Polyketones are manufactured by reacting an aromatic carboxylic acid with a biractive aromatic compound, using as a catalyst a combination of a carboxylic acid anhydride and phosphoric acid, or equivalent thereof. The product polymers are useful as molding resins.

Polyketones are manufactured by the phosphoric acid/carboxylic acid anhydride catalyzed reaction of a dicarboxylic acid with an electron rich aromatic compound which behaves as a difunctional compound.
Polyketones, especially aromatic polyketones, are important engineering polymers, often having the advantages of chemical resistance, good high temperature properties, good tensile properties, and others. Typical engineering polyketones are poly(etheretherketone) (PEEK) (I), and poly(etherketone) (PEK) ((II), having the repeat units
Most commonly these polymers have been made by the condensation of an aromatic hydroxy compound with an aromatic fluoride. For example, PEEK may be made by the reaction of 4,4xe2x80x2-difluorobenzophenone with the dianion of hydroquinone, while PEK may be made by the reaction of 4,4xe2x80x2-difluorobenzophenone with the dianion of 4,4xe2x80x2-dihydroxybenzophenone, or the base promoted self condensation of 4-fluoro-4xe2x80x2-hydroxybenzophenone. While these reactions suffice to make the desired polymers, they have serious disadvantages. The benzophenone monomers required are expensive, and the reactions produce byproducts such as inorganic fluorides which must be properly disposed of
Another method of making aromatic ketones is the Friedel-Crafts synthesis. While this may employ somewhat cheaper ingredients the reaction is often more difficult to run and unwanted byproducts are produced. For example at least stoichiometric quantities of a Lewis acid such as aluminum chloride must be used, which later must be separated from the polymer and discarded or otherwise used. Therefore improved methods of making polyketones are desired.
T. P. Smyth et al. J. Org. Chem, vol. 63, p. 8946-8951 (1998) describe a reaction for forming aromatic ketones reacting a carboxylic acid with an aromatic compound using as an activation system, a combination of phosphoric acid and trifluoroacetic anhydride. No mention is made of using such a reaction to form polymers.
U.S. Pat. No. 4,861,856 discloses a process for preparing polyketones and poly (ketone -sulfone) polymers, whereby reactive aromatic compounds are contacted with aromatic dicarboxylic acids in the presence of trifluoroacetic anhydride and phosphorous pentoxide. U.S. Pat. No. 4,839,459 discloses a pros for preparing poly(ether-ketone) polymers.
EP A 229 470 to co-poly ketones, process for making them and process for blending them with other polymers.
This invention concerns, a process for the production of polyketones, comprising contacting an aromatic compound which is bireactive, a dicarboxylic acid, phosphoric acid, and a carboxylic acid anhydride.
By hydrocarbyl herein is meant a univalent radical containing carbon and hydrogen while substituted hydrocarbyl means hydrocarbyl substituted with one or more functional groups including complete replacement of the hydrogens). By hydrocarbylene is meant a divalent group containing only carbons and hydrogen containing two free valences to different carbon atoms by hydrocarbylene is meant a group containing carbon and hydrogen with to free valences to the same carbon atoms, each of these valences bound to a different atom. By substituted hydrocarbylene is meant a hydrocarbylene group substituted with one or more function groups, and in which all of the hydrogen may be replaced.
By a xe2x80x9cbireactivexe2x80x9d compound herein is meant a compound, such as an aromatic compound, in which substantially all molecules of that compound will each react twice in the ketone forming polymerization process. Since normally the xe2x80x9creactive groupxe2x80x9d in such a compound is a hydrogen bound to a carbon atom, which is not usually thought of as a functional group, this term is used.
By an xe2x80x9caromatic compound which is bireactivexe2x80x9d is meant a compound which contains at least one aromatic ring which is bireactive. This compound may contain more than one aromatic ring. If more than one aromatic ring is present it may be fused ring system such as found in naphthalene or anthracene a ring system connected directly by a covalent bond, such as is found in biphenyl, or a ring system connected through another group, such as is found in diphenyl ether, diphenylmethane, and 2,2-diphenylpropane. Other groups may be present
on the aromatic rings so long as do not interfere with the ketone forming polymerization reaction. It is preferred that the aromatic rings are carbocyclic rings. It is also preferred that the aromatic ring or rings of this compound are naphthyl ring systems or phenyl ring(s), more preferably phenyl rings. More than one aromatic compound which is bireactive may be present to form a copolymer.
T. P. Smyth, et al. postulate that the ketone forming reaction is an electrophilic attack on an aromatic ring of the bireactive compound. It is well known in the art that in such electrophilic reactions a substrate, such as the bireactive compound, is more reactive the more xe2x80x9celectron-richxe2x80x9d it is. Aromatic rings can be made more electron rich by having electron donating substituents attached to these rings. Such substituents include groups such as ether, alkyl, and tertiary amino, and are well known in the art. The presence of such groups will tend to make the bireactive compounds more reactive and ensure that it is in fact bireactive instead of monoreactive. Useful compounds for the bireactive compound include naphthalene, methylnaphthalene, methoxynaphthalene, benzyl ether, stilbene, diphenyl carbonate, benzyl phenyl ether, biphenyl, terphenyl, fluorene, and a compound of the formula
wherein R1 is xe2x80x94Oxe2x80x94 (diphenyl ether), alkylidene (for example xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, or (CH3)2C less than ), and R3 is hydrocarbylene, substituted hydrocarbylene or hydrocarbylidene, more preferably alkylene or alkylidene. Preferred bifunctional compounds are (III), especially when (III) is diphenyl ether. Useful groups for R3 include 1,2-ethylene, 1,3-phenylene and 1,4-phenylene. More than one bireactive aromatic compound may be present to give a copolyketone.
Any carboxylic acid anhydride may be used. Carboxylic acid anhydride here has the usual meaning, a compound of the formula R2C(O)O(O)CR2 wherein each R2 is independently hydrocarbyl or substituted hydrocarbyl. It is preferred that both of R2 are the same. It is preferred that Hammett "sgr"m for each of R2 is about 0.2 or more, more preferably 0.4 or more. Hammett "sgr"m constants are well known in the art, see for instance C. Hansch, et al., Chem. Rev., vol. 91, p. 185ff (1991). Preferred groups for R2 are perfluoroalkyl, and perfluoromethyl is especially preferred.
The dicarboxylic acid may be any organic dicarboxylic acid, and may contain other groups which do not interfere with the ketone forming reaction. Useful dicarboxylic acids include terephthalic acid, isophthalic acid, 4,4xe2x80x2-bibenzoic acid, 2-methylterephthalic acid, 2,6-naphthalene dicarboxylic acid, 2-chloroterephthalic acid, bis(4,4xe2x80x2-dicarboxyphenyl)ether, cyclohexane-dicarboxylic acid, norbornanedicarboxylic acid, 2,5-pyridinedicarboxylic acid, and 2,6-pyridinedicarboxylic acid. Preferred carboxylic acids are aromatic dicarboxylic acids, that is compounds in which the carboxyl groups are bound directly to aromatic rings. Preferred aromatic dicarboxylic acid are terephthalic acid, isophthalic acid, 4,4-bibenzoic acid and 2,6-napththalene dicarboxylic acid, and terephthalic acid and isophthalic acid are especially preferred. More than one dicarboxylic acid may be present in the process to give a copolyketone.
The molar ratio of the aromatic compound which is bireactive to dicarboxylic acid should preferably be about 1:1, especially preferably about 1.0:1.0, and more preferably 1.00:1.00, to achieve higher molecular weight polymer. This is normal for most condensation polymerizations to achieve higher molecular weight polymer. The molar ratio of carboxylic acid anhydride to dicarboxylic acid is preferably about 0.1 to about 20, more preferably about 2 to about 4. The molar ratio of phosphoric acid to dicarboxylic acid is preferably about 0.01 to about 2.0, more preferably about 0.05 to about 1.0.
The pressure at which the process is run is not critical, autogenous (for processes in which the boiling point of one or more of the reactants is exceeded) or atmospheric pressure being useful. In order to prevent unwanted side reactions such as hydrolysis of the carboxylic acid anhydride by atmospheric moisture, it is convenient to run the reaction under an inert atmosphere, such as nitrogen. The process may be agitated. A useful reaction temperature range is about 0xc2x0 C. to about 300xc2x0 C., preferably about 25xc2x0 C. to about 250xc2x0 C, more preferably about 30xc2x0 C. to about 200xc2x0 C.
The reaction may be run neat, i.e., without other added liquids or solids. It may also be run in the presence of another liquid. This liquid, which should be inert under reaction conditions, may be a solvent for one or more of the starting materials and/or product polymer, but one or more of the process ingredients may simply be suspended in the liquid. Suitable liquids includes alkanes such as octane, electron deficient aromatic compounds such as o-dichlorobenzene, and halogenated alkanes such as 1,2-dichloroethane. The process may be run as a batch, semi-batch or continuous reaction. For example a continuous reaction may be run in a continuous stirred tank reactor or a pipeline-type reactor. Such reaction systems are well known in the art.
Aromatic compounds that are trireactive or higher, or tri- or higher carboxylic acids may also be present in the process in small amounts (to produce a thermoplastic). Addition of these xe2x80x9cpolyfunctionalxe2x80x9d compounds will give branching, which may be desirable in the polymer for polymer processing reasons. However too much of these polyfunctional compounds will lead to crosslinking. Crosslinking is undesirable for making linear or branched (melt or solution processible) polymer, but may be desired is a thermoset resin is the desired product.
Included within the meaning of the ingredients added to this process are any combinations of (other) ingredients which are known to react to give the needed ingredients in situ.
The polymers produced by the process are useful as molding resins for various types of parts, such as parts that are heat and/or chemically resistant.
To a 50 mL Schlenk flask equipped with a nitrogen inlet was added 4.0 g 4-benzoylbenzoic acid (17.7 mmol) followed by 7.43 g trifluoroacetic anhydride (35.4 mmol). The mixture was cooled to 0xc2x0 C. using an external wet ice bath and 0.204 g of 85% phosphoric acid (1.77 mmol) solution was added. After allowing to stir for 30 min, 2.10 g anisole (19.4 mmol) was added. The solution was allowed to warm to room temperature and stir for an additional 30 min after which time the temperature was raised to 60xc2x0 C. The mixture was allowed to stir for 4 h at 60xc2x0 C. After allowing to cool to room temperature, the solution was diluted with chloroform, washed twice with 10% sodium carbonate (aq.) solution and once with water. The organic solution was dried (MgSO4) and the solvent was removed under reduced pressure to afford an off-white solid, which was a mixture of 80% 4-(4-methoxybenzoyl)benzophenone and 20% 4-(2-methoxybenzoyl)-benzophenone, as determined by 1H NMR.

To a 100 mL Schlenk flask was added 2.0 g (12.0 mmol) isophthalic acid followed by 10.1 g (48.1 mmol) trifluoroacetic anhydride. The mixture was cooled to 0xc2x0 C. and 2.80 g (24.3 mmol) of 85% phosphoric acid solution was added. The mixture was allowed to stir for 30 min at room temperature before 2.86 g (26.4 mmol) of anisole was added. After stirring for 30 min at room temperature the reaction was heated at 65xc2x0 C. for 4 hours. After cooling to room temperature the reaction was diluted with 150 mL chloroform and washed with 3xc3x9750 mL of 2% aqueous sodium carbonate and then 50 mL water. After drying (MgSO4), the solvent was removed by rotary evaporation to provide an amber oil. High Pressure Liquid Chromatographic analysis showed that 35% of the product was the ortho, para isomer, while 65% of the product was the para, para isomer.


A polymeric gel composition comprising a polymer including an anhydride unit and an alkenyl unit, a crosslinking agent, a maleated polyalkylene, an extender, and an organic fatty acid is provided. The polymeric gel composition has superior high-temperature stability, mechanical strength, and moldability.

The present invention relates to a high damping polymer gel composition with superior high-temperature stability, mechanical strength and moldability. The inventive composition is particularly useful as a molding material for various products.
The polymerization of isobutylene and maleic anhydride is known, as is the polymerization of styrene and maleic anhydride, and the polymerization of methyl vinyl ether and maleic anhydride. These polymerization techniques are carried out by free radical initiation. Further, imidization between a maleic anhydride and a primary amine group is a commonly known chemical reaction.
It has long been recognized that two or more polymers may be blended together to form a wide variety of random or structured morphologies to obtain products that potentially offer desirable combinations of characteristics. However, it maybe difficult or even impossible in practice to achieve many potential combinations through simple blending because of some inherent and fundamental problem. Frequently, the two polymers are thermodynamically immiscible, which precludes generating a truly homogeneous product. While it is sometimes desirable to have a two-phase structure, the situation at the interface between these two phases very often leads to problems. The typical case is one of high interfacial tension and poor adhesion between the two phases. This interfacial tension contributes, along with high viscosities, to the inherent difficulty of imparting the desired degree of dispersion to random mixtures and to their subsequent lack of stability, giving rise to gross separation or stratification during later processing or use. Poor adhesion leads, in part, to the very weak and brittle mechanical behavior often observed in dispersed blends and may render some highly structured morphologies impossible.
The present invention is a polymeric gel composition comprising a polymer including an anhydride unit and an alkenyl unit; a crosslinking agent; a maleated polyalkylene; an extender; and an organic fatty acid.
According to one embodiment of this invention, a grafted xe2x80x9ccentipedexe2x80x9d polymer of a maleated polyalkylene and a poly(alkenyl-co-maleimide) that is useful in producing high damping, soft materials with high service temperatures is provided. The centipede polymer can be formed by reacting polymeric constituents with a grafting agent, followed by mixture with an organic fatty acid.
It is an advantage of the invention to a produce centipede polymer composition that exhibits improved properties such as tensile strength, maximum elongation, tear strength, damping properties, high temperature compression set, and the like, with emphasis on the high temperature compression set. More particularly, the present inventive grafted poly(alkenyl-co-maleimide) copolymers combine with organic fatty acids to improve the tensile strength, tear strength, damping properties, and high-temperature compression set of the centipede polymer.
The polymer gel composition of the present invention contains: 0.5-200 parts by weight of a poly(alkenyl-co-maleimide) having at least one maleated polyalkylene segment grafted thereto through at least one functional linkage formed by a cross-linking reaction with a grafting agent; and greater than 0 to about 100 parts by weight of an organic fatty acid.
The poly(alkenyl-co-maleimide) is a xe2x80x9ccentipedexe2x80x9d polymer formed by imidizing a poly(alkenyl-co-maleic anhydride) with a primary amine. The xe2x80x9ccentipedexe2x80x9d polymer has a high molecular weight spine connected with many relatively short side chains formed from the addition of the primary amines. The length of the main chain usually equals or is longer than the entanglement length, which is herein defined theoretically as an order of magnitude of 100 repeating units, while the length of the side chains is much smaller than the entanglement length.
The preferred alkenyl benzene contributed monomer units of the poly(alkenyl benzene-co-maleimide) xe2x80x9ccentipedexe2x80x9d are any one or combination of styrene, xcex1-methylstyrene, 1-vinylnapthalene, 2-vinyl-napthalene, 1-xcex1-methylvinylnaphthalene, 2-xcex1-methylvinylnaphthalene, as well as alkyl, cycloalkyl, aryl, alkaryl, and aralkyl derivatives thereof, in which the total number of carbon atoms in the combined hydrocarbon is generally not greater than 12, as well as any di- or tri-vinyl aromatic hydrocarbons. The preferred vinyl aromatic hydrocarbons are either styrene or a-methylstyrene. The terms xe2x80x9calkenyl benzenexe2x80x9d and xe2x80x9cvinyl aromaticxe2x80x9d are understood to be interchangeable as used herein.
The preferred R1R2ethylene contributed monomer units of the poly(R1R2ethylene-co-maleimide) xe2x80x9ccentipedexe2x80x9d are any alkene such as ethylene, propylene, butylene, isobutylene, pentene, hexene, heptene, etc., as well as any di- or tri-alkene, with preference given to isobutylene.
The preferred alkyl vinyl ether contributed monomer units of the poly(alkyl vinyl ether-co-maleimide) xe2x80x9ccentipedexe2x80x9d are any one or combination of methyl vinyl ether, ethyl vinyl ether, propyl vinyl ether, butyl vinyl ether, and any other alkyl vinyl ether wherein the number of carbons in the alkyl substituent is between 1 and 12. The preferred alkyl vinyl ether is methyl vinyl ether.
The poly(alkenyl-co-maleimide) described herein are subsequently graft-reacted through a difunctional linking or grafting agent to a maleated polyalkene to yield a maleated polymer having at least one polyalkylene segment grafted thereto through the at least one functional linkage thus formed. The alkylene moiety of the polyalkene may be, for example, ethylene, propylene, and mixtures of both. The preferred polyalkene is polypropylene.
The maleated polypropylene may be any of the conventionally known polypropylene compounds that are subsequently maleated by methods known in the art. The polypropylene grafted segment or segments have molecular weights Mw of about 10,000 up to about 10,000,000, or higher, preferably about 20,000 to about 300,000.
The crystallinity, or tacticity, of the polypropylene may vary from being substantially amorphous to being completely crystalline, that is from about 10-100% crystallinity. Most typically, because of the extensive commercial use of isotactic polypropylene, the grafted polypropylene will be substantially crystalline, e.g., greater than about 90%. The polypropylene may be substantially free of ethylene. However, under certain circumstances small amounts of ethylene, on the order of less than about 10% by weight, may be incorporated. Furthermore, in certain instances the polypropylene contains small amounts of ethylene in copolymers known as xe2x80x9creactor copolymersxe2x80x9d. Thus, it is within the scope of the invention that the grafted polypropylenes contain minor amounts of ethylene, both as part of the ethylene-propylene segments and as polyethylene segments.
The maleated polypropylene of this invention contains from about 0.01 wt. % incorporated maleic anhydride, based upon the weight of the maleated polypropylene, up to about 5 wt. %. Preferably, the maleic anhydride content will be from about 0.01 to about 2 wt. %, most preferably about 0.03 to about 0.2 wt. %. As will be apparent, unreacted polypropylene will also be present in the reaction mix as will minor amounts of reaction by-products, such as decomposed free-radical initiator compounds and low molecular weight free-radical products. These by-products are substantially removed, by methods known in the art, e.g. sparging with nitrogen or washing with water. Maleic anhydride may not be left in substantial amounts in the polymer without detrimental effects on the subsequent reaction of the poly(alkenyl-co-maleimide) with the maleated polypropylene.
The poly(alkenyl-co-maleimide) of the instant invention is formed by reacting a poly(alkenyl-co-maleic anhydride) in the presence of a mono-primary amine at a temperature from about 100xc2x0 C. to about 300xc2x0 C. and at a pressure from about slightly above vacuum to about 20 atmospheres, under substantially dry conditions. The reactants are preferably dry mixed in the absence of solvents in a suitable mixing apparatus such as a Brabender mixer. It is preferable to purge the mixer with nitrogen prior to the charging of the reactants. The primary amine may be added in a singular charge or in sequential partial charges into the reactor containing a charge of poly(alkenyl-co-maleic anhydride). Preferably the primary amine is charged in ratio between 0.8 to 1.0 moles of amine per monomer contributed units of maleic anhydride in the poly(alkenyl-co-maleic anhydride).
Suitable primary amines include but are not limited to: alkyl amines; alkyl benzyl amines; alkyl phenyl amines; alkoxybenzyl amines; allyl aminobenzoates; alkoxy aniline; and other linear primary amines containing from 1 to 50 carbon atoms, preferably 6 to 30 carbon atoms in the alkyl and alkoxy substituents in these primary amines. It is understood that the alkyl and alkoxy substituents on the above discussed primary amines can be linear or branched, preferably linear, and saturated or unsaturated, preferably saturated. Exemplary, but not exclusive of such amines are hexylamine, octylamine, dodecylamine, and the like.
The poly(alkenyl-co-maleimide), prior to grafting with maleated polypropylene, preferably has a molecular weight range between about 10,000 and 500,000, and even more typically between about 150,000 and 450,000, where the molecular weight is weight-average (Mw).
The centipede polymer of the present invention may be prepared by any means well known in the art for combining such ingredients, such as blending, milling, or internal batch mixing. A rapid and convenient method of preparation comprises heating a mixture of the components to a temperature of about 50-290xc2x0 C.
The centipede polymers of this invention are preferably manufactured by mixing and dynamically heat-treating the components described above, namely, by melt-mixing. As for the mixing equipment, any conventional, generally known equipment such as an open-type mixing roll, closed-type Banbury mixer, closed-type Brabender mixer, extruding machine, kneader, continuous mixer, etc., is acceptable. The closed-type Brabender mixer is preferable, and mixing in an inactive gas environment, such as nitrogen or argon, is also preferable.
Grafting of maleated polyalkylene and poly(alkenyl-co-maleimeide) is performed by addition of a grafting agent containing two or more reactive functional groups. Acceptable functional groups include primary amine, secondary amine, carboxyl, formyl, hydroxyl, vinyl, etc. The preferred grafting agent is an organic diamine, which is added to a blend of maleated polyalkylene and poly(alkenyl-co-maleimeide) to partially cross-link the polyalkylene to the poly(alkenyl-co-maleimeide) through the maleate functional groups.
Suitable organic diamines or diamine mixtures containing two aliphatically or cycloaliphatically bound primary amino groups are used as grafting agents for the process according to the present invention. Such diamines include, for example, aliphatic or cycloaliphatic diamines corresponding to the following formula R1(NH2)2 wherein R1 represents an aliphatic hydrocarbon group having from 2 to 20 carbon atoms, a cycloaliphatic hydrocarbon group having from 4 to 20 carbon atoms, or an aromatic hydrocarbon group having from 6 to 20 carbon atoms or an N-heterocyclic ring having from 4 to 20 carbon atoms, e.g., ethylenediamine; 1,2- and 1,3-propylene diamine; 1,4-diaminobutane; 2,2-dimethyl-1,3-diaminopropane; 1,6-diaminohexane; 2,5-dimethyl-2,5-diaminohexane; 1,6-diamino-2,2,4-trimethyldiaminohexane; 1,8-diaminooctane; 1,10-diaminodecane; 1,11-diaminoundecane; 1,12-diaminododecane; 1-methyl-4-(aminoisopropyl)-cyclo-hexyl amine; 3-aminomethyl-3,5,5-trimethyl-cyclohexylamine; 1,2-bis-(amino-methyl)-cyclobutane; 1,2-diamino-3,6-dimethylbenzene; 1,2- and 1,4-diaminocyclo-hexane; 1,2-, 1,4-, 1,5-, and 1,8-diaminodecalin; 1-methyl-4-aminoisopropyl-cyclo-hexylamine; 4,4xe2x80x2-diamino-dicyclohexyl; 4,4xe2x80x2-diamino-dicyclohexyl methane; 2,2xe2x80x2-(bis-4-amino-cyclohexyl)-propane; 3,3xe2x80x2-dimethyl-4,4xe2x80x2-diaminodicyclohexyl methane; 1,2-bis-(4-aminocyclohexyl)-ethane; 3,3xe2x80x2,5,5xe2x80x2-tetramethyl-bis-(4-aminocyclohexyl)-methane and -propane; 1,4-bis-(2-aminoethyl)-benzene; benzidine; 4,4xe2x80x2-thiodianiline; 3,3xe2x80x2-dimeth-oxybenzidine; 2,4-diaminotoluene, diaminoditolylsulfone; 2,6-diaminopyridine; 4-methoxy-6-methyl-m-phenylenediamine; diaminodiphenyl ether; 4,4xe2x80x2-bis(o-toluidine); o-phenylenediamine; o-phenylenediamine, methylenebis(o-chloroaniline); bis(3,4-diaminophenyl)sulfone; diaminodiphenylsulfone; 4-chloro-o-phenylenediamine; m-aminobenzylamine; m-phenylenediamine; 4,4xe2x80x2-C1-C6-dianiline; 4,4xe2x80x2-methylene-dianiline; aniline-formaldehyde resin; trimethylene glycol di-p-aminobenzoate; bis-(2-aminoethyl)-amine, bis-(3-aminopropyl-amine, bis-(4-aminobutyl)-amine; bis-(6-aminohexyl)-amine, and isomeric mixtures of dipropylene triamine and dibutylene triamine. Mixtures of these diamines may also be used.
Other suitable polyamines for use as grafting agents in the process according to the present invention include bis-(aminoalkyl)-amines, preferably those having a total of from 4 to 12 carbon atoms, such as bis-(2-aminoethyl)amine, bis-(3-aminopropyl)amine, bis-(4-aminobutyl)amine, and bis-(6-aminohexyl)amine, and isomeric mixtures of dipropylene triamine and dibutylene triamine. Hexamethyl diamine, tetramethylene diamine, and especially 1,12-diaminododecane are preferably used.
The centipede polymers of the present invention have an extender added to the polymer during final processing. Suitable extenders include extender oils and low molecular weight compounds or components, such as the extenders including: naphthenic, aromatic, paraffinic, pthalic, and silicone oils. A preferred extender for the present invention is a pthalic oil. The preferred pthalic oil is di(tridecyl)phthalate from the C. P. Hall Company. This oil is added in the final stages of the preparation of the centipede polymer. The final centipede polymer can contain between 25 and 40% oil and is a thermoreversible elastomer.
After the centipede polymer is formed, a fatty acid is added. The fatty acid chosen for the present invention can be saturated, such as: butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, or stearic acid; or unsaturated, such as palmitoleic acid, oleic acid, linoleic acid, or linolenic acid. The preferred acids are saturated.
The fatty acids used may also be monofunctional or difunctional. Suitable monofunctional acids include butyric acid, caproic acid, caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, or mixtures thereof Suitable difunctional acids include sabaric acid, hexadecanedioc acid, dodecanedioc acid, 5-(octadecyloxy)isophthalic acid, and any other difunctional organic acids with up to 50 carbons.
Polyacids are also acceptable for use in the present invention. The preferred polyacids have a weight average molecular weight between about 500 to about 500,000. Suitable polyacids include poly(ethylene-co-acrylic acid), poly(propylene-co-acrylic acid), poly(acrylic acid), and other polyacids containing acrylic acid, acrylonitrile, and acrylamide monomer units, and mixtures thereof Generally, these polyacids may have an acrylic acid weight percent between about 0.2% to about 100%.
In general, the preferred organic fatty acids in the present invention are both mono and di functional, also preferred are low Mw polyacids. The preferred acrylic acid content of the polyacids is less than about 25%.
Generally, about 5 to 65 parts by weight of organic fatty acid can be mixed with about 35 to 100 parts by weight of centipede polymer. The resulting gel has a high temperature compression set at 100xc2x0 C. of less than about 40%, and at 130xc2x0 of less than about 50%. The Shore A hardness for the centipede polymer mixed with fatty acid is between about 10 and 55, and the tan xcex4 at temperatures greater than 20xc2x0 C. is greater than about 0.25.
In summary, the molded polymers produced from the blend of the present centipede polymer and fatty acid retain elastomeric characterstics and are useful in high damping applications.
It is frequently desirable to include other additives well known in the rubber art to the compositions of the present application. Stabilizers, antioxidants, conventional fillers, reinforcing agents, reinforcing resins, pigments, fragrances, and the like are examples of some such additives. Specific examples of useful antioxidants and stabilizers include 2-(2xe2x80x2-hydroxy-5xe2x80x2-methylphenyl)benzotriazole, nickel di-butyl-di-thiocarbamate, zinc di-butyl-di-thiocarbamate, tris(nonylphenyl)phosphite, 2,6-di-t-butyl-4-methylphenol, and the like. Exemplary conventional fillers and pigments include silica, carbon black, titanium dioxide, iron oxide, and the like. These compounding ingredients are incorporated in suitable amounts depending upon the contemplated use of the product, preferably in the range of 1-350 parts of additives or compounding ingredients per 100 parts of the polymer composition.
A reinforcement may be defined as the material that is added to a resinous matrix to improve the strength of the polymer. Most of these reinforcing materials are inorganic or organic products of high molecular weight. Various examples include glass fibers, asbestos, boron fibers, carbon and graphite fibers, whiskers, quartz and silica fibers, ceramic fibers, metal fibers, natural organic fibers, and synthetic organic fibers. Other elastomers and resins are also useful to enhance specific properties like damping properties, adhesion, and processability. Examples of other elastomers and resins include adhesive-like products including Reostomer (produced by Riken-Vinyl, Inc.), hydrogenated polystyrene-(medium or high 3,4) polyisoprene-polystyrene block compolymers such as Hybler (produced by Kurare, Inc.), polynorbornenes such as Norsorex (produced by Nippon Zeon, Inc.), and the like. In this case the foregoing materials are equally applicable to the instant centipede polymer compositions.
Damping is the absorption of mechanical energy by a material in contact with the source of that energy. It is desirable to damp or mitigate the transmission of mechanical energy from, for example, a motor, engine, or power source to its surroundings. Elastomeric materials are often used for this purpose. It is desirable that such materials be highly effective in converting this mechanical energy into heat rather than transmitting it to the surroundings. It is further desirable that this damping or conversion is effective over a wide range of temperatures and frequencies commonly found near motors, automobiles, trucks, trains, planes, and the like.
The compositions of the present invention are favorably used in the manufacturing of any product in which some of the following properties are advantageous: a degree of softness, heat resistance, decent mechanical properties, elasticity and/or high damping. The compositions of the present invention can be used in all industry fields, in particular, in the fabrication of automotive parts, tire tread rubbers, household electrical appliances, industrial machinery, precision instruments, transport machinery, constructions, engineering, medical instruments, and tire rubber formulations.
Representative examples of the composition of the present invention are in the fabrication of damping materials and vibration restraining materials. These uses involve connecting materials such as sealing materials, packing, gaskets, and grommets, supporting materials, such as mounts, holders, and insulators, and cushion materials such as stoppers, cushions, and bumpers. These materials are also used in equipment producing vibration or noise and household electrical appliances, such as in air-conditioners, laundry machines, refrigerators, electric fans, vacuums, dryers, printers, and ventilator fans. These materials are also suitable for impact absorbing materials in audio equipment and electronic or electrical equipment, sporting goods, and shoes.
The present invention will also be useful in any application where a superior high temperature compression set is desirable. With a compression set of less than 50% at 130xc2x0 C., this composition can be used in a variety of high temperature applications. One example of this would be as coatings, especially for windows and car windshields which retain heat and cause polymers with lower service temperatures to melt.


A sensing system for vehicle passive restraints including a restraints control module (38) in communication with a frontal impact accelerometer (40) and a pair of side impact sensors (46) mounted remotely in satellite sensor housings (44). Also mounted within one of the satellite housings (44) is a roll rate sensor (52), employing a common communication link (48) with one of the side impact sensors (46), for communicating with the restraints control module (38).

The present invention relates to sensor systems employed for determining actuation of safety restraints in a vehicle and more particularly for sensor systems that detect possible rollover conditions of a vehicle.
Conventional passive restraints systems are generally configured with a sensor system set up to detect frontal collisions of a vehicle and actuate passive restraints to better protect the occupants. More recently, the sensor systems are set up to also detect certain side impact situations and the passive restraints are configured to protect passengers for these side impact situations as well. For the frontal impacts, a common sensing system includes a single point impact sensor that is mounted near the center of the vehicle and oriented to detect fore-aft (longitudinal) acceleration of the vehicle, and employs this signal to determine when and which passive restraints to actuate. These may be, for example, front airbags or seat belt pretensioners.
Additionally, in order to now detect side impacts of the vehicle, some sensor systems employ side satellite sensors that are oriented to detect side-to-side (lateral) acceleration of the vehicle. These side satellite sensors are typically mounted in or near the side doors of the vehicle to obtain an earlier detection of a side impact than a centrally mounted acceleration sensor might. These side satellite sensors are then electrically connected to a restraints control module, along with the single point impact sensor. This necessitates separate housings and wiring for each of the satellite sensors, with the associated costs and packaging concerns.
An additional type of sensing for vehicle passive restraint actuation is now becoming more desirable, rollover detection. A roll rate sensor, unlike typical frontal and side impact sensors, measures a vehicle""s angular position with respect to the ground or the rate of change in angular position over time. By measuring one of these types of physical parameters, passive restraints may be deployed specifically to provide protection for vehicle occupants under certain vehicle rollover conditions. The typical accelerometers employed for frontal and side impacts are generally not suitable for such use; even if oriented properly, the output needs to be subjected to exhaustive calculations before actuation decisions can be made. On the other hand, by adding a separate roll rate sensor, packaging and wiring for this additional sensor is now a concern in addition to the cost.
In its embodiments, the present invention contemplates a sensor system for use with passive restraints in a vehicle having a longitudinally directed vehicle centerline. The sensor system includes a longitudinal impact sensor located generally adjacent the longitudinally directed vehicle center line, and a restraints control module in communication with the longitudinal impact sensor. A first satellite sensor housing is mounted in the vehicle spaced from the restraints control module, and a lateral impact sensor is mounted in the satellite sensor housing and in communication with the restraints control module via a first communication link. The sensor system also includes a roll rate sensor mounted in the satellite sensor housing and in communication with the restraints control module via the first communication link.
Accordingly, an object of the present invention is to provide a passive restraint sensing system that includes both frontal impact sensors located near or in a main restraints control module as well as side satellite sensor housings that also incorporate a rollover detection sensor.
An advantage of the present invention is that the rollover sensor is incorporated into a side satellite sensor housing, minimizing the need for extra wiring and packaging another housing, thus reducing the cost of the overall sensor system.
Another advantage of the present invention is that the cost and complexity of the sensor system is reduced, while still providing the additional function of vehicle rollover detection.

Sensing system for vehicle passive restrants


The present invention relates to methods for preventing the development of epithelial ovarian cancer by administering a Vitamin D compound in an amount capable of increasing apoptosis in non-neoplastic ovarian epithelial cells of the female subject.

Ovarian cancer is the fourth leading cause of cancer deaths among women in the United States and causes more deaths than all other gynecologic malignancies combined. In the United States, a woman""s lifetime risk of developing ovarian cancer is 1 in 70. In 1992, about 21,000 cases of ovarian cancer were reported, and about 13,000 women died from the disease. Chapter 321, Ovarian Cancer, Harrison""s Principles of Internal Medicine, 13th ed., Isselbacher et al., eds., McGraw-Hill, N.Y. (1994), pages 1853-1858; American Cancer Society Statistics, Cancer J. Clinicians, 45:30 (1995). Epithelial ovarian cancer, the most common ovarian cancer, has a distinctive pattern of spread: cancer cells may migrate through the peritoneum to produce multiple metastatic nodules in the visceral and parietal peritoneum and the hemidiaphragms. In addition cancer cells metastasize through the lymphatic and blood vessels to areas such as the liver, lung and brain. Early stage ovarian cancer is often asymptomatic and is detected coincidentally by palpating an ovarian mass on pelvic examination. In premenopausal patients, about 95% of these masses are benign. Even after menopause, 70% of masses are benign but detection of any enlargement requires exploratory surgery. In postmenopausal women with a pelvic mass, a markedly elevated serum CA-125 level of greater than 65 U/ml indicates malignancy with a 96% positive predictive value. Chapter 321, Ovarian Cancer, Harrison""s Principles of Internal Medicine, supra.
Epithelial ovarian cancer is seldom encountered in women less than 35 years of age. Its incidence increases sharply with advancing age and peaks at ages 75 to 80, with the median age being 60 years. The single most important risk factor for this cancer is a strong family history of breast or ovarian cancer. In families in which ovarian, breast, endometrial or colon cancer can be tracked as an apparent autosomal dominant trait, the risk of this cancer can be as high as 50%. Having a single first-degree relative with ovarian cancer increases a woman""s risk by at least three-fold, and having a personal history of breast or colorectal cancer increases the risk of subsequently developing ovarian cancer by two-fold. Chapter 321, Ovarian Cancer, Harrison""s Principles of Internal Medicine, supra. In addition, those with identifiable genetic mutations in genes such as BRCA1 also have an increased risk. Baker et al., Etiology, Biology, and Epidemiology of Ovarian Cancer, Seminars in Surgical Oncology 10: 242-248, 1994; Amus et al., Genetic Epidemiology of Epithelial Ovarian Cancer, Cancer 71: 566-72, 1993; Whitmore, Characteristics Relating To Ovarian Cancer Risk: Implications for Preventing and Detection, Gynecologie Oncology 55, 515-19, 1994. Oncogenes associated with ovarian cancers include the HER-2/neu (c-erbB-2) gene, which is overexpressed in a third of ovarian cancers, the fins oncogene, and abnormalities in the p53 gene, which are seen in about half of ovarian cancers. A number of environmental factors have also been associated with a higher risk of epithelial ovarian cancer, including a high fat diet and intake of lactose in subjects with relatively low tissue levels of galactose-1-phosphate uridyl transferase.
Previously, there has existed no established pharmaceutical approach to the prevention of ovarian cancer. For all women, especially those at high risk of developing this disease, the only available option has been surgical removal of the ovaries, with all of the attendant risks and subsequent adverse health consequences due to resulting estrogen deficiency.
Of interest to the present invention is the disclosure of co-owned and copending U.S. patent application Ser. No. 08/713,834 filed Sep. 13, 1996 entitled xe2x80x9cPrevention of Ovarian Cancer by Administration of Progestin Productsxe2x80x9d the disclosure of which is hereby incorporated by reference. This application discloses a method for preventing the development of epithelial ovarian cancer by administering progestin products, either alone or in combination with other agents, such as estrogen products. Specifically, a method is described for preventing ovarian cancer comprising administering to a female subject an amount of progestin product effective to increase apoptosis in ovarian epithelial cells of the female subject. Apoptosis is one of the most important mechanisms used for the elimination of cells that have sustained DNA damage and which are thus prone to transformation into malignant neoplasms. Thus, increasing apoptosis of ovarial epithelial cells will prevent the transformation of non-neoplastic, including normal and dysplastic, cells into neoplastic cells.
Vitamin D is a fat soluble vitamin which is essential as a positive regulator of calcium homeostasis. In the skin 7-Dehydrocholesterol (pro-Vitamin D3) is photolyzed by ultraviolet light to pre-Vitamin D3, which spontaneously isomerizes to Vitamin D3. Vitamin D3 (cholecalciferol), the structure of which is set out below, is converted into an active hormone by hydroxylation reactions occurring in the liver to produce 25-hydroxyvitamin D3 which is then converted in the kidneys to produce 1,25-dihydroxyvitamin D3 (1,25-dihydroxycholecalciferol, calcitriol, 1,25(OH)2D3) which is transported via the blood to its classic target organs, namely, the intestine, kidney, and bones. Vitamin D3 and 1,25-dihydroxy vitamin D3 are shown below:
Vitammin D deficiency in childhood produces rickts, which is characterized by inadequate calcification of cartilage and bone. In adults, Vitamin D deficiency lead to softening and weakening of bones, known as osteomalacia. The major therapeutic uses of Vitamin D are divided into four categories: (1) prophylaxis and cure of nutritional rickets, (2) treatment of metabolic rickets and osteomalacia, particularly in the setting of chronic renal failure, (3) treatment of hypoparathyroidism, and (4) prevention and treatment of osteoporosis. Recommended daily dietary allowances of Vitamin D by the Food and Nutrition Board of the United states National Research Council (1989) were 10 mg cholecalciferol (400 IU Vitamin D) daily for females age 11-24 and 5 mg cholecalciferol (200 IU Vitamin D) daily for females age 25 and older. Normal serum levels of 25-hydroxyvitamin D3 are not closely regulated and it has a biological half-life of several weeks with blood levels typically ranging from 15 to 80 ng/mL. Serum levels of 1,25-dihydroxyvitamin D3 are more closely regulated and typically range from 15-60 pg/mL. Serum 1,25-dihydroxyvitamin D3 has a half-life of 6-8 hours. 1,25-dihydroxyvitamin D3 partitions into cells by virtue of its lipophilicity, binds to intracellular receptors, and translocates to the nucleus where the complex controls the transcription of a number of genes, many of which relate to calcium metabolism. Corder et al., Cancer Epidemiology, Biomarkers and Prevention 2:467-472 (1993).
Certain compounds are known to upregulate the functional human Vitamin D receptor (xe2x80x9cVDRxe2x80x9d). For example, Santiso-Mere et al., Molecular Endocrinology Vol. 7, No. 7, pp.833-839 (1993) teach the expression of functional human vitamin D receptor (VDR) in Saccharomyces cerevisiae. This reference further teaches up-regulation of the VDR by 1,25-dihydroxyvitamin D3. Davoodi et al., J. Steroid Biochem. Molec. Biol. 54: No. 3/4, pp. 147-153 (1995) relates to the effect of 1,25-dihydroxyvitamin D3 on upregulation of the VDR. Davoodi et al. teach that progestins and trans-retinoic acid may also upregulate the VDR. Davoodi et al., at pp. 149-50.
Vitamin D and its analogues and derivatives are taught to have possible utility in the treatment, rather than prevention, of cancers by retarding tumor growth and in stimulating the differentiation of malignant cells to normal cells. For example, 1,25-dihydroxyvitamin D3 possesses potent antileukemic activity by virtue of inducing the differentiation of leukemia cells to non-malignant macrophages.
Colston et al., Endocrinology Vol. 108, No. 3, 1083-1086 (1981) may have been the first to report antitumor effects of Vitamin D. This study reported the presence of specific, high-affinity receptors for 1,25-dihydroxy-vitamin D3 in malignant melanoma and that in vitro administration of 1,25-dihydroxy-vitamin D3 produced a marked increase in cell doubling time. Sato et al., Tohoku J. exp. Med. 138:445-446 (1982) reported the utility of 1a-Hydroxyvitamin D3 in in vivo experiments relating to treatment of Sarcoma 180 and Lewis lung carcinoma implanted into mice. In these experiments the Vitamin D suppressed tumor growth or inhibited pulmonary metastases. Disman et al., Cancer Research 47: 21-25 (1987) disclose the utility of 1,25-dihydroxyvitamin D3 in inhibiting the growth of human colonic cancer xenografts in mice. Dokoh et al., Cancer Research 44: 2103-2109 (1984) disclose the utility of 1,25-dihydroxyvitamin D3 on cultured osteogenic sarcoma cells. The utility of 1,25-dihydroxyvitamin D3 for inducing differentiation of leukemic cells is also known. See Mangelsdorf et al., J. Cell Biol. Vol. 98, 391-398 (1984).
Chida et al., Cancer Research 45: 5426-5430 (1985) describe the inhibition of the promotional phase of 7,12-dimethylbenz[a]anthracene-induced skin carcinogenesis in mice by 1,25-dihydroxyvitamin D3. Oikawa et al., Anti-Cancer Drugs 2: 475-480 (1991) disclose the antitumor effect of 22-oxa-1a,25-dihydroxyvitamin D3 on rat mammary tumors induced by 7,12-dimethylbenz[a]anthracene.
Vitamin D and its metabolic products while potentially useful in retarding tumor growth have the disadvantage that they are very potent calcemic agents that cause elevated blood calcium levels by stimulating intestinal calcium absorption and bone calcium resorption. Accordingly, there has been a desire in the art for Vitamin D analogues and derivatives having variant activities such that, for example, antileukemic activity is enhanced without concomitant enhancement of calcemic activity. Frampton et al., Cancer Research 43: 4443-4447 (1983) disclose the inhibition of human breast cancer cell growth in vitro. The vitamin D3 metabolites 1,24,25-(OH)3D3 and 1,25,26-(OH)3D3 were identified as analogues which would be effective in inhibiting tumor cell growth without exhibiting unacceptable bone resorption and hypercalcemia. Sporn et al., Proc. Am. Assn. Cancer Res. No. 34 Abstracts p. 622 (March 1993) report the utility of the vitamin D analogue 1,25-dihydroxy-16-ene-23-yne-26, 27-hexafluorocholecalciferol having greater potency than 1,25-dihydroxycholecalciferol in differentiating HL-60 leukemic cells but which is less active in its hypercalcemic effects.
There also exists a large patent literature relating to the use of Vitamin D analogues for retarding tumor growth and treatment of leukemias. Partridge et al., U.S. Pat. No. 4,594,340 teaches the syntheses of the Vitamin D analogues 25,26-dehydro-1a,24R-dihydroxycholecalciferol and 25,26-dehydro-1a,24S-dihydroxycholecalciferol as differentiation inducing agents and anti-proliferation agents useful in treating osteoporosis, tumors and leukemia. DeLuca et al., U.S. Pat. No. 4,800,198 discloses the use of secosterol compounds sharing structural similarity with Vitamin D for inducing differentiation of malignant cells in methods of treatment of leukemic disorders.
Binderup et al., U.S. Pat. No. 5,190,935 disclose Vitamin D analogues having antiproliferative effects on cancer cells. Calverly et al., U.S. Pat. No. 5,206,229 disclose Vitamin D analogues exhibiting antiinflammatory and immunomodulating effects which also exhibit strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells. DeLuca et al., U.S. Pat. No. 5,246,925 disclose 1a-hydroxy-19-nor-vitamin D analogues which exhibit activity in arresting the proliferation of undifferentiated cells, including malignant cells, and in inducing their differentiation. Ikekawa et al., U.S. Pat. No. 5,278,155 disclose Fluorine-containing vitamin D3 analogues which showed in vitro activity in inducing differentiation of human colonic cancer cells. DeLuca et al., U.S. Pat. No. 5,373,004 disclose 26,28-methylene-1a, 25-dihydroxyvitamin D2 compounds having unique preferential calcemic activity. Calverley et al., U.S. Pat. No. 5,374,629 disclose Vitamin D analogues having antiinflammatory and immunomodulating effects as well as strong activity in inducing differentiation and inhibiting proliferation of cancer cells. DeLuca et al., U.S. Pat. No. 5,380,720 disclose 1a-hydroxy-22-iodinated vitamin D3 compounds capable of inducing relatively high differentiation of malignant cells. Hansen et al., U.S. Pat. No. 5,387,582 disclose Vitamin D analogues having activity in inducing differentiation of cancer cells and skin cells. Posner et al., U.S. Pat. No. 5,389,622 disclose a Vitamin D3 analogue having growth inhibition activities against murine kerotinocyte cells. Calverley et al., U.S. Pat. No. 5,401,731 disclose Vitamin D analogues having activity in the prophylaxis of autoimmune diseases.
Neef et al., U.S. Pat. No. 5,411,949 disclose 23-Oxa-derivatives of Vitamin D having proliferation inhibiting and cell-differentiation effects. Doran et al., U.S. Pat. No. 5,428,029 disclose Vitamin D3 fluorinated analogues as agents for the treatment of tumors such as breast cancer, as agents for the treatment of neoplastic diseases such as leukemia, and as agents for the treatment of sebaceous gland diseases. Neef et al., U.S. Pat. No. 5,446,035 disclose 20-methyl-substituted Vitamin D derivatives exhibiting improved induction of cell differentiation as compared to calcitriol in an HL-60 cell line. Baggiolini et al., U.S. Pat. No. 5,451,574and U.S. Pat. No. 5,512,554 disclose Vitamin D3 fluoridated analogues as agents for treatment of cancer, such as leukemia and or hyperproliferative skin diseases such as psoriasis. DeLuca et al., U.S. Pat. No. 5,484,782 disclose (E)-20(22)-dehydrovitamin D compounds having relatively high HL-60 cell differentiation activity. Neef et al., U.S. Pat. No. 5,532,228 disclose Vitamin D derivatives having cell proliferation-inhibiting and cell-differentiating activity. DeLuca et al., U.S. Pat. No. 5,536,713 disclose 19-nor-Vitamin D3 compounds with substituents at the 2-position which exhibit activity in inducing differentiation of malignant cells with little or no bone calcification activity. Dore et al., U.S. Pat. No. 5,547,947 disclose methods of inducing inhibition or loss of cell proliferation in solid tumors utilizing a Vitamin D3 analogue alone or in combination with a trans retinoic acid. Grue-Sorensen et al., U.S. Pat. No. 5,554,599 disclose 22-thio Vitamin D derivatives exhibiting antiinflammatory and immunomodulating effects which also exhibit strong activity in inducing differentiation and inhibiting undesirable proliferation of certain cells.
The use of 1,25-dihydroxyvitamin D3 for treatment of gynecologic neoplasms including ovarian carcinomas is proposed in various references, but its efficacy against ovarian cancer cells is unclear. Moreover, there is no suggestion that Vitamin D will inhibit conversion of non-neoplastic ovarian cells to neoplastic ovarian cells or will promote apoptosis in non-neoplastic ovarian cells. Specifically, Christopherson et al., Am. J. Obstet Gynecol. Vol 155, No. 6. 1293-1296 (1986) report that 1,25-dihydroxhcholecalciferol is useful in inhibiting the replication of various malignant human cells but that administration of 1,25-dihydroxhcholecalciferol in ovarian adenocarcinoma cells was associated with an increase in the rate of cancer cell growth when treated at a concentration of 10 nmol/L. In contrast, Saunders et al., Gynecologic Oncology 44: 131-136 (1992); and Saunders et al., Gynecologic Oncology 51: 155-159 (1993) report the in vitro inhibition of endometrial carcinoma cell growth by the combination of 1,25-dihydroxyvitamin D3 with the antineoplastic agent carboplatin; and Saunders et al., AntiCancer Drugs 6 562-569 (1995) report inhibition of growth in breast and ovarian carcinoma cells by 1,25-dihydroxyvitamin D3, when combined with retinoic acid and dexamethasone. Thus, based on the results of these studies, it is unclear whether Vitamin D is itself useful for the inhibition of ovarian cancer cell growth. More significantly, none of these studies describe the effect, or suggest any effect, of Vitamin D on growth or apoptosis of non-neoplastic ovarian epithelial cells.
Similarly, while references suggest that Vitamin D may be effective to induce apoptosis in breast cancer cells, those references do not suggest that Vitamin D may effect the growth or apoptosis of non-neoplastic breast cells. For example, Welsh, Biochem. Cell Biol. 72: 537-545 (1994) discloses the in vitro use of 1,25-dihydroxyvitamin D3 in combination with the antiestrogen 4-hydroxytamoxifen to induce apoptosis in the breast cancer cell line MCF-7. However, Welsh makes no suggestion that Vitamin D3 can induce apoptosis in normal or non-malignant cells.
The teachings of Narvaez et al., Endocrinology Vol. 137, No. 2 pp 400-409 (1996) are in accord with the references discussed above. Narvaez et al. teach (1) that Vitamin D can have effects on malignant cells, but the effects are cell type specific and unpredictable and (2) that, to the extent tested, Vitamin D did not have any effect on non-malignant cells. Specifically, Narvaez et al., teach that 1,25-dihydroxyvitamin D3 is a negative growth regulator of breast cancer epithelial cells and that its effects are mediated via the nuclear vitamin D receptor (VDR). The reference also suggests that the reduction in the in vitro growth of the MCF-7 breast cancer cell line in response to 1,25-dihydroxyvitamin D3 is associated with morphological and biochemical evidence of cancer cell death by apoptosis. Narvaez et al. disclose selection of a variant line of MCF-7 cells resistant to the growth inhibitory effects of 1,25-(OH)2D3. The MCF-7D3Res cells express the VDR but are resistant to induction of apoptosis in response to 1,25-(OH)2D3 and structurally related compounds. Despite vitamin D3 resistance, the MCF-7D3Res cells are sensitive to induction of apoptosis in response to antiestrogens.
Narvaez et al. further teach that Vitamin D had no apoptotic effect on the normal cells which they studied. Specifically, the reference teaches that doses of the vitamin D analog EB 1089 which cause breast tumor regression in rats have no growth or apoptotic effects in vivo on normal intestine and kidney cells of rats treated with the analog. Narvaez et al. further investigated the possibility that 1,25-dihydroxyvitamin D3 might be able to induce apoptosis in cell lines of normal tissues such as intestinal crypt cells and normal renal epithelial cells which express high levels of the VDR and known vitamin D3-regulated proteins. Although the 1,25-dihydroxy vitamin D3 induced vitamin D dependent proteins in both cell lines, no evidence of apoptosis was observed even when the cells were treated with 500 nM 1,25-dihydroxy vitamin D3. In addition, no inhibitory effects on growth nor induction of apoptosis were observed in the intestine or kidney cells of rats treated with a vitamin D analogue (EB1089) in doses previously shown to cause breast tumor regression.
Narvaez et al. state that these and other data xe2x80x9csuggest that although a functional VDR may be necessary for the growth regulatory effects of 1,25-(OH)2D3, its activation is not sufficient for triggering these effects. Thus, we hypothesize that induction of apoptosis by the 1,25-(OH)2D3-VDR complex is cell type specific.xe2x80x9d Accordingly, although the effects of Vitamin D are mediated by the VDR, the expression of the receptor by cells does not determine how they will respond to Vitamin D. For example, Vitamin D has potent effects on kidney cells and intestinal cells relating to calcium homeostasis, but does not cause apoptosis. On the other hand, Vitamin D might inhibit the growth of certain malignant cell lines or cause apoptosis of such cell lines. The only specific cell types for which Narvaez et al. were able to establish apoptosis through administration of Vitamin D were certain malignant cells. Narvaez et al. observed no apoptotic effect on any non-malignant cells studied. Accordingly, although ovarian epithelial cells express the VDR it would not have been expected by those skilled in the art that Vitamin D would have apoptotic effects on normal ovarian epithelial cells.
Also of interest to the present invention is the epidemiologic study of Lefkowitz et al., International Journal of Epidemiology vol 23, No. 6 pp 1133-1136 (1994) reporting that sunlight exposure may reduce the risk of ovarian cancer mortality. Using population based data regarding ovarian cancer mortality in large cities across the United States, as well as geographically based long-term sunlight data reported by the National Oceanic and Atmospheric Administration, the authors found an inverse correlation between regional sunlight exposure and ovarian cancer mortality risk. The publication refers to the antineoplastic effect of vitamin D against cancer lines and tumors as demonstrated in in vivo and in vitro studies and suggests that this antineoplastic effect may be reducing the ovarian cancer mortality rates for the regions with more sunlight. Thus, this study teaches that Vitamin D may have an effect on malignant cells. There is no teaching or suggestion that sunlight may have any effect on non-neoplastic cells or that the protective effect of sunlight may be mediated by an effect of enhanced levels of Vitamin D on non-neoplastic ovarian epithelial cells in vivo.
Studzinski et al., Cancer Research 55:4012-4022 (1995) also discuss the potential effect of Vitamin D from sunlight on retarding neoplastic progression of various cancers. Studzinski et al. refer to evidence that Vitamin D retards growth of cancer cells in vivo and in vitro, induces differentiation of cancer cells, and induces apoptosis in cancer cells, and that these effects may prevent cancer progression. Studzinski et al. do not suggest or imply that Vitamin D may have a preventative benefit through effect on non-malignant cells.
Thus, while the art reports various therapeutic activities of Vitamin D and its analogues and derivatives in retarding tumor growth, the effect of Vitamin D on ovarian carcinoma cells is unclear. Moreover there exists no suggestion that Vitamin D has activity in causing apoptosis in non-neoplastic cells or in inhibiting the conversion of non-neoplastic cells to neoplastic cells in any manner. Accordingly, there remains a need in the art for methods and compositions which will prevent cancers such as ovarian epithelial cancer by inhibiting the conversion of normal and dysplastic ovarian epithelial cells to neoplastic cells.
The present invention provides a method for preventing the development of epithelial ovarian cancer by administering an effective amount of Vitamin D compounds including Vitamin D and biologically active analogues and derivatives thereof to a female subject.
While the inventors do not wish to be bound by any particular theory, the present invention is based on the discovery that administration of Vitamin D compounds results in an accelerated rate of apoptosis in vitro in non-neoplastic human ovarian epithelial cells including benign and dysplastic ovarian epithelial cells. Apoptosis is one of the most important mechanisms used for the elimination of cells that have sustained DNA damage and which are thus prone to transformation into malignant neoplasms. By augmenting the apoptosis pathway, Vitamin D compounds including Vitamin D and biologically active analogues and derivatives thereof may thus enhance the efficient removal of pre-neoplastic ovarian epithelial cells, thereby decreasing the risk of developing epithelial ovarian carcinoma.
Thus, the invention provides methods of inhibiting conversion of non-neoplastic ovarian epithelial cells to neoplastic cells comprising administering to a female subject an amount of Vitamin D or a biologically active analogue or derivative thereof effective to increase apoptosis in non-neoplastic ovarian epithelial cells of a female subject. The invention further provides methods of increasing apoptosis of non-neoplastic ovarian epithelial cells of a female subject comprising administering to a female subject an amount of Vitamin D or a biologically active analogue or derivative thereof effective to increase apoptosis in ovarian epithelial cells of the subject.
The present invention generally relates to methods for preventing the development of epithelial ovarian cancer by administering Vitamin D compounds in an amount effective to increase apoptosis of ovarian epithelial cells. The invention also provides a method of increasing apoptosis in ovarian epithelial cells of a female subject comprising administering to a female subject an amount of a Vitamin D compound including Vitamin D or an analogue or derivative thereof effective to increase apoptosis in ovarian epithelial cells of the female subject.
The present invention is related to the discovery that administration of 1,25-dihydroxyvitamin D3 and 24,25-dihydroxyvitamin D3 each induced an accelerated rate of apoptosis in vitro in human ovarian epithelial cells. Apoptosis is a process whereby a genetic program within the cell is activated to trigger a specific series of events within the cell eventually leading to the death and efficient disposal of the cell. Richard Lockshin, Zahra Zakeri, The Biology of Cell Death and Its Relationship to Aging in Cellular Aging and Cell Death, pp. 167-180, 1996. Wiley-Liss Inc., Editors: N. J. Holbrook, G. Martin, R. Lockshin. C. Miligan, L. Schwartz, Programmed Cell Death During Development of Animals in Cellular Aging and Cell Death, pp. 181-208, 1996. Wiley-Liss Inc. P53-Dependent Apoptosis in Tumor Progression and in Cancer Therapy, Scott W. Lowe, H. Earl Ruley in Cellular Aging and Cell Death, pp. 209-234, 1996. Wiley-Liss, Inc.
For cells that have sustained DNA damage, apoptosis is one of the most important mechanisms used for the elimination of these cells, the preservation of which could otherwise lead to the development of malignant neoplasms. Canman et al., DNA Damage Responses: P-53 Induction, Cell Cycle Pertubations, and Apoptosis, Cold Spring Harbor Symp. Quant. Biol., 59:277-286 (1994). Thus, the apoptosis pathway is a virtually universal safeguard to prevent the persistence and proliferation of damaged cells that can be lethal to the organism. For normal tissues, the processes of cell proliferation and cell death are usually in a steady-state balance, and the apoptosis mechanism not only serves to prevent overgrowth of tissue, but also to eliminate those cells that are aberrant and therefore prone to resist normal growth regulatory controls.
An accelerated rate of apoptosis would facilitate the destruction and thereby removal of ovarian surface epithelial cells which have defective DNA and which have the potential to transform into malignant neoplasms. Given the importance of the apoptotic pathway for removal of abnormal cells from tissues, and thus the protection of normal tissues from neoplastic transformation, it is possible that the induction of apoptosis by Vitamin D is one mechanism underlying the effect of exposure to sunlight in reducing the risk of ovarian cancer.
The term xe2x80x9cVitamin D compoundxe2x80x9d including xe2x80x9cVitamin Dxe2x80x9d xe2x80x9cVitamin D analoguexe2x80x9d or xe2x80x9cVitamin D derivativexe2x80x9d as used herein includes any compound which activates the Vitamin D Receptor, by binding or otherwise, either in its form of administration or in a form to which it is converted by processing by the human body. This definition thus includes each of Vitamins D1, D2, D3, D4 and D5 and the various known analogues and derivatives thereof and any other agent that has Vitamin D activity or is an agonist thereof and that thereby increases the rate of apoptosis in ovarian epithelial cells. It is contemplated that not only presently available Vitamin D analogues and derivatives but also Vitamin D analogues and derivatives introduced in the future will be useful according to the present invention. Given the ability to produce the VDR recombinantly as described by Santiso-Mere et al., supra and models for determining VDR activation efficiency those of ordinary skill would be capable of identifying suitable Vitamin D compounds useful for practice of the present invention. Suitable analogues and derivatives are expected to include but are not limited to the following: 1a-hydroxyvitamin D3; 25-hydroxyvitamin D3; 1,24,25-(OH)3D3; 24,25-(OH)2D3; 1,25,26-(OH)3D3; 24,25-(OH)2D3; 1,25-dihydroxy- 16-ene-23-yne-26, 27-hexafluorocholecalciferol; 25,26-dehydro-1a,24R-dihydroxycholecalciferol and 25,26-dehydro-1a,24S-dihydroxycholecalciferol; 1a-hydroxy-19-nor-vitamin D analogues; 26,28-methylene-1a,25-dihydroxyvitamin D2 compounds; 1a-hydroxy-22-iodinated vitamin D3 compounds; 23-Oxa-derivatives of Vitamin D; and fluorinated Vitamin D analogues; 20-methyl-substituted Vitamin D derivatives; (E)-20(22)-Dehydrovitamin D compounds; 19-nor-Vitamin D3 compounds with substituents at the 2-position; and 22-thio Vitamin D derivatives.
Appropriate dosages to increase the induction of apoptosis of non-neoplastic ovarian epithelial cells may be determined by those of skill in the art depending upon the identity of the Vitamin D compound and its method of administration. For example, preferred dosages of the Vitamin D compound effective to increase apoptosis of non-neoplastic ovarial epithelial cells range from 0.0001 to 1.0 mg/kg of body weight (based upon the apoptotic potency of 1,25-dihydroxyvitamin D3) with dosages ranging from about 0.005 to 0.75 mg/kg being more preferred and dosages of about 0.05 to 0.5 mg/kg being particularly preferred. It is hypothesized that even higher dosages of 1,25-dihydroxyvitamin D3 may be more effective in inducing apoptosis. A Vitamin D analogue that has greater potency than 1,25-dihydroxyvitamin D3 in inducing apoptosis and/or which does not have the deleterious side effects of 1,25-dihydroxyvitamin D3, such as hypercalcemia, could be administered at a dosage equivalent much higher than 1.0 mg/kg of 1,25-dihydroxyvitamin D3. While the potency and bioavailability of other Vitamin D compounds and analogues may vary, those of skill in the art can determine their apoptotic potency in relation to 1,25-dihydroxyvitamin D3 and appropriate dosages and regimens of administration through use of in vitro testing methods such as disclosed in the accompanying example.
Prophylactic regimens for administration of Vitamin D compounds for normal female individuals and for those at increased risk of ovarian epithelial cancer can include daily or other periodic administration of Vitamin D compounds. It is contemplated that preferred regimens for prevention of ovarian cancer may comprise periodic administration of relatively larger dosages of Vitamin D compounds on a monthly or less than monthly basis rather than more frequent administration. The larger dosage would preferably range from a dosage equivalent to at least 400 I.U., more preferably a dosage equivalent to at least 2000 I.U., or still more preferably a dosage equivalent to 4000 I.U. According to such a regimen, a larger dosage of a Vitamin D compound might induce apoptosis in a large cohort of normal or dysplastic epithelial cells which over a period of time have become available for apoptosis. The treatment is then repeated some time later when another cohort of epithelial. cells is capable of being induced for apoptosis. It is contemplated that one mode of administration may be administering the Vitamin D compound for a brief period sufficient to produce apoptotic turnover of damaged ovarian cells, followed by repeated dosing periods at intervals, for example 1, 3, 6, or 9 months or 1, 3, 5, or 10 years, selected to provide apoptotic turnover adequate to prevent malignant transformations. The most preferable mode for administration would be one that maximizes the apoptotic turnover of ovarian epithelial cells and minimizes any side effects. The advantage of a technique of using large doses of Vitamin D on an infrequent basis is that it may minimize the adverse calcemic effects of a more frequent administration of Vitamin D compounds. The efficacy of such a technique is supported by the recognition that 1,25-dihydroxyvitamin D3, the active metabolite of Vitamin D, has a relatively short serum half-life and that its apoptotic effect may be based on transient surges in serum levels. It is also possible that the apoptotic effect may not result entirely from the interaction of 1,25-dihydroxyvitamin D3 (or its analogues) with the Vitamin D receptor but result from the effects of other Vitamin D compounds such as 25 hydroxyvitamin D3 on the VDR. Furthermore, the inventors do not wish to be bound by the theory presented above for the efficacy of Vitamin D in preventing epithelial ovarian cancer. While it is believed that increased apoptosis is the responsible mechanism, it may be that other mechanisms are responsible.
In one mode of practicing this invention, it is first determined that a patient does not display any signs of ovarian cancer. The patient may in the alternative or addition be determined to be a female at high risk of developing ovarian cancer. A regimen of Vitamin D product, alone or in combination with other compounds, is then prescribed for the female patient.
As a further aspect of the invention it is contemplated that Vitamin D and analogues and derivatives thereof may be co-administered with other agents which promote apoptosis of non-neoplastic ovarian epithelial cells. One particularly preferred class of agents are the progestins as disclosed in co-owned and copending U.S. patent application Ser. No. 08/713,834 filed Sep. 13, 1996, the disclosure of which is incorporated herein by reference. According to one preferred aspect of the invention, Vitamin D compounds may be administered in combination with a progestin product in amounts which will induce apoptosis of non-neoplastic epithelial cells. It is contemplated that combinations of Vitamin D compounds and progestins will exhibit not only additive but synergistic effects in the induction of apoptosis of non-neoplastic ovarian epithelial cells. In this manner the adverse physiological effects of administering larger quantities of Vitamin D compounds and of progestin products can be minimized.
The term xe2x80x9cprogestin productxe2x80x9d as used herein includes any drug which binds to the progestin receptor and induces a progestational effect. This definition thus includes all of the known progestins, derivatives of progesterone or testosterone that have progestin activity, and progestin agonists. It is contemplated that not only presently available progestins but also progestins introduced in the future will be useful according to the present invention. The known synthetic progestins are mainly derivatives of 17-alpha-hydroxy-progesterone or 19-nortestosterone. These progestins can be classified into three groups: the pregnane, estrane, and gonane derivatives. Progestin products may be administered at a variety of dosages including at a dose less than or equal to a dose equivalent to 10 mg daily of norethindrone, more preferably less than or equal to 1 mg daily, or less than or equal to 0.2 mg daily, and possibly as low as 0.05 mg daily of a norethindrone equivalent dose. According to a preferred aspect of the invention, a vitamin D compound and a progestin may be coadministered as a pharmaceutical composition preferably in a single unit dosage, such as a tablet, for inhibiting the conversion of non-neoplastic ovarian epithelial cells to neoplastic cells. The pharmaceutical composition comprises a Vitamin D compound and a progestin product in amounts which are together effective to increase apoptosis in non-neoplastic ovarian epithelial cells. Preferred pharmaceutical compositions include those wherein the Vitamin D compound is present at a dosage equivalent of from 0.0001 to 1.0 mg 1,25-dihydroxyvitamin D3/kg of body weight and wherein the progestin product is present at a dosage less than, or equal to, a dosage equivalent to 10 mg of norethindrone or 1 mg of norethindrone. More preferred compositions comprise those wherein the Vitamin D compound is present at a dosage equivalent of from 0.005 to 0.1 mg 1,25-dihydroxyvitamin D3/kg of body weight and wherein the progestin product is present at a dosage less than or equal to a dosage equivalent to 1 mg of norethindrone.
According to another dosage regimen a progestin product may be administered at a dose higher than 10 mg daily of a norethindrone equivalent dose. The oral preparations currently on the market are: norgestrel 0.075 mg, medroxyprogesterone acetate 2.5 mg, 5.0 mg, and 10.0 mg, norethindrone 0.35 mg, and norethindrone acetate 0.50 mg but it is contemplated that any of the progestins would be useful for combination with Vitamin D.
It is hypothesized that the combination of Vitamin D and progestins would have a synergistic effect, with reduced adverse side effects, based at least in part on the ability of the progestin compounds to upregulate the VDR. For that reason, it is contemplated in another aspect of the present invention that other compounds known to upregulate the VDR may be co-administered with the Vitamin D compounds. Such compounds include Vitamin A derivatives, such as retinoic acid, and also include dexamethasone.
Another aspect of the present invention involves the use of Vitamin D in combination with hormones at levels sufficient to provide the dual benefits of contraceptive protection and prevention of ovarian cancer. As discussed above, Vitamin D can be co-administered with progestins. Similarly, Vitamin D can be co-administered with estrogens and progestins at levels sufficient to provide contraceptive protection. The levels of estrogen and/or progestin for contraceptive protection are well known in the art. (See Speroffet al., Clinical Gynecologic Endocrinology and Infertility (Chap. 15), 4th Ed. 1989, incorporated herein by reference).
Yet another aspect of the present motion involves the co-administration of Vitamin D with hormones at levels sufficient for hormone replacement therapy. Estrogen is the primary agent in hormone replacement therapy. Postmenopausal women are generally given estrogen alone, or with low doses of progestins. The hormones may be administered continuously or cyclically. Continuous administration is typically 0.625 mg Premarin(copyright) (a conjugated equine estrogen) daily or its equivalent, with a 2.5 mg Provera(copyright) (medroxyprogesterone acetate) daily. Cyclical administration is typically 25 consecutive days of 0.625 mg Premarin(copyright) daily, with 10 mg Provera(copyright) daily on days 16 through 25, followed by 5 days of no hormone treatment (during which time these women will menstruate). (See Danforth""s Obstetrics and Gynecology, Chapter 42, 7th Ed. 1994, incorporated herein by reference). Exemplary regimens according to this aspect of the present invention include doses of Vitamin D compounds with estrogen (with or without other compounds such as progestins) at levels sufficient for hormone replacement therapy.
Estrogen is believed to be possibly linked to ovarian cancer. For that reason, the combination of Vitamin D with estrogen would provide a pharmaceutical composition which would reduce the risk of developing ovarian cancer.
xe2x80x9cConcurrent administrationxe2x80x9d or xe2x80x9cco-administrationxe2x80x9d as used herein includes administration of the agents together, or before or after each other. The agents may be administered by different routes. For example, one agent may be administered intravenously while the second agent is administered intramuscularly, intravenously or orally. They may be administered simultaneously or sequentially, as long as they are given in a manner sufficient to allow both agents to achieve effective concentrations in the body. The preferred manner of co-administration for all the combinations described above is a single unit dosage, such as a single tablet.
All doses given herein are appropriate for a female subject of about 60 kg weight; the dosages naturally will vary more or less depending on the weight of the subject. The doses may be increased or decreased, and the duration of treatment may be shortened or lengthened as determined by the treating physician. The frequency of dosing will depend on the pharmacokinetics parameters of the agents and the route of administration. The optimal pharmaceutical formulation will be determined by one skilled in the art depending upon the route of administration and desired dosage. See for example, Remington""s Pharmaceutical Sciences, 18th Ed. (1990, Mack Publishing Co., Easton, Pa. 18042) pages 1435-1712, the disclosure of which is hereby incorporated by reference. Such formulations may influence the physical state, stability, rate of in vivo release, and rate of in vivo clearance of the administered agents.
Those of ordinary skill in the art will readily optimize effective dosages and concurrent administration regimens as determined by good medical practice and the clinical condition of the individual patient. Regardless of the manner of administration, the specific dose may be calculated according to body weight, body surface area or organ size. Further refinement of the calculations necessary to determine the appropriate dosage for treatment involving each of the above mentioned formulations is routinely made by those of ordinary skill in the art and is within the ability of tasks routinely performed by them without undue experimentation, especially in light of the dosage information and assays disclosed herein. Appropriate dosages may be ascertained through use of established assays for determining dosages in conjunction with appropriate dose-response data. The final dosage regimen will be determined by the attending physician, considering various factors which modify the action of drugs, e.g. the drug""s specific activity, the responsiveness of the subject, the age, condition, body weight, diet and sunlight exposure of the patient, the severity of any infection, time of administration and other clinical factors. Given the teachings herein those of ordinary skill would be able to determine appropriate dosage levels of Vitamin D compounds for inducing apoptosis of non-neoplastic ovarian epithelial cells.
It is contemplated that the routes of delivery of Vitamin D compounds including Vitamin D and biologically active analogues and derivatives thereof (either alone or in combination with other pharmaceuticals) could include oral, sublingual, injectable (including short-acting, depot, implant and pellet forms injected subcutaneously or intramuscularly), vaginal creams, suppositories, pessaries, rings, rectal suppositories, intrauterine devices, and transdermal forms such as patches and creams.
The term xe2x80x9cfemales at high risk of developing ovarian cancerxe2x80x9d includes females with a family history of breast or ovarian cancer, females with a prior history of breast or ovarian cancer, or females with a mutation in the BRCA1 gene or any other mutation shown to be associated with a high risk of developing ovarian cancer.

Prevention of ovarian cancer by administration of a vitamin D compound


Methods of and equipment for converting existing standard motion picture theatres to one having highly immersive, large fields of view are addressed. Aspects of the methods include moving motion picture screens closer to the audience and employing different projection equipment to avoid or minimize appearance of unrealistic or non-natural image artifacts. Alternative sound systems too are detailed, as is placement of various loudspeakers relative to, for example, projection screens or theatre walls.

Motion picture exhibition has seen a number of changes since its inception in the late 19th century. Generally, the main variables in motion picture exhibition have been the dimensions of the theatre enclosure and correspondingly the number of seats therein, the size of the screen upon which images were projected and the dimensions or format of the film negative which contained the images for presentation. Although a number of film formats were considered, one format, 35 mm wide film having an image aspect ratio of 4:3 became the industry standard. Motion picture theatres gradually evolved in size from smaller theatres to larger so-called palace theatres featuring several hundred to thousands of seats, balconies, and elaborate facades. Despite the impressive and somewhat regal atmosphere these theatres continued to feature 35 mm film projected onto narrow width screen. Eventually in the late 1920s, motion picture producers and exhibitors started experimenting with larger film formats which could enhance the visual immersion of theatre patrons and live up to the size and scope of the large palace theatres.
Some of the wide gauge/wide screen processes that appeared to challenge the 35 mm film standard included Magnascope, Polyvision, Hypergonar and Fox Grandeur. Magnascope used a novel magnifying lens to enlarge a standard 35 mm frame. Polyvision used multiple 35 mm film projectors to stitch together a composite image, while Fox Grandeur replaced 35 mm film entirely with a new 70 mm wide film format. Finally Hypergonar used a novel method of anamorphically squeezing images onto a 35 mm frame during filming and then reversing the process upon projection to fill a larger projection screen.
Although technically and aesthetically successful, the proposed wide screen systems failed to replace 35 mm as a film standard in the economically depressed 1930s and were soon abandoned. Conditions had changed somewhat by the early 1950s and the motion picture industry saw a resurgence of proposals for wide gauge/wide screen systems. Foremost among the new systems were Cinerama, a multiple 35 mm projection system, Cinemascope, an anamorphic system, Vistavision a 35 mm 8 perforation format system and Todd AO, a wide gauge system using a 70 mm 5 perforation 30 frame per second format. The new formats were successful at the box office and survived for a number of years, but none was able to seriously challenge the 35 mm film standard.
A third wave of wide gauge/wide screen motion picture exhibition started in 1969, led by IMAX Corporation, which featured the use of horizontally travelling 70 mm film with a film frame of 15 perforations in width resulting in an image area about ten times that of standard 35 mm. In addition to the large film format IMAX® re-conceptualized the theatre viewing space by providing significantly larger screens which extended beyond spectators fields of view, steeply raked seating area to give unobstructed viewing of said large screen, and high fidelity six channel sound to surround the audience. The net result of these advances was a theatre experience in which audience members were immersed in image and sound as never before. IMAX® theatres were successful in the institutional and exhibit marketplace. Other competing large format systems include Showscan's 70 mm 5 perforation film projected at 60 frames per second (versus the standard 24 fps) and Iwerk's 70 mm 5, 8 and 15 perforation film systems.
In most cases IMAX® systems were installed in custom designed motion picture theatres having a large volume to house both the large screen and a steeply raked seating deck. Occasionally IMAX® projection systems were placed in large hall converted stage theatres. IMAX® screens could be placed in front of the stages in such theatrical structures without building structure modifications because of the large existing clear height. In some cases, such as at the Museum of Natural History in New York City, a retractable IMAX® screen was placed in front of the stage that had an existing 35 mm screen at the back of the stage. Some seats at the side of the theatre near the position of the IMAX® screen were removed because the visual quality at those locations was poor. The slope of the seating areas in these theatrical theatres is typically shallow, and financial constraints prevented conversion to a more desirable steeper slope. As a result, the viewing conditions in such converted theatres were not optimized for viewing IMAX® motion pictures.
Grand theatres of the type frequented in the 1920s thru 1950s were sometimes converted to house the emerging wide gauge/widescreen systems of the 1950s. Conversion consisted of changing the width and curvature of the screen to match the new wider picture aspect ratio and removing a relatively high percentage of seats that no longer had viable viewing conditions. Screen centres were basically positioned at the original screen centre position at the rear wall of the theatre, and the rake of seats in the theatres was not a consideration in the conversion process.
Another type of theatre conversion addresses the desire to present motion pictures in either of two common aspect ratio formats, which are 1:85:1 and 2.35:1. The conversion process involves adjusting the curtain masking around the screen to suit the format of presentation as well as changing the lens and aperture plate. The position of the screen itself does not change.
A major trend in the motion picture industry starting in the 1970s was to group a number of small 35 mm film theatres into one large complex, or so-called multiplex theatre. These theatres, although profitable, did not provide patrons with a quality viewing experience. Over time movie attendance declined partly because of new home entertainment technologies such as cable TV, video cassette recorders, and home movie rentals. In the 1990s the motion picture exhibition industry responded to declining movie attendance by building new theatres offering stadium seating—placing each row of seats on its own tier—to improve the sight lines and thus the viewing experience of patrons. This industry advance has been very successful in improving movie attendance and is now an expected feature for theatre patrons; conventional low slope seating decks are seen as "old" and inferior. (LA Business Journal). The new stadium seat theatres, while an improvement over traditional multiplex theatres, still rely on standard 35 mm film projectors and do not provide patrons with a wide field of view or highly immersive experience.
It should be noted that in the later half of the 1990s the use of digital projectors began in a few multiplex cinemas. This trend in time will increase as digital projection systems get better in quality and higher in image resolution.
Another aspect of the conversion is to improve the quality of the audio portion of the immersive experience in a multiplex type theatre. Sound systems for cinema have evolved over the decades and the trend continues as an ongoing effort to attract the paying viewer. The surround sound systems used in today's Multiplex theatres can provide a degree of "ambience" in the audio experience but these systems still lack the ability to create realistic immersive audio.
From the time "talkies" were introduced, motion picture cinemas had "monaural" sound systems, having only one loudspeaker located behind the center of the screen. The sound experience in such a cinema was very one dimensional and flat, with no ability to simulate sounds coming from directions other than the center of the picture. In order to improve the audio experience, cinema designers and equipment suppliers experimented with a variety of multiple loudspeaker ("multi-channel") schemes designed to immerse the audience in a sound field which could add to the "suspension of disbelief" desired by filmmakers. One of the earliest attempts at multi-channel sound was the premier of Walt Disney's "Fantasia" in 1939. Disney experimented with a number of sound system loudspeaker configurations as outlined in an article by William E. Garity and John N. A. Hawkins published in the August 1941 issue of the journal of the SMPTE. The last two versions of the Fantasound system, known as Mark IX and X, used 5 loudspeakers and sound from 3 separate tracks. The loudspeakers were positioned such that 3 were behind the screen (i.e. left, center, and right) and one loudspeaker was in each rear corner. The two sets of rear corner loudspeakers were switched in to supplement or replace the corresponding left and right front loudspeakers at select times during the picture presentation. Unfortunately, the war and economics cut short Disney's sound system experiments. In the early 1950's, Cinerama brought multi-channel sound to the forefront again with 5 to 7 loudspeaker channels located around the audience.
During the 1950's there were several theatres equipped for the playback of multi-channel sound, of which there were primarily two formats both using magnetic stripes printed on the film. The CinemaScope 35 mm film format provided four discrete channels, consisting of 3 loudspeakers behind the screen and a monaural surround channel provided by several small loudspeakers located on the side and rear walls of the cinema. These surround loudspeakers provided a degree of "ambience" to the sound experience in combination with the directional sound produced by the 3 screen loudspeakers, and thus added to the immersive effects presented to the audience. The Todd-AO 70 mm film format added two additional loudspeakers behind the screen, Left Center and Right Center, between the center loudspeaker and the left and right speakers.
In the 1970's, Dolby pioneered several advances in cinema sound, including extended low-frequency sound (sub-bass), noise reduction, and Stereo Optical sound. Dolby Stereo Optical provided 4 channels of sound (left, center, right, and mono surround) using an encoding technique to store the analog soundtrack on two analog optically printed stripes on the film. This became the standard for normal cinemas, and remains in use today in non-digital cinemas.
In 1979, Dolby added to the immersive effects of cinema sound by developing stereo surrounds, in which the left distributed loudspeaker channel could reproduce different sounds than the right channel. But, the surround effects were still effectively ambience sounds, and were unable to reproduce directionality with any precision due to the distributed configuration of the surround loudspeakers.
In the 1980's, IMAX® Corporation standardized on a 6-channel sound system with a discrete surround sound configuration and a separate sub-bass channel for IMAX® Theatres. This type of system provides substantially better sound imaging by utilizing custom-designed loudspeakers located in each rear corner behind the audience, each powered by a separate audio channel. The immersive effects of this type system are much more impressive, and allow the filmmaker the ability to position sound more precisely—directly in front of, in front above, around, and behind the audience.
In 1987, Imax installed the first Digital Sound Reproducer in an IMAX Theatre. By 1990, uncompressed Digital Sound was available to all IMAX Theatres. Also in 1990, with the release of the movie "Dick Tracy," CDS uncompressed digital sound on 35 mm film was introduced to the general cinema industry by a joint venture of Orcon and Kodak.
Because CDS was not compatible with standard optical sound on 35 mm film, the CDS format was discontinued soon thereafter.
Between 1992 and 1993, three systems of digital sound for cinema were released—Dolby Digital, DTS, and Sony SDDS. All three of these formats utilized some form of digital compression to reduce the storage requirements (on CD-ROM for DTS) or to allow the digital audio signal to be printed on the 35 mm film (with Dolby Digital and SDDS) without displacing the optical track as did the CDS system. While these systems use different compression techniques—some considered "better sounding" than others—IMAX Digital Sound remains the only uncompressed digital cinema sound format in general use today.
All three of the digital sound systems used in conventional 35 mm and digital cinemas make use of the same distributed side and rear surround loudspeakers to create a sense of ambience for the film soundtrack. Even though these digital systems may sound "better" than the older optical systems, sound immersion remains limited due to the inability of multiple distributed loudspeakers to provide precise directionality and image placement.
Motion picture exhibitors have expressed interest in providing additional quality improvements to mainstream motion pictures by adding a special, custom designed, smaller scale Imax theatre to their multiplexes. This has proved popular with patrons and exhibitors, but has not been widely adopted because of high costs associated with constructing the adjunct theatre.
It is desirable to be able to provide mainstream multiplex theatres with the same manner of widescreen presentation experience as large hall custom designed theatres, but at a lower, more affordable cost. There is a need to be able to economically convert an existing mainstream multiplex motion picture theatre into a widescreen theatre that is qualitatively superior in terms of projected image quality, field of view, and of a more realistic immersive audio experience that does not exist in multiplex type theatres. As a result of having overbuilt the number of multiplex theatres the economics of this situation dictates that converting existing multiplex theatres makes better sense than building additional new multiplexes with larger screen sizes. The following discussion of the inventive approach by the applicant addresses this need.

This patent is subject to a terminal disclaimer.

Conversion of cinema theatre to a super cinema theatre