The invention relates to a new process for preparing (1xcex1,2xcex2,4xcex2,5xcex1,7xcex2)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane-bromide.

The invention relates to a new process for preparing (1xcex1,2xcex2,4xcex2,5xcex1,7xcex2)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane-bromide.
The compound (1xcex1,2xcex2,4xcex2,5xcex1,7xcex2)-7-[(hydroxydi-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azoniatricyclo[3.3.1.02,4] nonane-bromide is known from European Patent Application EP 418 716 A1 and has the following chemical structure:
The compound has valuable pharmacological properties and is known by the name tiotropium bromide (BA679). Tiotropium bromide is a highly effective anticholinergic and can therefore provide therapeutic benefit in the treatment of asthma or COPD (chronic obstructive pulmonary disease).
Tiotropium bromide is preferably administered by inhalation. Suitable inhalable powders packed into appropriate capsules (inhalettes) may be used, which are administered using corresponding powder inhalers. Alternatively, it may be administered by the use of suitable inhalable aerosols. These also include powdered inhalable aerosols which contain, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.
In view of its great efficacy, tiotropium bromide can be used in low therapeutic doses. On the one hand this imposes particular demands on the pharmaceutical production of the formulation to be used, and on the other hand it is particularly necessary to develop an industrial process for synthesising tiotropium bromide which ensures that the product is prepared not only in a good yield but also with exceptional purity,
European Patent Application EP 418 716 A1 discloses a method of synthesising tiotropium bromide. It corresponds to the method diagrammatically shown in Diagram 1.
Diagram 1
In a first step, scopine (II) is reacted with methyl di-(2-thienyl)-glycolate-(III) to form di-(2-thienyl)-glycolic acid scopine ester (IV), which is then quaternized to form tiotropium bromide.
It has been found that, surprisingly, tiotropium bromide can be obtained in much purer form if it is synthesised by a different method from that described in EP 418 716 A1. This alternative and surprisingly more advantageous method is diagrammatically illustrated in Diagram 2.
Diagram 2
Starting from the tropenol (V) known in the art and reacting with di-(2-thienyl)-glycolic acid derivatives (VI), first the tropenol di-(2-thienyl)-glycolate (VII) is formed. This is converted into the corresponding scopine ester (IV) by epoxidation of the olefinic double bond.
Accordingly, the present invention relates to a process for preparing tiotropium bromide (I)
characterised in that the tropenol ester of formula (VII)
is oxidised to form the scopine ester of formula (IV)
which is then quaternized with methyl bromide to form tiotropium bromide (I).
Because of the central importance of the tropenol ester of formula (VII) according to the invention, in another aspect, the present invention relates generally to the use of the tropenol ester (VII), optionally in the form of the acid addition salts thereof, for preparing tiotropium bromide (I). In another aspect, the present invention relates to the use of the tropenol ester (VII), optionally in the form of the acid addition salts thereof, for preparing the scopine ester of formula (IV).
When tropenol ester (VII) is used in the form of an acid addition salt for preparing the scopine ester (IV), this acid addition salt is preferably selected from among hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate; the hydrochloride and hydrobromide are particularly preferred.
According to another aspect, the present invention relates to a process for preparing tiotropium bromide of formula (I)
characterised in that in a first step tropenol of formula (V),
optionally in the form of the acid addition salts thereof, is reacted with an ester of formula (VI)
wherein R denotes a group selected from among hydroxy, methoxy, ethoxy, Oxe2x80x94N-succinimide, Oxe2x80x94N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, xe2x80x94S-methyl, xe2x80x94S-ethyl and xe2x80x94S-phenyl, to form the tropenol ester of formula (VII)
which is then epoxidised in a second step to form the scopine ester of formula (IV)
and this is then quaternized in a third step using methylbromide to obtain tiotropium bromide (I).
Because of the central importance of the tropenol (V) as a starting material for preparing tiotropium bromide (I), in another aspect the present invention further relates to the use of tropenol (V), optionally in the form of the acid addition salts thereof, as a starting material for preparing tiotropium bromide (I).
To prepare the tropenol ester (VII), tropenol, optionally in the form of an acid addition salt thereof selected from among the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate, preferably in the form of the hydrochloride or hydrobromide, most preferably in the form of the hydrochloride, is taken up in a suitable organic solvent, preferably in a solvent selected from among toluene, benzene, n-butylacetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidinone, preferably selected from among toluene, benzene, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidinone, most preferably toluene or benzene, toluene being most particularly preferred as the solvent. According to the invention, 0.5-3 l, preferably 0.75-2.5 l, most preferably between 1.25 and 1.75 l of organic solvent are used per mol of tropenol (V) put in.
If tropenol is used in the form of an acid addition salt thereof, a base is added to the resulting mixture to liberate the tropenol. Suitable bases according to the invention are inorganic or organic bases, organic amines being particularly preferred. Organic amines which may be used include triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylpyrrolidine, N-methylmorpholine or ammonia, the use of triethylamine, diisopropylethylamine, pyridine or ammonia being particularly preferred, while ammonia is most particularly preferred. At least 1 mol, preferably 1.25 to 2.5 mol, most preferably 1.5 to 2 mol of amine are added, per mol of tropenol salt used. The amine may be added at temperatures of between 0 and 60xc2x0 C., preferably 15 to 50xc2x0 C., most preferably 20 to 30xc2x0 C. After the amine has been added, the suspension obtained is stirred at constant temperature for between 0.1 to 5 h, preferably between 0.5 to 2.5 h, most preferably between 0.75 and 1.5 h.
The ammonium salt thus obtained is filtered off and optionally washed with the organic solvent mentioned above. Between 0.1 and 1.5 l, preferably 0.3-1.0 l of solvent are used per mol of tropenol (V) put in.
Some of the solvent is distilled off in vacuo at elevated temperature, preferably at 30-80xc2x0 C., most preferably at 40 to 60xc2x0 C. The distillation temperature naturally depends on the choice of solvent used. Depending on the choice of solvent, the vacuum is adjusted so that distillation takes place in the temperature range specified above. Between 0.25 and 2 l, preferably 0.5-1.5 l of solvent are distilled off per mol of tropenol (V) put in. After the specified amount of solvent has been distilled off, the reaction solution is cooled to a temperature range of from 0-50xc2x0 C., preferably to 15-35xc2x0 C., and the di-(2-thienyl)glycolic acid derivative (VI) is added. Di-(2-thienyl)glycolic acid derivatives (VI) which may be used according to the invention are those compounds wherein R denotes hydroxy, methoxy, ethoxy, Oxe2x80x94N-succinimide, Oxe2x80x94N-phthalimide, phenyloxy, nitrophenyloxy, fluorophenyloxy, pentafluorophenyloxy, vinyloxy, xe2x80x94S-methyl, xe2x80x94S-ethyl or xe2x80x94S-phenyl. It is particularly preferred to use the compound (VI) wherein R denotes hydroxy, methoxy or ethoxy, most preferably methoxy or hydroxy. If the compound wherein R is hydroxy is used as the compound (VI), the reaction may be carried out in the presence of coupling reagents such as carbonyldiimidazole, carbonyldi-1,2,4-triazole, dicyclohexylcarbodiimide or ethyl-dimethylaminopropylcarbodiimide. Between 1 and 2 mol of compound (VI) are used per mol of tropenol (V) put in. Preferably, 1-1.5 mol of (VI) are used, and most preferably stoichiometric amounts of (VI) compared with (V) are used according to the invention. The reaction mixture obtained may optionally be heated to form a solution. A temperature in the range from 30-80xc2x0 C., preferably from 40-60xc2x0 C., most preferably about 45-55xc2x0 C. is chosen.
The solution thus obtained is then added to another solution or mixture of an inorganic or organic base in one of the abovementioned solvents, preferably in the solvent which is used to prepare the mixture of (V) and (VI). Between 0.2 and 2.0 l, preferably 0.4-1.5 l, most preferably 0.5 to 1.0 l of solvent are used per mol of tropenol (V) put in, in order to prepare the solution or mixture containing a base. Where R equals methoxy, ethoxy, vinyloxy, phenyloxy, xe2x80x94S-methyl, xe2x80x94S-ethyl or xe2x80x94S-phenyl the reaction is carried out in the presence of an organic or inorganic base. The organic bases used are preferably organic amines, most preferably diisopropylethylamines, triethylamines, cyclic amines such as DBU or pyridine. Suitable inorganic bases are the alkali metal or alkaline earth metal carbonates, the alkoxides and hydrides of lithium, sodium, potassium, calcium such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. Most preferably, the inorganic base used is one of the abovementioned hydrides or alkoxides, preferably one of the abovementioned hydrides, the use of sodium hydride being particularly preferred according to the invention. At least stoichiometric amounts of base are used per mol of tropenol (V). Preferably, 1-3 mol, most preferably 1.25-2.5 mol, even more preferably 1.5 to 2 mol of base are used per mol of tropenol (V).
The solution of (V) and (VI) is combined with the base-containing solution or mixture described above, preferably over a period of 0.2-2.0 h, preferably over a period of 0.5 to 1.5 h. If an ester in which R denotes methoxy or ethoxy is used as the compound (VI), for example, it may be necessary to distil off the resulting alcohol at 40-90xc2x0 C., preferably at 50 to 80xc2x0 C., most preferably at 60-75xc2x0 C. in vacuo, preferably at 150 to 500 mbar, most preferably at 200-350 mbar, particularly preferably at 250-300 mbar. This procedure shifts the equilibrium of the reaction towards the tropenol ester (VII). Under these reaction conditions, some of the solvent is also distilled off. After the distillation is complete (about 5 to 10 h), the quantity of solvent distilled off can be added to the reaction solution if desired.
In any case, once distillation is complete, the solution obtained is cooled down again to a temperature range of below 40xc2x0 C., preferably 0-35xc2x0 C., most preferably 10-25xc2x0 C. Hydrochloric acid is added to this mixture at constant temperature over a period of 0.2 to 2 h, preferably 0.4-0.6 h. The hydrochloric acid may be added either in the form of aqueous solutions or as a gas; the addition of aqueous solutions is preferred. Preferably, concentrated hydrochloric acid (36%) dissolved in water is added. Between 1 and 4 mol, preferably 1.5-3 mol, most preferably 2.0 to 2.5 mol HCl are preferably added per mol of tropenol (V) used. Preferably, 0.1-0.4 kg, most preferably 0.15-0.25 kg of 36% aqueous hydrochloric acid dissolved in 10-20 liters, preferably in 12-17 liters of water are added per mol of tropenol (V).
After everything has been added and the mixture has been thoroughly stirred the aqueous phase is separated off. It is then washed with a suitable water-immiscible organic solvent. The preferred solvent is a water-immiscible solvent selected from among methylene chloride and n-butylacetate, preferably methylene chloride. If desired, the first organic phase used to extract the aqueous phase is discarded and the extraction process is repeated once more.
The aqueous phase, optionally after previously being washed with one of the abovementioned water-immiscible solvents, is mixed once more with the water-immiscible solvent. Preferably 1-5 l, preferably 2-4 l, most preferably 2.5-3.5 l of the water-immiscible solvent are used per mol of tropenol (V) originally put in. The mixture thus obtained is combined with an inorganic base, preferably selected from the alkali metal or alkaline earth metal carbonates of lithium, sodium, potassium, calcium such as, for example, sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, sodium carbonate being particularly preferred, and thus adjusted to a pH of 7.5 to 11, preferably 8 to 10. The inorganic base is preferably added in the form of aqueous solutions. For example, according to the invention, it is particularly preferable to add 0.05 to 0.4 kg, preferably 0.1 to 0.2 kg of inorganic base dissolved in 0.25 to 1.5 l, preferably in 0.5 to 1 l, most preferably in 0.7 to 0.8 L of water per mol of tropenol (V) used.
After thorough mixing of the reaction mixture obtained, the aqueous phase is separated off and extracted one or more times with the water-immiscible solvent mentioned earlier. A total of 1-8 l, preferably 2-6 l, most preferably 3-5 l of the abovementioned water-immiscible solvent are used to extract the aqueous phase per mol of tropenol (V) originally used. The combined organic phases are subsequently freed from solvent by distillation at elevated temperature, preferably at 30-90xc2x0 C., most preferably at 50-70xc2x0 C. The temperature ranges specified above are highly dependent on the choice of solvent used, as will be apparent to anyone skilled in the art. If desired, a vacuum may also be applied for this distillative elimination of the solvent so as to keep the temperature within the temperature ranges defined hereinbefore. With solvents which are distilled off below the maximum temperature ranges defined above, the maximum distillation temperature will naturally be the boiling point of the solvent in question.
The residue remaining after distillation is taken up in an organic solvent. This solvent can be selected from among the solvents which may be used according to this specification to carry out the reaction of (V) and (VI) to form (VII). Preferably the same solvent is used as in this reaction. 1-5 l, preferably 1.5-4 l, preferably 2-3 l of solvent are used to dissolve the residue per mol of tropenol (V) originally used. The solution thus obtained is heated, to not more than the boiling temperature of the solvent, preferably to a range of from 50-100xc2x0 C., most preferably 80-95xc2x0 C. The heated solution is slowly cooled to a temperature in the range from xe2x88x9210xc2x0 C. to 20xc2x0 C., preferably 0-10xc2x0 C. The tropenol ester (VII) is obtained in the form of colourless crystals which are separated off and dried. Drying is preferably carried out under inert gas at temperatures from 30-50xc2x0 C.
The tropenol ester (VII) thus obtained is then epoxidised as described hereinafter to form the scopine ester (IV). A suitable solvent, preferably selected from among water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, most preferably dimethylformamide, is placed in a suitable reaction apparatus and heated to a temperature in the range from 30-70xc2x0 C., preferably 40-60xc2x0 C. 2-10 l, preferably 3-8 l, preferably 4-7 l, most preferably 5-6 l of solvent are used per mol of tropenol ester (VII) used. The tropenol ester (VII) is added to the solvent which has been heated as described above and the resulting mixture is stirred at constant temperature until a clear solution is obtained.
An epoxidising agent is then added batchwise to this solution at a temperature in the range from 20-50xc2x0 C., preferably at 35-45xc2x0 C. The preferred epoxidising agent is preferably vanadium pentoxide mixed with H2O2, most preferably an H2O2-urea complex in combination with vanadium pentoxide. Preferably, the hydrogen peroxide urea complex and vanadium pentoxide are added batchwise alternately, most preferably water is also added. 0.1-0.5 kg, preferably 0.15-0.3 kg of hydrogen peroxide-urea complex, 0.1-1.0 l, preferably 0.15-0.7 l, most preferably 0.2-0.4 l water as well as 0.001-0.1 kg, preferably 0.005-0.05 kg, most preferably 0.01-0.025 kg of vanadium pentoxide are used per mol of tropenol ester (VII) used. After everything has been added, the mixture is stirred for a period of 1-6 h, preferably 1.5-4 h, preferably 2-3 h at a temperature of 30-70xc2x0 C., preferably 40-60xc2x0 C., most preferably 45-55xc2x0 C.
It is then cooled to a temperature in the range from 10-30xc2x0 C., preferably to 15-25xc2x0 C. and adjusted to a pH of 2.5-5.5, preferably a pH of 3.5-4.5 with hydrochloric acid. The hydrochloric acid may be added either in the form of aqueous solutions or as a gas, the addition of aqueous solutions being preferred. Preferably, concentrated hydrochloric acid (36%) dissolved in water is added. After thorough mixing, an inorganic salt is added, preferably sodium hydrogen sulphite. This is preferably added in the form of aqueous solutions. Most preferably, 20-100 g, preferably 30-80 g, most preferably 40-60 g of inorganic salt dissolved in 0.1-1 l, preferably 0.3-0.7 l of water (in each case per mol of compound (VII) used) are added per mol of tropenol ester (VII) used. Some of the solvent is distilled off at an internal temperature of 20-50xc2x0 C., preferably 30-40xc2x0 C. About 2-8 l, preferably 3-6 l of the solvent is eliminated per mol of compound put in. After cooling to about 15-25xc2x0 C. Clarcel (Celite) is added (in an amount of about 40-100 g, preferably 60-80 g per mol of compound (VII) put in). By again adding hydrochloric acid, preferably dilute aqueous hydrochloric acid, a pH of 1-3, preferably 1.5-2.5 is obtained. Preferably, 10-30 g, preferably 15-20 g of 36% hydrochloric acid, dissolved in 5-15 l, preferably 8-12 l of water (per mol of (VII) put in) are used per mol of compound (VII) used.
The solution obtained is filtered and optionally extracted one, two or three times with a suitable, water-immiscible solvent. Preferably, a water-immiscible solvent selected from among methylene chloride and n-butylacetate, preferably methylene chloride, is used. The organic phases used to extract the aqueous phase are discarded.
The aqueous phase is mixed once again with the water-immiscible solvent, optionally after previous washing with one of the water-immiscible solvents mentioned above. Preferably, 1-5 l, preferably 2-4 l, most preferably 2.5-3.5 l of the water-immiscible solvent are used per mol of tropenol ester (VII) originally put in. The resulting mixture is combined with an inorganic base, preferably selected from the alkali metal or alkaline earth metal carbonates of lithium, sodium, potassium or calcium, such as, for example, sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, sodium carbonate being particularly preferred, and adjusted to a pH of 8 to 11, preferably 9 to 10.5. The inorganic base is preferably added in the form of aqueous solutions. For example and according to the invention, most preferably, 0.05 to 0.4 kg, preferably 0.15 to 0.3 kg of sodium carbonate dissolved in 0.25 to 2 l, preferably in 0.75 to 1.25 l are added per mol of ester (VII) used.
After thorough mixing of the reaction mixture obtained, the aqueous phase is separated off and extracted one or more times with the water-immiscible solvent mentioned earlier. A total of 1-5 l, preferably 2-4 l of the abovementioned water-immiscible solvent are used to extract the aqueous phase per mol of tropenol ester (VII) originally used. The combined organic phases are subsequently freed from solvent by distillation at preferably 25-50xc2x0 C., most preferably at 30-40xc2x0 C. The temperature ranges specified above are highly dependent on the choice of solvent used, as will be apparent to anyone skilled in the art. If desired, a vacuum may also be applied for this distillative elimination of the solvent so as to keep the temperature within the temperature ranges defined hereinbefore. Preferably, distillation is carried out under a slight vacuum at 500-800 mbar, preferably at 600-700 mbar. About 2-6 l, preferably 3-5 l of the solvent is distilled off per mol of the ester (VII) originally put in.
It may possibly be necessary to eliminate impurities in the form of secondary amines at this point. This is done, according to the invention, by using organic carboxylic acid halides, preferably acid chlorides selected from among acetyl chloride, propionic acid chloride or butyric acid chloride. Acetyl chloride is preferably used. Usually, between 5 and 30 g, preferably 10-20 g of carboxylic acid halide are used per mol of ester (VII) originally used. After the addition of the carboxylic acid halide at 15-25xc2x0 C. the mixture is stirred for 15 minutes to 1.5 h, preferably between 30 and 45 minutes at constant temperature.
Then the mixture is brought to a temperature in the range from 10-30xc2x0 C., preferably to 15-25xc2x0 C., and adjusted to a pH of 1-3, preferably a pH of 1.5-2.5 with hydrochloric acid. The hydrochloric acid may be added either in the form of aqueous solutions or as a gas; it is preferably added as an aqueous solution. Preferably, concentrated hydrochloric acid (36%) dissolved in water is added. Preferably, 0.05-0.5 kg, preferably 0.075-1.25 kg of 36% hydrochloric acid, dissolved in 5-15 l, preferably 8-12 l of water (per mol of (VII) used) are used per mol of compound (VII) put in. The organic phase is separated off and discarded.
The aqueous phase is mixed once again with the water-immiscible solvent, optionally after previous washing with one of the water-immiscible solvents mentioned above. Preferably, 1-5 l, preferably 2-4 l, most preferably 2.5-3.5 l of the water-immiscible solvent are used per mol of tropenol ester (VII) originally put in. The resulting mixture is combined with an inorganic base, preferably selected from the alkali metal or alkaline earth metal carbonates of lithium, sodium, potassium or calcium, such as, for example, sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, sodium carbonate being particularly preferred, and adjusted to a pH of 8 to 11, preferably 9 to 10.5. The inorganic base is preferably added in the form of aqueous solutions. For example and according to the invention, most preferably, 0.05 to 0.4 kg, preferably 0.1 to 0.2 kg of sodium carbonate dissolved in 0.25 to 2 l, preferably in 0.7 to 1.2 l are added per mol of ester (VII) used.
After thorough mixing of the reaction mixture obtained, the aqueous phase is separated off and extracted once or preferably twice with the water-immiscible solvent mentioned earlier. A total of 0.5-2.5 l, preferably 1-2 l of the abovementioned water-immiscible solvent are used to extract the aqueous phase per mol of tropenol ester (VII) originally used. The combined organic phases are subsequently freed from solvent by distillation at preferably 25-50xc2x0 C., most preferably at 30-40xc2x0 C. (about 1-3 l, preferably 1.5-2.5 l solvent are eliminated per mol of ester (VII) used). A solvent selected from among dimethylformamide, dimethylacetamide, N-methylpyrrolidinone or dichloromethane, preferably dimethylformamide, is then added. Between 1 and 5 kg, preferably between 1.5 and 4 kg, most preferably between 2 and 3 kg of solvent are used per mol of ester (VII) put in. The remaining traces of the water-immiscible solvent used previously for extraction are distilled off from this solution under a slight vacuum (600-700 mbar) and at a temperature of 30-40xc2x0 C. The solution of scopine ester (IV) thus obtained is used directly in the next step without any further isolation of the intermediate compound.
In order to prepare tiotropium bromide (I), methyl bromide is introduced into the scopine ester solution obtainable according to the instructions provided hereinbefore at 10-30xc2x0 C., preferably at 15-25xc2x0 C. As a solution of scopine ester (IV) is used in this step without any measurement of the yield of the preceding step, the quantities specified below relate to the tropenol ester (VII) originally put in. At least 1 mol of methylbromide is used per mol of scopine ester (IV). 0.1-0.2 kg, preferably 0.11-0.15 kg of methylbromide are preferably used according to the invention per mol of tropenol ester (VII) used. After all the methylbromide has been added the mixture is stirred at 15-35xc2x0 C. for 1-3 days, preferably for 48-72 hours. Then the solvent dimethylformamide is partly distilled off in vacuo at 30-60xc2x0 C., preferably at 45-55xc2x0 C. The vacuum is selected so that the solvent is distilled off within the temperature ranges mentioned above. About 0.5-2.0 l, preferably 1.0-1.75 l of solvent are distilled off per mol of tropenol ester (VII) used and then cooled to about 5-20xc2x0 C., preferably 10-15xc2x0 C. At this temperature, the mixture is stirred until the crude product has fully crystallised and the crystals precipitated are separated off and dried at 30-50xc2x0 C. under inert gas, preferably nitrogen.
The product may be further purified by crystallisation from methanol. About 2-8 l, preferably 3-7 l, most preferably 4-5 l of methanol are used per 1 mol of tiotropium bromide (I) and the mixture thus obtained is refluxed until the product dissolves. It is then cooled to 0-15xc2x0 C., preferably 3-7xc2x0 C. and the product crystallises with stirring. After total crystallisation, the crystals are separated off and finally dried at 30-50xc2x0 C. under an inert gas, preferably nitrogen.
The product thus obtained may optionally be converted into its monohydrate. To do this, the following method may be used.
In a reaction vessel of suitable size the solvent is mixed with tiotropium bromide. 0.4 to 1.5 kg, preferably 0.6 to 1 kg, most preferably about 0.8 kg of water are used as solvent per mol of tiotropium bromide used. The resulting mixture is heated with stirring, preferably to more than 50xc2x0 C., most preferably to more than 60xc2x0 C. The maximum temperature which can be used is determined by the boiling point of the water used as solvent. Preferably the mixture is heated to a range of 80-90xc2x0 C.
Activated charcoal, dry or moistened with water, is added to this solution. Preferably, 10 to 50 g, most preferably 15 to 35 g, particularly preferably 25 g of activated charcoal are used per mol of tiotropium bromide put in. If desired, the activated charcoal may be suspended in water before being added to the solution containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, most preferably about 135 g of water are used per mol of tiotropium bromide put in, in order to suspend the activated charcoal. If the activated charcoal is suspended in water before being added to the solution containing tiotropium bromide, it is advisable to rinse with the same amount of water.
Stirring is continued for between 5 and 60 minutes, preferably between 10 and 30 minutes, most preferably about 15 minutes at constant temperature after the addition of the activated charcoal and the resulting mixture is filtered to eliminate the activated charcoal. The filter is then rinsed with water. This is done using 140 to 400 g, preferably 200 to 320 g, most preferably about 270 g of water per mol of tiotropium bromide used.
The filtrate is then slowly cooled, preferably to a temperature of 20-25xc2x0 C. Cooling is preferably carried out at a cooling rate of 1 to 10xc2x0 C. per 10 to 30 minutes, preferably 2 to 8xc2x0 C. per 10 to 30 minutes, most preferably 3 to 5xc2x0 C. per 10 to 20 minutes, particularly preferably 3 to 5xc2x0 C. per 20 minutes approximately. If desired, the cooling to 20 to 25xc2x0 C. may be followed by further cooling to below 20xc2x0 C., most preferably to 10 to 15xc2x0 C. After the cooling has taken place, the mixture is stirred for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, most preferably about one hour, in order to complete the crystallisation.
Finally, the crystals formed are isolated by filtering or suction filtering of the solvent. If it proves necessary to subject the crystals obtained to another washing step, it is advisable to use water or acetone as washing solvent. 0.1 to 1.0 l, preferably 0.2 to 0.5 l, most preferably about 0.3 l of solvent may be used per mol of tiotropium bromide used in order to wash the tiotropium bromide monohydrate crystals obtained. If desired, the washing step may be repeated.
The product obtained is dried in vacuo or using circulating hot air to achieve a water content of 2.5-4.0%.

Process for preparing an anticholinergic


The invention relates to besylate salts of the compound of formula (I):

This invention relates to salts of a short acting benzodiazepine, and to use of the salts as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes.
European Patent No. 1,183,243 describes short-acting benzodiazepines that include a carboxylic acid ester moiety and are inactivated by non-specific tissue esterases. An organ-independent elimination mechanism is predicted to be characteristic of these benzodiazepines, providing a more predictable and reproducible pharmacodynamic profile. The compounds are suitable for therapeutic purposes, including sedative-hypnotic, anxiolytic, muscle relaxant and anticonvulsant purposes. The compounds are short-acting CNS depressants that are useful to be administered intravenously in the following clinical settings: preoperative sedation, anxiolysis, and amnestic use for perioperative events; conscious sedation during short diagnostic, operative or endoscopic procedures; as a component for the induction and maintenance of general anesthesia, prior and/or concomitant to the administration of other anaesthetic or analgesic agents; ICU sedation.
One of the compounds disclosed in EP 1,183,243 (in Example Ic-8, page 36) is Methyl 3-[(4S)-8-bromo-1-methyl-6-(2-pyridinyl)-4H-imidazol [1,2-a] [1,4]benzodiazepin-4-yl] propanoate, as shown in formula (I) below:

Whilst the free base of formula (I) is stable when stored at 5° C., samples stored at 40° C./75% relative humidity (open) are observed to deliquesce, become yellow to orange in colour, and show notable decreases in content relative to initial (see Example 1 below).
It has now surprisingly been found that the compound of formula (I) forms highly crystalline mono (benzenesulfonic acid) besylate salts that are easily isolated from a range of pharmaceutically acceptable solvents and show good thermal stability, low hygroscopicity and high aqueous solubility.

This patent is subject to a terminal disclaimer.

Short-acting benzodiazepine salts and their polymorphic forms

Abstract: Methods of preparing the salts, and their use as medicaments, in particular for sedative or hypnotic, anxiolytic, muscle relaxant, or anticonvulsant purposes is also described.


A ceiling fixture hangar having an adjustable elongated first support and an adjustable elongated second support. Each of the first and second supports have first and second ends. Each of the ends of the first support is securable to a ceiling joist. The first end of the second support is slidably connected between the two ends of the first support. A mounting plate is secured to the second end of the second support which is adapted to receive a fixture.

Conventional supports are known for mounting fixtures to a standard ceiling during construction as well as retrofit installations in existing structures.
However, in today's energy conscious society many buildings are being built or renovated with drop ceilings to reduce heating and cooling costs as well as to reduce noise. These drop ceilings are installed in a variety of ceiling beam configurations, including I-beam, T-beam and tubular beam joists.
In addition, not only are fixtures, such as chandeliers and ceiling fans becoming heavier than prior art fixtures, but building codes are becoming more strict. Thus, there is a need for a fixture mounting assembly which can be readily and securely installed into a drop ceiling and yet carry relatively high static loads such as a chandelier and dynamic loads such as a ceiling fan.
There is likewise a need for a fixture mounting assembly which can be used for new construction as well as for retrofit installations which is easier to operate, stronger, and more stable than existing devices.


This invention relates to a process for preparing biological glue components from a plasma pool which combines high recovery, quality product and viral safety. In first instance, a triple viral inactivated product comprising fibrogen, fibronectin and FXIII is obtained by treating a concentrate thereof first with a viricide solvent/detergent solution, second with viral nanofiltration, and third with heat. The recovery of a good quality product is not compromised by the process of the invention. In second instance, the same steps are reproduced for obtaining a triple viral safe thrombin product. In that case, a known proprietary process has been improved to increase the recovery of active thrombin by about two fold. One of the steps which increase the yield of thrombin is the dilution of the prothrombin solution with water 4 volumes to 1 volume prothrombin prior to acid precipitation.

The biological glues are adhesive protein concentrates composed of fibrin generated from fibrinogen activated by thrombin and factor XIII in presence of calcium ions. The adhesive power of blood clot, due to it network of polymerized fibrin, has been known for a long time. Fibrin has been used since the beginning of this century as an adhesive and discovered by Bergel in 1909 who recognized it as a physiological gluing substance and moreover ascribed it healing properties. This discovery was immediately followed by Grey's work in 1915 using fibrin tampons to stop brain, liver haemorrhages and in cerebral surgery. However, it is only in 1944 that Cronkite, then Tidrick and Warner used fibrinogen together with thrombin to secure skin graft. But the low concentration of these products did not allow a good quality adhesion nor a lasting effect. Since 1946, owing to important scientific research by E. J. Cohn on the fractionation of plasma proteins, coagulation proteins in particular have been used, and few years later the mechanism of coagulation and main coagulation proteins, notably factor XIII, were elucidated. In 1975, Matras was the first to use fibrin adhesive properties through highly concentrated fibrinogen. Since then, the biological glues have definitely supplanted the synthetic glues and are increasingly used in human clinical practice.
The biological glues introduce a new approach to surgeries and sutures. Surgeons have sought for a long time an effective, easy-to-use and above all easily tolerated adhesive that could be used in addition to or in replacement of sutures. Surgical sutures are important nowadays. However, numerous problems arise such as intolerance or toxicity. Blood, through its coagulation properties, has always represented for surgeons an ideal model of biological gluing but the use of biological glues prepared from human source raises a viral transmission problem. Virus transmission hazards depend greatly on the purification methods of plasma concentrates. For human clinical use, the biological glues must be prepared with the severe treatments for viral inactivation without affecting the quality of the products. Research is still under way to develop an adhesive combining the following properties:
high viral safety PA1 sufficient adhesivity PA1 good elasticity PA1 good hold on adjacent tissues PA1 absence of toxicity PA1 absence of metabolic action PA1 good tolerance PA1 a) recovering the supernatant obtained from step a) of the method of claim 1; PA1 b) diafiltering said supernatant against an exchanged low or free salt solution; PA1 c) diluting said diafiltered supernatant until the obtention of a prothrombin solution of about 100 mosmoles/kg of weight or lower; PA1 d) precipitating prothrombin by adding an acidic solution until a pH of about 5.2 is obtained; PA1 e) solubilizing the precipitate of step d) in a solution having a near neutral pH; PA1 f) converting the prothrombin of step e) into thrombin in the presence of a diluting solution of calcium chloride to achieve a concentration of calcium chloride of about 20 to about 30 mM; PA1 g) incubating said thrombin with a viricide solvent/detergent solution in an amount sufficient to inactivate lipid-containing viruses; PA1 h) purifying the incubated material by sequential ion-exchange chromatography using a single sulfalkyl-activated polysaccharide cation exchange medium selected from the group consisting of a sulfakyl-activated polyagarose, a sulfakyl-activated polydextran and a noncompressible composite medium of sulfalkyl-activated dextran and silica particles having a high selectivity for thrombin using as an eluting agent at least three and increasing concentrations of an aqueous buffer solution; and PA1 i) recovering thrombin peak eluate from the chromatography of h) and exchanging the buffer of the eluate with a physiologically compatible stabilizing formulation buffer for stabilizing the recovered thrombin and recovering a formulation buffer solution of thrombin.
The U.S. Pat. Nos. 5,290,918 and 5,395,923 issued to Haemacure Biotech Corp. described the methods of preparation and use of a concentrate of fibrinogen, Factor XIII and fibronectin for therapeutic purposes.
Because of its coagulation properties, the concentrate rich in fibrinogen and Factor XIII provides clinicians with a precious and effective tool for surgery, where haemostatic properties are greatly needed. The fields of clinical applications may be: neurosurgery, cardiovascular surgery, plastic surgery (skin graft), ORL surgery, stomatology, orthopedic surgery, general surgery and traumatology.
The main protein in this concentrate is fibrinogen which, through an enzymatic reaction in presence of thrombin and calcium ions, produces fibrinopeptides A and B permitting the formation of fibrin monomers. These monomers polymerize quickly and become soluble fibrin. Then, the fibrin stabilizing factor (Factor XIII), under the agency of calcium ions forms covalent bonds with the dissolved fibrin, which make it stable and insoluble in an acidic medium or in the presence of urea.
The fibrin thus formed is irreversible, stable and fully plays its role as coagulant. It resists fibrinolysis because of its high concentration, plasminogen free fibrinogen and keeps its shape as a result of the absence of exudation. This concentrate has the following characteristics: excellent stability after being dissolved again in a aqueous solution, solubilization at room temperature in a few minutes, good elasticity and, lastly, a good adhesion.
These characteristics depend only on the method of preparation from plasma. This is a simple, quick method easily adaptable to industrial production. All the concentrate biological and biochemical are preserved, and the product meets clinical requirements.
The use of blood-borne products always posed viral transmission problems despite available virological tests. The safest way to provide blood-borne safe products is to systematically inactivate viruses suspected to be present using appropriate techniques without deteriorating the biochemical properties of the plasma products. Numerous methods of viral inactivation based upon the nature of the viruses and the type of the proteins to be isolated are currently known, which is reflected by the increasing body of scientific publication in this respect.
The most widely used plasma products are albumin, immunoglobulins and concentrates of coagulation factors. In 1948, Gellis et al. were the first to use a method of inactivating viruses by heating an albumin preparation at 60.degree. C. for ten hours. This method is currently used since that date due to its verified efficacy to reduce risks of viral transmission. The same method has been applied to the preparation of immunoglobulins G (IgG) with the same efficacy. This efficacy can be related to the method of purification of these blood products, particularly the use of a complete fractionation procedure as described by Cohn, or Kistler and Nitschmann.
The use of ethanol in numerous steps of fractionation of albumin and IgGs allows for a repartition of the quantity of viruses in different fractions. Ethanol is known as a disinfecting agent against pathogenic agents, such as viruses, as mentioned by Henin et al. (1988) and Morgenthaler (1989).
Pasteurization of albumin and IgGs appeared at the beginning of the 50s. This technique, however, was directed to inactivation of hepatitis virus (hepatitis B and non A-non B). Curran et al. (1984) raised the issue of viral transmission of HIV type by transfusion or the use of other blood derivatives, particularly coagulation factors. Since then, methods of viral inactivation focused on HIV. No HIV transmission was signaled from the use of albumin or IgGs, this lack of viral transmission being assigned to the step of pasteurization (Mitra et al. (1986)). Coagulation factors such as factor VIII and IX are widely used by hemophilic patients. Heimburger et al. (1980) have applied to these products the same pasteurization technique as described for albumin for inactivating viruses during the preparation of factor VIII in the presence of glycine and sucrose, in order to avoid proteic denaturation under thermal denaturation at 60.degree. C. for ten hours. Their studies demonstrated the efficacy of inactivation of HIV, hepatitis B and hepatitis non A-non B. Hilfenhaus et al. (1985, 1986) confirmed that pasteurization is an efficient method for inactivating viruses such as HIV during the preparation of a concentrate of factor VIII. Tabor et al. (1982) inactivated hepatitis B virus by heating antithrombin III in the presence of citrate as a stabilizing agent. Hollinger et al. (1984) heated a concentrate of factor VIII in a lyophilized state for reducing the risk of transmission of HIV and hepatitis. Piszkiewicz et al. (1988) demonstrated that heat treatment of lyophilized concentrates of coagulation factors did not have any significant effect on the activity of these factors. These authors stressed that it was not obvious to find any production of neoantigens due to heat treatment. Studies on viral inactivation by heat treatment were conducted by Piszkiewicz et al. in preparations of "anti-hemophilic factors" (Hemofil.RTM. T, Hemofil.RTM. CT), wherein the latter were heated during 72 hours at 60.degree. C., and during the preparation of anticoagulant inhibitor complexes (Autoplex.RTM. T), factor IX complex (Proplex.RTM. SX-T and Proplex.RTM.) T), wherein the latter were heated during 144 hours at 60.degree. C. There has been no report on HIV seroconversion due to the use of any of the five heat-treated coagulation products. Hemofil.RTM. T concentrate made from plasma which has been screened of HBsAg and anti-HBc has been found not to transmit NANBH in a simian study. However, use of the same product made from plasma screened only for HBsAg resulted in NANBH in patients (Colombo et al. 1985). Hemofil.RTM. T is currently manufactured from plasma which is nonreactive for HBsAg and has normal ALT levels.
Viruses as well as proteins are more stable and more resistant to heat when in a dry state (lyophilized). The temperature and the duration of heating appear to vary upon the nature of the proteins to minimize denaturation thereof. However, the efficacy of viral inactivation have never been reported as perfect: NANBH transmission has been signaled by Colombo et al. HIV transmission has been reported by White et al. (1986) and Van den Berg et al. (1986). For these reasons, Winkelman et al. (1985) heated concentrate of factor VIII (type 8Y), factor IX (type 9A), factor VII, factor XI and thrombin at 80.degree. C. for 72 hours. Studies conducted on 29 patients having received these heat-treated products have shown that there was no seroconversion of HIV of HB and that there was a significative reduction of the incidence of transmission of NANBH.
Other methods of viral inactivation have been developed using a light sources (UV, gamma rays, and laser) to irradiate the infectious agents in plasma. The following are cited as references: Oliphant et al.: Homologous serum jaundice: experimental inactivation of etiologic agent in serum by ultraviolet irradiation (Publ. Health Rep 1946; 61: 598-600), Wolf et al.: Ultraviolet irradiation of human plasma to control homologous serum jaundice (JAMA 1947; 135; 476477), Blanchard et al.: Methods of protection against homologous serum hepatitis. II. The inactivation of hepatitis virus serum with ultraviolet rays (JAMA 1948; 138:341), Murray et al. Effect of ultraviolet radiation on the infectivity of icterogenic plasma (JAMA 1955: 157: 8-14). Gurzadyan et al.: Mechanism of high power picosecond laser UV irradiation of viruses and bacterial plasmids (Photochem. Photobiol. 1981; 3: 835-838), Redfield et al.: Psoralen inactivation of influenza and herpes simplex virus and of viral infected cells (Infect Immun 1981; 32: 1216-1226), Heindrich et al.: Clinical evaluation of the hepatitis safety of beta-propiolactone-ultraviolet treated factor IX concentrate (PPBS), (Throm. Res. 1982; 28: 75), Kitchen et al.: Effect of gamma irradiation of the human immunodeficiency virus and human coagulation proteins (Vox Sang, 1989, 56: 233-229).
For more than ten years, one of the most currently used method for viral inactivation of viruses in blood-borne products is a method combining the use of a solvent and a detergent. This method has been developed by Neurath and Horowitz (U.S. Pat. No. 4,540,573 issued in September 1985, U.S. Pat. No. 4,613,501, U.S. Pat. No. 4,764,369 issued in August 1988; U.S. Pat. No. 4,820,805 issued in April 1989; U.S. Pat. No. 4,841,023 issued in June 1989 and U.S. Pat. No. 5,541,294 issued in July 1996). The mixture or solvent/detergent (Tri(n-butyl) phosphate/detergent) typically inactivates enveloped viruses such as HIV, HTLV-I, HBV and EBV.
Solvent/detergent method is however not sufficient to provide safe plasma products, because of the eventual presence of non-enveloped viruses such as parvovirus and poliovirus which are insensitive to solvent/detergent. Another technique has been recently introduced for eliminating non-enveloped viruses on which solvent/detergent has no effect. This technique is a nanofiltration. Nanofilters are composed with microporous fibers and have been commercialized under the name Planova BMM (Asahi Chemical Industries, Tokyo, Japan). The porosity of these filters varies from about 15 to 35 nm. These filters can retain certain types of viruses having a size larger than about 25 nm. These filters are efficient for eliminating viruses such as HIV-I (80-100 nm), HBB (42 nm), HCV (<80 nm), hepatitis Delta virus (35 nm), bovine viral diarrhea virus (60-70 nm), Sindbis virus (60-70 nm), reovirus type 3 (60-80 nm), poliovirus Sabin type 1(25-30 nm), human parvovirus (20-25 nm); Sekiguchi et al.: Possibility of hepatite B virus (HBV) removal from human plasma using regenerated cellulose hollow fiber (BMM) (Membrane, 1989; 14: 253-261), Hamamoto et al.: A novel method for removal of human immunodeficiency virus: filtration with porous polymeric membranes (Vox sang., 1989; 56: 230-236), Tsurumi et al.: Structure of cuprammonium regenerated cellulose hollow fiber (BMM hollow fiber) for virus removal (Polym. J. 1990, 22: 751-758), Ishikawa et al.: Novel determination method of size of virus in solution using cuprammonium regenerated cellulose membrane (BMM) (Membrane, 1991; 16:101-111), Tomokiyo et al.: Studies on virus elimination and inactivation effect of highly purified F-VIII concentrate (The clinical report, 1991; 25: 271-275), Manabe: Virus removal and inactivation in process validation (Animal Cell Technology: Basic & Applied Aspects (Murakami, H., Shirahata, S., Tachibana, H. eds, 1992, 15-30), Burnouf et al.: Strategy of virus removal/inactivation of plasma-derived products: Interest of nanofiltration as a new virus elimination method (manuscript submitted to JAACT 93).
Rubinstein et al. used a double viral inactivation of factor VIII concentrate by treating the latter with solvent/detergent and heating at 100.degree. C. for 30 minutes the final product. Upon these authors, thermal treatment of the final product allows the inactivation of nonlipid-enveloped non A-non B hepatitis viruses. Heat treatment of the final product is also a cautious measure in case of accidental viral contamination during manipulation or due to the equipment (Vox Sang, 1991: 60: 60).
Recently, Proba et al. introduced a triple viral inactivation during the preparation of thrombin: (1) solvent/detergent treatment, (2) nanofiltration and (3) heat treatment at 100.degree. C. for one hour of the lyophilized product (U.S. Pat. No. 5,506,127 issued to Haemacure Biotech Inc.).
The triple viral inactivation treatment confers an increased safety in the use of blood-borne products, particularly coagulation factors or biological glue.
Nobody has described a three viral inactivation step process for preparing a concentrate of other coagulation factors such as fibrinogen. Furthermore, the viral inactivation steps may also mean that the addition of numerous steps in a process of making blood-borne products will lead to a diminution of recovery of useful products. There is still room to improve recovery of blood-borne products and this, not at the expense of viral safety and product quality, or to improve product safety without sacrificing the recovery and nature of the product.

Process for producing thrombin from plasma


Systems and methods determine the position of a touch on a surface of a device, such as a touch-sensitive device, by using position-dependent electrical charges. In such a method, the position of a touching implement is determined on the sensing surface of a device. The method includes generating signals on the surface of the device to create a position-dependent electrical charge on the touching implement; and measuring the position-dependent electrical charge to indicate a coordinate on the sensing surface for establishing the position of the touching implement.

There are numerous approaches for sensing the location of the touch of a finger or a corded or free stylus on the surface of a touch-sensitive device, typically placed over the face of an electronic display or used as a free-standing touch tablet or off-display touch pad. Sensing methods have included resistive and capacitive sensing using resistive surface layers, as well as technology such as acoustic wave and inductive electromagnetic sensing.
Most recently, such touch-sensitive devices have been widely distributed in forms spanning various industries including but not limited to entertainment such as gaming and a wide variety of presentation-directed industries such as business and educational applications.

System and method for determining touch positions based on position-dependent electrical charges


A hand tool used for removing wax from a surfboard incorporating associated accessories. The wax removal element of the present invention constitutes a substantially rectangular scraping panel that can be resiliently flexed along the elongated axis of the panel. One of the elongated edges of the panel is extended into a plurality of uniform gouging members that are adapted to penetrate the wax to prepare the wax mounted on the surfboard to be removed. The edge of the panel opposed to the scraping members is beveled to provide an edge that is adapted to remove the wax from the surfboard. Rotatably coupled to the bottom surface of the scraping panel are one or more accessories and hand tools used for maintenance of the surfboard and for the personal employment of the user.

1. Field of the Invention
The present invention generally relates to a hand tool for performing maintenance on a surfboard and in particular a hand tool for removing wax from a surfboard incorporating accessories for additional surfboard maintenance.
2. Description of the Prior Art
It is common to coat a surface of a surfboard with wax. Wax can either be applied manually or by melting the wax. Under either circumstance, the tools disclosed by the prior art to remove the wax are complex, are easily broken or otherwise fail to perform their intended function.
The prior art discloses hand held blade-type scrapers to remove wax from surfboards and other like surfaces. Often the scraper is simply a generally rectangular metal or plastic plate having one or more relatively sharp edges. While this tool is adequate for skis that have flat surfaces, it is unusable for surfboards that are constructed with curved surfaces to minimize drag in water. The present invention resolves this problem by providing a substantially rectangular scraping panel that can adapt to the curvature of the surfboard.
The present invention substantially resolves the inadequacies of the hand tools disclosed in the prior art. A flexible scraping panel incorporates means for loosening the wax that may be hardened on the surface of a surfboard and a second beveled surface for removing the wax. The flexibility of the scraper along an axis thereof permits the tool to adapt to the curvature of the surfboard. To provide ease of use and efficiency, hand tools and accessories used for the maintenance of surfboards or for personal use by the user are rotatably coupled to the scraping panels. The tools can include a fin-key adapted to remove a fin from a surfboard, a screwdriver and an accessory mounting plate that can employ personal accessories such as a bottle opener.

Hand tool for removal of wax from a surfboard incorporating manual accessories


A fixing assembly for attaching a fixing to a workpiece, having a fixing and a resilient member. The fixing includes an aperture and is adapted for mating with the workpiece and holding the fixture. The resilient member includes a first portion secured in the aperture, and a second portion adapted for frictional engagement with a nosepiece of a fastener-driving tool.

Fixings for attaching a fixture to a workpiece, and methods of securing fixings to a workpiece using a fastener-driving tool, such as a nail gun, are known. U.S. Pat. No. 5,484,094 discloses a fastener-driving tool for securing a washer plate made of magnetizable steel to a workpiece. A strip of fasteners are connected by a polymeric sleeve and fed into the tool. The tool has a nosepiece that is adapted to drive the fasteners, one at a time, from the nosepiece, into a workpiece. A workpiece-contacting probe includes two permanent magnets, and is mounted to the nosepiece for magnetically holding the washer plate between the nosepiece and the workpiece. A fastener is driven from the nosepiece, through the washer plate held by the workpiece-contacting probe, and into the workpiece. In U.S. Pat. No. 6,598,775, a hammer head assembly for driving a nail into objects to be fastened includes a nail holder mounted in a hollow mounting base and a magnet provided inside the nail holder and to attract a nail for driving into the workpiece.
It would be desirable to have a fixing for securing a fixture to a workpiece that can be easily attached to a nosepiece of fastener-driving tools, adapted for use with any of the variety of fixings that are typically secured to a workpiece using a fastener, such as a nail or pin, and without requiring the use of an adaptor or other special attachments to the nosepiece of the fastener driving tool for retaining the fixing to the nosepiece.

Method and apparatus for fixing assembly having resilient tool connection


A means for minimizing time for a system/device initial program load (IPL) in a system that will not support instruction prefetching when executing IPL code out of non-volatile memory. The IPL code is organized into a first portion and second portion. The first portion is executed from the non-volatile memory device to configure system memory; the first portion also provides initial control of cache inhibit and cache enable by way of software control. The cache-enabling code is strategically located at a memory page boundary such that the system hardware will disable instruction prefetching in an adjoining page lust past this cache enabling software code. After the first portion of IPL code configures system memory, the second portion is copied into memory through the L2 cache and executed from memory with cache enabled to allow speculative instruction prefetching.

1. Technical Field
The present invention pertains to electronic devices and systems, and more particularly to an improved method and apparatus for starting up or booting an electronic device such as a data processing system.
2. Description of Related Art
Many devices in use today include electronics that control the operation of at least some portion of the device. While data processing systems are the traditional types of systems that contain such electronics, electronic control is appearing in many other types of devices such as automobiles, telephones and other types of consumer electronics devices, and even home appliances. These types of devices typically have programming code stored within the device that gets executed when the device is initially turned-on or powered-up. This code, and its execution, may be called many different things, such as a boot-up, power-up, start-up or initial program load (IPL) of the device. Some types of systems, such as personal computers, are notoriously slow in providing a ready state after an initial power-up and IPL of the computer.
Many of today's data processing and other types of electronic controlled systems have different types of memory included therein for use by the system. Non-volatile memory, which maintains the value of data stored therein even when there is no power connected to it, is typically used to store the initial start-up or boot code for a data processing system or electronic controlled device. This start-up or boot code is what is executed by a central processing unit (CPU) or controller of the system or device to perform system initialization. This boot code is maintained in non-volatile memory so that the memory contents are maintained even when power is removed from the system or device.
One particular type of non-volatile memory that is used for such boot code is called flash memory. This type of memory device is generally easy to read from, but requires fairly sophisticated control and sequencing of voltage values on various input/output (I/O) pins in order to write/program data into the device.
Volatile memory, such as dynamic RAM (DRAM), is also traditionally contained in a data processing system or electronic controlled device, and is generally used by the CPU or controller as its main or system memory for reading and writing data using traditional memory access techniques.
When the system/device is first powered-up, the system/device is typically designed such that the CPU or controller will begin execution by accessing a boot-up reset vector at a given memory location which contains the starting address of where to begin program execution or sequencing of boot-up code. This boot-up code, also called firmware or internal code, provides functionality to initialize, test and otherwise set-up various system/device aspects, such as initial hardware configuration, etc. and then load an operating or control system into main memory for subsequent execution. In some types of computer systems, this boot code is also known as basic input and output (BIOS) code. Execution control is then passed from the flash memory to system memory for continuing with system initialization and operation by the operating or control system. The reason for partially booting-up using flash memory programming and then transferring control to continue the boot-up sequence from main system memory is that flash memory is much more expensive than main system memory (which is typically comprised of DRAM memory), and therefore system designers want to use as little flash memory in their designs as possible to hold down on costs. Obviously, the more functionality that is provided by the program stored in flash memory, the larger the size (and associated cost) of flash memory that will be required by the system/device.
Cache memory, which is typically comprised of high-speed static RAM (SRAM) devices, is also generally provided in a data processing system for holding instructions and/or data that are likely to be accessed in the near term by a CPU or controller. Because CPUs/controllers have increased in operating speed at a much faster pace than RAM as technology has progressed, without adequate system design, a CPU/controller could waste much of its time waiting to obtain instructions or data from memory, rather than performing calculations. One of the fastest types of RAM, Static RAM (SRAM), is generally too expensive to use for all of system's memory needs. As a compromise, computers generally come with a relatively small amount of SRAM that is used as cache memory. If a CPU instruction or data stored in cache is required again, the computer can access the cache for the instruction/data rather than having to access the relatively slower DRAM. Since the cache memory is organized more efficiently, the time to find and retrieve information is reduced and the CPU is not left waiting for more information. Many CPUs/controllers have two types of cache: level 1 and level 2. Level 1 (L1) cache has a very fast access time, and is typically embedded as part of the CPU/controller integrated circuit device itself. Level 2 (L2) is typically situated near, but separate from, the CPU/controller and has an interconnecting bus to the CPU/controller. Modern CPUs/controllers may also have both L1 and L2 caches integrated into the devices. Some systems also have a separate instruction cache and data cache.
Prefetching is another technique for improving the overall performance of a data processing system. For example, instead of only reading a next instruction from memory for execution by a CPU/controller, an instruction prefetch unit can monitor the instruction stream being executed by the CPU/controller and make educated guesses as to which instructions stored in main system memory are likely to be executed in the future, and thus should be prefetched into the instruction cache so that they are already there in high-speed cache and ready to be read by the CPU/controller (thus avoiding delays or latency that would otherwise occur if the instruction/data were not fetched until actually being called-for by the CPU/controller). One way to make these educated guesses for instruction prefetching is to monitor the instruction stream for instructions that cause execution to occur non-sequentially, such as a conditional JUMP instruction, and predict which condition will exist when the instruction is actually executed to thereby prefetch any non-sequential instructions in the predicted path. If there are no instructions that would cause the instruction stream to deviate from its current sequential execution, then the next n instructions in the sequentially executed data stream can be prefetched into the instruction cache. These types of instruction prefetching, as well as similar techniques for prefetching of data, are commonly known to many hardware and system designers.
These types of instruction and data prefetching are very common for systems where a program to be executed has been loaded into general usage system memory such as DRAM. However, in certain situations such as when executing boot-up or IPL code out of flash memory, some systems inhibit instruction or data prefetching into cache by running in a cache-inhibit mode. This may occur, for example, if the cache line size is different from the size of an interconnecting bus. By running in a cache-inhibited mode, where instructions and data cannot be cached and prefetched, access latencies occur each time a new instruction or data is accessed and there is a significant impact in the performance of the system. As this cache-inhibit mode is typically done for certain systems when they are executing their boot-up code out of flash or other type of non-volatile memory, the system initial-program load (IPL) or boot-up time is greatly increased. This increase in boot time is not only an annoyance to end-users, but also to test engineers and/or technicians as it increases the time required to boot-up and test a device, thus generally slowing down the overall efficiency for manufacturing such systems and devices.
It would thus be desirable to provide an improved method, apparatus and program product that would mitigate this inability to use a cache for prefetching during system/device IPL or boot-up.

Technique for system initial program load or boot-up of electronic devices and systems

International Business Machines Corporation


A fiber optic optical transducer or encoder is described. The outputs of two detectors receiving signals from an optical multiplexer/demultiplexer arrangement are compared to determine whether a given code bit is "on" or "off". When the bit is "on" the power received by the second detector will, for example, be greater than the power received by a first detector. When the bit is "off" the reverse is true. A simple power level comparison thus determines the logic state of each given code bit.

This invention relates to a fiber optic optical transducer, and more particularly, the invention relates to such a transducer which produces digital information.
Electrically passive optical transducers or encoders using fiber optic components have become of considerable interest for a wide variety of applications. Numerous applications exist for rotary and linear encoders which are capable of producing digital information. In order, however, for these encoders to find widespread application, it was determined that multiplexing of the encoder signals is required to reduce the number of fibers and to improve reliability.
The first effort in this direction used time division multiplex techniques. In such an arrangement, an optical fiber delivers a short duration optical pulse to the encoder. The encoder uses fiber optic couplers and fiber optic delay lines to time multiplex the binary encoder output signals as a sequence of optical pulses. This approach has several disadvantages which are all primarily associated with the need for the use of fiber optics delay lines. Conventionally, a delay line spool would be used, and this was found to be bulky and expensive to wind. Moreover, the fibers arranged in this configuration are subject to breakage when exposed to temperature extremes.
These and other difficulties with time division multiplexing caused experimentation with and the subsequent use of wavelength division multiplexing techniques.
Fiber optic encoders for creating the encoded wavelength division multiplex signal generally involve the use of a grated index rod lens (GRIN lens) having a glass wedge-grating assembly arranged at an end thereof. Broadband light enters the encoder system through the encoder input fiber and passes through a fiber coupler to the multiplexer/encoder. The multiplexer disperses the broadband spectrum of received light across the channels of a reflective code plate in wavelength bands. Those wavelengths directed to a channel in the logic zero state are, for example, absorbed by the code plate, while those wavelengths directed to a channel in the logic one state are, for example, reflected by the code plate and then retransmitted to the multiplexer input/output fiber by the grating-lens assembly. A coupler then directs the reflected light to a separate encoder output fiber for transmission from the encoder. Dual transmission fibers communicate the reflected light information to a receiver/demultiplexer. The demultiplexing operation is performed by a second grating assembly which, for example, disperses the spectrum on to a photo diode array. In the latter, each diode, for example, might correspond with a given wavelength band. The totality of the array then corresponds with a given code word, and the logical values of the bits forming the code word are determined by whether or not the elements of the array are actuated, i.e., whether or not there is reflected light appearing in the corresponding wavelength bands.
In these prior art fiber optic transducer assemblies, the decision as to whether a given photodiode is to be actuated indicating light in the corresponding wavelength band is generally by comparison of the value of the reflected light with some t value. It can be readily seen that in a system such as there are ample possibilities for power level variations for example, the light source and along the lengths of the fiber optic cables. Consequently, system power losses and corresponding level variations have produced errors in the presence or absence of reflected light in a given band. The errors produced by these threshold comparisons cast considerable doubt on the efficacy of this technique optically encoding sensed information.

Digital wavelength division multiplex optical transducer having an improved decoder


A method for performing market-adapted price planning for a plurality of target products including determining a current price for each target product of the target products, obtaining market prices for a plurality of products competitive to each of the target products, calculating a median price of the market prices for products competitive to each of said target products, associating one of a plurality of product price types with each of the target products, determining a set of pricing parameters for each of the product price types, and determining a potential new price for each of the target products based on the pricing parameters for the product price type associated with the target product and the median price for products competitive to the target product.

1. Field of the Invention
The present invention relates to methods for pricing products in a marketplace and, in particular, to a method implemented by a computer for pricing products based on pricing information gathered from the marketplace.
2. Background of the Invention
When making price decisions, it is important to consider market price sensitivity. If sensitivity is high, greater care must be exercised; it is often necessary to price closer to "market." However, market price sensitivity is not easy to measure; its application has heretofore been limited especially in situations where there are a large number, or diversity, of products to be priced.
Automobile service parts are a case in point. An automaker must make discrete decisions about hundreds of thousands of part numbers. In order to make such pricing decisions a manageable task, broad generalizations are often made. In this regard, one popular pricing method is "cost plus," that is, the cost of a product, plus a certain percentage. One drawback to such a method is that it does not predict how the pricing of a particular product, or a particular line of products, is positioned in the marketplace. Thus, the product may be priced way too high, in which case, sales volumes will likely be reduced or the product may be priced way too low, in which case, the manufacturer could probably have made a higher margin on the product.

Method for performing market-adapted price planning


In a folding blade shaft of a folding cylinder of a drum folding apparatus, the drive shaft and spindle are connected so that the slanting of these parts does not cause any damage to the machine. To this end, the drive shaft and the spindle are connected to each other via a disk packet and centered by a radial rocker bearing.

1. Field of the Invention
The invention relates to a folding blade shaft of a folding cylinder of a drum folding apparatus.
2. Description of the Prior Art
In folding cylinders, the folding blade shaft, which is composed of a drive shaft and a spindle, is mounted with these parts in the driving gears. When the folding blade is stopped, twisting of the driving gears can ensue, which leads to slanting of the folding blade shaft. This slanting stresses and damages the mounting of the drive shaft and, in some cases, the feather key connection of the coupling flanges that connect the drive shaft and the spindle.

Folding blade shaft of a folding cylinder


An improved efficiency thermoelectric system and method of making such a thermoelectric system are disclosed. Significant thermal isolation between thermoelectric elements in at least one direction across a thermoelectric system provides increased efficiency over conventional thermoelectric arrays. Significant thermal isolation is also provided for at least one heat exchanger coupled to the thermoelectric elements. In one embodiment, the properties, such as resistance or current flow, of the thermoelectric elements may also be varied in at least one direction across a thermoelectric array. In addition, the mechanical configuration of the thermoelectric elements may be varied, in one embodiment, according to dynamic adjustment criteria.

1. Field of the Invention
The present invention relates to improved thermoelectrics for producing heat and/or cold conditions with a greater efficiency.
2. Description of the Related Art
Thermoelectric devices (TEs) utilize the properties of certain materials to develop a thermal gradient across the material in the presence of current flow. Conventional thermoelectric devices utilize P-type and N-type semiconductors as the thermoelectric material within the device. These are physically and electrically configured in such a manner that the desired function of heating or cooling.
Some fundamental equations, theories, studies, test methods and data related to TEs for cooling and heating are described in H. J. Goldsmid, Electronic Refrigeration, Pion Ltd., 207 Brondesbury Park, London, NW2 5JN, England (1986). The most common configuration used in thermoelectric devices today is illustrated in FIG. 1. Generally, P-type and N-type thermoelectric elements 102 are arrayed in a rectangular assembly 100 between two substrates 104. A current, I, passes through both element types. The elements are connected in series via copper shunts 106 soldered to the ends of the elements 102. A DC voltage 108, when applied, creates a temperature gradient across the TE elements. FIG. 2 for flow and FIG. 3 for an object both illustrate general diagrams of systems using the TE assembly 100 of FIG. 1.
When electrical current passes through the thermoelectric elements, one end of the thermoelectric elements becomes cooler and the other end becomes warmer. TE's are commonly used to cool liquids, gases and objects.
The basic equations for TE devices in the most common form are as follows:
                              q          c                =                              α                                                                                IT              c                                -                                    1              2                                                  I              2                                    R                    -                      K                                                                          Δ                                                                          T                                              (        1        )                                          q          in                =                              α                                                                          I                                                                          Δ                                                                          T                    +                                    I              2                                    R                                              (        2        )                                          q          h                =                              α                                                                          I                                                                                T              h                                +                                    1              2                                                  I              2                                    R                    -                      K                                                                          Δ                                                                          T                                              (        3        )            where qc is the cooling rate (heat content removal rate from the cold side), qin is the power input to the system, and qh is the heat output of the system, wherein:
α=Seebeck Coefficient
I=Current Flow
Tc=Cold side absolute temperature
Th=Hot side absolute temperature
R=Electrical resistance
K=Thermal conductance
Herein α, R and K are assumed constant, or suitably averaged values over the appropriate temperature ranges.
Under steady state conditions the energy in and out balances:qc+qin=qh  (4)Further, to analyze performance in the terms used within the refrigeration and heating industries, the following definitions are needed:
                    β        =                                            q              c                                      q              in                                =                      Cooling                                                                          Coefficient                                                                          of                                                                          Performance                                                                                (              COP              )                                                          (        5        )                                γ        =                                            q              h                                      q              in                                =                      Heating                                                                          COP                                              (        6        )                                          From                                                                          (            4            )                          ;                                                                                q              c                                      q              in                                +                                    q              in                                      q              in                                      =                              q            h                                q            in                                              (        7        )                                          β          +          1                =        γ                            (        8        )            So β and γ are closely connected, and γ is always greater than β by unity.
If these equations are manipulated, conditions can be found under which either β or γ are maximum or qc or qh are maximum.
If β maximum is designated by, βm, and the COP for qc maximum by, βcm, the result is as follows:
                              β          m                =                                            T              c                                      Δ                                                                                T                c                                                                    (                                                                                1                    +                                          ZT                      m                                                                      -                                                      T                    h                                                        T                    c                                                                                1                    +                                          ZT                      m                                                                      +                1                                      )                                              (        9        )                                                      β            cm                    =                                    (                                                                                1                      2                                                                                ZT                      c                                                        -                                      Δ                                                                                T                                                                                ZT                    c                                                                          T                    h                                                              )                                                                                where                          ;                            (        10        )                                Z        =                                            α              2                        RK                    =                                                                      α                  2                                                ρ                            λ                        =                          Figure                                                                                of                                                                                Merit                                                          (        11        )                                                      T            m                    =                                                                      T                  c                                +                                  T                  h                                            2                                                                                and                          ;                            (        12        )            Wherein:
λ=Material Thermal Conductivity; and
ρ=Material Electrical Resistivity
Note that for simple solid shapes with parallel sides, K=λ×area/length. Similarly R=(ρ×length)/area. Thus, any change in shape, such as a change in length, area, conality, etc., can affect both K and R. Also, if the shapes of flexible elements are changed by mechanical or other means, both K and R can change.
βm and qcm depend only on Z, Tc and Th. Thus, Z is named the figure of merit and is basic parameter that characterizes the performance of TE systems. The magnitude of Z governs thermoelectric performance in the geometry of FIG. 1, and in most all other geometries and usages of thermoelectrics today.
For today's materials, thermoelectric devices have certain aerospace and some commercial uses. However, usages are limited, because system efficiencies are too low to compete with those of most refrigeration systems employing freon-like fluids (such as those used in refrigerators, car HVAC systems, building HVAC systems, home air conditioners and the like).
The limitation becomes apparent when the maximum thermoelectric efficiency from Equation 9 is compared with Cm, the Carnot cycle efficiency (the theoretical maximum system efficiency for any cooling system);
                                          β            m                                C            m                          =                                                                              T                  c                                                  Δ                                                                                T                                                                          (                                                                                1                        +                                                  ZT                          m                                                                                -                                                                  T                        h                                                                    T                        c                                                                                1                        +                                                  ZT                          m                                                                                +                    1                                                  )                                                                    T                c                                            Δ                                                                                T                                              =                      (                                                                                1                    +                                          ZT                      m                                                                      -                                                      T                    h                                                        T                    c                                                                                1                    +                                          ZT                      m                                                                      +                1                                      )                                              (        13        )            Note, as a check if Z→∞, β→Cm. The best commercial TE materials have Z such that the product;ZTa≈1
Several commercial materials have a ZTa=1 over some narrow temperature range, but ZTa does not exceed unity in present commercial materials. This is illustrated in FIG. 4. Some experimental materials exhibit ZTa=2 to 4, but these are not in production. Generally, as better materials may become commercially available, they do not obviate the benefits of the present inventions.
Several configurations for thermoelectric devices are in current use for automobile seat cooling systems, for portable coolers and refrigerators, for high efficiency liquid systems for scientific applications, for the cooling of electronics and fiber optic systems and for cooling of infrared sensing system.
All of these devices have in common that the Th is equalized over the hot side of the TE, and similarly, Tc is equalized over the cold side. In most such devices, the TEs use an alumina substrate (a good thermal conductor) for the hot and cold side end plates and copper or aluminum fins or blocks as heat exchangers on at least one side.
Thus, to a good approximation, conditions can be represented by the diagram in FIG. 5. In this case ΔT has been split into the cold side at ΔTc and hot side ΔTh whereΔT=ΔTc+ΔTh.Using (1) and (2) in (5):
                    β        =                                            q              c                                      q              in                                =                                                    α                                                                                IT                  c                                            -                                                1                  2                                                                  I                  2                                                R                            -                              K                                                                                Δ                                                                                T                                                                    α                                                                                I                                                                                Δ                                                                                T                            +                                                I                  2                                                R                                                                        (        14        )
But ΔT is the sum of ΔTc and ΔTh. So, for example, if ΔTc=ΔTh then ΔT=2ΔTc. Since the efficiency decreases with increasing ΔT, it is highly desirable to make ΔT as small as possible. One option is to have the fluid flowing by the hot side be very large compared to that by the cold side. For this case, the equation for heat flow from the hot side is:qh=CpMΔTh  (15)where CpM is the heat capacity of the fluid passing the hot side per unit time (e.g., per second).
Thus, if CpM is very large for a given required qh, ΔTh will be very small. However, this has the disadvantage of requiring large fans or pumps and a large volume of waste fluid (that is, fluid not cooled, but exhausted as part of the process to achieve more efficient cooling).
A second option is to make the heat sink on the hot side very large so that the heat is dissipated passively. Examples would be a low power TE in a car with the hot side in very good thermal contact with the vehicle chassis, or a TE system in a submarine with the TE in good thermal contact with the hull and hence, the ocean water. In general, however, these methods are difficult to implement or cost, weight, size or other conditions limit their use. The result is that ΔT is substantially larger than ΔTc in most devices, and efficiency suffers accordingly.

Thermoelectrics utilizing thermal isolation


A steering column mounting bracket is provided with break-away capsules integrally formed therewith from the same material as the mounting bracket allowing the capsules to have a more consistent break-away load and reduce noise within the cabin of a vehicle.

The present invention relates generally to steering column support structures, and more particularly to a steering column support structure including capsules that securely hold the steering column to the instrument panel without hindering the collapse of the steering column during an accident.
It is desirable to have a steering column of a vehicle that is securely attached to the frame of the automobile so as to ensure safe operation thereof for the life of the automobile. Generally, this is accomplished by bolting the steering column to the instrument panel which is further secured to the frame of the automobile. However, it has become desirous to allow for the steering column to disengage from the instrument panel and collapse upon the application of a force during an accident.
It is known in the art to attempt to solve these contradictory goals by using polymer capsules (such as disclosed in commonly assigned U.S. Pat. No. 5,390,955, herein incorporated by reference) to support the mounting bracket of the steering column that are designed in such a way as to break-away under a given force. Thus, the steering column is allowed to axially collapse upon the application of a force in the event of an accident.
However, the polymer capsule may change in shape which can cause the capsules to xe2x80x9ccreep.xe2x80x9d This creep may cause buzz/squeak/rattle (BSR) problems which are unwanted during the operation of the vehicle. Furthermore, the polymer capsules can become damaged prior to installation thus requiring the disposal of the part.
It is an object of the present invention to provide a break-away capsule that will overcome the disadvantages of the prior art polymer capsules. This object will be accomplished by forming the capsule from the same material as the remainder of the steering column mounting bracket. This will allow the capsules to have a more consistent break-away load, not be susceptible to BSR, and not break unintentionally during installation.
Further areas of applicability of the present invention will become apparent from the detailed description provided hereinafter. It should be understood however that the detailed description and specific examples, while indicating preferred embodiments of the invention, are intended for purposes of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.

Steering column having magnesium capsules in the upper mounting bracket