The present invention relates to a process for the manufacture of a porous polymer, wherein a composition comprising a polymerizable component, a porogen having an inverse temperature dependent solubility and a solvent are polymerized at a temperature around the cloud point temperature of the composition. The porous polymers obtainable according to the process of the invention are useful, for example, as materials for the manufacture of biomedical devices and prostheses, including ophthalmic devices such as contact lenses or artificial corneas.

The present invention relates to a process for the manufacture of hydrogels with a high water content and porosity, exhibiting a surfactant-induced narrow pore size distribution and their use for various biomedical applications, especially contact lenses including extended-wear contact lenses and long-term implants.
In many applications it has been found advantageous for polymers to be porous. The degree of porosity required depends on the application. For example, membrane filtration depends on the use of microporous polymers to effect separations of various materials. Macroporous sheets of chemically resistant polymers find extensive use as cell dividers in cells for electrolysis or electricity storage. Macroporous materials (open cell foams) produced through the use of blowing agents are used as cushioning materials. Porous materials have also found use in medicine as the medium for the dispensing of medicinal compounds, in medical implants for cell encapsulation or tissue ingrowth, and to achieve certain mechanical properties such as viscoelasticity.
Pores may be formed in the polymer during the process of manufacturing an article of the desired shape or may be formed in the article after manufacture. A preferred process for the manufacture of porous polymers comprises the polymerization of a polymerizable component in the presence of an inert material often referred to as a porogen. Subsequent leaching of the porogen gives rise to interstices throughout the formed polymer material. However, this process is usually complicated by extensive extraction procedures necessary for a complete removal of the conventionally used porogens. A further possible disadvantage of this process is the difficulty of stabilising the suspension of porogen in the polymerization mixture. Unstable suspensions can lead to an non-homogeneous and unacceptable product. In many cases, extensive optimisation of the viscosity of the system and the type of porogen is needed to obtain a satisfactory result. In addition the procedure is limited in terms of the availability of porogens suitable for introducing the desired ranges of pore sizes. Beyond this, conventional porogens lead to a broad pore size distribution.
It now has surprisingly been found that specific surfactants, in particular surfactants with an inverse temperature dependent solubility, contribute to a narrow pore size distribution and greatly simplify porogen-removal after the polymerization process. Used as porogens, these surfactants offer an advantage in the preparation of porous matrices due to their unique inverse temperature dependent solubility property. With the proper choice of a porogen having a specific cloud point temperature, it is possible to achieve a system or formulation where the porogen forms a homogeneous phase with the polymerizable components before the cure. Due to their inverse temperature dependent solubility behavior, the porogens form aggregates during the cure at a temperature around the cloud point temperature of the composition. Therefore, curing of this formulation around its cloud point temperature leaves an imprint of the defined aggregation structure of the surfactants in the polymerized hydrogel membranes. These aggregates are then easily removed from the matrix polymer at a temperature below their cloud point in a suitable extraction medium that swells the polymer, leaving a porous hydrogel behind with a narrow pore size distribution created by the aggregated porogen that is now removed. In addition, different porogens impart different levels of porosity to the hydrogel membranes.
Hence, an object of the present invention is to provide a process for the manufacture of a hydratable porous polymer comprising the steps of:
(a) providing a homogeneous composition at a temperature below the cloud point temperature of the composition comprising
(i) a polymerizable component that comprises at least one polymerizable hydrophilic monomer or macromer,
(ii) a porogen having an inverse temperature dependent solubility, and
(iii) a solvent;
(b) subjecting the composition to a polymerization reaction at or above the cloud point temperature of the composition; and
(c) removing the porogen from the resulting porous polymer at a temperature below the cloud point temperature of the composition.
The polymerizable component according to step (a) may in principle contain any hydrophilic ethylenically unsaturated compound as long as the composition as a whole is homogenious at easy accessible temperatures, for example at room temperature, and the inverse temperature dependent solubility of the porogen is retained in the formulation. Examples of polymerizable hydrophilic monomers that may be part of the polymerizable component according to step (a) are, for example, (i) acrylic or methacrylic acid; (ii) a C1-C18-alkyl ester of acrylic or methacrylic acid which may be substituted in the alkyl portion by hydroxy; (iii) acrylamide or a N-mono- or N,N-di-C1-C4-alkyl acrylamide, for example N,N-dimethyl acrylamide; (iv) a 5- or 6-membered heteroaromatic or heteroaliphatic monomer having one N-atom and in addition no further heteroatom or an additional N- or O-heteroatom, or a 5 to 7-membered lactame, for example N-vinylpyrrolidon, N-vinylimidazol, N-vinyl-2-methylimidazol or N-acryloyl morpholine; (v) a sulfocontaining monomer, preferably an ethylenically unsaturated compound having from 2 to 18 C-atoms which is substituted by a sulfo group or a suitable salt thereof, for example methallyl-sulfonic acid, styrenesulfonic acid, sulfopropylmethacrylate, sulfopropylacrylate, 2-acrylamido-2-methylpropanesulfonic acid, vinyl sulfonic acid, or a suitable salt thereof, for example an alkaline salt or ammonium salt, in particular the sodium or potassium salt; or (vi) allyl alcohol, vinyl acetate or vinyl alcohol, which can be used in each case alone, or in mixtures with other ethylenically unsaturated monomers.
A suitable hydrophilic macromer that the polymerizable component may comprise is, for example, a vinylfunctionalized polyvinyl alcohol, polyalkylene oxide or N-vinylpyrrolidone homo- or copolymer. The macromer may contain one or more than one ethylenically unsaturated double bond. A preferred hydrophilic macromer is a vinylfunctionalized polyvinyl alcohol or polyethylene oxide, in particular a vinylfunctionalized polyvinyl alcohol, for example as described in U.S. Pat. No. 5,508,317, issued to Beat Mxc3xcller on Apr. 16, 1996, which is incorporated herein by reference. The weight average molecular weight of the hydrophilic macromer may vary within wide limits; a suitable range is from about 2000 up to 1,000,000. Preferably, the hydrophilic macromer has a molecular weight of up to 300,000, especially up to approximately 100,000 and especially preferably from about 5000 to about 50,000.
In a preferred embodiment of the invention the polymerizable component comprises one or more different hydrophilic monomers selected from the group consisting of hydroxyethyl acrylate, hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylic acid, methacrylic acid, acrylamide, N,N-dimethyl acrylamide, N-acryloyl morpholine, vinyl acetate, vinyl alcohol, methallylsulfonic acid, styrenesulfonic acid, sulfopropylmethacrylate, sulfopropylacrylate, 2-acrylamido-2-methylpropanesulfonic acid, vinyl sulfonic acid, and a suitable salt thereof.
An even more preferred embodiment of the invention concerns a polymerizable component comprising one or more different monomers selected from the group consisting of hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylamide, N,N-dimethyl acrylamide, sodium methallylsulfonate, sodium styrenesulfonate, potassium sulfopropylmethacrylate and potassium sulfopropylacrylate.
In addition, the polymerizable component may contain a low molecular weight crosslinker. A suitable crosslinker, if present, is, for example, a low molecular weight di- or polyvinylic crosslinking agent such as ethylenglycol diacrylate or dimethacrylate, di-, tri- or tetraethylen-glycol diacrylate or dimethacrylate, allyl (meth)acrylate, a C2-C8-alkylene diacrylate or dimethacrylate, divinyl ether, divinyl sulfone, di- and trivinylbenzene, trimethylolpropane triacrylate or trimethacrylate, pentaerythritol tetraacrylate or tetramethacrylate, bisphenol A diacrylate or dimethacrylate, methylene bisacrylamide or -bismethacrylamide, ethylene bisacrylamide or ethylene bismethacrylamide, triallyl phthalate or diallyl phthalate. The average weight average molecular weight of the crosslinker is, for example, up to 1000, preferably up to 750 and most preferably up to 500. Preferred crosslinkers according to the invention are ethyleneglycol-dimethacrylate, pentaerythritoltetraacrylate or pentaerythritoltetramethacrylate. The polymerizable component according to step (a) preferably comprises a low molecular weight crosslinker.
Preferably, the polymerizable component consists of 50 to 99.9% by weight of one or more different ethylenically unsaturated monomers and from 0.1 to 50% by weight of a low molecular weight crosslinker. More preferably, the polymerizable component consists of 80 to 99.5% by weight of one or more different ethylenically unsaturated monomers and from 0.5 to 20% by weight of a low molecular weight crosslinker. Even more preferably, the polymerizable component consists of 85 to 99.5% by weight of one or more different ethylenically unsaturated monomers and from 0.5 to 15% by weight of a low molecular weight crosslinker.
A preferred polymerizable component consists of one or more monomers selected from the group consisting of hydroxyethyl methacrylate, N-vinyl pyrrolidone, acrylamide, N,N-dimethyl acrylamide, sodium methallylsulfonate, sodium styrenesulfonate, potassium sulfopropylmethacrylate and potassium sulfopropylacrylate and of a low molecular weight crosslinker selected from the group consisting of ethyleneglycol-dimethacrylate, pentaerythritoltetraacrylate or pentaerythritoltetramethacrylate. A particularly preferred polymerizable component consists of hydroxyethyl methacrylate or of a mixture of hydroxyethyl methacrylate and a sulfomonomer selected from the group consisting of sodium methallylsulfonate, sodium styrenesulfonate, potassium sulfopropylmethacrylate and potassium sulfopropylacrylate, and of a low molecular weight crosslinker selected from the group consisting of ethyleneglycol-dimethacrylate, pentaerythritoltetraacrylate or pentaerythritoltetramethacrylate.
The amount of polymerizable component (i) that is present in the composition according to step (a) may vary within wide limits. A suitable weight range of the polymerizable component is, for example, from 10 to 94% by weight, preferably from 20 to 90% by weight and most preferably from 25 to 85% by weight, in each case relative to the entire weight of the composition of step (a).
The porogen may in principle be any compound that forms a homogenious solution with the polymerizable component at convenient temperatures, in particular at room temperature, and which retains its inverse temperature dependent solubility property in the composition. A screening method for investigating inverse temperature dependent solubility (ITDS) characteristics of a formulation is given below in the working examples. A group of suitable porogens are, for example, polyalkylene block copolymers, such as polyethylene-polypropylene, polyethylene-polybutylene or polyethylene-polypropylene-polybutylene block copolymers, in particular polymeric surfactants belonging to the class of block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) of the formula PEO-PPO-PEO, called Normal Pluronics, or of the formula PPO-PEO-PPO, called Reverse Pluronics, which are commercially available under the trade names Pluronics(copyright) and Tetronics(copyright), having a range of chemical structures, molecular weights and sizes. These Pluronics have a unique property called the xe2x80x9cinverse temperature dependent solubilityxe2x80x9d which implies that in specific solvents the polymer solubility decreases with increasing temperature. The temperature at which the polymer phase separates is called the xe2x80x9ccloud pointxe2x80x9d or the xe2x80x9ccritical solution temperaturexe2x80x9d. Dependent on their chemical structure and molecular weight, Pluronics have different cloud points which may vary within wide limits, for example between room temperature or lower and 100xc2x0 C. or preferably between 30xc2x0 C. and 100xc2x0 C.
The amount of porogen (ii) that is present in the composition according to step (a) may vary within wide limits. A suitable weight range of the porogen is, for example, xe2x89xa73% by weight, advantageously from 3 to 85% by weight, preferably from 3 to 50% by weight, more preferably from 5 to 40% by weight, and most preferably from 5 to 25% by weight, in each case relative to the entire weight of the composition of step (a).
Suitable solvents according to step (a) include, for example, water, C1-C4-alkanols, C1-C6-alkylamines, C2-C6-alkylethers, C1-C4-alkyl esters of carboxylic acids such as ethyl acetate, carboxy amides such as N,N-dimethyl formamide, fluorinated alkanols, and mixtures thereof. In most cases such solvents are added to reduce viscosity of the solution or to make the solution easier to dispense, for example into molds. A preferred solvent is water, a C1-C2-alkanol or a mixture thereof. In case of a Pluronics(copyright) as porogen the solvent is water or an aqueous solution comprising for example one of the above-mentioned organic solvents, and is in particular water. The amount of solvent that is present in the composition according to step (a) may vary within wide limits. A suitable weight range of the solvent (iii) is, for example, from 3 to 75% by weight, preferably from 5 to 60% by weight and most preferably from 5 to 55% by weight, in each case relative to the entire weight of the composition of step (a).
The composition according to step (a) may contain further components, for example a polymerization initiator. Suitable polymerization initiators are typically those that are initiating a radical polymerization of ethylenically unsaturated compounds. The radical polymerization may be induced thermally, or preferably by UV irradiation. Redox initiation may also be used.
Suitable thermal polymerization initiators are known to the skilled artisan and comprise for example peroxides, hydroperoxides, azo-bis(alkyl- or cycloalkylnitriles), persulfates, percarbonates or mixtures thereof. Examples are benzoylperoxide, tert.-butyl peroxide, di-tert.-butyl-diperoxyphthalate, tert.-butyl hydroperoxide, azo-bis(isobutyronitrile), 1,1xe2x80x2-azo-bis (1-cyclohexanecarbonitrile), 2,2xe2x80x2-azo-bis(2,4-dimethylvaleronitrile), 4,4xe2x80x2-azo-bis(4-cyanovaleric acid and the like.
Initiators for the radiation-induced polymerization, so-called photoinitiators, may belong to different types, for example to the thioxanthone type ord to the benzoin type. Useful photoinitiators include for example benzophenones substituted with an ionic moiety, a hydrophilic moiety or both such as 4-trimethylaminomethyl benzophenone hydrochloride or benzophenone sodium 4-methanesulfonate; benzoin C1-C4alkyl ether such as benzoin methyl ether; thioxanthones substituted with an ionic moiety, a hydrophilic moiety or both such as 3-(2-hydroxy-3-trimethylaminopropoxy) thioxanthone hydrochloride, 3-(3-trimethylaminopropoxy) thioxanthone hydrochloride, thioxanthone 3-(2-ethoxysulfonic acid) sodium salt or thioxanthone 3-(3-propoxysulfonic acid) sodium salt; or phenyl ketones such as 1-hydroxycyclohexylphenyl ketone, (2-hydroxy-2-propyl)(4-diethylene glycol phenyl)ketone, (2-hydroxy-2-propyl)(phenyl-4-butanecarboxylate)ketone; or commercial products such as Darocure(trademark) or Irgacure(trademark) types, e.g. Darocure 1173 or Irgacure 2959.
The composition according to step (a) preferably comprises a polymerization initiator, in particular a photoinitiator. The polymerization initiator is present in an amount of, for example, 0.05 to about 1.5% by weight, preferably 0.1 to 1.0% by weight and particularly preferably 0.08 to 0.5% by weight, based on the entire polymerizable component in each case.
Minor amounts of property modifying components may optionally be added to the mixture before polymerization.
The polymerizable component may be mixed with the porogen, the solvent and other optional components by any convenient means. For example the polymerizable component may be mixed with the porogen, the solvent and other optional components by shaking or stirring. The order in which the components are added to the mixture is not narrowly critical. The mixing of the components is performed at a temperature below the cloud point temperature of the resulting composition, for example at a temperature of from about 0 to 80xc2x0 C., preferably from 5 to 50xc2x0 C., more preferably from 10 to 30xc2x0 C. and in particular at room temperature.
The compositions of the invention may be polymerized by any convenient method generally as described above with reference to the initiation of the polymerizable component. Suitable polymerization conditions will be apparent to those skilled in the art. The compositions are cured at a temperature at or above the cloud point temperature of the mixture. The cloud point temperature of a preferred composition according to the invention using, for example, a Pluronics(copyright) porogen is typically in the range of from about 30 to 60xc2x0 C., preferably from about 30 to 45xc2x0 C. and most preferably of from about 30 to 40xc2x0 C. Accordingly, the polymerization reaction is advantageously carried out at a temperature within the above given temperature ranges. According to a preferred embodiment of the process of the invention, the temperature inside the curing chamber is kept constant at the desired curing temperature, that is at a temperature at or above the cloud point temperature of the composition to be cured, and the homogenious composition of the polymerizable component, the porogen, the solvent(s) and other optional components is inserted into the curing chamber just before the commencement of the curing. The polymerization time may vary within wide limits but is suitably chosen as to be in the range of from about 1 minute to 1 hour, preferably from about 3 to 30 minutes and most preferably from 5 to 15 minutes.
After the polymerization reaction the porogen, solvent(s) and the like may be removed from the porous polymer by any convenient means. Suitable means for removal of the porogen (or solvent) include solvent extraction, washing or leaching. Preferred means for removal of the porogen are solvent extraction and washing. Typically, the removal of the porogen is carried out a temperature below the cloud point temperature of the porogen. Preferably, the resulting porous polymers are first of all extracted at room temperature in a suitable swelling solvent, such as in a C1-C4-alcohol or in a mixture of water and a C1-C4-alcohol, followed by a treatment with water. Following extraction, the resulting porous polymers are preferably equilibrated in water.
The process of the present invention is useful for generating materials of various pore sizes and morphologies. The upper limit of average pore size of individual pores is about 5 microns, with 100 nanometers being typical, while pores of around 10 nanometers in diameter may also be obtained.
The polymers prepared according to the present invention have a water content which is, when fully swollen in water, between about 30 and about 70 weight percent. In addition, the polymers that are obtainable according to the process of the invention exhibit a narrow pore size distribution. In case of a small size porogen this leads to polymers with a high optical clarity, which makes them useful for biomedical applications, particularly for ophthalmic devices such contact lenses. In case of larger size porogens translucent or turbid polymers are obtained which are, for example, useful as membranes. Since the size of the pores can be selected by using a specific porogen it is possible to make the polymers selectively permeable to small proteins like vitamin B-12 or albumin.
In one embodiment the porous polymer may be in the form of a closed-cell structure with discrete pores dispersed throughout the polymer.
In a further preferred embodiment the pores may form an interpenetrating network. It is more useful to characterise these morphologies in terms of permeability of the polymer to molecules of defined molecular weight.
The form of the polymeric material may vary within wide limits. Examples are particles, granules, capsules, fibres, tubes, films or membranes, preferably moldings of all kinds such as ophthalmic moldings, in particular contact lenses.
The polymers of the invention are characterized in particular by a high biocompatibility, biostability, non-cytotoxicity, cell growth capability and antifouling properties. Said properties make them suitable as materials for the attachment and growth of human or animal cells in vivo or in vitro, medical implants (such as implantable semipermeable membrane materials, tissue implants in cosmetic surgery, implants containing hormone secreting cells such as pancreatic islet cells, breast implants, artificial joints and the like), in artificial organs, tissue culture apparatus (such as bottles, trays, dishes and the like), in biological reactors (such as those used in the production of valuable proteins and other components by cell culture), in optical instruments, such as microscope slides and the like. The polymers obtainable according to this invention are especially suitable for materials that are designed for long-term implantation.
Ocular prostheses, such as corneal implants, may be made by polymerization in moulds as described above and, optionally, the resultant polymer may be fabricated or machined to the desired conformation.
Corneal implants may be placed by way of conventional surgical techniques beneath, within, or through corneal epithelial tissue, or within the corneal stroma or other tissue layers of the cornea. Such implants may change the optical properties of the cornea (such as to correct visual deficiencies) and/or change the appearance of the eye, such as pupil colouration. A corneal implant may comprise an optical axis region which on implantation covers the pupil and provides visual acuity, and a less transparent region which surrounds the periphery of the optical axis region. Alternatively the implant may have the same visual acuity across its dimensions.
The polymers produced according to the present invention may be formed into other useful articles using conventional moulding and processing techniques as are well known in the art. Given the visual transparency of the polymers of the present invention, they may find use in tissue culture apparatus, optical instruments, microscope slides and the like.
A further aspect of this invention is the use of the porous hydrogel in film or sheet form as a membrane or a filter. Such porous film may be laminated with another support film to form a composite. Such applications may involve permeability to gases or liquids.
The porous polymers of the present invention may be suitable, for example, for use in the fields of membrane filters and separation, in the field of industrial biotechnology, and in the biomedical field.
Examples for the field of membrane filters and separation are industrial membranes, e.g. for micro filtration and ultra filtration, for example in the food, dairy, juice, or low alcohol beer industries, waste water treatment, home reverse osmosis, or membrane distillation using osmotic pressure.
Examples or the field of industrial biotechnology are supports for synthetic and biological ligands or receptors for bioreactors and biosensors, sustained release devices for active compounds, or capacitors.
Further examples for the biomedical field, besides ophthalmic devices, are dialysis and blood filtration, encapsulated biological implants, e.g. pancreatic islets, implanted glucose monitors, drug delivery patches and devices, wound healing and dressing, artificial skin, vascular grafts, regenerative templates or patches for wound healing, (soft) tissue augmentation, percutaneous fixation devices or artificial organs.
The present invention is further described in the following non-limiting examples. If not other wise specified, all parts are by weight. Temperatures are in degrees Celsius. Molecular weights of macromers or polymers are weight average molecular weights if not otherwise specified.


This invention relates to methods for the prophylaxis or treatment of diabetic nephropathy comprising, administering as an active ingredient, a compound, or salt thereof, of formula (I)

This invention relates to a prophylactic or therapeutic drug containing an angiotensin II antagonistic compound or salt thereof as the active constituent, for diabetic nephropathy or glomerulonephritis.
The kidneys are a major target organ of hypertension. Prolonged hypertension induces various renal impairments, mainly through renovascular lesions. Among them, contraction of renal vessels and degenerative lesions of elastic fibers lead to further elevation of the blood pressure. It is generally believed that hypertension raises renal intraglomerular pressure, which overloads the glomeruli, stimulating fibrosis and enlargement of the mesangial region, which advances to hardening of the glomeruli. In diabetic nephropathy as well, elevation in intraglomerular pressure is followed by trace albuminuria, progressing to the sclerosis of the glomeruli. Eventually, renal functions decline, resulting in chronic renal failure requiring artificial dialysis therapy. In recent years, 20% of patients with end-stage renal failure who commence artificial dialysis have diabetic nephropathy as the underlying disease. The number of patients likely to receive artificial dialysis tends to increase year after year, posing a critical problem in the medical care system. At present, it is said that there are few ideal pharmaceutical therapies for chronic renal failure, and even that blood-pressure-lowering therapy may aggravate rather than improve renal failure.
Angiotensin II antagonistic compounds are known as a therapeutic drug for cardiovascular diseases, e.g., hypertension, cardiac diseases (heart enlargement, heart failure, myocardial infarction, etc.), apoplexy, nephritis, etc. (European Patent Official Gazette (EPO) 459136A). The mechanism of their action is considered to be based on inhibition of binding to the angiotensin II receptor of angiotensin II, which possesses intense vasoconstrictive action. EP 459136A1 describes the availability of angiotensin II antagonists in the treatment of nephropathy or nephritis.
Many data of clinical and experimental studies have been reported on the relation between renal diseases and hypertension. It is now established that the kidneys are directly or indirectly involved in the onset of hypertension, and also are apt to be affected by hypertension. However, hypertension in chronic glomerulonephritis has been poorly elucidated, particularly as to causative factors, effects of hypertension on the course of nephritis, and prophylactic effects of blood pressure lowering therapy.
Currently, nephritis is considered to be a clinical picture of different diseases with different entities. In accordance with the popularization of renal biopsy, renal diseases have been reviewed, resulting in their redefinition as a wide range of diseases characterized by proteinuria (xe2x80x9cShibata""s Internal Medicine of the Kidneys,xe2x80x9d by Seiichi Shibata, Bunkodo, 1988). Glomerulonephritis, once regarded as a single disease, has been differentiated into glomerulonephritis, chronic pyelonephritis, IgA nephropathy, periarteritis nodosa, gout, diabetes, systemic lupus erythematosus (SLE), hepatic infarction, hereditary renal disease, amyloidosis, and Wegener""s sarcoma.
Diabetes associated with hypertension facilitates cardiovascular impairment and/or other organ complications, greatly affecting life expectancy. Accordingly, it is important to control blood pressure within the normal range during treatment, along with the control of diabetes and the improvement or prevention of arteriosclerosis.
This invention provides a prophylactic or therapeutic drug for diabetic nephropathy or glomerular nephritis.
Under the above-mentioned circumstances, the inventors intensively studied to develop a drug for the prophylaxis or treatment of nephropathy or nephritis. Ultimately, they found that compounds possessing angiotensin II antagonistic action, represented by a particular structural formula, are very effective in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis. The present invention was thus accomplished.
Namely, this invention relates to a prophylactic or therapeutic drug for diabetic nephropathy or glomerulonephritis, containing, as the active constituent, a compound or salt thereof represented by formula (I):
(wherein R1 stands for H or an optionally substituted hydrocarbon residue; R2 stands for an optionally esterified carboxyl group; R3 stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring having one or two optional substituents in addition to R2; Y stands for a bond, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94 (wherein m stands for 0, 1 or 2), or xe2x80x94N(R4)xe2x80x94 (wherein R4 stands for H or an optionally substituted alkyl group)).
The invented compounds used for prophylactic or therapeutic purposes, as represented by formula (I), are structurally very prominently characterized by the coexistence of R2, standing for an optionally esterified carboxyl group, and R3, standing for a group actually or potentially capable of forming an anion. This structural characteristic contributes to the onset of very intense prophylactic or therapeutic effect on diabetic nephropathy or glomerulonephritis.
The compounds of this invention, possessing angiotensin II antagonistic action, represented by formula (I), can be favorably used in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis.
In formula (I), R1 stands for H or an optionally substituted hydrocarbon residue.
Examples of the hydrocarbon residue represented by R1 include alkyl, alkenyl, alkynyl, cycloalkyl, aryl and aralkyl groups. Among them alkyl, alkenyl and cycloalkyl groups are preferable.
The alkyl group represented by R1 is a straight chain or branched lower alkyl group having 1 to about 8 carbon atoms, as exemplified by methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, i-pentyl, hexyl, heptyl or octyl.
The alkenyl group represented by R1 is a straight chain or branched lower alkenyl group having 2 to about 8 carbon atoms, as exemplified by vinyl, propenyl, 2-butenyl, 3-butenyl, isobutenyl or 2-octenyl.
The alkynyl group represented by R1 is a straight chain or branched lower alkynyl group having 2 to about 8 carbon atoms, as exemplified by ethynyl, 2-propinyl, 2-butynyl, 2-pentynyl or 2-octynyl.
The cycloalkyl group represented by R1 is a lower cycloalkyl group having 3 to about 6 carbon atoms, as exemplified by cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
The above mentioned alkyl, alkenyl, alkynyl or cycloalkyl group may optionally be substituted with hydroxyl group, an optionally substituted amino group (e.g. amino, N-lower (C1-4) alkylamino or N,N-dilower (C1-4) alkylamino), halogen, a lower (C1-4) alkoxy group, a lower (C1-4) alkylthio group.
The aralkyl group represented by R1 is, for example, a phenyl-lower (C1-4) alkyl such as benzyl or phenethyl, and the aryl group represented by R1 is, for example, phenyl.
The above mentioned aralkyl or aryl group may optionally have, on any position of its benzene ring, for example, halogen (e.g. F, Cl or Br), nitro, an optionally substituted amino group (e.g. amino, N-lower (C1-4) alkylamino or N,N-dilower (C1-4) alkylamino), lower (C1-4) alkoxy (e.g. methoxy or ethoxy), lower (C1-4) alkylthio (e.g. methylthio or ethylthio) or lower (C1-4) alkyl (e.g. methyl or ethyl).
Among the above mentioned groups represented by R1, optionally substituted alkyl, alkenyl or cycloalkyl groups (e.g. a lower (C1-5) alkyl, lower (C2-5) alkenyl or lower (C3-6) cycloalkyl group optionally substituted with hydroxyl group, amino group, halogen or a lower (C1-4) alkoxy group) are preferable.
Y stands for a bond, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94 (wherein m is 0, 1 or 2) or xe2x80x94N(R4)xe2x80x94 (wherein R4 is hydrogen or an optionally substituted lower alkyl group). Y is preferably a bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94N(R4)xe2x80x94 (wherein R4 is hydrogen or a lower (C1-4) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl)).
With respect to formula (I) above, the group for R3, capable of forming an anion (a group having a hydrogen atom capable of leaving as a proton), or a group capable of changing thereto, is exemplified by 5- to 7-membered (preferably 5- or 6-membered) monocyclic heterocyclic ring residues which contain one or more of N, S and O and which may be substituted (preferably N-containing heterocyclic residues having a hydrogen atom capable of leaving as a proton), and groups capable of changing thereto in vivo. Such groups include the following:
The chemical bond between the group for R3 and the partner phenyl group may be a carbon-carbon bond as shown above, or a nitrogen-carbon bond via one of the several nitrogen atoms when the symbol g stands for xe2x80x94NHxe2x80x94 in the above formulas. For instance, when R3 is represented by
embodiments are
Other R3 examples binding through the nitrogen atom are
In the above groups, g stands for xe2x80x94CH2xe2x80x94, xe2x80x94NR7xe2x80x94, oxygen atom, or
 greater than xe2x95x90Z,  greater than xe2x95x90Zxe2x80x2 and  greater than xe2x95x90Zxe2x80x3 each stand for a carbonyl group, a thiocarbonyl group or an optionally oxidized sulfur atom (e.g., S, S(O), S(O)2) (preferably, a carbonyl or thiocarbonyl group; more preferably, a carbonyl group); m stands for the integer 0, 1 or 2; R7 stands for a hydrogen atom or an optionally substituted lower alkyl group (e.g. a lower (C1-4) alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, t-butyl)).
Preferable examples of R3 include 2,5-dihydro-5-oxo-1,2,4-oxadiazole ring residue, 2,5-dihydro-5-thioxo-1,2,4-oxadiazole ring residue or 2,5-dihydro-5-oxo-1,2,4-thiadiazole ring residue having xe2x80x94NH or xe2x80x94OH group as proton donor and carbonyl group, thiocarbonyl group or sulfinyl group as proton acceptor simulateneously.
And, while the heterocyclic residue represented by R3 may form a condensed ring by connecting the substituents on the ring, it is preferably a 5- to, 6-membered ring, more preferably a 5-membered heterocyclic residue. Especially, groups represented by the formula
wherein i stands for xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; j stands for  greater than Cxe2x95x90O,  greater than Cxe2x95x90S or  greater than S(O)m; m stands for the integer 0, 1 or 2 (in particular, 2,5-dihydro-5-oxo-1,2,4-oxadiazole-3-yl; 2,5-dihydro-5-thioxo-1,2,4-oxadiazole-3-yl; 2,5-dihydro-5-oxo-1,2,4-thiadiazole-3-yl) are preferable. R3 can be substituted at the ortho, meta or para position, most preferably at the ortho position.
In addition, the above-mentioned heterocyclic residue (R3) have the following tautomeric isomers:
In
when Z=0, and g=0
the three tautomeric isomers a, b and c exist.
The heterocyclic residue represented by the above formula comprises all of these a, b and c.
Moreover, R3 may be a, carboxyl group, tetrazolyl group, trifluoromethanesulfonamide group (xe2x80x94NHSO2CF3), phosphate group, sulfonic group, cyano group, or lower (C1-4) alkoxycarbonyl group; these groups each may be protected by an optionally substituted lower alkyl or acyl group. Any group capable of forming an anion biologically or physiologically (e.g. through biological reactions such as oxidation, reduction or hydrolysis caused by enzymes in the body) or chemically, or a group capable of changing thereto is acceptable.
As R3, a tetrazolyl or carboxyl (preferably tetrazolyl) group optionally protected by an optionally substituted lower (C1-4) alkyl (e.g., methyl, triphenylmethyl, methoxymethyl, ethoxymethyl, p-methoxybenzyl, p-nitrobenzyl, etc.) or acyl (e.g., lower (C2-5) alkanoyl, benzoyl, etc.) group is preferable. R3 can be replaced at the ortho, meta or para position, most preferably at the ortho position.
X stands for a covalent bond between the 2 phenyl rings or a spacer having a chain length of 1 to 2 atoms as the linear moiety between the adjoining phenylene group and phenyl group. Preferably, X is a covalent bond. The spacer having a chain length of 1 to 2 atoms may consist of a divalent chain in which the number of atoms composing the straight chain portion is either 1 or 2, and may have a side chain. For example, a lower (C1-4) alkylene, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94, xe2x80x94Sxe2x80x94CH2xe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, etc. are listed.
n stands for the integer 1 or 2 (preferably 1).
The formula represented by the above-mentioned R3, X and n:
is preferably represented by the formula:
R2 in formula (I) is an optionally esterified carboxyl group.
The optionally esterified carboxyl group as R2 includes the group represented by the formula xe2x80x94COxe2x80x94D [wherein D stands for a hydroxyl group or an optionally substituted alkoxyl group {e.g., a lower (C1-6) alkoxyl group whose alkyl portion is optionally substituted with a hydroxyl, optionally substituted amino (e.g., amino, dimethylamino, diethylamino, piperidino, molphorino, etc.), halogen, lower (C1-6) alkoxyl, lower (C1-6) alkylthio or optionally substituted dioxolanyl (e.g., 5-methyl-2-oxo-1,3-dioxolane-4-yl, etc.) group, or the group represented by the formula xe2x80x94Oxe2x80x94CH(R6)xe2x80x94OCOR5 [wherein R6 stands for H, a lower (C1-6) straight chain or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, isopentyl neopentyl, etc.), a lower (C2-6) straight chain or branched alkenyl group or a lower (C3-8) cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.); R5 stands for a lower (C1-6) straight chain or branched alkyl group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, etc.), a lower (C2-6) straight chain or branched alkenyl group, a lower (C3-8) cycloalkyl group (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.), a lower (C1-3) alkyl group substituted with C3-8 cycloalkyl (e.g. cyclopentyl, cyclohexyl, cycloheptyl) or an optionally substituted aryl group such as phenyl group (e.g., benzyl, p-chlorobenzyl, phenetyl, cyclopentylmethyl, cyclohexylmethyl, etc.), a lower (C2-3) alkenyl group optionally substituted with C3-8 cycloalkyl or an optionally substituted aryl group such as phenyl (e.g., cinnamyl, etc. having alkenyl moiety such as vinyl, propenyl, allyl and isopropenyl, etc.), an aryl group such as optionally substituted phenyl (e.g., phenyl, p-tolyl, naphtyl, etc.), a lower (C1-6) straight chain or branched alkoxyl group (e.g., methoxyl, ethoxyl, n-propoxyl, isopropoxyl, n-butoxyl, isobutoxyl, sec-butoxyl, t-butoxyl, n-pentyloxyl, isopentyloxyl, neopentyloxyl, etc.), a lower (C2-8) straight chain or branched alkenyloxyl group (e.g., allyloxyl, isobutenyloxyl, etc.), a lower (C3-8) cycloalkyloxyl group (e.g., cyclopentyloxyl, cyclohexyloxyl, cycloheptyloxyl, etc.), a lower (C1-3) alkoxyl group substituted with a C3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an aryl group such as optionally substituted phenyl (e.g., benzyloxy, phenethyloxy, cyclopentylmethyloxy and cyclohexylmethyloxy having alkoxy moiety such as methoxy, ethoxy, n-propoxy and isopropoxy), a lower (C2-3) lower alkenyloxy group substituted with a C3-8 cycloalkyl (e.g., cyclopentyl, cyclohexyl, cycloheptyl, etc.) or an optionally substituted aryl group such as phenyl group (e.g., cinnamyloxy etc. having alkenyloxy moiety such as vinyloxy, propenyloxy, allyloxy, isopropenyloxy, etc.), or an optionally substituted aryloxyl group such as phenoxyl (e.g., phenoxyl, p-nitrophenoxyl, naphtoxyl, etc.,)}]. The substituent for R2 may be a group actually or potentially capable of forming an anion [e.g., tetrazolyl group, trifluoromethanesulfonamide group, phosphate group or sulfonic group optionally protected by an alkyl {e.g., lower (C1-4) alkyl, etc.} or acyl {e.g., lower (C2-5) alkanoyl, optionally substituted benzoyl, etc.} group].
For example, the following substituents are listed: xe2x80x94COOH and its salts, xe2x80x94COOMe, xe2x80x94COOEt, xe2x80x94COOtBu, xe2x80x94COOPr, pivaloyloxymethoxycarbonyl, 1-(cyclohexyloxycarbonyloxy)ethoxycarbonyl, (5-methyl-2-oxo-1,3-dioxolane-4-yl)methoxycarbonyl, acetoxymethoxycarbonyl, propionyloxymethoxycarbonyl, n-butylyloxymethoxycarbonyl, isobutylyloxymethoxycarbonyl, 1-(ethoxycarbonyloxy)ethoxycarbonyl, 1-(acetoxy)ethoxycarbonyl, 1-(isobutylyloxy)ethoxycarbonyl, cyclohexylcarbonyloxymethoxycarbonyl, benzoyloxymethoxycarbonyl, cinnamiloxycarbonyl and cyclopentylcarbonyloxymethoxycarbonyl, etc. Furthermore, R2 may be any of the groups actually or potentially capable of forming an anion (e.g., COOxe2x80x94 or its derivatives, etc.) under biologic, or physiologic, conditions (e.g., oxidation or reduction induced by an enzyme present in the living body; in vivo reaction such as hydrolysis) or chemically. R2 may also be a carboxyl group or its prodrug. R2 may be a group capable of being biologically or chemically biotransformed to an anion.
Among the groups described as R2, preferable ones include carboxyl, esterified carboxyl (e.g. methyl ester, ethyl ester or an ester formed by binding of a group represented by the above mentioned formula xe2x80x94Oxe2x80x94CH(R6)xe2x80x94OCOR5 to carbonyl) and optionally protected tetrazolyl, carboaldehyde and hydroxymethyl.
In general formula (I), ring A may have, in addition to the group represented by R2, another substituent, e.g., a halogen atom (e.g., F, Cl, Br, etc.), cyano group, nitro group, lower (C1-4) alkyl group, lower (C1-4) alkoxyl group, optionally substituted amino group {e.g., amino, N-lower (C1-4) alkylamino (e.g., methylamino, etc.), N,N-dilower (C1-4) alkylamino (e.g., dimethylamino, etc.), N-arylamino (e.g., phenylamino, etc.), alicyclic amino (e.g., morpholino, piperidino, piperazino, N-phenylpiperazino, etc.), etc.}, a group represented by the formula xe2x80x94COxe2x80x94Dxe2x80x2 (wherein Dxe2x80x2 stands for a hydroxyl group or a lower (C1-4) alkoxyl group whose alkyl moiety may be substituted with a hydroxyl group, lower (C1-4) alkoxyl group, lower (C2-6) alkanoyloxy (e.g., acetoxyl, pivaloyloxyl, etc.) or lower (C1-6) alkoxycarbonyloxyl (e.g., methoxycarbonyloxyl, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy, etc.) group], or tetrazolyl, trifluoromethanesulfonamide, phosphoric acid or sulfonic acid group which may be protected by lower (C1-4) alkyl or acyl group (e.g., lower (C2-5) alkanoyl, optionally substituted benzoyl, etc.); among them, a lower (C1-4) alkyl group and a halogen group are preferable. Of these substituents, one or two may simultaneously substitute for groups at available positions in the ring.
Among the compounds represented by the above mentioned formula (I), compounds represented by formula (Ixe2x80x2) are preferred:
[wherein ring A stands for a benzene ring which may have another 1 or 2 substituents in addition to the group represented by R2; R1 stands for H or an optionally substituted lower (C1-6) alkyl (preferably lower (C1-4) alkyl); Y stands for O, N(H) or S; R2 is a group represented by the formula xe2x80x94COxe2x80x94Dxe2x80x3 [wherein Dxe2x80x3 stands for hydroxyl group, or a lower (C1-4) alkoxy whose alkyl moiety is optionally substituted with hydroxyl group, amino, halogen, a lower (C2-6) alkanoyloxy (e.g. acetyloxy and pivaloyloxy, etc.), lower (C4-7) cycloalkanoyloxy, lower (C1-6) alkoxycarbonyloxy (e.g. methoxycarbonyloxy, ethoxycarbonyloxy), lower (C3-7) cycloalkoxycarbonyloxy (e.g. cyclohexyloxycarbonyloxy) or a lower (C1-4) alkoxy; R3 stands for a tetrazolyl, carboxyl group or groups represented by the formula,
wherein i stands for xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; j stands for  greater than Cxe2x95x90O,  greater than Cxe2x95x90S or  greater than S(O)m; and m is of the same meaning as defined above, which are optionally protected with optionally substituted lower (C1-4) alkyl (e.g. methyl, triphenylmethyl, methoxymethyl, acetyloxymethyl, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, 1-(cyclohexyloxycarbonyloxy)ethyl and pivaloyloxymethyl, etc.) or an acyl group (e.g. a lower C2-5 alkanoyl and benzoyl, etc.).; n is 1 or 2.
In the formula (Ixe2x80x2), substituents on the optionally substituted lower alkyl for R1 include a hydroxyl group, an amino group, halogen and a lower (C1-4) alkoxy group.
In the formula (Ixe2x80x2), ring A is a benzene ring which may have a substituent, in addition to the group R2, such as a halogen (e.g., F, Cl, Br), lower (C1-4) alkyl, lower (C1-4) alkoxy, nitro, a group represented by the formula xe2x80x94COxe2x80x94Dxe2x80x2, wherein Dxe2x80x2 represents a hydroxyl group or a lower (C1-4) alkoxy whose alkyl moiety may be substituted with a hydroxyl group, lower (C1-4) alkoxy, lower (C2-6) alkanoyloxy (e.g., acetoxy, pivaloyloxy, etc.) or lower (C1-6) alkoxycarbonyloxy (e.g., methoxycarbonyloxy, ethoxycarbonyloxy, cyclohexyloxycarbonyloxy), or an amino which may be substituted with a lower (C1-4) alkyl (preferably a substituent such as a lower (C1-4) alkyl or halogen). More preferably, A is a benzene ring which has no substituent in addition to the group represented by the formula R2.
As the salt thereof, pharmaceutically acceptable salts are used, e.g., a salt with an inorganic base, organic base, inorganic acid, organic acid, or basic or acidic amino acid. Inorganic bases appropriate to form the salt include alkali metals such as sodium and potassium, alkali soil metals such as calcium and magnesium, aluminum and ammonium. Organic bases appropriate to form the salt include trimethylamine, triethylamine, pyridine, picoline, ethanolamine, jetanolamine, triethanolamine, dicyclohexylamine, and N,Nxe2x80x2-dibenzylethylenediamine. Inorganic acids appropriate to form the salt include hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid, and phosphoric acid. Organic acids appropriate to form the salt include formic acid, acetic add, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. Basic amino acids to form the salt include arginine, lysine and ornithine. Acidic amino acids to form the salt include aspartic acid and glutamic acid.
As an active ingredient of the present invention, the compounds described in the Examples of Japan Provisional Publication No. 364171/1992 and EP520423 are preferred.
The compounds represented by general formula (I) were, for instance, disclosed in Provisional Publication Nos. 9373/1992 and 364171/1992, and EP520423, and can be manufactured as described in these publications.
Compound (I) or salts thereof possessing angiotensin II antagonistic action referred to in the present invention are of sufficiently low toxicity to be used as a pharmaceutical for animals, particularly mammals (e.g., humans, dogs, rabbits, rats, mice, etc.), in the prophylaxis or treatment of diabetic nephropathy or glomerulonephritis.
Compound (I) or salts thereof represented by general formula (I) can be administered by the oral route, non-oral route, inhalation, rectal injection, or topical administration, as pharmaceutical constituents or preparations (e.g., powder, granules, tablets, pills, capsules, injection, syrup, emulsion, elixir, suspension, solution, etc.). At least one compound of the present invention can be used singly or in mixture with a carrier allowable as a pharmaceutical (adjuvant, vehicle, supportive agent, and/or diluting agent).
The constituents of a pharmaceutical can be prepared according to the usual manner. In the present specification, the non-oral route includes subcutaneous injection, intravenous injection, intramuscular injection, peritoneal injection and intravenous drip. For prescription injection, sterile aqueous or oily suspensions for injection can be prepared by using an appropriate emulsifier or humidifier and a suspending agent, according to known methods. The sterile prescription agent for injection may be a non-toxic, non-orally administrable diluting agent such as aqueous solution or a sterile injectable solution or suspension in a solvent. As the usable vehicle or solvent, water, Ringer""s solution, isotonic saline, etc. are allowed; as an ordinary solvent, or suspending solvent, sterile involatile oil can be used. For these purposes, any kind of involatile oil and fatty acid can be used, including natural or synthetic or semisynthetic fatty oils or fatty acids; natural or synthetic or semisynthtetic mono- or di- or tri-glycerides.
The suppository for rectal administration can be manufactured via a particular process, in which the drug is mixed with an appropriate, non-irritant supporting agent, e.g., cocoa butter or polyethylene glycol, that is solid at normal temperature but liquid at intestinal temperature and therefore melts in the rectum to release the drug.
As the solid-type dosage form for oral administration, powder, granules, tablets, pills and capsules are listed as mentioned above. In these dosage forms, the active constituent compound can be mixed with at least one additive, including sucrose, lactose, cellulose, mannitol, maltitol, dextran, starches, agar, arginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatin, collagen, casein, albumin, synthetic or semisynthetic polymer, and glyceride. These dosage forms can also contain other type(s) of additives, e.g., inactive diluting agent, lubricant such as magnesium stearate, paraben, preserving agent such as sorbic acid, ascorbic acid, xcex1-tocopherol, antioxidant such as cysteine, disintegrator, binder, thickener, buffering agent, sweetening agent, flavoring agent, perfuming agent, etc. Tablets and pills can be further processed into enteric coated preparations. The liquid preparations for oral administration include emulsion, syrup, elixir, suspension and solution preparations allowable for medical use. These preparations may contain inactive diluting agents ordinarily used in said field, e.g., water.
The dosage for a particular patient is determined according to age, body weight, general health conditions, sex, diet, administration time, administration method, excretion rate, drug combination, and severity of the illness being treated, in consideration of those or other factors.
The compounds and salts thereof represented by general formula (I) can be safely used at low toxicity level; the daily dose varies with patient condition, body weight, type of compound, administration route, etc.; e.g., non-orally, i.e. for subcutaneous, intravenous, intramuscular or intrarectal use, approximately 0.01-50 mg/person/day, preferably 0.01-20 mg/person/day, and orally, approximately 0.01-150 mg/person/day, preferably 0.1-100 mg/person/day, are recommended.
The invention is described in more detail with reference to examples. However, the invention is not limited to the specific embodiments.

Prophylactic or therapeutic drug for renal diseases

Abstract: wherein R1 stands for H or lower alkyl; R2 stands for an optionally esterified carboxyl group; R3 stands for a group actually or potentially capable of forming an anion; X shows that the phenylene and phenyl groups bind to each other directly or through a spacer having an atomic chain length of two or less; n stands for 1 or 2; ring A stands for a benzene ring; Y stands for a bond, xe2x80x94Oxe2x80x94, xe2x80x94S(O)mxe2x80x94 wherein m stands for 0, 1 or 2, or xe2x80x94N(R4)xe2x80x94 wherein R4 stands for H or an optionally substituted alkyl group).


The invention relates to alteration of a linear low density polyethylene which is ordinarily free of long chain branching to introduce long chain branching into the polymer.

The invention relates to terpolymers of ethylene, an alpha olefin of 3 to 10 carbon atoms, preferably 4 to 10 carbon atoms, and a diene which contains 7 to 10 carbon atoms. The presence of the diene coincides with long chain branching in the terpolymer; the copolymer free of the diene exhibits no long chain branching. Long chain branching is desirable as it increases the processability of the resulting polymerization product.
This invention discloses that in a linear copolymer comprising ethylene and an amount of an alpha olefin, which is free of long chain branching, exhibiting a numerical value of MFR (I21/I2, measured according to ASTM D-1238) of 16 to 20 and Mw/Mn value of 2.0 to 3.5, the modification comprises a terpolymer containing an amount of alpha olefin, ethylene and units of a diene containing 7 to 10 carbon atoms, wherein the diene is present in an amount effective to increase the numerical value of MFR. The terpolymer exhibits Mw/Mn which is substantially identical to that of the corresponding linear copolymer without diene. The diene is selected from the group consisting of 1,7-octadiene, 1,8-nonadiene and admixtures thereof.
Terpolymers of ethylene, an alpha olefin, and a diene have been produced using a supported activated metallocene catalyst. Use of the metallocene catalyst led to high comonomer incorporation of the substituted olefins. Very small amounts of diene cause a substantial change in resin MFR[I21/I2, measured according to ASTM D-1238, Conditions E and F] without a significant change in Mw/Mn [compared to the counterpart resin free of any diene]. This change in resin MFR with substantially constant Mw/Mn is indicative of the introduction of long chain branching into the resin.
The invention relates to terpolymers which contain ethylene units, units of an alpha olefin and as the third component a diene containing 7 to 10, preferably 7 to 9, carbon atoms. These terpolymers contain at least 80, usually at least 90, wt. % of ethylene units. The terpolymers contain up to 20 wt. % of alpha mono-olefin of 3 to 10 carbon atoms and 0.1 to 20 wt. % of diene of 7 to 10 carbon atoms.
Monomers
The monomers used in addition to ethylene comprise C3-C10 alpha-olefins. Preferably, the products contain at least 80 wt. % ethylene units. The alpha olefins, alpha-monolefins, used with the ethylene in the present invention preferably contain 3 to 8 carbon atoms. Suitable alpha olefins include propylene, butene-1, pentene-1, hexene-1, 4-methylpentene-1, heptene-1, octene-1 and admixtures thereof. Preferably, the alpha-olefin comonomer comprise 1-butene, 1-hexene, 1-octene and admixtures thereof. The most preferred alpha olefin is hexene-1. Particular examples of combinations of the ethylene and alpha olefin include ethylene/1-butene, ethylene/1-hexene, ethylene/4-methyl-1-pentene, ethylene/1-butene/1-hexene, ethylene/propylene/1-hexene and ethylene/propylene/1-butene. Hydrogen may be used as a chain transfer agent in the polymerization reaction of the present invention. Any gas inert to the catalyst and reactants can also be present in the gas stream.
The diene preferably contains 6 to 10 carbon atoms, preferably 7 to 9 carbon atoms. Examples of the diene include 1,6-heptadiene; 1,7-octadiene; 1,8-nonadiene, 1,5-hexadiene and 1,9-decadiene were also used in the invention, but with lesser effect, than dienes of 7 to 9 carbon atoms on the change in MFR.
These products are prepared in the presence of a catalyst, described below, preferably under either slurry or more preferably under fluid bed gas phase catalytic polymerization conditions described below.
The products contain 0.1 to 2 ppm of transition metal, e.g., zirconium. The products also contain 5 to 100 ppm, preferably 10-50 ppm, of aluminum. Transition metal, e.g., zirconium and aluminum content of the products, is attributable to catalyst residues. The catalysts used to make the products of the invention are metallocenes of zirconium activated by aluminoxane.
The products are characterized by a density as low as 0.88 and up to less than 0.965 and preferably less than 0.94 g/cc. For applications herein, the density is greater than about 0.88, generally greater than 0.900 up to less than 0.965, preferably ranging from about 0.90 to 0.93 g/cm3.
The products of the invention exhibit a MI which can range up to 150 and up to 300 e.g., ranging from 0.01 to 300.
The low density products of the invention exhibit a melt flow ratio (MFR) which is at least 16, preferably from 16 to 60, and most preferably from 16 to 45. MFR is the ratio I21/I2 [wherein I21 is measured at 190xc2x0 C. in accordance with ASTM D-1238, Condition F and I2 is measured at 190xc2x0 C. in accordance with ASTM D-1238, Condition E].
The Mw/Mn of these products ranges from about 2.0 to about 3.5. Mw is the weight average molecular weight and Mn is the number average molecular weight, each of which is calculated from molecular weight distribution measured by GPC (gel permeation chromatography). Products have been produced with Mw/Mn lower than 2.5, in the range of 2.0 to 3.5, preferably in the range of 2 to 3.
The Catalyst
The catalyst compositions employed to produce resins of the present invention contain one transition metal provided as a metallocene. The catalysts comprise a carrier, an activator of cocatalysts and at least one metallocene.
The carrier material is a solid, particulate, porous, inorganic or organic materials, but preferably inorganic material, such as an oxide of silicon and/or of aluminum. The carrier material is used in the form of a dry powder having an average particle size of from about 1 micron to about 250 microns, preferably from about 10 microns to about 150 microns. If necessary, the treated carrier material may be sieved to insure that the particles have an average particle size of preferably less than 150 microns. This is highly desirable in forming narrow molecular weight LLDPE, to reduce gels. The surface area of the carrier is at least about 3 square meters per gram (m2/gm), and preferably at least about 50 m2/gm up to about 350 m2/gm. When the carrier is silica, it is heated to preferably about 100xc2x0 C. to about 850xc2x0 C. and most preferably at about 250xc2x0 C. The carrier material must have at least some active hydroxyl (OH) groups to produce the catalyst composition of this invention.
In the most preferred embodiment, the carrier is silica which, prior to the use thereof in the first catalyst synthesis step, has been dehydrated by fluidizing it with nitrogen and heating at about 250xc2x0 C. for about 4 hours to achieve a surface hydroxyl group concentration of about 1.8 millimoles per gram (mmols/gm). The silica of the most preferred embodiment is a high surface area, amorphous silica (surface area=300 m2/gm; pore volume of 1.65 cm3/gm), and it is a material marketed under the trade names of Davison 952-1836, Davison 952 or Davison 955 by the Davison Chemical Division of W. R. Grace and Company.
To form the catalysts, all catalyst precursor components can be dissolved with an activator or cocatalyst such as aluminoxane and reacted with a carrier. The carrier material is reacted with an aluminoxane solution, preferably methylaluminoxane, in a process described below. The class of aluminoxanes comprises oligomeric linear and/or cyclic alkylaluminoxanes represented by the formula:
Rxe2x80x94(Al(R)xe2x80x94O)nxe2x80x94AlR2 for oligomeric, linear aluminoxanes and
(xe2x80x94Al(R)xe2x80x94Oxe2x80x94)m for oligomeric cyclic aluminoxane
wherein n is 1-40, preferably 10-20, m is 3-40, preferably 3-20 and R is a C1-C8 alkyl group and preferably methyl. Methylaluminoxane (MAO) is a mixture of oligomers with a very wide distribution of molecular weights and usually with an average molecular weight of about 1000. MAO is typically kept in solution in toluene.
In one preferred embodiment of aluminoxane, incorporation into the carrier depends on the pore volume of the silica. In this embodiment, the process of impregnating the carrier material is by infusion of the aluminoxane solution, without forming a slurry of the carrier material, such as silica, in the aluminoxane solution. The volume of the solution of the aluminoxane is sufficient to fill the pores of the carrier material without forming a slurry in which the volume of the solution exceeds the pore volume of the silica; accordingly and preferably, the maximum volume of the aluminoxane solution is and does not exceed the total pore volume of the carrier material sample. [It has been discovered that up to 30% excess of solvent volume based on the silica pores can be used without producing a silica slurry during impregnation.] That maximum volume of the aluminoxane solution insures that no slurry of silica is formed. Accordingly, if the pore volume of the carrier material is 1.65 cm3/g, then the volume of aluminoxane will be equal to or less than 1.65 cm3/gram of carrier material. As a result of this proviso, the impregnated carrier material will appear dry immediately following impregnation although the pores of the carrier will be filled with inter alia solvent.
Solvent may be removed from the aluminoxane impregnated pores of the carrier material by heating and/or under a positive pressure induced by an inert gas, such as nitrogen. If employed, the conditions in this step are controlled to reduce, if not to eliminate, agglomeration of impregnated carrier particles and/or cross-linking of the aluminoxane. In this step, solvent can be removed by evaporation effected at relatively low elevated temperatures of above about 40xc2x0 C. and below about 50xc2x0 C. Although solvent can be removed by evaporation at relatively higher temperatures than that defined by the range above 40xc2x0 C. and below about 50xc2x0 C., very short heating times schedules must be employed.
In a preferred embodiment, the metallocene is added to the solution of the aluminoxane prior to reacting the carrier with the solution. The maximum volume of the aluminoxane solution also including the metallocene can be the total pore volume of the carrier material sample. The mole ratio of aluminoxane provided aluminum, expressed as Al, to metallocene metal expressed as M (e.g. Zr), ranges from 50 to 500, preferably 75 to 300, and most preferably 100 to 200. An added advantage of the present invention is that the Al:Zr ratio can be directly controlled. In a further preferred embodiment, the aluminoxane and metallocene compound are mixed together at a temperature of about 20xc2x0 C. to 80xc2x0 C., for 0.1 to 6.0 hours, prior to reaction with the carrier. The solvent for the metallocene and aluminoxane can be appropriate solvents, such as aromatic hydrocarbons, halogenated hydrocarbon or halogenated aromatic hydrocarbons, preferably toluene.
In an alternative synthesis of the catalyst, the volume of solution of alumoxane contacted carrier can be dispersed in a second solvent. A critical aspect of the alternative impregnation process is the use of a second liquid medium in addition to the alumoxane solution. The liquid medium is a hydrocarbon which contains 5 to 20 carbon atoms. Illustrative compounds which can be used as the liquid medium include pentane, isopentane, hexane, isohexane, heptane, octane, nonane, decane, dodecane, cyclopentane, cyclohexane, and cycloheptane or mixture thereof. Isomers of these hydrocarbons could also be used. The volume of the second liquid medium in the alternative synthesis is also critical in that this volume must be sufficient to form a slurry. In general, this volume should be 2 to 15 times the pore volume of the support as measured by nitrogen adsorption method (BET method). For example, for a silica support with 1.5 cc/g pore volume, a minimum of 3 cc of the second medium, e.g. hexane, and a maximum of 20 cc/g silica would be employed.
The metallocene compound has the formula CpmMAnBp in which Cp is an unsubstituted or substituted cyclopentadienyl group, M is zirconium or hafnium and A and B belong to the group including a halogen atom, hydrogen or an alkyl group. In the above formula of the metallocene compound, the preferred transition metal atom M is zirconium. In the above formula of the metallocene compound, the Cp group is an unsubstituted, a mono- or a poly-substituted cyclopentadienyl group. The substituents on the cyclopentadienyl group can be preferably straight-chain or branched C1-C6 alkyl groups. The cyclopentadienyl group can be also a part of a bicyclic or a tricyclic moiety such as indenyl, tetrahydroindenyl, fluorenyl or a partially hydrogenated fluorenyl group, as well as a part of a substituted bicyclic or tricyclic moiety. In the case when m in the above formula of the metallocene compound is equal to 2, the cyclopentadienyl groups can be also bridged by polymethylene or dialkylsilane groups, such as xe2x80x94CH2xe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, xe2x80x94CRxe2x80x2Rxe2x80x3xe2x80x94 and xe2x80x94CRxe2x80x2Rxe2x80x3xe2x80x94CRxe2x80x2Rxe2x80x3xe2x80x94 where Rxe2x80x2 and Rxe2x80x3 are short alkyl groups or hydrogen, xe2x80x94Si(CH3)2xe2x80x94, Si(CH3)2xe2x80x94CH2xe2x80x94CH2xe2x80x94Si(CH3)2xe2x80x94 and similar bridge groups. If the A and B substituents in the above formula of the metallocene compound are halogen atoms, they belong to the group of fluorine, chlorine, bromine or iodine. If the substituents A and B in the above formula of the metallocene compound are alkyl or aromatic groups, they are preferably straight-chain or branched C1-C8 alkyl groups, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl or n-octyl.
Suitable metallocene compounds include bis(cyclopentadienyl)metal dihalides, bis(cyclopentadienyl)metal hydridohalides, bis(cyclopentadienyl)metal monoalkyl monohalides, bis(cyclopentadienyl)metal dialkyls and bis(indenyl)metal dihalides wherein the metal is titanium, zirconium or hafnium, halide groups are preferably chlorine and the alkyl groups are C1-C6 alkyls. Illustrative, but non-limiting, examples of metallocenes include bis(cyclopentadienyl)zirconium dichloride, bis(cyclopentadienyl)hafnium dichloride, bis(cyclopentadienyl)zirconium dimethyl, bis(cyclopentadienyl)hafnium dimethyl, bis(cyclopentadienyl)zirconium hydridochloride, bis(cyclopentadienyl)hafnium hydridochloride, bis(pentamethylcyclopentadienyl)zirconium dichloride, bis(pentamethylcyclopentadienyl)hafnium dichloride, bis(n-butylcyclopentadienyl)-zirconium dichloride, bis(iso-butylcyclopentadienyl) zirconium dichloride, bis(dimethylcyclopentadienyl) zirconium dichloride, cyclopentadienyl-zirconium trichloride, bis(indenyl)zirconium dichloride, bis(4,5,6,7-tetrahydro-1-indenyl)zirconium dichloride, and ethylene-[bis(4,5,6,7-tetrahydro-1-indenyl)] zirconium dichloride. The metallocene compounds utilized within the embodiment of this art can be used as crystalline solids, as solutions in aromatic hydrocarbons or in a supported form.
The catalyst comprising a metallocene compound and an aluminoxane in particulate form is fed to the fluid bed reactor for gas phase polymerizations and copolymerizations of ethylene and higher alpha olefins.
The Process Conditions
When polymerization is undertaken in the gas phase, fluidized bed, it is essential to operate the fluid bed reactor at a temperature below the sintering temperature of the polymer particles. To insure that sintering will not occur, operating temperatures below the sintering temperature are desired. For the production of ethylene polymers in the process of the present invention an operating temperature for olefin polymerization of about 60xc2x0 C. to 115xc2x0 C. is preferred, and a temperature of about 75xc2x0 C. to 95xc2x0 C. is most preferred.
The reactor is operated at pressures of about 100 to 350 psi.
In fluidized bed reactors, the superficial gas velocity of the gaseous reaction mixture through the bed must exceed the minimum flow required for fluidization, and preferably is at least 0.2 feet per second above the minimum flow. A xe2x80x9cdiluentxe2x80x9d gas is employed with the comonomers; it is nonreactive under the conditions in the polymerization reactor. The diluent gas can be nitrogen, argon, helium, methane, ethane, and the like. Ordinarily the superficial gas velocity does not exceed 5.0 feet per second, and most usually no more than 2.5 feet per second is sufficient. The feed stream of gaseous monomer, with or without inert gaseous diluents, is fed into the reactor at a space time yield of about 2 to 10 pounds/hour/cubic foot of bed volume.
The copolymer product produced in the presence of the preferred catalysts, described above, in a gas phase fluid bed process.
For film production, the products may contain any of various additives conventionally added to polymer compositions such as lubricants, microtaic, stabilizer, antioxidants, compatibilizers, pigments, etc. These reagents can be employed to stabilize the products against oxidation. The products of the invention can be blended with another linear polymer or copolymer of ethylene having a density of 0.910 to 0.97 g/cc.; for example, the other linear polymer or copolymer can be one produced by a free radical polymerization, at pressures which exceed 350 psi. The polymers can be added directly to a blown film extruder, e.g., a Sterling extruder, to produce films having a thickness, for example of about 0.5 to 5 mils.


Continuous process for preparing polyoxymethylene homo- or copolymers by bulk polymerization of the monomers in the presence of cationic initiators, and also, if desired, in the presence of regulators, where during the polymerization both the monomers and the polymer are present in molten form and, if desired, the polymer is then deactivated, and the melt is discharged, cooled and pelletized, which comprises discharging, cooling and pelletizing the polymer at an elevated pressure and in the presence of a liquid.

The invention relates to an improved continuous process for preparing polyoxymethylenes.
It is known that oxymethylene polymers can be prepared by continuous bulk polymerization of the monomers in the presence of cationic initiators. This polymerization is frequently carried out in kneaders or in extruders. The temperature profile here can be such that the resultant oxymethylene polymer is produced either in solid form (DE-A 1 161 421, DE-A 1 495 228, DE-A 1 720 358, DE-A 3 018 898), or else as a melt (DE-A 3 147 309). The work-up of the polymer produced in solid form is known, and for this see: DE-A 3147309, DE-A 3628561, EP-A 678535, EP-A 699965 and DE-A 4423617.
The polymer produced as a melt is further processed in a downstream devolatilizing and finishing reactor. For this, the melt is conveyed directly from the extruder to this reactor without undergoing any phase change between these stages of the process (DE-A 3 147 309). In this downstream reactor, the thermal degradation of the unstable chain ends of the polymer takes place. The removal of the unconverted monomers and of the decomposition products arising during the thermal degradation, in particular formaldehyde, takes place by evaporation, mostly in vented extruders.
Since the monomers used are generally not completely converted to the polymer, their vapor pressure has a foaming effect on the polymer melt as soon as the pressure on the melt is reduced to atmospheric pressure (see DE-A 3 147 309).
It is an object of the present invention, therefore, to provide an improved continuous process for preparing polyoxymethylenes which has the following advantages over the prior art:
The tendency to form a foam during devolatilization should be reduced, and the production of fines during pelletization minimized. The pellets should be compact. The throughputs in the finishing extruder should be increased and the energy requirement lowered.
We have found that this object is achieved by means of a continuous process for preparing polyoxymethylene homo- or copolymers by bulk polymerization of the monomers in the presence of cationic initiators, and also, if desired, in the presence of regulators, where during the polymerization both the monomers and the polymer are present in molten form and, if desired, the polymer is then deactivated, and the melt is discharged, cooled and pelletized, which comprises discharging, cooling and pelletizing the polymer at an elevated pressure and in the presence of a liquid.
The process may in principle be carried out on any screw machinery with high mixing effectiveness. Preferred devices are extruders, Buss kneaders and flow tubes with or without static mixing elements, preferably twin-screw extruders.
In a first step of the novel process, polyoxymethylene homo- or copolymer is melted in a preferably heated zone.
Polymers of this type are known to the skilled worker and are described in the literature.
These polymers very generally have at least 50 mol % of repeat xe2x80x94CH2Oxe2x80x94 units in their main polymer chain.
The homopolymers are generally prepared by polymerizing formaldehyde or trioxane, preferably in the presence of suitable catalysts.
For the purposes of the present invention, polyoxymethylene copolymers are preferred, particularly those which, besides the xe2x80x94CH2Oxe2x80x94 repeat units, also have up to 50 mol %, preferably from 0.1 to 20 mol %, in particular from 0.3 to 10 mol %, and very particularly preferably from 2 to 6 mol %, of repeat units
where R1 to R4, independently of one another, are hydrogen, C1-C4-alkyl or halogen-substituted alkyl having from 1 to 4 carbon atoms, and R5 is xe2x80x94CH2xe2x80x94, xe2x80x94CH2Oxe2x80x94, C1-C4-alkyl- or C1-C4-haloalkyl-substituted methylene or a corresponding oxymethylene group, and n is from 0 to 3. These groups may be advantageously introduced into the copolymers by ring-opening of cyclic ethers. Preferred cyclic ethers have the formula
where R1 to R5 and n are as defined above. Mention may be made, merely as examples, of ethylene oxide, propylene 1,2-oxide, butylene 1,2-oxide, butylene 1,3-oxide, 1,3-dioxane, 1,3-dioxolane and 1,3-dioxepan as cyclic ethers, and also linear oligo- and polyformals, such as polydioxolane or polydioxepan, as comonomers.
Other suitable oxymethylene terpolymers are those prepared, for example, by reacting trioxane, one of the cyclic ethers described above and a third monomer, preferably bifunctional compounds of the formula
where Z is a chemical bond, xe2x80x94Oxe2x80x94 or xe2x80x94OROxe2x80x94 (Rxe2x95x90C1-C8-alkylene or C2-C8-cycloalkylene).
Preferred monomers of this type are ethylene diglycide, diglycidyl ether and diethers made from glycidyl compounds and formaldehyde, dioxane or trioxane in a molar ratio of 2:1, and also diethers made from 2 mol of glycidyl compound and 1 mol of an aliphatic diol having from 2 to 8 carbon atoms, for example the diglycidyl ethers of ethylene glycol, 1,4-butanediol, 1,3-butanediol, 1,3-cyclobutanediol, 1,2-propanediol or 1,4-cyclohexanediol, to mention merely a few examples.
Processes for preparing the homo- and copolymers described above are known to the person skilled in the art and are described in the literature, and further details would therefore be superfluous here.
The preferred polyoxymethylene copolymers have melting points of at least 150xc2x0 C. and molecular weights (weight average) Mw of from 5000 to 200,000, preferably from 7000 to 150,000.
Particular preference is given to end-group-stabilized polyoxymethylene polymers which have Cxe2x80x94C bonds at the ends of the chains.
The molten polymer causes what is known as melt sealing in the polymerization which follows, so that volatile constituents remain in the extruder, for example. The abovementioned monomers or a mixture of these, together or in succession with cationic initiators, are fed into the polymer melt. The temperature of the reaction mixture during the feed is preferably from 62 to 114xc2x0 C., in particular from 70 to 90xc2x0 C.
The novel process is preferably employed for the homo- or copolymerization of trioxane. However, in principle any of the monomers described above, including tetroxane, for example, may be used as monomer.
The monomers, for example trioxane, are preferably fed molten and generally at from 60 to 120xc2x0 C. Since the polymerization is generally exothermic, it is merely necessary to melt the polymer by supplying energy at the start of the novel process. The heat of polymerization generated is then sufficient to melt the polyoxymethylene homo- or copolymer formed.
The molecular weights of the polymer may, if desired, be adjusted to the desired values by using the customary (trioxane) polymerization regulators. Possible regulators are acetals and, respectively, formals of monohydric alcohols, the alcohols themselves, and also the small amounts of water whose presence can generally never be completely avoided and which function as a chain transfer agent. The amounts used of the regulators are from 10 to 10,000 ppm, preferably from 100 to 1000 ppm.
The initiators used are the customary cationic (trioxane) polymerization initiators. Suitable initiators are protonic acids, such as fluorinated or chlorinated alkyl- or arylsulfonic acids, e.g. trifluoromethanesulfonic acid, or Lewis acids, such as tin tetrachloride, arsenic pentafluoride, phosphorus pentafluoride and boron trifluoride, or else their complex compounds and salt-type compounds, e.g. boron trifluoride etherates and triphenylmethyl hexafluorophosphate. The amounts used of the catalysts are from about 0.01 to 1000 ppm, preferably from 0.05 to 10 ppm. It is generally advisable to add the catalyst in dilute form, preferably at concentrations of from 0.005 to 5% by weight. Solvents which may be used for this purpose are inert compounds, such as aliphatic or cycloaliphatic hydrocarbons, halogenated aliphatic hydrocarbons, glycol ethers, etc.
Monomers, initiators and, if desired, regulators may be premixed in any desired manner, or else added separately from one another to the polymerization reactor. There may also be provision of comonomer feed points along the reactor.
According to the invention, the temperature and pressure in the polymerization zone are to be selected in such a way that monomers and polymer are molten. For example, trioxane melts at from about 60 to 65xc2x0 C., and its boiling point at atmospheric pressure is 115xc2x0 C. Since the polymerization temperatures are relatively high, the polymerization generally takes place at elevated pressure, preferably from 1.5 to 500 bar, in particular from 5 to 50 bar. Under the reaction conditions, trioxane is in equilibrium with from about 1.5 to 2% of formaldehyde, at least some of which is present as a gas in the closed system. The oxymethylene homopolymer has a melting point of about 176xc2x0 C., and if relatively large amounts of comonomers have been incorporated the melting point can be lowered to about 150xc2x0 C., and it can be still further reduced by unconverted trioxane. The temperature of the melt in the polymerization reactor should not exceed 300xc2x0 C., since at high temperatures of this nature oxymethylene polymers decompose. The particularly preferred temperature range is from 150 to 200xc2x0 C. The melt temperature of the monomer/polymer mixture is very difficult to measure precisely, but some indication is given by the external temperature of the polymerization reactor. It is important that the polymer is produced in molten form.
The residence time of the polymerization mixture in the polymerization zone is preferably from 0.1 to 20 min, in particular from 0.4 to 5 min. The polymerization is preferably conducted to a conversion of at least 30%, in particular more than 60%. Under favorable conditions it is also possible to achieve conversions of 80% and above.
It is preferable for the polymerization mixture to be deactivated immediately following the polymerization, without any phase change taking place.
The deactivation of the catalyst residues generally takes place by adding deactivators to the polymerization melt. Examples of suitable deactivators are ammonia, aliphatic or aromatic amines, alcohols, salts which react as bases, such as sodium carbonate or borax, or else water. The amounts of these added to the polymers are preferably up to 1% by weight.
The spatial separation of the deactivation reactor with respect to the polymerization reactor is such that the polymer/monomer melt can move without hindrance from one to the other but penetration of the deactivators into the polymerization reactor is reliably prevented. The separation is brought about by constrictions incorporated, which locally increase the flow rate of the melt, for example by melt flow restrictors if extruders are used. The design of the deactivation reactor is such that there is thorough mixing of the polymer/monomer melt within a short time. In the case of extruders this can be achieved in practice by incorporating particular kneading elements or back-mixing elements. The temperature in the deactivation reactor is preferably from 150 to 300xc2x0 C. It is also possible for stabilizers to be added straightaway to the melt in the deactivation reactor, preferably together with the deactivators.


An authoring tool has a graphical user interface enabling interactive authoring of a multimedia presentation including temporal and nontemporal media. The graphical user interface enables specification of the temporal and spatial relationships among the media and playback of the presentation with the specified temporal and spatial relationships. The spatial and temporal relationships among the media may be changed independently of each other. The presentation may be viewed interactively under the control of the author during the authoring process without encoding the audio and video data into a streaming media data file for combination with the other media, simulating behavior of a browser that would receive a streaming media data file. The multimedia presentation may include elements that initiate playback of the presentation from a specified point in time. After authoring of the presentation is completed, the authoring tool assists in encoding and transferring the presentation for distribution. Information about the distribution format and location may be stored as user-defined profiles. Communication with the distribution location may be tested and presentation and the distribution information may be audited prior to encoding and transfer to reduce errors. A presentation is encoded according to the defined temporal and spatial relationships and the distribution format and location information to produce and encoded presentation. The encoded presentation and any supporting media data are transferred to the distribution location, such as a server. A streaming media server may be used for streaming media, whereas other data may be stored on a conventional data server. Accounts may be provided for a streaming media server for authors to publish their presentations. The authoring tool may be associated with a service that uses the streaming media server. Such streaming media servers also may be a source of stock footage for use by authors.

A variety of systems are used for authoring multimedia presentations such as motion pictures, television shows, advertisements for television, presentations on digital versatile disks (DVDs), interactive hypermedia, and other presentations. Such authoring systems generally provide a user interface and a process through which multimedia data is captured and stored, and through which the multimedia presentation is created, reviewed and published for distribution. The user interface and process for authoring generally depend on the kind of presentation being created and what the system developer believes is intuitive and enables an author to work creatively, flexibly and quickly.
Some multimedia presentations are primarily nontemporal presentations. That is, any change in the presentation typically depends on user activity or other event, instead of the passage of time. Some nontemporal multimedia presentations may include temporal components. For example, a user may cause a video to be displayed that is related to a text document by selecting a hyperlink to the video in the document.
Other multimedia presentations are primarily temporal presentations incorporating audio and/or video material, and optionally other media related to the temporal media. Primarily temporal media presentations that are well known today include streaming media formats such as QuickTime, Real Media, Windows Media Technology and SMIL, and formats that encode data in the vertical blanking interval of a television signal, such as used by WebTV, ATVEF, and other similar formats.
A variety of authoring tools have been developed for different kinds of presentations. Tools for processing combined temporal and nontemporal media include those described in PCT Publication No. WO99/52045, corresponding to U.S. patent application Ser. No. 09/054,861, and PCT Publication No. WO96/31829, corresponding to U.S. patent application Ser. No. 08/417,974, and U.S. Pat. No. 5,659,793 and U.S. Pat. No. 5,428,731.

Authoring system for combining temporal and nontemporal digital media