-hydroxyl position of the C-4-(2-hydroxyethoxy)-5,7,3′,4′-tetra-O-benzylepicatechin by the introduction of a tert-butyldimethylsilyl (TBDMS) group by reaction with tert-butyldimethylsilyl chloride in imidazole in the presence of 4-dimethyl-aminopyridine (DMAP) (88% yield), (iii) introduction of an 8-bromo group by reaction with N-bromosuccinimide at −40° C. in methylene chloride (100%), and (iv) removal of the TBDMS group by reaction with tetrabutyl ammonium fluoride (TBAF) in tetrahydrofuran (92%). In the improved two step processes 5,7,3′,4′-tetra-O-benzyl-epicatechin or -catechin is (i) activated by reaction with ethylene glycol in the presence of DDQ and (ii) blocked by bromination with N-bromosuccinimide or (i) 5,7,3′,4′-(tetra-O-benzyl)-epicatechin or -catechin is blocked by bromination and then (ii) activated. The overall yield for the two step process is about 63% when the monomer is epicatechin and the activation is done first and about 67% when the monomer is epicatechin and the blocking is done first. The synthetic procyanidin oligomers are identical to the procyanidin oligomers isolated from cocoa bean extracts by normal-phase HPLC. The regio-and stereochemistry of the interflavan linkages has been established by partial thiolysis (see Hör, M. et al., Phytochemistry 1996 , 42 , 109 ). For the tetramer the upper interflavan linkage is 4β,8 and the lower portion of the molecule is identical to the trimer which has also been subjected to partial thiolysis with both linkages being identified as 4β,8 (see Hör et al.). Since in the course of the present chain extension process the first three interflavan linkages formed are exclusively 4β,8 linkages, the same must be true for the additional interflavan linkages present in the higher oligomers. When tested in several breast cancer cell lines, both the synthetic and natural procyanidin pentamer, and to a lesser extent the tetramer, inhibited cell growth. Using the MDA MB-231 cell line, it was established that this outcome is based on the induction of cell cycle arrest in the G 0 /G 1 phase. Subsequent cell death is more likely necrotic rather than apoptotic. Control experiments demonstrate that the procyanidin itself, rather than hydrogen peroxide, is the causative agent. detailed-description description="Detailed Description" end="lead"? |
Fragrance and flavour compositions |
The invention relates to phenyl-cycloalkanes of formula (I) wherein the groups R1 to R6 are defined in the specification. |
1. A fragrance or flavour composition comprising a compound of formula (I) wherein, R1 is hydrogen, OH, or alkoxy having 1 to 3 carbon atoms, R2 is hydrogen, OH, or alkoxy having 1 to 3 carbon atoms, with the proviso that compounds of formula (I), wherein R1 and R2 are both hydrogen are excluded, or R1 and R2 taken together is a divalent radical —O—CH2—O—, R3 is hydrogen, or —CH3, R4 is hydrogen, or —CH3, or R3 and R4 taken together is a divalent radical (CH2)n, C(CH3)2, or CH(CH3) which forms a cycloalkane ring together with the carbon atoms to which it is attached, R5 is hydrogen, or —CH3, R6 is hydrogen, or —CH3, or R5 and R6 taken together is a divalent radical (CH2)n, (CH2)n−CH(CH3), or (CH2)n−1C(CH3)2 which forms a cycloalkane ring together with the carbon atoms to which it is attached, n is an integer 1, 2, or 3, and wherein at least one cycloalkane ring is present. 2. A composition according to claim 1 wherein R3 and R4 taken together is a divalent radical —CH2— which forms a cycloalkane ring together with the carbon atoms to which it is attached, R5 and R6 taken together is a divalent radical —CH2— which forms a cycloalkane ring together with the carbon atoms to which it is attached. 3. A composition according to claim 1 wherein the compound of formula (I) is selected from the group consisting of 1-Cyclopropylmethyl-4-methoxy-benzene, 4-Cyclopropylmethyl-2-methoxy-phenol, 4-Cyclopropylmethyl-1,2-dimethoxy-benzene, 2-Methoxy-4-(2-methyl-cyclopropyl)-phenol, 1-Cyclobutylmethyl-4-methoxy-benzene and 1-Cyclopentylmethyl-4-methoxy-benzne. 4. A composition according to claim 1 wherein the compound of formula (I) is 1-Cyclopropylmethyl-4-methoxy-benzene. 5. A fragranced product comprising a compound of the formula (I) as defined in claim 1 present in an amount ranging from 0.001% to 10%, preferably from 0.1% to 5%. 6. A fragranced product according to claim 5 comprising a compound of formula (I) selected from the group consisting of 1-Cyclopropylmethyl-4-methoxy-benzene, 4-Cyclopropylmethyl-2-methoxy-phenol, 4-Cyclopropylmethyl-1,2-dimethoxy-benzene, 2-Methoxy-4-(2-methyl-cyclopropyl)-phenol, 1-Cyclobutylmethyl-4-methoxy-benzene and 1-Cyclopentylmethyl-4-methoxy-benzne. 7. A fragranced product according to claim 5 comprising 1-Cyclopropylmethyl-4-methoxy-benzene. 8. A flavoured product comprising a compound of the formula (I) as defined in claim 1 present in an amount ranging from 0.001 to 1000 mg/kg, more preferably from 0.05 to 500 mg/kg. 9. A method of improving a flavour or fragrance composition comprising the step of adding thereto one or more compounds of the formula (I). 10. A method of improving a flavour or fragrance composition comprising the step of adding thereto one or more compounds of the formula (I) selected from the group consisting of 1-Cyclopropylmethyl-4-methoxy-benzene, 4-Cyclopropylmethyl-2-methoxy-phenol, 4-Cyclopropylmethyl-1,2-dimethoxy-benzene, 2-Methoxy-4-(2-methyl-cyclopropyl)-phenol, 1-Cyclobutylmethyl-4-methoxy-benzene and 1-Cyclopentylmethyl-4-methoxy-benzne. 11. A method of improving a flavour or fragrance composition comprising the step of adding thereto 1-Cyclopropylmethyl-4-methoxy-benzene. 12. A compound of formula (I) wherein R1 is hydrogen, OH, or alkoxy having 1 to 3 carbon atoms, R2 is hydrogen, OH, or alkoxy having 1 to 3 carbon atoms, with the proviso that compounds of formula (I), wherein i) R1, R2 is hydrogen, ii) R1 is hydrogen and R2 is methoxy, iii) R1 is hydrogen and R2 is hydroxy are excluded, or R1 and R2 taken together is a divalent radical —O—CH2—O—, R3 is hydrogen, R4 is hydrogen, or R3 and R4 taken together is a divalent radical —CH2— which forms a cycloalkane ring together with the carbon atoms to which it is attached, R5 is hydrogen, R6 is hydrogen, or R5 and R6 taken together is a divalent radical —CH2— which forms a cycloalkane ring together with the carbon atoms to which it is attached, and wherein at least one cycloalkane ring is present. |
Fabric-cleaning compositions |
The invention is concerned with post-foaming cleaning compositions which may be dispensed from a pressurised container. The compositions contain a post-foaming agent, for example a volatile hydrocarbon which boils and causes the composition to fizz on the surface of a fabric to be cleaned thereby enhancing the cleaning effect. The compositions contain high amount of volatile hydrocarbon, i.e. about 20 to 40% by weight, and a surfactant component consisting of or comprising a fatty alcohol ethoxylate. |
1. A post-foaming cleaning composition comprising a post-foaming agent in an amount of about 20 to 40% by weight. 2. A composition according to claim 1 wherein the post-foaming agent is a volatile hydrocarbon. 3. A composition according to claim 1 wherein the composition is a microemulsion. 4. A post-foaming microemulsion cleaning composition of claim 1 further comprising a hydrophilic component, a hydrophobic component, a surfactant component comprising at least 7% by weight aliphatic alcohol ethoxylate, and wherein the post-foaming agent is a volatile hydrocarbon. 5. A packaged monophasic post-foaming cleaning composition comprising the cleaning composition of claim 1. 6. A packaged composition according to claim 1 wherein the packaging is provided by an aerosol canister. 7. A packaged composition according to claim 1 wherein the post-foaming agent is a volatile hydrocarbon. 8. A packaged composition according to claim 1 wherein the composition is a microemulsion. 9. A composition according to claim 1 comprising 20 to 40 weight percent (wt %) deionised water; 20 to 40 wt % n-butane; 15.75% to 19.25 wt % isoparaffinic hydrocarbon with a boiling point of 113 to 143° C.; 7.5 to 9.3 wt % isopropanol; 6.0 to 13.0 wt % fatty alcohol ethoxylate (HLB 4 to 10); 2.5 to 3.1 wt % sodium di-alkyl sulphosuccinate (75%); 1.9 to 2.3 wt % of a fatty alcohol alkoxylate having a cloud point in water of between 28 and 42 DEG C; 2.5 to 3.1% oleic acid; 0.32 to 0.38 wt % sodium hydroxide (47%); optionally 0.1 to 1.0 wt % of a fragrance material; and optionally 0.005 to 0.1 wt % of a preservative. 10. A composition according to claim 9 comprising 28.126 wt % Deionised water; 30 wt % n-butane; 17.5 wt % Isoparaffinic hydrocarbon with a boiling point of 113-143; 8.4 wt % Isopropanol; 7.7 wt % C13-C15 linear alcohol ethoxyiate 3EO; 2.8 wt % Sodium di-alkyl sulphosuccinate 75%; 2.8 wt % Oleic acid; 2.1 wt % Fatty alcohol alkoxylate having a cloud point in water of between 28 and 42° C.; 0.35 wt % Sodium hydroxide 47%; 0.210 wt % fragrance; and 0.014 wt % preservative. 11. A method of pre-spotting a stained fabric comprising the step of applying thereto a composition of claim 1. 12. A method of pre-spotting a stained fabric of claim 11 comprising the step of applying thereto a composition wherein the composition comprises 20 to 40 weight percent (wt %) deionised water; 20 to 40 wt % n-butane; 15.75% to 19.25 wt % isoparaffinic hydrocarbon with a boiling point of 113 to 143° C.; 7.5 to 9.3 wt % isopropanol; 6.0 to 13.0 wt % fatty alcohol ethoxylate (HLB 4 to 10); 2.5 to 3.1 wt % sodium di-alkyl sulphosuccinate (75%); 1.9 to 2.3 wt % of a fatty alcohol alkoxylate having a cloud point in water of between 28 and 42 DEG C.; 2.5 to 3.1% oleic acid; 0.32 to 0.38 wt % sodium hydroxide (47%); optionally 0.1 to 1.0 wt % of a fragrance material; and optionally 0.005 to 0.1 wt % of a preservative. 13. A method of pre-spotting a stained fabric of claim 12 comprising the step of applying thereto a composition wherein the composition comprises 28.126 wt % Deionised water; 30 wt % n-butane; 17.5 wt % Isoparaffinic hydrocarbon with a boiling point of 113-143; 8.4 wt % Isopropanol; 7.7 wt % C13-C15 linear alcohol ethoxylate 3EO; 2.8 wt % Sodium di-alkyl sulphosuccinate 75%; 2.8 wt % Oleic acid; 2.1 wt % Fatty alcohol alkoxylate having a cloud point in water of between 28 and 42° C.; 0.35 wt % Sodium hydroxide 47%; 0.210 wt % fragrance; and 0.014 wt % preservative 14. A composition according to claim 2 wherein the composition is a microemulsion. 15. A composition according to claim 14 wherein the composition further comprises a hydrophilic component, a hydrophobic component, a surfactant component comprising at least 7% by weight aliphatic alcohol ethoxylate, and wherein the post-foaming agent is a volatile hydrocarbon. 16. A packaged monophasic post-foaming cleaning composition of claim 5 wherein the packaging is provided by an aerosol canister, the post-foaming agent is a volatile hydrocarbon and wherein the composition is a microemulsion. 17. A method of pre-spotting a stained fabric comprising the step of applying thereto a composition of claim 5. 18. A method of pre-spotting a stained fabric comprising the step of applying thereto a composition of claim 16. |
Solution for forming ultra hydrophilic photocatalyst film, construct provided with the film and process for producing the same |
A coating film forming liquid containing a saccharide, and titanium oxide fine particles having peroxy groups or titanium oxide fine particles not having peroxy groups is applied onto a surface of a substrate such as glass, metal or a tile, and then heating is carried out at a high temperature, thus forming on the substrate a super-hydrophilic photocatalytic coating film that contains titanium oxide fine particles and has a water contact angle in a state in which the photocatalyst is not excited of less than 10°. |
1. A super-hydrophilic photocatalytic coating film forming liquid characterized by containing a saccharide and titanium oxide fine particles. 2. A super-hydrophilic photocatalytic coating film forming liquid according to claim 1, characterized in that said saccharide is a monosaccharide or a disaccharide. 3. A super-hydrophilic photocatalytic coating film forming liquid according to claim 1, characterized in that said titanium oxide fine particles are of amorphous type or anatase type. 4. A super-hydrophilic photocatalytic coating film forming liquid according to claim 1, characterized in that said titanium oxide fine particles coexist with a calcium compound or silica or zirconium. 5. A super-hydrophilic photocatalytic coating film forming liquid according to any one of claims 1 through 4 claim 1, characterized in that said titanium oxide fine particles have peroxy groups. 6. A structure having a super-hydrophilic photocatalytic coating film, the structure having the super-hydrophilic photocatalytic coating film on a surface thereof, and being characterized in that the water contact angle of the coating film in a state in which the photocatalyst is not excited is less than 100. 7. The structure having a super-hydrophilic photocatalytic coating film according to claim 6, characterized in that said super-hydrophilic photocatalytic coating film contains titanium oxide fine particles. 8. The structure having a super-hydrophilic photocatalytic coating film according to claim 6, characterized in that said titanium oxide fine particles coexist with a calcium compound or silica or zirconium. 9. The structure having a super-hydrophilic photocatalytic coating film according to claim 6, characterized in that said structure is glass, metal or a ceramic. 10. A method of manufacturing a structure having a super-hydrophilic photocatalytic coating film, characterized by applying a coating film forming liquid containing a saccharide and titanium oxide fine particles onto a surface of a prescribed structure, and then heating, thus forming a coating film containing the titanium oxide fine particles. 11. A method of manufacturing a structure having a super-hydrophilic photocatalytic coating film, characterized by applying a coating film forming liquid containing a saccharide and titanium oxide fine particles coexisting with a calcium compound or silica or zirconium onto a surface of a prescribed structure, and then heating, thus forming a coating film containing the titanium oxide fine particles. 12. The method of manufacturing a structure having a super-hydrophilic photocatalytic coating film according to claim 10, characterized in that said titanium oxide fine particles have peroxy groups. 13. The method of manufacturing a structure having a super-hydrophilic photocatalytic coating film according to claim 10, characterized in that the temperature of said heating is 400 to 800° C. 14. The method of manufacturing a structure having a super-hydrophilic photocatalytic coating film according to claim 11, characterized in that said titanium oxide fine particles have peroxy groups. 15. The method of manufacturing a structure having a super-hydrophilic photocatalytic coating film according to claim 11, characterized in that the temperature of said heating is 400 to 800° C. |
<SOH> BACKGROUND ART <EOH>Applying a titanium-containing substance onto a surface of any of various materials, for example any of various building materials such as glass, a ceramic or a tile, to form a photocatalytic coating film comprising titanium oxide (titania), and thus realizing any of various functions such as an anti-fouling function, an antimicrobial function, a gas decomposing function or a harmful organic matter decomposing function realized through the photocatalytic ability of the coating film, is something that has been carried out from hitherto. Regarding the method of forming such a titanium oxide coating film, for example a method is known in which a dispersion containing fine particles of a titanium oxide or a solution of a titanium compound is applied onto the substrate surface, and then after the application, drying or if necessary low-temperature baking is carried out. In particular, it is known that as the titanium oxide used for realizing the photocatalytic ability, not only titanium dioxide such as anatase-type or rutile-type titanium oxide, but also a titanium oxide having peroxy groups, i.e. titanium peroxide, can be used. With regard to this titanium peroxide, it is also known that only the anatase type has catalytic ability (Japanese Patent Application Laid-open No. 9-124865). Due to such anatase-type titanium peroxide having photocatalytic ability as mentioned above, the above-mentioned patent document also describes using this anatase-type titanium peroxide as a photocatalytic film by forming a coating film thereof on a substrate surface of any of various structures. Moreover, regarding the amorphous type, there is no photocatalytic ability, but the bonding ability is excellent, and hence use as a photocatalyst particle binder when forming a photocatalytic coating film has been proposed (Japanese Patent Application Laid-open No. 9-262481). However, a coating film formed from anatase-type titanium peroxide has photocatalytic ability as described above, and yet the electrical conductivity is insufficient, and hence such a coating film has not been adequate for use as an electromagnetic wave shield, an antistatic material or the like. A coating film formation technique for improving the electrical conductivity has thus already been proposed (Japanese Patent Application Laid-open No. 11-315592), but this coating film formation technique has not been adequate since the formation process is complex. To resolve such problems, the present inventors have developed a titanium peroxide-containing aqueous liquid that enables a coating film having photocatalytic ability, and electrical conductivity useful for electromagnetic wave shielding, prevention of static and so on to be formed more easily, and have already filed patent applications (Japanese Patent Application No. 2001-4506, Japanese Patent Application No. 2001-250468). However, although this titanium peroxide-containing aqueous liquid has high functionality and is easy to use, the hardness has not been sufficient for forming a serviceable coating film having photocatalytic ability on glass, resin sheets, metal plates and so on. The present inventors thus focussed on this point, and also developed art for a coating film forming liquid capable of forming a high-hardness photocatalytic coating film, and have already filed a patent application (Japanese Patent Application No. 2002-11493). [Problems to be Solved] However, in the case of forming a coating film on the surface of glass, metal or the like using a conventional titanium peroxide-containing aqueous liquid as described above or a titanium oxide-containing liquid in which titanium oxide is dispersed in a liquid containing a substance having an alkyl silicate structure, it has been observed that under environments in which the photocatalytic ability is not readily exhibited, for example in bathrooms or washrooms or inside automobiles, fogging may arise on mirrors or on glass surfaces inside automobiles, and hence the hydrophilicity and anti-fogging ability have not been adequate for mirrors, glass and so on. |
Simulation method for estimating performance of product made of viscoelastic material |
A simulation method includes the step of momently measuring a value of each of a strain, a strain speed, and a stress generated in the viscoelastic material, deriving time history data of a viscous drag, the strain speed and the stress, thereby deriving a relationship among the strain, the strain speed, and the viscous drag and setting the product as a product model whose performance is analyzed; inputting the relationship to the product model; and computing a stress and strain of a deviation component by using a deviation main strain and a deviation main strain speed converted from an entire coordinate system into a main strain coordinate system and a main strain speed coordinate system respectively to thereby conduct a simulation in consideration of a change of the viscous drag which occurs in dependence of a variation of the strain and the strain speed. |
1. A simulation method of estimating performance of a product made of a viscoelastic material, comprising the steps of: momently measuring a value of each of a strain, a strain speed, and a stress generated in said viscoelastic material in a measuring condition equivalent to a condition in which said product composed of said viscoelastic material is actually used; deriving time history data of a viscous drag of said viscoelastic material from time history data of each of said strain, said strain speed, and said stress and a viscoelastic model in which a viscosity of said viscoelastic material is considered, thereby deriving a relationship among said strain, said strain speed, and said viscous drag; in estimating the performance of said product model whose performance is analyzed and made of said viscoelastic material said product model is divided into a large number of elements said relationship is inputted to said product model, and an analysis is executed by a finite element method in consideration of a change of said viscous drag in dependence on a variation of said strain and said strain speed; and resolving said strain and said strain speed of an entire coordinate system generated in each element into deviation components and volume components, and converting said strain and said strain speed of said deviation components from said entire coordinate system into a main strain coordinate system and a main strain speed coordinate system respectively; and determining a viscous drag for a coordinate axis of each of said main strain coordinate system and said main strain speed coordinate system by using a converted deviation main strain and a converted deviation main strain speed. 2. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 1, wherein said viscoelastic material shows nonlinearity in a property thereof. 3. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 1, wherein a split Hopkinson rod testing machine measures said strain, said strain speed, and said stress. 4. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 1, wherein a maximum value of said strain generated in said viscoelastic material at said measuring time is in a range of 0.05 to 0.50 and/or a maximum value of said strain speed is in a range of 500/s to 10000/s. 5. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 1, wherein said viscoelastic material is used for a golf ball, and said product model is a golf ball. 6. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 5, wherein a phenomenon of a collision between said golf ball and a hitting object assumed to be a golf club head is simulated to estimate a behavior of said golf ball at the time of said collision. 7. A simulation method of estimating performance of a product made of a viscoelastic material, comprising the steps of: momently measuring a value of each of a strain, a strain speed, and a stress generated in said product made of a viscoelastic material equivalent to a condition in which said product composed of said viscoelastic material is actually used; deriving a plurality of different rigidities from time history data of each of said strain and said stress and deriving a correspondence relationship among said strain, said strain speed, and said rigidities, thereby deriving a relationship among said strain, said strain speed, and said rigidities; in estimating the performance of said product model whose performance is analyzed and made of a viscoelastic material said product model is divided into a large number of elements, said relationship is inputted to said product model, and an analysis is executed by a finite element method in consideration of a change of said rigidities in dependence on a variation of said strain and said strain speed; and resolving said strain and said strain speed of an entire coordinate system generated in each element into deviation components and volume components, and converting said strain and said strain speed of said deviation components from said entire coordinate system into a main strain coordinate system and a main strain speed coordinate system respectively; and determining a rigidity for a coordinate axis of each of said main strain coordinate system and said main strain speed coordinate system by using a converted deviation main strain and a converted deviation main strain speed. 8. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 7, wherein time history data of a viscous drag of said viscoelastic material is derived from time history data of each of said strain, said strain speed, and said stress and a viscoelastic model in which a viscosity of said viscoelastic material is considered; and a change of said rigidity and that of said viscous drag are considered. 9. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 7, wherein said viscoelastic material shows nonlinearity in a property thereof. 10. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 7, wherein a split Hopkinson rod testing machine measures said strain, said strain speed, and said stress. 11. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 7, wherein a maximum value of said strain generated in said viscoelastic material at said measuring time is in a range of 0.05 to 0.50 and/or a maximum value of said strain speed is in a range of 500/s to 10000/s. 12. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 7, wherein said viscoelastic material is used for a golf ball, and said product model is a golf ball. 13. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 12, wherein a phenomenon of a collision between said golf ball and a hitting object assumed to be a golf club head is simulated to estimate a behavior of said golf ball at a time of said collision. 14. A simulation method of estimating performance of a product made of a viscoelastic material, comprising the steps of: momently measuring a value of each of a strain, a strain speed, and a stress generated in said product made of a viscoelastic material in a measuring condition equivalent to a condition in which said product composed of said viscoelastic material is actually used; deriving time history data of a viscous drag of said viscoelastic material separately in a strain increase state and a strain decrease state or a strain restoration state from time history data of each of said strain, said strain speed, and said stress and a viscoelastic model in which a viscosity of said viscoelastic material is considered, thereby deriving a relationship among said strain, said strain speed, and said viscous drag; in estimating the performance of said product model whose performance is analyzed and made of said viscoelastic material, said product model is divided into a large number of elements, said relationship is inputted to said product model, and an analysis is executed by a finite element method in consideration of a difference in said viscous drag between said strain increase state and said strain decrease state or said strain restoration state; and resolving said strain and said strain speed of an entire coordinate system generated in each element into deviation components and volume components, and converting said strain and said strain speed of said deviation components from said entire coordinate system into a main strain coordinate system and a main strain speed coordinate system respectively; and determining a viscous drag different between said strain increase state and said strain decrease or said strain restoration state for a coordinate axis of each of said main strain coordinate system and said main strain speed coordinate system when strains having an equal value are generated in said viscoelastic material, by using a converted deviation main strain and a converted deviation main strain speed. 15. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 14, wherein a norm which is the magnitude of a main strain is computed for each of said elements, and said computed norm is compared with a norm of a previous step in a simulation to determine that said main strain is in said increase state when said norm has increased, and to determine that said main strain is in said decrease state when said norm has decreased. 16. The simulation method of estimating performance of a product made of a viscoelastic material according to claim 14, wherein said viscoelastic material shows nonlinearity in a property thereof. 17. The simulation method according to claim 14, wherein a split Hopkinson rod testing machine measures said strain, said strain speed, and said stress. 18. The simulation method according to claim 14, wherein a maximum value of said strain generated in said viscoelastic material at said measuring time is in a range of 0.05 to 0.50 and/or a maximum value of said strain speed is in a range of 500/s to 10000/s. 19. The simulation method according to claim 14, wherein said viscoelastic material is used for a golf ball, and said product model is a golf ball. 20. The simulation method according to claim 19, wherein a phenomenon of a collision between said golf ball and a hitting object assumed to be a golf club head is simulated to estimate a behavior of said golf ball at a time of said collision. |
<SOH> BACKGROUND ART <EOH>A viscoelastic material represented by a macromolecular material such as rubber or elastomer is widely applied to various products such as tires, balls to be used in sports, rolls for printing machines. In various products composed of the viscoelastic material or a metal material, to save cost and time, development of products by using a simulation are made in various industrial fields. For example, to estimate the restitution performance of a golf ball, simulation methods of actual ball-hitting tests are proposed. In conducting the simulation, property values of a composing material of a ball measured by a viscoelastic spectrum meter for measuring the rigidity, the viscosity of the material and a tension testing machine for measuring the modulus of longitudinal elasticity (Young's modulus) thereof are used as input data in the simulation. In particular, because the viscoelastic spectrum meter measures the property values of a dynamic strain-applied specimen, the viscoelastic spectrum meter is useful for simulating products composed of the viscoelastic material. However in measurement conducted by using the viscoelastic spectrum meter and the tension testing machine for measuring the modulus of longitudinal elasticity, a large deformation amount cannot be imparted to the specimen. Thus a maximum strain speed applied to the specimen composed of the viscoelastic material at a measuring time is as low as 0.001/s to 1.0/s and a maximum compression strain is also as low as 0.0001 to 0.02. A product composed of the viscoelastic material may deform at a high speed and greatly owing to the influence of an external force applied thereto when it is actually used. For example, when the golf ball is hit, a maximum strain speed of a material for the golf ball is as high as 500/s to 5000/s, and a maximum compression strain thereof is as large as 0.05-0.50. As described above, the viscoelastic spectrum meter and the tension testing machine for measuring the modulus of longitudinal elasticity are incapable of measuring the property values of the viscoelastic material in a condition equivalent to a condition where the product composed of the viscoelastic material deforms quickly and greatly when it is actually used. Thus the maximum strain speed of the viscoelastic material and its maximum compression strain measured at a simulation time are much different from those measured at the time when the product composed of it is actually used. Therefore the conventional simulation method of inputting the property value obtained by using the viscoelastic spectrum meter and the tension testing machine is incapable of accomplishing an accurate simulation by taking the property of the viscoelastic material into consideration. That is, it is known that the deformation behavior of the viscoelastic material when an impact load is applied thereto is different from that of the viscoelastic material when a static load is applied thereto. That is, the deformation behavior of the viscoelastic material is greatly influenced by a deformation amount or a deformation speed. In particular, when a macromolecular material such as rubber and elastomer is subjected to the impact load, it deforms at a speed as high as several seconds by 10000 or several seconds by 1000 and as greatly as by several tens of percentages in a quantitative respect. There are many viscoelastic materials that deform at such a high speed and in such a large amount. To develop products efficiently, there is a demand for development of a simulation method capable of conducting an accurate simulation. More specifically, the performance of a product such as the golf ball to which an impact is applied when it is used depends on a dynamic behavior in a condition where it deforms at a high speed and greatly. The performance of the product also depends on the characteristic of the material thereof. Therefore to develop a product, it is indispensable to conduct an accurate simulation in a condition equivalent to a condition in which the product composed of the material is actually used. Some viscoelastic materials change in its property value such as its rigidity (modulus of longitudinal elasticity and modulus of transverse elasticity) and loss coefficient in dependence on the magnitude of a strain and a strain speed when an external force such as an impact load is applied thereto. That is, the viscoelastic material is diverse in its deformation speed and deformation magnitude. Thus depending on the deformation speed and the deformation magnitude, the viscoelastic material has a property that it changes not linearly but highly nonlinearly. More specifically, as the viscoelastic material is deformed by an external force applied thereto and strained increasingly, the loop area of an S-S (strain-stress) curve increases, and the property such as the loss coefficient thereof changes in dependence on a deformation state (speed and magnitude of deformation) thereof, thus showing nonlinearity in its property. Many viscoelastic materials have a high nonlinearity in their properties. Thus there is a demand for development of a simulation method capable of simulating a product composed of such a viscoelastic material. However there are no methods capable of accurately expressing a phenomenon that the property of the viscoelastic material, for example, its rigidity (modulus of longitudinal elasticity and modulus of transverse elasticity) and loss coefficient changes nonlinearly in a high extent in dependence on the deformation speed and deformation magnitude thereof. Simulations have been hitherto conducted on the assumption that the property value of the viscoelastic material composing the golf ball or the like hardly changes. Consequently the conventional simulation method has a disadvantage that it is incapable of correctly estimating the performance of the product composed of the viscoelastic material in an actual use. Thus to estimate the performance of the product, trial manufacture cannot but be made. The present invention has been made in view of the above-described situation. Thus, it is an object of the present invention to accurately estimate the performance of a product composed of a viscoelastic material showing nonlinearity in its property, for example, a product composed of a viscoelastic material whose rigidity such as the modulus of longitudinal elasticity changes in dependence on a magnitude of a strain and that of a strain speed, by conducting a simulation in a condition in which the product is actually used. |
<SOH> BRIEF DESCRIPTION OF THE DRAWINGS <EOH>FIG. 1 shows time history data of a strain ε in a first mode of the present invention of the present invention. FIG. 2 shows time history data of a strain speed ε′ in the first mode of the present invention. FIG. 3 shows time history data of a stress σ in the first mode of the present invention. FIG. 4 shows a strain-stress curve and a method of computing a modulus of longitudinal elasticity in the first mode of the present invention. FIG. 5 shows a two-component Voight model used as a viscoelastic model of the first mode of the present invention. FIG. 6 shows time history data of a viscous drag in the first mode of the present invention. FIG. 7 shows the relationship between the strain and the viscous drag in the first mode of the present invention. FIG. 8 shows the relationship between the strain and the strain speed in the first mode of the present invention. FIG. 9 shows a division situation of a golf ball model by means of meshes. FIG. 10 shows a situation of a collision between a hollow rod model made of aluminum and a golf ball model. FIG. 10A shows a situation before the collision. FIG. 10B shows a situation at the time of the collision. FIG. 10C shows a situation after the collision. FIG. 11 shows a method of computing a loss coefficient. FIG. 12 shows time history data of a strain ε in a second mode of the present invention. FIG. 13 shows time history data of a strain speed ε′ in the second mode of the present invention. FIG. 14 shows time history data of a stress σ in the second mode of the present invention. FIG. 15 shows a strain-stress curve and a method of computing a modulus of longitudinal elasticity in the second mode of the present invention. FIG. 16 shows time history data of a viscous drag in the second mode of the present invention. FIG. 17 shows the relationship between the strain and the viscous drag in the second mode of the present invention. FIG. 18 shows time history data of a strain ε in a third mode of the present invention of the present invention. FIG. 19 shows time history data of a strain speed ε′ in the third mode of the present invention. FIG. 20 shows time history data of a stress σ in the third mode of the present invention. FIG. 21 shows a strain-stress curve and a method of computing a modulus of longitudinal elasticity in the third mode of the present invention. FIG. 22 shows time history data of a viscous drag in the third mode of the present invention. FIG. 23 shows the relationship between the strain and the viscous drag in the third mode of the present invention. FIG. 24 shows the relationship between the strain and the strain speed in the third mode of the present invention. FIG. 25 is an illustrative front view showing a split Hopkinson rod testing machine. FIG. 26 shows a state of a time history of a strain of a specimen. detailed-description description="Detailed Description" end="lead"? |
Quote and supply management system |
A computerised management system for a business schedules a date to provide a quote for the provision of a product or service, in response to a client request; stores data relating to a quote approved by a client; schedules resources, such as labour and goods, required for the provision of the product or service relating to an approved quote; and stores a provision deadline corresponding to the date by which the product or service should be provided to the client. |
1. A management system for a business, which management system is adapted for implementation by a computer, the management system comprising a job inquiry and quotation means which is adapted to receive data relating to a request from a client to provide a quote for the provision of at least one product and/or service and operate a quote scheduling means to retrieve predetermined quote data whereby a schedule is created for a quote date being a date for providing the quote to the client, a job management means which is adapted to receive data relating to a successful quote approved by a client, including the or each product and or service requested by the client and operate an operations scheduling means to retrieve predetermined operations data to create an operations schedule to schedule resources required for the provision of the or each product and/or service for the successful quote and store a provision deadline being the date by which the product and/or service of the successful quote should be provided to the client who approved the successful quote. 2. The management system as claimed in claim 1 wherein the operations scheduling means is adapted to schedule labour and goods required for the provision of the or each product and/or service for each successful quote. 3. The management system as claimed in claim 2 wherein the resources include labour and goods. 4. The management system as claimed in claim 2 or 3 wherein the operations scheduling means is adapted to schedule procedures involving the resources, which procedures enable the provision of the or each product and/or service for each successful quote. 5. The management system as claimed in claim 4 including an administration means which is adapted to record data relating to input and output costs of the business being managed by the management system. 6. The management system as claimed in claim 4 or 5 wherein the job enquiry and quotation means is adapted to create a job enquiry labour database for storing names of persons able to act on the enquiry and provide the quote. 7. The management system as claimed in claim 6 wherein the job enquiry and quotation means is adapted to create a database of products and/or services available for the quote. 8. The management system as claimed in claim 7 wherein the operations scheduling means includes quote allocation means which is adapted to allocate a quote person from the job enquiry labour database to provide the quote. 9. The management system as claimed in claim 8 wherein the job enquiry and quotation means is adapted to create a pending quotes request database including data relating to the client requesting quote and the or each product and/or service for which a quote is requested. 10. The management system as claimed in claim 9 wherein the quote data includes the quote person, the client, the product and/or service, the date for visiting the client and the due date for supplying the quote to the client. 11. The management system as claimed in claim 10 wherein the job enquiry and quotation means includes quote monitoring means for monitoring when each quote request is answered by the quote person. 12. The management system as claimed in claim 11 wherein the job enquiry and quotation means is adapted to create a source of enquiry database which includes a list of sources of enquiries. 13. The management system as claimed in claim 12 including a setting means which is adapted to receive reference data relating to each product and/or service available to the business. 14. The management system as claimed in claim 13 wherein the job enquiry and quotation means includes a data entry means which is adapted to receive data relating to the request from a client, being a new job and create a file for each new job. 15. The management system as claimed in claim 14 wherein each job file includes data relating to the client and the product and/or service requested by the client. 16. The management system as claimed in claim 15 wherein the quote allocation means is adapted to retrieve quote persons names from the job enquiry labour database whereby one or more quote persons names may be added to the new job file to thereby provide the quote requested by the client. 17. The management system as claimed in claim 16 wherein the quote allocation means is adapted to automatically search databases and allocate a quote person to a new job based on predetermined criteria relating to jobs already allocated to the quote person. 18. The management system as claimed in claim 17 wherein the quote monitoring means includes an overdue indicator which is adapted to provide an overdue output indication if a quote request is not answered by the due date by the quote person. 19. The management system as claimed in claim 18 wherein the job enquiry and quotation means is adapted to record unsuccessful quotes and data related thereto. 20. The management system as claimed in claim 19 wherein the job enquiry and quotation means includes a job enquiry manifest means for creating a job manifest for each quote request using data from any one or more of the databases. 21. The management system as claimed in claim 20 wherein the job enquiry manifest means is adapted to create a job manifest for each quote person. 22. The management system as claimed in claim 21 wherein the job manifest includes data relating to each quote request including client details, product and/or service details and due date details. 23. The management system as claimed in claim 1 or claim 22 wherein the job management means is adapted to create a resourcing database including data relating to each product and/or service available to be provided by the business, raw materials available to make the or each type of product and/or service and resource labour available to provide each type of product and/or service. 24. The management system as claimed in claim 23 wherein the job management means includes a manufacturing operation means which includes procedures required to manufacture at least one type of product. 25. The management system as claimed in claim 24 wherein the manufacturing operation means includes timing data for setting times for commencing and finishing procedures required for manufacture of one or more products. 26. The management system as claimed in claim 25 wherein the operation scheduling means includes resource allocation means which is adapted to retrieve data from the resourcing database and allocate resource labour to produce at least one product and/or service required for one or more clients. 27. The management system as claimed in claim 26 wherein the operations scheduling means is adapted to create a file having data relating to a job/quote, being a successful quote, the products and/or services associated with the job/quote and the manufacturing operation means. 28. The management system as claimed in claim 27 wherein the manufacturing operation means includes a plurality of manufacturing operations options, each manufacturing operation option being adapted to store data relating to procedures required to complete at least one manufacturing process for a product. 29. The management system as claimed in claim 28 wherein the manufacturing operation means includes a process scheduler which is adapted to store timing data for at least one of the manufacturing operations for a particular job/quote and calculate and produce timing data associated with other manufacturing operations for the job/quote. 30. The management system as claimed in claim 29 wherein the resource allocation means is adapted to retrieve procedures from the manufacturing operation means, which procedures are required to produce the/each product and/or service whereby a resourcing manifest is able to be created including data relating to the requested product and/or service of the successful quote, the job/quote, the allocated product resource labour and completion date for providing the/each product and/or service whereby it is available for the client of the successful quote. 31. The management system as claimed in claim 1 or 30 including provision control means which is adapted to record each provision date, being the date for providing the or each product and/or service of a successful quote to the associated client. 32. The management system as claimed in claim 31 wherein the provision control means is adapted to create a provision database including data on each provision person available to provide the or each service to an associated client. 33. The management system as claimed in claim 32 wherein the provision control means is adapted to create a provision manifest including the name of each provision person to provide the or each product and/or service, the job/quote, provision procedures including procedures to provide the or each product and/or service to an associated client and a provision deadline being a deadline for providing the or each product and/or service to the associated client. 34. A computer program for controlling a business, the computer program comprising a job inquiry and quotation means which is adapted to control a data processor to receive and store data relating to a request from a client to provide a quote for the provision of at least one product and/or service and operate a quote scheduling means to schedule a quote data being a date for providing the quote to the client, and a job management means which is adapted to control a data processor to receive data relating to each successful quote approved by each client including the or each product and/or service requested by each client, control an operations scheduling means which is adapted to schedule labour and goods required for the provision of the or each product and/or service for each successful quote and store a provision deadline for each successful quote, the provision deadline being the date by which the product and/or service of the successful quote should be provided to the client who approved the successful quote. 35. A computer program as claimed in claim 34 wherein the quote scheduling means is adapted to schedule quote labour to provide the quote, a quote deadline for the quote labour to provide the quote, a visit deadline being a date for the quote labour to visit the client and obtain data relating to preparing the quote and control the data processor to set up a quote labour manifest including data relating to selected successful quotes allocated to the quote labour. |
<SOH> BACKGROUND OF THE INVENTION <EOH>The process of servicing a product in a retail and/or wholesale market is both complicated and time consuming. The demand on a business to perform to a high level while keeping control of costs is difficult and with a limited time available to ensure that all the required processes are carried out it is extremely difficult to effectively manage the performance of many varied processes. As an example during particularly busy periods the focus of many businesses is on the most urgent and pressing issues at the time and they rely on manual processes to ensure that other required duties are addressed during this period. Therefore reporting systems within the business are often minimal, leading to problems arising that are often difficult to rectify. There are areas outside the “quote and service” areas such as debtors, payroll etc that require constant monitoring. Because smaller businesses tend to operate with small profit margins, quite often there are insufficient resources to control all the areas of business management that need to be controlled. The aim of the present invention is to provide a management system which is able to assist management of a business. In its preferred form the invention provides a management system which is able to be implemented utilising data processing hardware and software to assist with management of a business. Existing software systems for businesses primarily are concerned with accounting functions of a business. Some software systems also include electronic diaries for business management purposes, but these electronic diaries do little to assist with management of a business. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to the present invention there is provided a management system for a business, which management system is adapted for implementation by a computer, the management system comprising a job inquiry and quotation means which is adapted to receive data relating to a request from a client to provide a quote for the provision of at least one product and/or service and operate a quote scheduling means to retrieve predetermined quote data whereby a schedule is created for a quote date being a date for providing the quote to the client, a job management means which is adapted to receive data relating to a successful quote approved by a client, including the or each product and or service requested by the client and operate an operations scheduling means to retrieve predetermined operations data to create an operations schedule to schedule resources required for the provision of the or each product and/or service for the successful quote and store a provision deadline being the date by which the product and/or service of the successful quote should be provided to the client who approved the successful quote. Preferably the operations scheduling means is adapted to schedule labour and goods required for the provision of the or each product and/or service for each successful quote. Preferably the resources includes labour and goods. It is preferred that the operations scheduling means is adapted to schedule procedures involving the resources, which procedures enable the provision of the or each product and/or service for each successful quote. Preferably the management system includes an administration means which is adapted to record data relating to input and output costs of the business being managed by the management system. It is preferred that the job inquiry and quotation means comprises a module in a computer program. The job management means may comprise a module in a computer program. The job inquiry and quotation means and job management means preferably include separate input icons accessible from a main menu of the management system. The administration module may be adapted to communicate accounting data from the management system to an independent accounting program. Alternatively the administration means comprises accounting procedural processes for providing accounting reports. It is preferred that the job inquiry and quotation means is adapted to create a job inquiry labour database for storing names of persons able to act on the inquiry and provide the quote. Preferably the job inquiry and quotation means is adapted to create a database of products and/or services available for the quote. The operations scheduling means preferably includes quote allocation means which is adapted to allocate a quote person from the job inquiry labour database to provide the quote. Preferably the job inquiry and quotation means is adapted to create a pending quotes request database including data relating to the client requesting the quote and the or each product and/or service for which a quote is requested. Preferably the quote data includes the quote person, the client, the product and/or service, the date for visiting a client and the due date for supplying the quote. The job inquiry and quotation means may include quote monitoring means for monitoring when each quote request is answered by the quote person. Preferably the job inquiry and quotation means is adapted to create a source of inquiry database which includes a list of sources of inquiries. It is preferred that the management system includes a settings means which is adapted to receive reference data relating to each product and/or service available to the business. Preferably the job inquiry and quotation means includes a data entry means which is adapted to receive data relating to the request from a client, being a new job, and create a file for each new job. It is preferred that each job file includes data relating to the client and the product and/or service requested by the client. It is preferred that the data entry means includes the quote scheduling means. Preferably the quote allocation means is adapted to retrieve quote persons names from the job inquiry labour database whereby one or more quote persons names may be added to the new job file to thereby provide the quote requested by the client. According to one embodiment the quote allocation means automatically searches databases and allocates a quote person to a new job based on predetermined criteria relating to jobs already allocated to the quote person. According to a further embodiment of the invention the quote allocation means is adapted to retrieve data from databases and create a file for each quote person which file includes data relating to each quote/job, the quote person has yet to provide. Preferably the quote allocation means is adapted to create a file listing all jobs/quotes which do not have a quote person allocated thereto. It is preferred that the quote allocation means includes a quote person scheduling means for determining the quote person with the least amount of jobs/quotes and allocating the new jobs/quote to that quote person. The source of inquiry database may include files with fields for different types of advertising, names of referees, names of exhibitions or any other source of obtaining an inquiry. Preferably the quote monitoring means includes an overdue indicator which is adapted to provide an overdue output indication if a quote request is not answered by the due date. The job inquiry and quotation means preferably is adapted to record unsuccessful quotes and data related thereto. The job inquiry and quotation means may include quote report means which is adapted to retrieve data from the job inquiry labour database, the products and/or services database, the quote request database and quote monitoring means and process selected retrieved data to output statistical data including one or more of the following: inquiry source, quote person, client location and type, product, service, speed of quote provision, cancellation of quote request by client, cost quoted and strike rates. Preferably the job inquiry and quotation means includes a job inquiry manifest means for creating a job manifest for each quote request using data from anyone or more of the databases. It is preferred that the job inquiry manifest means is adapted to create a job manifest for each quote person. Preferably each job manifest includes data relating to each quote request including client details, product and/or service details and due date details. Preferably the job inquiry manifest means is adapted to create a job manifest for each quote person. The job inquiry and quotation means preferably includes a job leads manifest means for creating a job leads manifest including a list of all leads which may be the source of a request for a quote for a product and/or service. It is preferred that the job leads manifest includes data relating to the names of any potential new client associated with the lead. It is preferred that the quote scheduling means is adapted to schedule quote labour, a visit deadline, being a date for the quote labour to visit the client and obtain data required to prepare the quote. It is preferred that the job inquiry and quotation means includes quote management report means which is adapted to retrieve data from databases and create files grouping predetermined types of data together. According to one embodiment the predetermined data types grouped together may be that relating to a quote person, a region where clients are located, an advertising source or other statistical information. It is preferred that the job inquiry and quotation means includes a quote job control means which is adapted to retrieve data relating to jobs with an expired due date. It is preferred that a job/quote file includes a completion date field which is adapted to receive a completion date that is before the due date. The quote job control means is adapted to add a job/quote file to the quote job control file if the current date is past the due date and there is no completion date in the completion date field. It is preferred that the quote job control means is adapted to create an unallocated jobs file which is adapted to retrieve files for job/quotes which do not have a quote person entered in the quote person field. The job management means may include a resource database including data relating to each product and/or service able to be provided by the business, raw materials available to make the or each type of product and/or service and resource labour available to provide each type of product and/or service. The resource labour may include manufacturing labour available to manufacture one or more types of product. The resource database may include data relating to each type of product available in stock. Preferably the resourcing database includes data relating to raw materials and/or products which need to be outsourced. The job management means may include a manufacturing operation means which includes procedures required to manufacture at least one type of product. The manufacturing operation means may include timing data for setting times for commencing and finishing procedures required for manufacture of one or more products. The operations scheduling means may include resource allocation means which is adapted to retrieve data from the resource database and allocate resource labour to produce at least one product and/or service required for one or more clients. It is preferred that the predetermined operations data includes that data stored in the resource database. It is preferred that the operations scheduling means is adapted to create a file having data relating to a job/quote, the products and/or services associated with the job/quote and the manufacturing operating means. It is preferred that the manufacturing operation means includes a plurality of manufacturing operations options, each manufacturing operation option being adapted to store data relating to procedures required to complete at least one manufacturing process for a product. It is preferred that the manufacturing operation means includes a process scheduler which is adapted to store timing data for at least one of the manufacturing operations for a particular job/quote and calculate and produce timing data associated with other manufacturing operations for the job/quote. It is preferred that the process scheduler creates a file which is able to be viewed on a computer screen. It is preferred that the management system is able to create files for data stored in any one of the data bases and present this on a computer screen for viewing. It is preferred that any file created by the management system is able to be viewed on a computer screen. It is preferred that the process scheduler is able to reschedule a job/quote by comparing a completion date received for that job/quote with completion dates for other job/quotes stored on a process scheduler data base. It is preferred that the process scheduler is adapted to retrieve data from the operations schedule. It is preferred that the product resource labour is adapted to either manufacture product or procure product from a source outside the business. The resource allocation means is preferably adapted to retrieve procedures from the manufacturing operation means, which procedures are required to produce the/each product and/or service whereby a resourcing manifest is able to be created including data relating to the requested product and/or service of the successful quote, the allocated product resource labour and completion date for providing the/each product and/or service whereby it is available for the client of the successful quote. Preferably the management system includes provision control means which is adapted to record each provision date, being the date for providing the or each product and/or service of a successful quote to the associated client. It is preferred that the provision control means retrieves the completion date from the resourcing manifest. Preferably the resourcing allocation means is adapted to allocate provision labour, including a provision person, being labour for providing the or each available product and/or service of a successful quote to an associated client. The provision control means may include a provision database including data on each provision person available to provide the or each service to an associated client. The provision control means may be adapted to create a provision manifest including the name of each provision person to provide the or each product and/or service, provision procedures including procedures to provide the or each product and/or service to an associated client and a provision deadline being a deadline for providing the or each product and/or service to the associated client. The provision control means may include a provision overdue data indicator which is adapted to output an indicator for indicating when the provision date has passed and the or each product and/or service has not been provided to the associated client. It is preferred that the provision control means comprises an installation control means which is adapted to record an installation date or dates for installing the or each available product and/or service to the associated client. According to a preferred embodiment of the present invention the job management means includes the provision control means. It is preferred that the provision control means is a module in a computer program associated with controlling activities associated with labour and products required to install a product at a clients residence. Preferably the job management means includes an outsourcing means which is adapted to retrieve data from a job/quote if the job/quote includes a product and/or service which the business does not have. It is preferred that the order means is adapted to create a file listing all jobs/quotes and their products and/or services which must be ordered from outside the business. It is preferred that the order means includes an order due date field for entering a date by which the order should be filled. According to another embodiment of the present invention the job management means includes a check measure means which is adapted to receive data from a particular job/quote and create a file listing measurements of products required for that particular job/quote, whereby a checking procedure is able to be initiated. It is preferable that the manufacturing schedule includes a check measure field which indicates that measurements have been checked. It is preferred that the check measurement field overrides manufacturing operations from being accessible/commenced until the check measurements field has been completed. It is preferred that the operation scheduling means is adapted to transmit data to the provision control means for each job/quote which has been approved, which data includes a check measure request which is to be actioned by a provision person. It is preferred that the management system is in the form of a computer program which is able to control a data processor utilising the job inquiry and quotation means and the job management means. According to another aspect of the present invention there is provided a computer program for controlling a business, the computer program comprising a job inquiry and quotation means which is adapted to control a data processor to receive and store data relating to a request from a client to provide a quote for the provision of at least one product and/or service and operate a quote scheduling means to schedule a quote data being a date for providing the quote to the client, and a job management means which is adapted to control a data processor to receive data relating to each successful quote approved by each client including the or each product and/or service requested by each client, control an operations scheduling means which is adapted to schedule labour and goods required for the provision of the or each product and/or service for each successful quote and store a provision deadline for each successful quote, the provision deadline being the date by which the product and/or service of the successful quote should be provided to the client who approved the successful quote. Preferably the quote scheduling means is adapted to schedule quote labour to provide the quote. The quote scheduling means may be adapted to schedule a quote deadline for the quote labour to provide the quote. Preferably the quote scheduling means is adapted to schedule a visit deadline being a date for the quote labour to visit the client and obtain data required to prepare the quote. According to one embodiment the quote scheduling means is adapted to control the data processor to set up a quote labour manifest including data relating to selected successful quotes allocated to the quote labour. The quote labour manifest preferably includes data relating to any one or more of the following: the source of inquiry of the quote; the client associated with the quote including the client type and location; the or each type of product and/or service for which a quote is required by the associated client; deadline for providing the quote; deadline for visiting the client to obtain data for providing the quote; accounting data including costs and revenue; Strike rates, being the number of successful quotes per quote. It is preferred that the job inquiry and quotation means is adapted to set up a leads manifest being a database of information relating to potential sources of request for quotes. It is preferred that the leads manifest includes a follow up deadline which provides a prompt to contact the lead to ascertain whether a quote is required. Preferably the operations scheduling means is adapted to schedule for each successful quote a completion date, being a date by which the or each product and/or service requested by each client, should be made available to provide the or each client. Preferably the operations scheduling means is adapted to schedule for each successful quote provision labour to provide available products and/or services to a respective client. The operations scheduling means may be adapted to schedule resource labour, being labour for providing the or each product and/or service of the successful quote by the completion date. The operations scheduling means may be adapted to schedule product resource procedures for each type of product and/or service of each successful quote whereby resource labour can provide the or each product and/or service by the completion date. Preferably the operations scheduling means is adapted to allocate provision labour to provide the or each product and/or service to a client of a successful quote by a provision deadline, being the date the or each product and/or service should be provided to the client of the successful quote. Preferably the computer program includes an exceptions means which is adapted to output an exceptions indicator whenever any deadline is passed without necessary actions being taken. It is preferred that the computer program includes management report means for retrieving selected data stored on a data processor as a result of controlling operations by the job inquiry and quotation means and the job management means. It is preferred that the management report means is adapted to retrieve data from any manifest stored on a data processor under the control of the computer program. It is preferred that the operations scheduling means is adapted to communicate with an operations procedure means of the computer program to retrieve predetermined data on procedures required in order to provide at least one of the products and/or services, whereby labour allocated to provide the or each product and/or service is able to access the operations procedures to follow the procedures and provide the or each product and/or service by the completion date. Preferably the operation procedure means provides a time period for providing at least one of the products and/or services. The words “comprising, having, including” should be interpreted in an inclusive sense, meaning that additional features may also be added. |
Device for electrically heating a vertically erect chamber |
The invention relates to a device for electrically heating a vertically erect chamber, for example, a reactor, to high temperatures (≧1000° C.) and/or with high power (30 to 1000 kW per zone), comprising several heating zones arranged vertically one above the other. The components of the de- vice, with the exception of the insulating components, are made from graphite materials. The aim of the invention is to embody and develop the device such that the largest possible degree of stability and functional capability for the whole device is achieved with low constructional complexity. The device should in particular be capable of heating very tall chambers. The above is achieved in that each zone (Z) comprises a number of supports (1), arranged in an essentially even distribution around the chamber (R) for heating, which simultaneously serve as electrical supplies for the heater, and in that the heater for each zone (Z) is arranged such as to be fixed at one end thereof and longitudinally displaceable at the other end thereof. |
1. A device for electrically heating a vertically erect chamber, to a high temperature and/or with high power, comprising several heating zones arranged vertically one above the other and each being provided with an electrical supply, characterized in that that each zone comprises a number of supports, arranged in an essentially even distribution around the chamber for heating, which simultaneously serve as electrical supplies for the heaters, consisting o£ heating elements and heating element connectors, and that the heater for each zone is arranged such as to be fixed at one end thereof and longitudinally displaceable at the other end thereof 2. A device according to claim 1, characterized in that the heaters are longitudinally displaced by means of guide pins that are located opposite of the electrical supplies. 3. A device according to claim 1, characterized in that the heaters of each zone are arranged on a sole plate and that each sole plate is partitioned in at least one of two and three electrically separate areas. 4. A device according to claim 3, characterized in that the sole plates are connected electrically conductive to all supports in one level by means of joining elements. 5. A device according to claim 1, characterized in that the joining elements connect two supports at a time that are arranged one above the other. 6. A device according to claim 4, characterized in that the joining elements and the ends of the supports are provided with a conical fit. 7. A device according to claim 6, characterized in that the angle of the conical fit is dimensioned such that no automatic interlocking occurs. 8. A device according to claim 4, characterized in that in order to restrict the forces occurring between the joining elements and the supports compressible packs made from expanded graphite are provided. 9. A device according to claim 1, characterized in that the supports are made from graphite material. 10. A device according to claim 3, characterized in that the sole plates are made from CFC materials. 11. A device according to claim 4, characterized in that the joining elements are made from isostatically pressed finest-corn graphites of highest solidity. 12. A device according to claim 1, characterized in that the insulating construction parts are made from Al2O3, BN or AlN. 13. A device according to claim 1, characterized in that each zone comprises a pre-assembled unit comprising a sole plate with insulating components, joining elements with their insulation rings, heating elements with heating element connectors, joining elements, guide pins sand supports. |
Adjustable autofixing sling for treatment of urinary incontinence |
The present invention relates to a sling for treatment of urinary incontinence, consisting of a band which comprises a middle part (2) and two end parts (3), the said sling being such that the said middle part is perforated and the two end parts constitute an autofixing system, the invention also relates to a kit containing, in a sterile manner, at least one sling. |
1. A sling (1) for treatment of urinary incontinence, comprising a band having a middle part (2) and two end parts (3), characterized in that said middle part is perforated and said two end parts constitute an autofixing apparatus, wherein said autofixing apparatus is elastic and adapted to stretch and is designed to stimulate muscle pressure and formation of fibroid tissue to secure said sling when implanted. 2. The sling according to claim 1, characterized in that at least one of the two end parts is made of multiple subunits, the shape of these subunits being selected from the group consisting of conical, triangular, rectangular, square, trapezoidal, rhomboidal, oval, cylindrical, and multispheric shape, whereby said subunits retain their shape when passing through tissues and when surrounded by tissues, said tissues surrounding said subunits thereby conforming to the shape of said subunits thereby retaining said sling in place. 3. The sling according to claim 2, characterized in that at least one of the two end parts is made of conical subunits. 4. The sling according to claim 2, characterized in that the base of each subunit is flat. 5. The sling according to claim 1, characterized in that the middle part (2) is made up of a biocompatible biological or a biocompatible synthetic material. 6. The sling according to claim 5, characterized in that the middle part (2) comprises synthetic materials selected from polyesters, polypropylenes, polyurethanes, polyamides, nylons, silicones, polytetrafluoroethylenes, polyethylene terephthalates, latex, or other theremo-hardened or thermo-formed plastics or gums; or biological materials selected from bovine pericardium, different types of collagen, or other animal or human derivatives such as processed fascia lata, porcine small intestinal submucosa, and tissue regeneration matrix. 7. The sling according to claim 6, characterized in that the middle part (2) is made of silicone or knitted mesh. 8. The sling according to claim 1, characterized in that the middle part contains a reinforcement preferably comprising a polyester mesh. 9. The sling according to claim 1, characterized in that the end parts are made of a material selected from polyesters, polypropylenes, polyurethanes, polyamides, nylons, silicones, polytetrafluoroethylenes, polyethylene terephthalates, latex or other thermo-hardened or thermo-formed plastics or gums. 10 The sling according to claim 1 characterized in that at least one of the end parts contain a perforation. 11. The sling according to claim 1, characterized in that the sling is at least partially impregnated with or covered by an antibiotic, and antimicrobial agent or a combination of both. 12. The sling according to claim 2, characterized in that said sling has two end parts having conical subunits. 13. The sling according to claim 2, characterized in that said sling has two end parts having multispheric shaped subunits. 14. The sling according to claim 1, characterized in that the middle part of the sling has perforations throughout its surface, the shape of the perforations being selected from the group consisting of oval, rectangular, square, circular or any combination thereof. 15. The sling according to claim 14 characterized in that the perforations are symmetrically or randomly distributed. 16. A kit containing, in a sterile manner, at least one sling as defined in claim 1. 17. The sling according to claim 2 characterized in that the base of each subunit has a fish-hook shape. 18. A sling for treatment of urinary incontinence comprising a middle part comprising a flexible web of biocompatible synthetic or natural material and two opposing elongated end parts attached to opposite ends of said middle part and made up of multiple recurring subunits of biocompatible synthetic or natural material, said middle part having a plurality of perforations therethrough and adapted to support a human urethra, and said end parts being adapted for insertion through human muscle tissue whereby said recurring subunits engage said muscle tissue and constitute an autofixing apparatus. 19. The sling of claim 18 further comprising a coating or impregnant of antibiotic or antimicrobial agents or both. 20. The sling of claim 18, wherein said biocompatible synthetic or natural materials are selected from polyesters, polypropylenes, polyurethanes, polyamides, nylons, silicones, polytetrafluoroethylenes, polyethylene terephthalates, latex, bovine pericardium, collagen, processed fascia lata, porcine small intestinal submucosa and tissue regeneration matrix. |
Soldering nozzle for wave soldering printed circuit boards |
The invention relates to a soldering nozzle for wave soldering printed circuit boards with electric components, which comprises rows of solder outlets arranged transversely with respect to the direction of conveyance of the printed circuit boards. Said solder outlets are arranged in a staggered manner from row to row in the direction of conveyance, whereby at least two rows are provided with solder outlets embodied in the form of slots and in each row the slots are arranged parallel to each other in a slanted position with respect to the conveyor device, whereby the slanted position of each row is reversed in relation to the direction of conveyance. |
1. Solder nozzle (7) for the wave soldering of printed-circuit boards (9) with electrical components, said solder nozzle (7) having rows (18, 19, 20) of solder outlet openings disposed transversely to the conveying direction (10) of the printed-circuit boards (9), said rows (18, 19, 20) of solder outlet openings being offset with respect to each other from row to row in the conveying direction, characterized in that at least two rows (18, 19, 20) of solder outlet openings, each in the form of slits (21), are provided and in each row the slits (21) are disposed parallel to each other at an oblique position with respect to the conveying direction (10), the oblique position being reversed from row to row with respect to the conveying direction (10). 2. Solder nozzle according to claim 1, characterized in that the slits (21) of one row are disposed with respect to the conveying direction substantially between the following ends of the slits of the next row. 3. Solder nozzle according to claim 1, characterized in that, with respect to the plane of the printed-circuit boards (9), the slits are inclined in the material of the solder nozzle (7) in such a manner that, from row to row, there result flow directions of the solder which are directed in alternately inclined manner at the printed-circuit boards (9), with the result that, in successive rows, there results a flow direction of the solder whose component transverse to the conveying direction (10) runs in opposite directions from row to row. 4. Solder nozzle according to claim 1, characterized in that disposed between rows with inclined slits is a row with slits aligned substantially at right angles to the plane of the printed-circuit boards (9). |
Diagnostic methods and agents |
The present invention relates generally to a method for detecting an aberrant cell in a subject or in a biological sample from said subject and agents useful for same. The presence of the aberrant cell or group of aberrant cells provides an indication of a particular disease or condition or a propensity for development of a disease or condition. More particularly, the present invention contemplates a method for detecting a cell associated with cancer or having a propensity to develop into a cancer cell in a subject or in a biological sample from said subject by determining the relative increase in the presence of a LIM kinase protein or a related enzyme or a relative increase in LIM kinase activity or a relative increase in the presence of expression products from a gene encoding a LIM kinase or a related protein. The present invention further provides a method for diagnosing the presence of a cancer or cancerous-like growth or distinguishing between an invasive and non-invasive cancer in a subject or in a biological sample from said subject by screening for up-regulation of a LIM kinase or a related protein in a cell or group of cells or an up-regulation in the presence of expression products of genetic sequences encoding a LIM kinase or a related protein. The present invention provides diagnostic agents useful for detecting LIM kinase or expression products of genetic material encoding LIM kinase. Such diagnostic agents include immunointeractive molecules, such as antibodies, and genetic probes for detecting expression products of LIM kinase genes. The present invention further provides genetically modified animals exhibiting altered levels of LIM kinase. Such animals are useful models for screening for anti-cancer agents. |
1. A method for detecting an aberrant cell in a subject or in a biological sample from said subject, said method comprising contacting cells, cell extracts, serum or other sample from said subject or said biological sample with an immunointeractive molecule specific for a LIM kinase or antigenic portion thereof and screening for the level of immunointeractive molecule-LIM kinase complex formations wherein an elevated presence of said complex relative to a normal cell is indicative of an aberrant cell. 2. The method of claim 1 wherein the subject is a mammal. 3. The method of claim 2 wherein the subject is a human. 4. The method of any one of claims 1 to 3 wherein the immunointeractive molecule is an immunoglobulin. 5. The method of claim 4 wherein the immunoglobulin is a monoclonal antibody. 6. The method of claim 4 wherein the immunoglobulin is a polyclonal antibody. 7. The method of claim 1 wherein the LIM kinase is LIM kinase 1. 8. The method of claim 1 wherein the LIM kinase is LIM kinase 2. 9. A method for detecting an aberrant cell in a subject or in a biological sample from said subject, said method comprising screening the level of an expression product of a gene encoding a LIM kinase wherein an elevated level of said expression product compared to a normal cell is indicative of an aberrant cell. 10. The method of claim 9 wherein the subject is a mammal. 11. The method of claim 10 wherein the subject is a human. 12. The method of claim 9 wherein the LIM kinase is LIM kinase 1. 13. The method of claim 9 wherein the LIM kinase is LIM kinase 2. 14. The method of claim 9 wherein the expression product is mRNA or cDNA. 15. A method for diagnosing the presence of cancer or cancer-like growth in a subject, said method comprising contacting cells or cell extracts from said subject or a biological sample from said subject with a LIM kinase-binding effective amount of an antibody having specificity for said LIM kinase or an antigenic determinant or epitope thereon and then quantitatively or qualitatively determining the level of a LIM kinase-antibody complex wherein the presence of elevated levels of said complex compared to a normal cell is indicative of the presence of a cancer. 16. A method for diagnosing the presence of a cancer in a subject, said method comprising obtaining mRNA from cells of said subject or from a biological sample from said subject and optionally generating cDNA and contacting said mRNA or cDNA with a genetic probe capable of hybridizing to and/or amplifying all or part of a nucleotide sequence encoding LIM kinase or its complementary nucleotide sequence and then detecting the level of said mRNA or cDNA wherein the presence of elevated levels of said mRNA or cDNA compared to normal controls is indicative of the presence of cancer. 17. The method of claim 15 or 16 wherein the LIM kinase is LIM kinase 1. 18. The method of claim 15 or 16 wherein the LIM kinase is LIM kinase 2. 19. The method of claim 15 or 16 wherein the subject is a mammal. 20. The method of claim 19 wherein the mammal is a human. 21. The method of claim 16 wherein mRNA levels are determined by PCR. 22. The method of claim 21 wherein the PCR is real-time PCR. 23. A deimmunized antibody molecule having specificity for an epitope recognized by a monoclonal antibody to LIM kinase wherein at least one of the CDRs of the variable domain of said deimmunized antibody is derived from the said monoclonal antibody to LIM kinase and the remaining immunoglobulin-derived parts of the deimmunized antibody molecule are derived from an immunoglobulin or an analog thereof from the host for which the antibody is to be deimmunized. 24. A method for detecting cancer cells in a human patient, said method comprising introducing into said patient a deimmunized form of a non-human derived monoclonal antibody specific for human LIM kinase or an antigenic determinant thereon labeled with a reporter molecule, allowing dissemination of the labeled antibody throughout the circulatory system, or to selected parts of the circulatory system and then subjecting said patient to reporter molecule-detection means to identify the location of the antibody. 25. The method of claim 24 wherein the cancer comprises hyperplastic/neoplastic cells of hematopoietic origin. 26. The method of claim 25 wherein the cancer is selected from acute promyeloid leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, prolymphocytic leukemia, hairy cell leukemia or Wodenstrom's macroglobulinemia. 27. The method of claim 25 or 26 wherein the cancer is breast cancer. 28. The method of claim 25 or 26 wherein the cancer is in the lung, gastrointestinal trait or genito-urinary tract. 29. The method of claim 25 or 26 wherein the cancer is fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcimona, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilm's tumor, cervical cancer, testicular tumor, lung carcinoma, small cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medullobalstoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oliogdendroglioma, meningioma, melanoma, neuroblastoma or retinoblastoma. 30. A method for the treatment of a patient having cancer, said method comprising administering to said human a cancer cell growth inhibiting-effective amount of an antibody having specificity for human LIM kinase and being substantially non-immunogenic and further comprising a cell growth inhibiting or cell killing agent fused, bound or otherwise associated thereto. 31. A method of treating a patient having cancer or a related condition, said method comprising the administration to said patient of a LIM kinase-inhibiting effective amount of an agent for a time and under conditions sufficient to inhibit the activity of LIM kinase or reduce levels of LIM kinase and to reduce cancer cell growth. 32. A composition comprising an agent capable of acting as a modulator of LIM kinase activity or gene expression and one or more pharmaceutically acceptable carriers and/or diluents. 33. A method for the treatment of a patient having cancer, said method comprising administering to said human, a genetic composition comprising a genetic construct which down-regulates expression of a gene encoding LIM kinase. 34. Use of a monoclonal antibody to LIM kinase in the manufacture of a quantitative or semi-quantitative diagnostic kit to determine relative levels of LIM kinase in suspected cancer cells from a patient. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Bibliographic details of the publications referred to in this specification are collected at the end of the description. Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country. Cancer is one of the most debilitating disease conditions affecting humans and the incidence and prevalence of cancer is increasing. A number of risk factors are associated with the development of cancer or with the likelihood of development of cancer and these include genetic predispositions, familial forms of cancer and environmental factors. The environment is constantly changing and populations are exposed to high levels of potentially toxic compounds on a daily basis. The increasing affluence of populations and societies also means expansion of industrial endeavours and many of these industries use potentially toxic compounds. There is a need, therefore, to provide to rapid detection of cancer cells and to use this information to effect early diagnosis of and clinical intervention in the treatment or prophylaxis of the cancer. A number of cancer markers have been proposed. However, as the threat of cancer increases and as the population grows older, it is important to search for new markers which may be more efficacious or accurate in a cancer assay. Furthermore, it is significant that there is currently no diagnostic test for ovarian cancer. As a result, this cancer is usually metastatic when identified and this is then often too late for interventionist or preventionist therapy. In work leading up to the present invention, the inventors investigated LIM kinase. This enzyme contains two LIM motifs at the N-terminal portion of the molecule. Two forms of LIM kinase are known, LIM kinase 1 and LIM kinase 2. LIM kinase is important in regulating actin dynamics and hence has a role in cell division, development and migration. The present inventors have now determined that LIM kinase is up-regulated in cancer cells and in particular invasive cancer cells relative to normal cells or non-invasive cancer cells. This provides a useful marker for the diagnosis of cancer by immunological and genetic assays and permits development of cancer targeting agents for cancer imaging and to generate anti-cancer agents. |
<SOH> SUMMARY OF THE INVENTION <EOH>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 element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers. The present invention is predicated in part on the determination that LIM kinase is up-regulated in cancer cells and in particular invasive cancer cells relative to normal or non-invasive cancer cells. LIM kinase is an enzyme involved in the regulation of actin dynamics and is particularly important for cell division, development and migration. The identification of a cancer-specific marker permits development of a range of diagnostic agents, including cancer imaging agents and cancer targeting agents having therapeutic applications. Accordingly, the present invention in one aspect contemplates a method for detecting an aberrant cell in a subject or in a biological sample from the subject by contacting cells, cell extracts, serum or other sample from the subjects or said biological sample with an immunointeractive molecule specific for a LIM kinase or antigenic portion thereof and screening for the level of immunointeractive molecule-LIM kinase complex formation wherein an elevated presence of the complex relative to a normal cell is indicative of an aberrant cell. In an alternative embodiment, the aberrant cell is detected at the genetic level by screening for the level of an expression of a gene encoding a LIM kinase wherein an elevated level of the expression product compared to a normal cell is indicative of an aberrant cell. Real-time PCR as well as other PCR procedures are useful for determining transcriptional activity. Elevated levels of LIM kinase gene transcriptional activity is proposed to be indicative of cancer or a propensity for development of cancer. These methods are useful inter alia for diagnosing the presence of cancer or cancer-like growth in a subject. For example, cells or cell extracts are screened immunologically for the presence of elevated levels of LIM kinase. Alternatively, mRNA is obtained from cells of a subject or from a biological sample from a subject and cDNA optionally generated. The mRNA or cDNA is then contacted with a genetic probe capable of hybridizing to and/or amplifying all or part of a nucleotide sequence encoding LIM kinase or its complementary nucleotide sequence and then the level of the mRNA or cDNA is detected wherein the presence of elevated levels of the mRNA or cDNA compared to normal controls is indicative of the presence of cancer. These tests are not only useful for diagnosing the presence of a primary cancer but also for assessing the risk of remission based on monitoring residual cancer cells. The present invention further contemplates diagnostic and therapeutic agents. In one embodiment, the present invention provides a deimmunized antibody molecule having specificity for an epitope recognized by a monoclonal antibody to LIM kinase wherein at least one of the CDRs of the variable domain of the deimmunized antibody is derived from the the monoclonal antibody to LIM kinase and the remaining immunoglobulin-derived parts of the deimmunized antibody molecule are derived from an immunoglobulin or an analog thereof from the host for which the antibody is to be deimmunized. The deimmunized antibody may be used, for example, for cancer imaging. In one embodiment, the method comprises introducing into a patient a deimmunized form of a non-human derived monoclonal antibody specific for human LIM kinase or an antigenic determinant thereon labeled with a reporter molecule, allowing dissemination of the labeled antibody throughout the circulatory system, or to selected parts of the circulatory system and then subjecting the patient to reporter molecule-detection means to identify the location of the antibody. Yet another aspect of the present invention contemplates a method for the treatment of a patient having cancer by administering to the human a cancer cell growth inhibiting-effective amount of an antibody having specificity for human LIM kinase wherein the antibody is substantially non-immunogenic and further comprises a cell growth inhibiting or cell killing agent fused, bound or otherwise associated thereto. The method may alternatively involve the use of genetic means to inhibit LIM kinase gene expression. The present invention may also extend to the use of modulators of LIM kinase activity to inhibit LIM kinase and reduce cancer cell growth. Some conditions may also benefit from promoting cell growth by up-regulating LIM kinase activity. Reference to “modulators” of LIM kinase activity include agents which act at the protein level or the level of LIM kinase gene expression or post-transcriptional processes. The present invention contemplates, therefore, compositions comprising the cancer targeting agents of the present invention and one or more pharmaceutically acceptable carriers and/or diluents. The compositions may also comprise modulators of LIM kinase gene expression or protein activity. Yet another aspect of the present invention contemplates the use of a monoclonal antibody to LIM kinase in the manufacture of a quantitative or semi-quantitative diagnostic kit to determine relative levels of LIM kinase in suspected cancer cells from a patient. The kit may come with instructions for use and may be automated or semi-automated or in a form which is compatible with automated machine or software. |
METHOD AND APPARATUS FOR HEATING A SLURRY TO A PREDETERMINED TEMPERATURE |
The temperature of a metallurgical slurry in a heater vessel is accurately controlled by heating a first portion of the slurry in the heater vessel by contact with a heating medium such as steam, and by adding to the heater vessel controlled portions of a slurry at lower temperature. The lower temperature slurry may be added to the heater vessel in an intermittent or continuous manner, with addition of the lower temperature slurry being regulated by a valve, the operation of which is controlled by a control device which receives temperature information from one or more temperature sensors. |
1. An apparatus for heating a slurry to a predetermined temperature, comprising: (a) a heater vessel having a slurry heating section and a slurry collection section downstream of the slurry heating section, wherein slurry heated in the heating section is collected in the collection section; (b) a heating medium inlet through which a heating medium for heating the slurry enters the heater vessel; (c) a first slurry inlet through which a first portion of the slurry enters the vessel and contacts the heating medium in the heating section; (d) a second slurry inlet through which a second portion of the slurry enters the vessel, the second slurry inlet being located relative to the heating section such that a temperature of the second portion of the slurry entering the collection section is lower than a temperature of the first portion of the slurry entering the collection section; (e) a slurry outlet adjacent the collection section; (f) temperature sensing means for sensing the temperature of the slurry in the collection section; (g) a valve for controlling flow of the second portion of the slurry into the vessel through the second slurry inlet so as to control the temperature of the slurry in the collection section. 2. The apparatus according to claim 1, wherein the second slurry inlet is located such that the second portion of the slurry bypasses at least a portion of the heating section. 3. The apparatus according to claim 1, wherein the second slurry inlet is located downstream of the heating section such that the second portion of the slurry flows directly into the collection section without passing through the heating section. 4. The apparatus according to claim 1, wherein the slurry heating section is located in an upper portion of the heater vessel and the collection section is located in a lower portion of the heater vessel. 5. The apparatus according to claim 4, wherein the first slurry inlet is located above the slurry heating section, and the heating medium inlet is located below the slurry heating section, and wherein the heating medium is a gas which passes upward through the heating vessel in countercurrent flow relative to the first portion of the slurry. 6. The apparatus according to claim 4, wherein the slurry heating section comprises a plurality of baffles over which the first portion of the slurry flows. 7. The apparatus according to claim 1, further comprising a first conduit through which the first portion of the slurry is delivered to the heater vessel, and a second conduit through which the second portion of the slurry is delivered to the heater vessel, the valve controlling flow of the slurry through the second conduit. 8. The apparatus according to claim 7, wherein both the first conduit and second conduit receive slurry from a third conduit. 9. The apparatus according to claim 1, wherein the valve adjustably controls the flow of slurry to the heater vessel between a zero flow rate and a maximum flow rate. 10. A method for heating a slurry to a predetermined temperature in a heater vessel having a slurry heating section and a slurry collection section downstream of the slurry heating section, the method comprising: (a) feeding a heating medium into the heater vessel such that the heating medium passes through the heating section; (b) feeding a first portion of the slurry into the heater vessel such that the first portion of the slurry passes through the heating section and is heated by the heating medium; (c) controllably feeding a second portion of the slurry into the heater vessel such that it bypasses at least a portion of the heating section; (d) collecting the first and second portions of the slurry in the collection section, wherein a temperature of the second portion of the slurry as it enters the collection section is lower than a temperature of the first portion of the slurry as it enters the collection section; and (e) monitoring a temperature of the slurry collected in the collection section; wherein the feeding of the second portion of the slurry into the heater vessel is controlled such that when the temperature of the slurry collected in the collection section exceeds the predetermined temperature, the second portion of the slurry is added into the heater vessel to lower the temperature of the slurry in the collection section, and when the temperature of the slurry in the collection section is less than the predetermined temperature, addition of the second portion of the slurry to the heater vessel is diminished or discontinued. 11. The method according to claim 10, wherein the heating medium is a gas. 12. The method according to claim 10, wherein the heating medium is steam. 13. The method according to claim 10, wherein the heating medium is fed into the heater vessel downstream of the heating section and passes upwardly through the heating section. 14. The method according to claim 10, wherein the first portion of the slurry enters the heater vessel in an upper portion thereof, and flows downward through the heating section by gravity. 15. The method according to claim 10, wherein the second portion of the slurry bypasses the heating section and flows directly into the collection section. 16. The method according to claim 10, wherein the first portion of the slurry and the heating medium are continuously fed into the heater vessel. 17. The method according to claim 10, wherein the temperature of the slurry collected in the collection section is monitored continuously. 18. The method according to claim 10, wherein the slurry collected in the collection section is continuously withdrawn through an outlet located at a bottom of the collection section. 19. The method according to claim 10, wherein the second portion of the slurry is continuously fed into the heater vessel. |
<SOH> BACKGROUND OF THE INVENTION <EOH>A number of metallurgical processes involve the treatment of aqueous slurries containing solid, metal-containing particles. In one such metallurgical process, an aqueous slurry of a mineral or metal-containing compound is subjected to leaching or oxidation at elevated temperatures and pressures in an autoclave. In order to maximize the efficiency of the leaching or oxidation process, it is preferred to preheat the slurry before feeding it into the autoclave. For this purpose, a heater vessel is provided upstream of the autoclave. The slurry is heated by contact with a heating medium inside the heater vessel. The heating medium typically comprises steam generated by an autoclave flashing process. It is preferred that the temperature of the slurry be heated to within a narrow temperature range inside the heater vessel. The temperature of the discharge slurry is typically maintained by controlling the flash steam pressure in the apparatus (by venting). However, precise control of the slurry temperature is difficult to achieve in this manner as there are a number of other process variables such as autoclave throughput, heating medium composition, feed slurry specific heat capacity and boiling point elevation, which affect the quantity and quality of heating medium condensed by the process, and control of the vent gas flow is not always practical. Accordingly, there is a need for improved apparatus and methods for heating slurries in a heater vessel. |
<SOH> SUMMARY OF THE INVENTION <EOH>The present invention overcomes the disadvantages of the prior art by providing an apparatus and method for heating a slurry to a predetermined temperature. According to the invention, a first portion of the slurry is heated in the heater vessel as in the prior art by contact with the heating medium. The heated slurry is combined with controlled portions of slurry at a lower temperature to accurately maintain the temperature of the heated slurry within the accepted range. The inventors have found that the method and apparatus for heating slurry according to the invention allows more accurate control of the temperature of the slurry heated within the heater vessel. In one aspect, the present invention provides an apparatus for heating a slurry to a predetermined temperature, comprising: (a) a heater vessel having a slurry heating section and a slurry collection section downstream of the slurry heating section, wherein slurry heated in the heating section is collected in the collection section; (b) a heating medium inlet through which a heating medium for heating the slurry enters the heater vessel; (c) a first slurry inlet through which a first portion of the slurry enters the vessel and contacts the heating medium in the heating section; (d) a second slurry inlet through which a second portion of the slurry enters the vessel, the second slurry inlet being located relative to the heating section such that a temperature of the second portion of the slurry entering the collection section is lower than a temperature of the first portion of the slurry entering the collection section; (e) a slurry outlet adjacent the collection section; (f) temperature sensing means for sensing the temperature of the slurry in the collection section; and (g) a valve for controlling flow of the second portion of the slurry into the vessel through the second slurry inlet so as to control the temperature of the slurry in the collection section. In another aspect, the present invention provides a method for heating a slurry to a predetermined temperature in a heater vessel having a slurry heating section and a slurry collection section downstream of the slurry heating section, the method comprising: (a) feeding a heating medium into the heater vessel such that the heating medium passes through the heating section; (b) feeding a first portion of the slurry into the heater vessel such that the first portion of the slurry passes through the heating section and is heated by the heating medium; (c) controllably feeding a second portion of the slurry into the heater vessel such that it bypasses at least a portion of the heating section; (d) collecting the first and second portions of the slurry in the collection section, wherein a temperature of the second portion of the slurry as it enters the collection section is lower than a temperature of the first portion of the slurry as it enters the collection section; and (e) monitoring a temperature of the slurry collected in the collection section; wherein the feeding of the second portion of the slurry into the heater vessel is controlled such that when the temperature of the slurry collected in the collection section exceeds the predetermined temperature, the second portion of the slurry is added into the heater vessel to lower the temperature of the slurry in the collection section, and when the temperature of the slurry in the collection section is less than the predetermined temperature, addition of the second portion of the slurry to the heater vessel is diminished or discontinued. |
Geographic information system having dynamic data model |
A geographic information system includes a data model server, and computer software executing on a computer server. The data model server includes a business data model and a spatial data model. The business data model includes business attribute data, and the spatial data model includes spatial attribute data associated with the business attribute data. One of the data models includes meta-data defining relationships between the data. The computer software includes a GIS engine in communication with the data models. The GIS engine is configured to manipulate the data attributes in accordance with a user request, and to render the manipulated data on the client terminal. |
1. A geographic information system comprising: a data model server including a business data model and a spatial data model, the business data model including business attribute data, the spatial data model including spatial attribute data associated with the business attribute data, one of the data models including meta-data defining relationships between the data; and computer software executing on the computer server, the computer software including a GIS engine in communication with the data models, the GIS engine being configured to manipulate the data attributes in accordance with a user request and to render the manipulated data on the client terminal. 2. The geographic information system according to claim 1, wherein the GIS engine is configured to render the manipulated data by generating code for effecting a vector graphics update by the client terminal. 3. The geographic information system according to claim 2, wherein the data model includes user-specific data, and the GIS engine is configured to effect the graphics update in accordance with the user-specific data. 4. A GIS computer server in communication with a data model server, the data model server including a business data database and a spatial data database, the business data database including business attribute data, the spatial data database including spatial attribute data associated with the business attribute data, one of the databases including meta-data defining relationships between the data, the GIS server including software defining a GIS engine, the GIS engine being configured: to receive from a client terminal an update to attributes associated with a selected data element from one of the data models; to update the one data model with the attribute update; and to update a rendering device on the client terminal in accordance with the attribute update. 5. The GIS server according to claim 4, wherein the GIS engine is configured to update the rendering device by generating code for effecting a vector graphics update by the client terminal. 6. The GIS server according to claim 5, wherein the data model includes user-specific data, and the GIS engine is configured to effect the graphics update in accordance with the user-specific data. 7. A method of rendering GIS data, comprising the steps of: maintaining an attribute data model including at least business attribute data, and a spatial data model including spatial attribute data associated with the business attribute data, the data models including meta-data defining relationships between the data; receiving from a client terminal a selection of the attribute data, and updating at least one of the data models in accordance with the data selection; and formatting the selected data in accordance with the associated meta-data for rendering by the client terminal. 8. The method according to claim 7, wherein the formatting step comprises generating code for effecting a vector graphics update by the client terminal. 9. The method according to claim 8, wherein the data model includes user-specific data, and the formatting step comprises effecting the graphics update in accordance with the user-specific data. 10. A computer-readable medium containing processing instructions thereon for a computer which, when executed by the computer, cause the computer to perform the steps of: maintaining an attribute data model including at least business attribute data, and a spatial data model including spatial attribute data associated with the business attribute data, the data models including meta-data defining relationships between the data; receiving from a client terminal a selection of the attribute data, and updating at least one of the data models in accordance with the data selection; and formatting the selected data in accordance with the associated meta-data for rendering by the client terminal. 11. The computer-readable medium according to claim 10, wherein the formatting step comprises generating code for effecting a vector graphics update by the client terminal. 12. The computer-readable medium according to claim 11, wherein the data model includes user-specific data, and the formatting step comprises effecting the graphics update in accordance with the user-specific data. |
<SOH> BACKGROUND OF THE INVENTION <EOH>Geographic information systems (GIS) provide a mechanism for associating and representing data having both a spatial and a tabular data component. GIS solutions are becoming increasingly popular in view of their ability to present a significant amount of data visually, and their ability to organize data based on geographical relevance. Conventional GIS solutions have included a database of spatial and text data, a GIS server for accessing the data in the database, and one or more user terminals in communication with the GIS server over a local area network (LAN). The user terminals are provided with software which depicts the spatial data in a predetermined manner, typically in the form of a map. The GIS server is provided with software which responds to requests from the user terminals for spatial data, thereby allowing the user to obtain different “aerial” views of selected areas within the map. With the quantity and variety of data available over wide area networks, however, attempts have been made to provide GIS solutions which can tap into diverse (and often incompatible) sources of data. For instance, Hougaard (U.S. Pat. No. 6,216,130) teaches a geographic-based information technology management system that includes an administrator server, and a user terminal in communication over a network, such as the Internet. The administrator server includes an administrator software application, and the user terminal includes a user software application. To initialize the GIS, the administrator locates data structures of interest (such as geographic data, tabular data, and application programs for accessing the data). The data structures can be located over the Internet, at the administrator server, or at the user terminal. The administrator then uses the administrator application to compile a series of data references which include address information (eg. URLs) to facilitate subsequent retrieval of the data structures, and display information which specifies the display format and other display properties of the data structure. The user application includes a user interface generated on the display screen of the user terminal. To view a data structure, the user communicates its selection via the user interface to the administrator application, and receives the appropriate address information and display information in response. The user then establishes communication with the selected data structures using the received address information, and receives the requested data and applications at the user application. The user interface then uses the retrieved applications to generate a map display of the retrieved geographical data, and a graphic/text display of the retrieved tabular data. The applications are also used to communicate changes on the map display (eg. selecting a point of interest) to the graphic/text display (and vice versa). Although Hougaard provides the administrator and user with some flexibility in assembling and accessing GIS data from a variety of sources of a wide area network, the views available to the user are limited by the data maintained by the data structures. Consequently, if, for example, a user wished to view a map of a city with apartment buildings, and then subsequently without apartment buildings, Hougaard would be unable to provide this solution unless the administrator was able to locate a data structure depicting the city with apartment buildings, and other data structure depicting the city without apartment buildings. Also, the requirement that the client download applications to view the selected data renders the solution cumbersome for use with devices having limited computing resources. Therefore, there remains a need for a GIS solution which provides the user with increased flexibility in the manner in which the data is presented. In addition, there remains a GIS solution which does not impose a significant computation burden on the rendering client. |
<SOH> SUMMARY OF THE INVENTION <EOH>According to a first aspect of the present invention, there is provided a geographic information system which includes a data model server, and computer software executing on a computer application server. The data model server includes a business data model and a spatial data model. The business data model includes business attribute data, and the spatial data model includes spatial attribute data associated with the business attribute data. One of the data models includes meta-data defining relationships between the data. The computer software includes a GIS engine in communication with the data models. The GIS engine is configured to manipulate the data attributes in accordance with a user request, and to render the manipulated data on the client terminal. According to a second aspect of the present invention, there is provided a GIS computer server in communication with a data model server. The data model server includes a business data database and a spatial data database. The business data database includes business attribute data, and the spatial data database includes spatial attribute data associated with the business attribute data. One of the databases includes meta-data defining relationships between the data. The GIS server includes software defining a GIS engine. The GIS engine is in communication with means for rendering the data on a computer terminal, and is configured: to receive from a client terminal an update to attributes associated with a selected data element from one of the data models; to update the one data model with the attribute update; and to update a rendering device on the client terminal in accordance with the attribute update. According to a third aspect of the present invention, there is provided a method of rendering GIS data, according to the steps of (1) maintaining an attribute data model including at least business attribute data, and a spatial data model including spatial attribute data associated with the business attribute data, the data models including meta-data defining relationships between the data; (2) receiving from a client terminal a selection of the attribute data, and updating at least one of the data models in accordance with the data selection; and (3) formatting the selected data in accordance with the associated meta-data for rendering by the client terminal. In one implementation of the invention, the GIS engine is configured to render the manipulated data by generating code for effecting a vector graphics update by the client terminal. Also, the data model includes user-specific data, and the GIS engine is configured to effect the graphics update in accordance with the user-specific data. Since the GIS engine does not merely establish alternate “aerial” views of the spatial data, but instead allows users to update the attribute data of the business and spatial attribute data models, the user is provided with increased flexibility in the manner in which the data can be presented and/or queried. Further, since the rendering of data on the client terminal is performed by the application server, rather than the client terminal, the computation burden on the rendering client is limited. |
Fixing device, clamping system and allocated tool |
The aim of the invention is to fix or detach tools (23, 38) comprising a disc-shaped tool body (21, 28), in particular cutting discs, rough-grinding discs or fan grinding discs, to or from a machine tool, in a simple manner, without involving complex and expensive resources. To achieve this, the invention provides a fixing device (1, 32), in addition to a tool that is designed to interact with the fixing device and has a disc-shaped tool body with a central opening, which together form a clamping system. According to the invention, the fixing device, which can be mounted onto a machine tool, or is attached to the machine tool in a fixed manner, comprises at least one radially outward-facing projection (5) of a lock that can be operated in the absence of a tool, said lock detachably connecting the fixing device to the tool. In the locked position, the radially outward-facing projection or projections (5) of the fixing device (1, 32) fits/fit over an inward-facing locking surface (22) of the tool, thus axially securing the tool body and mounting the latter so that it can rotate in a fixed manner. The radially outward-facing projection(s) (5) and a bearing surface (7, 35), on which the tool lies, are arranged so that they can be displaced axially in relation to one another, whereby said axial displacement path can be blocked by a centrifugal-force assembly (14, 17; 41, 43). |
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