A process for thermal and, optionally, catalytic upgrading and hydrogenation of hydrocarbons is described, wherein the hydrocarbons (oil) with a lower API grade is passed through one or more reactors connected in parallell or in series, preferably in series, in liquid state where it under pressure and intense agitation at a given temperature is thermally upgraded by increasing API, and that the product is discharged in liquid state, and whereby the agitation is effected by whipping elements, optionally made of a catalytic material acting as a catalyst in upgrading the oil in the reactor.

The present invention is related to a process for upgrading of heavy hydrocarbons (petroleumxe2x80x94crude oils) with a low API grade to a higher API grade in a reactor system involving heat, mechanical shear forces, pressure and catalytic action whereby the oil in converted into lighter fractions and its viscosity reduced.
Oil refining and the development of the internal combustion engine have continued since the latter part of the nineteenth century. Each has influenced the other in the course of this development, but it is the oil industry and its effect on almost every part of modern living that has been the most spectacular.
Crude oil is a mixture of literally hundreds of hydrocarbon compounds ranging in size from the smallest, methane, with only one carbon atom, to large compounds containing 200 or more. A major portion of these compounds are paraffins or isomers of paraffins. These are straight-chain hydrocarbon compounds such as butane, C4H10 which normally is denoted nC4. Isobutane on the other hand is denoted iC4.
The remaining hydrocarbon compounds are either cyclic paraffins called naphthenes or aromatics.
These families of hydrocarbons are called homologues, and because of the large quantity of these compounds which exist in crude oil, only the simplest of compounds in the homologues can be isolated to some degree of purity on a commercial scale. Generally, in refining projects, isolation of comparatively pure products are restricted to those compounds lighter than C7s. Most compounds, however, have been isolated and identified but only under strict and delicate laboratory conditions.
In the industry the products are restricted to groups of these hydrocarbons boiling between selective boiling ranges. Thus products are usually denoted by boiling points rather than by the compounds they contain.
Not all compounds contained in crude oil are pure hydrocarbons. The crude contains certain inorganic impurities such as sulphur, nitrogen and metals. By far the most common of these impurities are the organic sulphur compounds called mercaptans. These compounds are similar to hydrocarbons but with the addition of one or more sulphur atoms.
More complicated sulphur compounds also exist such as thiophenes in the high carbon number range homologues and disulphides in the middle distillate range. Because of the close relationship that exists between these sulphur compounds and neighbouring hydrocarbons in such characteristics as vapour pressures, the compounds can not be isolated by distillation processes on a commercial scale.
Organic chloride compounds are not usually removed from the crude as products but the corrosive effect attributed to these compounds on parts of refinery plants is always a source of concern. A considerable amount of investigation has been, and is still being, carried out on prevention of corrosion by HCI generated in the process from these organic chlorides.
The metals contained in crude are usually nickel, sodium and vanadium. Because these are not very volatile they are found in the heavier products of crude such as fuel oil. They only become a nuisance in certain cases when they can affect further processing of the oil, or if they exist in such large quantities in fuel oil as to limit the saleable value of the product. Their removal can be effected in such cases by an extraction process where they are removed as a part of a bituminous extract called asphaltenes.
Before leaving the subject of crude oil composition it is necessary to mention yet another series of organic compounds which, although not always present in the original crude, are often formed during the refining processes. These are unsaturated compounds. As mentioned earlier, most compounds contain carbon and hydrogen and are constituted in such a way that each carbon atom contains its full quota of four atoms, in the form of either hydrogen or carbon atoms. However, some of these molecules break down under conditions of high temperature and permanently lose one or more of those attached atoms. Such compounds are unstable and readily combine with themselves or other similar compounds to form polymers. They are called unsaturates while the stable hydrocarbons such as paraffins, cycloparaffins and aromatics are called saturated hydrocarbons. An example of such a compound is ethylene, which has the following formula C2H4.
Crude oil found in various parts of the world vary considerably in characteristics. This can readily be seen in the difference in specific gravity that exists between the crudes. For instance, Zelten crude (Libyan) has an API gravity of 39.0 while Bachequero crude has a gravity of 16.0. A Venezuela crude from the Orinoco basin has a gravity of 10 API. This difference is due to the fact that although each crude oil contains basically the same hydrocarbon compounds, the proportion of these hydrocarbons vary considerably from one crude to another. Thus some crudes are relatively rich in paraffins, and this is reflected by the waxy nature of the crude (most Middle East crudes fall into this group). Others contain more cycloparaffins and aromatics (such as Nigerian and some American West Coast crudes).
Although it is theoretically possible to produce any type of refined product from any crude, it is not usually economically feasible to do so. For instance, better yields of reformer stock for aromatics production is obtained from Nigerian crude than from Kuwait, while considerably more residium for fuel oil is obtained from Kuwait than Nigeria. To satisfy the demand of these two products, refineries often blend two such devious crudes, changing the proportion of the blend to satisfy the particular need. If product demands are seasonal, as in the case of many gas oils, imports of specifically selected crudes are scheduled to optimise the production of such cuts for the season.
Selectivity of crude type is comparatively easy to effect and is common practice in the refining industry where most oil companies have their own oil wells in various parts of the world. However, occasionally the demand for a particular product or the elimination of a low-value one becomes so persistent that major conversions of a chemical nature have to be adopted. Such processes as thermal and catalytic cracking and, more recently, hydrocracking are used to effect this.
In general, the products that are normally obtained from crude oil can be grouped as follows:
(1) Volatile products (these are the lightest products)
Propane LPG (liquefied petroleum gas)
Butane LPG
Light naphtha (C5s and nC6)
(2) Light distillates
Gasolines
Heavy naphtha (petrochem naphtha and base for paints)
Kerosene and jet fuels
(3) Middle distillates
Automotive diesel
Heating oils
Gas oils
(4) Fuels oils
Marine diesel
Bunker fuels (for ships)
(5) Lubricating oils
Motor
Spindle
Machine oils
(6) Waxes
Food and paper coating grade
Pharmaceutical grade
(7) Bitumen
Asphalt
Coke
Product form these groups are produced from distillation processes and treated to meet certain specifications. These specifications are the results of a compromise between desirable performance characteristics in the product and the ability to make such products from the crude and the processing facilities at hand. Wide rangs in physical properties are often tolerated in these specifications in order to cater for crude oil source, sales area and the product""s ultimate use.
Thermal cracking processes are the true workhorses of the oil-refining industry. The processes are relatively cheap when compared to the fluid cracker and the hydrocracker, but go a long way to achieving the oil-cracking objective of converting low-quality material into more valuable oil products. The process family of thermal crackers has three members:
Thermal crackers
Visbreakers
Cokers
The term xe2x80x98thermal crackingxe2x80x99 is usually given to those processes that convert heavy oil (usually fuel oil or residues) into lighter product stock such as LPG, naphtha, and middle distillates by applying only heat to the feed over a prescribed element of time. When applied to a specific process the term refers to the processing of atmospheric residues (long residue) to give the lighter products. xe2x80x98Visbreakingxe2x80x99 refers to the processing of vacuum residues (short residues) to reduce the viscosity of the oil only and thus to meet the requirements of a more valuable fuel oil stock. xe2x80x98Cokingxe2x80x99 refers to the most severe process in the thermal cracking family. Either long or short residues can be fed to this process whose objective is to produce the lighter distillate products and oil coke only. The coker process is extinctive-that is, it converts all the feed. In the other two processes there is usually some unconverted feed, although the thermal cracker can be designed to be xe2x80x98extinctivexe2x80x99 by recycling the unconverted oil. The three thermal cracking processes have the same basic configuration. This consists of a cracking furnace, a xe2x80x98soakingxe2x80x99 vessel or coil, and a product-recovery fractionator(s). The feed is first preheated by heat exchange with hot product streams before entering the cracking furnace or heater. The cracking furnace raises the temperature of the oil to its predetermined cracking temperature. This is always in excess of 490xc2x0 C., and by careful design of the heater coils, the oil is retained in the furnace at a prescribed cracking temperature for a predetermined period of time (the residence time). In some cases an additional coil section is added to the heater to allow the oil to xe2x80x98soakxe2x80x99 at a fixed temperature for a longer period of time. In other cases the oil leaves the furnace to enter a drum which retains the oil at its cracking temperature for a short time. In the coker process the oil leaves the furnace to enter one of a series of coker drums in which the oil is retained for a longer period of time at its coking temperature for the production of coke.
The cracked oil is quenched by a cold heavy oil product stream on leaving the soaking section to a temperature below its cracking temperature. It then enters a fractionator where the distillate products are separated and taken off similar to the crude distillation unit. In the case of the cokers the coke is removed from the drums by high-velocity water jets on a regular batch basis. The coking process summarised here refers to the more simple xe2x80x98delayed cokingxe2x80x99 process. There are other coking processes which are more complicated, such as the fluid coker and the proprietary Flexi coker.
The processes summarised above are the more common to be included in a fuel refinery""s configuration. In addition to these there will also be gas-treating processes and often some additional gasoline octane-enhancement processes.
Within all of the above mentioned technologies, there exist a number of patents related to each of the process with proprietary information of their performances.
But all of these processes have one goalxe2x80x94to upgrade or refine the produced crude oils to a saleable commodity which meets the requirement of the market.
A number of the world""s oil reserves consists of so-called heavy oils such as bitumen with a gravity below 16 API. Such deposits are located in countries as Canada, Trinidad, Kazakstan, Iran, Venezuela and part of the Middle East. Besides being a feed to the refineries with a reduced value, the low viscosity associated with such crude, give rise to huge transport problems of the same as the oil can not be pumped through pipelines without pre-treatment. One widespread method is to blend the low gravity oil with a higher gravity oil thus creating a pump-able blend. In addition to high gravity oil, nafta and water are also used as a blender. When using water as blender, this is always done together with an emulator which keeps the oil and water in an un-separable emulsion. Such an emulsion is the well-known Orimulsion created by crude from the Orinoco basin in Venezuela.
Even though the above mentioned processes fulfil their objectives, they are all known as is huge installations located on industrial sites (refineries). None of the known technologies are designed to be located close to the oil source (wells) with the objective to upgrade the oil before it is delivered to a traditional refinery.
The present invention aims in showing a new simplified method for upgrading heavy oil by cracking the oil whereby the transport properties of the crude is improved in addition to generate a far better feed-stock to the refinery. Furthermore the invention aims at showing that the process may be located close to the well-heads whereby a substantial savings can be obtained in transportation costs.
The process comprises of one or mere reactors arranged in series or parallel. In each reactor which is working with different temperature and pressure dependent upon the characteristics of the feed, there is arranged a rotating mixing device. The mixing device may be driven by any rotating source such as a combustion engine, electric motor, steam turbine and similar devices.
On the reactor or reactors, pipes are arranged for charge of feeding oil, discharge of produced oil, recycling of produced oil and a pipe for exhaust of generated steam and oil-gas. The feed oil is utilised as a cooling medium in the condenser in that the oil is pumped from the source through the condenser by a low pressure pump. In the condenser the oil will accumulat the heat of condensation from the evaporated effluents. The feed oil is further pumped through a heat exchanger where it is further heated by heat exchange from the produced oil leaving the reactor. The preheated feed-oil is then pumped into the reactor by a high pressure pump.
The condensed liquids from the condenser may either be charged to a separate tank system or being blended with the produced oil from the reactor.
As the process may operate with different pressure and temperature, having different residence time and may be affected catalytic by the material chosen in the part of the is mixer whipping the oil, the process is a thermal catalytic visbreaking cracking unit which combine the effects from each of these classic processes.
When the feed oil enters the reactor, it will be subject to strong shear forces from the mixer, proportional with the velocity (m/s) of the part of the mixer being in contact with the oil. The velocity and the load expressed in Watts on each element of the mixer acting on the oil is chosen such that the oil in addition to the shear forces also receives sufficient energy from the hydrodynamic energy transfer (resistance) between the oil and the elements to heat the oil to the desired process temperature. This is, on the other hand, not an absolute requirement for the process as additional energy can be delivered to the process form heated oil or water from a heat-jacket surrounding the reactor vessels. Energy may also be applied by injecting a designed amount of air or oxygen directly into the reactor to give a partial combustion of the oil in the reactor in order to heat the oil to the process temperature. When applying this, CO and CO2 are generated and leaves the reactor through the gas pipe and is vented of in the condenser as non-condensable gases.
To avoid evaporation of the oil in the process and to optimise the thermal load on the oil and increase efficiency, the reactor is pressurised at a pressure whereby the boiling point of the fraction of the oil in the reactor is higher than the operating temperature. Water in the feed oil will normally be evaporated under the existing conditions in the reactor related to temperature and pressure.
Exhaust of evaporated water and oil gas which may be driven off by the steam expansion, leave the reactor through the gas pipe including a pressure valve set to the actual reactor pressure. Thus, the effluents are entering the condenser at a pressure of approx. 1,1 bar.
The oil which is charged into the reactor will, due to the aggitation, be put into a rotating movement against the opposite end of the reactor. During this movement, the oil will be exposed to the mentioned shear forces and the catalytic effect from the material in the whipping elements and will be heated to the desired process temperature. In the opposite end of the reactor there is arranged a discharge pipe including a discharge device which may be a gear-pump or a valve. When process temperature is reached, the discharge device is activated and product is discharged with the consequence that the load on the drive drops. The reduced load activates the feed pump to maintain the load of the drive.
By certain types of oils it is necessary to increase the residence time in the reactor. To achieve this, a by-pass is arranged between the discharge pipe and the feed-pump whereby a portion of the oil in the reactor can be pumped back into the reactor.
The volume of pump around is dictated by the characteristics of the feed-oil and to what level upgrading is wanted.
Upgrading can furthermore be increased by having reactors operating with different pressure and temperature in series whereby the oil is pumped from the first reactor to the next and so on and is dischared in the last reactor as mentioned above. By this arrangement one or more of the reactors may act as a soaking or flash vessel. When operating as a soaking vessel, the reactor is given more or less the same temperature and pressure as in the previous reactor whereby the oil under agitation can soak a given time. When operating as a flash vessel, the reactor is operating at the same temperature but a reduced pressure whereby the accumulated energy in the oil will cause portion of the fractions in the oil to flash-evaporate which for some crude might be advantageous. The gases leaving the flash vessel can either be condensed in one operation or be separated further in a destillation column.
Furthermore the reactor can be made with different diameters whereby the velocity of the elements attached to the mixer will increase by increasing diameter. The increased velocity will give rise to increased mechanical shear forces. By such arrangement the reactor is operating under the same pressure and temperature.
As the energy can be delivered to the oil in the reactor in-situ, the theoretical energy-consumption to operate the process is equal to the caliometric energy requirement to heat the oil to the process temperature and the enthalpy in the steam and oil gas leaving the reactor through the gas pipe.
Still another feature of the invention is that the whipping elements have slots which change the direction of the oil thus creating momentum of bending force and increased mechanical shear forces and increased contact area to be affected by the catalytic effect from the material in the elements.

Process for thermal, and optionally catalytic, upgrading and hydrogenation of hydrocarbons


Devices for repairing and replacing a heart valve in various embodiments, the devices include at least first and second support rings connected together in a coiled configuration to abut opposite sides of a valve annulus. A replacement valve may be secured to the coil-shaped device. Various alternative fastening systems include suture fastening systems, mechanical fastening systems, shape memory alloy fastening systems and other fastening systems relying only on the resilience between adjacent coils. A method generally includes inserting a first end of the coil-shaped member through a valve annulus, rotating a first ring of the coil-shaped member into position on one side of the valve annulus and positioning at least a second ring of the coil-shaped member on an opposite side of the valve annulus.

The present invention generally relates to heart valve repair and replacement techniques and annuloplasty devices. More specifically, the invention relates to the repair and/or replacement of heart valves having various malformations and dysfunctions.
Diseased mitral and tricuspid valves frequently need replacement or repair. The mitral and tricuspid valve leaflets or supporting chordae may degenerate and weaken or the annulus may dilate leading to valve leak (insufficiency). The leaflets and chords may become calcified and thickened rendering them stenotic (obstructing forward flow). Finally, the valve relies on insertion of the chordae inside the ventricle. If the ventricle changes in shape, the valve support may become non-functional and the valve may leak.
Mitral and tricuspid valve replacement and repair are traditionally performed with a suture technique. During valve replacement, sutures are spaced around the annulus (the point where the valve leaflet attaches to the heart) and then the sutures are attached to a prosthetic valve. The valve is lowered into position and when the sutures are tied, the valve is fastened to the annulus. The surgeon may remove all or part of the valve leaflets before inserting the prosthetic valve. In valve repair, a diseased valve is left in situ and surgical procedures are performed to restore its function. Frequently an annuloplasty ring is used to reduce the size of the annulus. The ring serves to reduce the diameter of the annulus and allow the leaflets to oppose each other normally. Sutures are used to attach a prosthetic ring to the annulus and to assist in plicating the annulus.
In general, annuloplasty rings and replacement valves must be sutured to the valve annulus and this is time consuming and tedious. If the ring is severely malpositioned, then the stitches must be removed and the ring repositioned relative to the valve annulus during restitching. In other cases, a less than optimum annuloplasty may be tolerated by the surgeon rather than lengthening the time of surgery to restitch the ring.
During heart surgery, a premium is placed on reducing the amount of time used to replace and repair valves as the heart is frequently arrested and without perfusion. It would be very useful to have a method to efficiently attach a prosthesis into the mitral or tricuspid valve position. Furthermore such a method may have its greatest advantage in remotely attaching a valve repair or replacement device so that surgery could be avoided altogether.
Annuloplasty devices and methods and heart valve repair and replacement devices and techniques are therefore necessary to provide a more reliable and more easily accomplished valve repair and replacement.
The present invention generally provides a device for repairing a heart valve having an annulus and a plurality of leaflets for allowing and preventing blood flow through a patient""s heart. The device comprises a first support ring and a second support ring connected to the first support ring to form a coiled configuration. The first support ring is configured to abut one side of the valve annulus and the second support ring is configured to abut an opposite side of the valve annulus to thereby trap valve tissue, that is, annulus tissue and/or leaflet tissue, therebetween. This device may be used in those situations, for example, that have conventionally utilized annuloplasty rings, but the device of this invention may be applied in a much easier manner. The device may also be used to carry a replacement heart valve. The invention contemplates various embodiments of the device, including embodiments for catheter-based surgery and embodiments for open heart surgery.
In the various embodiments, the first and second support rings may have an inner core covered by an outer layer, such as a fabric layer, with the inner core being formed from a more rigid material than the outer layer. The first and second support rings may have generally triangular-shaped cross sections with flat sides opposing one another and trapping valve tissue therebetween. A plurality of fasteners may be used between the first and second support rings and, for example, these may comprise sharp projections. An actuating member may be used to actuate the fasteners to an extended position through the valve tissue. Other forms of fasteners are possible as well, including those comprising projections and complimentary receiving members on the first and second support rings. Shape memory alloys may be used to facilitate connection, such as by moving the first and second support rings together or moving fastening elements thereof into engagement.
At least the opposed surfaces of the first and second support rings may be roughened, such as by the use of fabric, coatings, knurling or the like to facilitate better engagement and retention of the support rings on the valve tissue. A removable sleeve may be carried by the first and second support rings for initially reducing friction between the respective rings and the valve tissue during initial engagement therewith, such as during rotation of the device on either side of the annulus. The sleeve may then be removed to expose the higher friction surfaces of the device to the valve tissue for better retention.
Preferably, the first and second support rings are formed integrally from a coiled rod, such as a metallic rod, with one end of the rod formed as a leading end and one end formed as a trailing end. These ends may be bent in opposite directions so that the leading end may be directed through the valve tissue and the trailing end may be grasped by an appropriate surgical implement. A carrier may be used to rotate the device into position on opposite sides of the valve annulus and then may be removed leaving the first and second support rings in place to trap the valve tissue therebetween. As another alternative, the carrier may be coil-shaped and the repair device may be rotated into place on only one side of the valve annulus similar to conventional rings. The carrier may then be rotated for removal while leaving the repair device in place. The first and second support rings may be adjustable in diameter to allow adjustment of the valve annulus.
When replacing a heart valve, a device of this invention again preferably comprises first and second support rings formed in a coiled configuration with a replacement valve coupled to at least one of the support rings. The replacement valve may be coupled in a releasable manner using any suitable fastening structure. For example, the replacement valve and one of the support rings may include mating engagement elements or the replacement valve may be directly threaded into one of the support rings. The replacement valve and one of the support rings may alternatively include respective cuffs adapted to receive sutures to fasten the replacement valve to the support ring. Optionally, one of the support rings may include a cuff with a movable fastening element which is engageable with the replacement valve. The fastening element may be formed from a shape memory alloy to facilitate its movement between an engaged and a disengaged position relative to the replacement valve.
The invention further contemplates various methods of repairing a heart valve including methods for fully replacing the heart valve. Generally, the method includes inserting a first end of a coil-shaped support through the tissue of a heart valve. A first ring of the coil-shaped support is then rotated in position on a first side of the annulus and a second ring of the coil-shaped support is positioned on an opposite side of the annulus. The first and second rings may then be fastened together to trap the annulus tissue therebetween, or the inherent resilience between the first and second rings may trap tissue without using separate fasteners. The coil-shaped support may be carried in its coiled form during the rotation step, or the coil-shaped support may be extended from a catheter positioned adjacent the annulus. Many other variations of these methods and additional methods will be apparent to those of ordinary skill upon review of this disclosure.
Various additional objectives, advantages and features of the invention will become more readily apparent to those of ordinary skill in the art upon review of the detailed description of the illustrative embodiments.

Annuloplasty devices and related heart valve repair methods


An ultrasonic metering device having two ultrasonic transducers, each having an ultrasonic conversion element and a wedge for holding the conversion element, mounted on a pair of mounting members which are adapted to be mounted on a pipe in which a fluid to be measured flows. The mounting members clamp the pipe with first end portions of the mounting members being hingedly coupled to each other. Tightening means is provided for coupling opposite free end portions of the mounting members which have clamped the pipe to thereby fixedly secure the mounting members to the pipe.

The present invention relates to an ultrasonic metering device with externally located ultrasonic transmitter-receivers. This device is structured so that it can be mounted on a pipe in which a fluid to be measured flows without altering the pipe and can be installed with a high accuracy.
Examples of an ultrasonic metering device of this general type are a flow meter, a densitometer and a current meter.
In mounting the ultrasonic metering device on a pipe, the following requirements should be satisfied:
(1) It is essential that the ultrasonic transmitter-receivers (hereinafter referred to as "ultrasonic transducers" when applicable) be correctly positioned relative to the pipe and relative to each other because the incident angle of the ultrasonic waves with respect to the fluid and the distance between the ultrasonic transducers greatly affect the accuracy of measurement.
(2) It is necessary that the ultrasonic transducers be sufficiently acoustically coupled to the pipe. Excellent sensitivity and accuracy cannot be obtained without satisfying this requirement.
(3) It is desirable that the ultrasonic transducers can be readily mounted on the pipe within a short period of time. One of the merits of the external mounting system resides in that the ultrasonic metering device can be freely mounted on pipes already installed in a plant.
Depending on the fluid carried by the pipe, the area around the pipe may not be suitable for the physical presence of workers such as due to the pipe being at high temperature, filled with poisonous gas or radioactive material. Thus, it is often required that the device can be readily and quickly mounted on a pipe even by unskilled persons without a need for adjustment.
However, no ultrasonic metering device satisfying all these requirements has yet been proposed in the art.


The present invention involves the identification and use of compositions for treating myeloma bone disease. The compositions inhibit proteasomal activity and decrease the activity of the transcription factor NF-xcexaB. Assessment of a candidate compound for its ability to inhibit production or activity of proteasomal enzymes or NF-xcexaB provides a useful means to identify agents to treat myeloma bone disease.

The invention relates to compositions and methods for use in treating bone disease associated with myeloma. More specifically, the invention concerns the use of inhibitors of proteasomal and NF-xcexaB activity for this purpose.
Multiple myeloma is the second most common hematologic malignancy producing some 15,000 new diagnosed cases each year in the United States with the number of existing myeloma patients numbering between 30,000 to 40,000 (Mundy et al. Seminar Oncol (1986) 3:291). Eighty percent of whom suffer from devastating osteolytic bone destruction caused by increases in osteoclast formation and activity (Mundy et al. (1986), supra). The associated bone destruction can cause severe bone pain, pathologic fractures, spinal cord compression, and life-threatening hypercalcemia. It has been reported that multiple myeloma cannot be cured by standard chemotherapy or stem cell transplantation (Attai et al. Blood (1996) 87(4):1495-1501).
Myeloma bone disease results in severe morbidity and potential mortality. Accordingly, the development of strategies and treatments that control the osteolytic bone destruction resulting in these patients has become of vital importance.
However, the pathologic mechanisms responsible for increased osteoclast activity in multiple myeloma patients are unknown. Further, the accompanying bone lesions that occur in the patients take on several pattern forms. Occasionally, patients develop discrete osteolytic lesions in association with solitary plasmacytomas. Other patients have diffuse osteopenia, which mimics the appearance of osteoporosis, and results from the diffuse dispersion of the myeloma cells throughout the axial skeleton. In most atients, there are multiple discrete lytic lesions occurring adjacent to nests of myeloma ells. Hypercalcemia occurs as a consequence of bone destruction in about one third of atients with advanced bone disease. Rarely do patients with myeloma fail to develop lytic lesions or bone loss, instead they have an increased new bone formation around myeloma cells. This rare situation is known as osteosclerotic myeloma.
Osteolytic bone lesions are the most common deleterious skeletal manifestation in patients with myeloma. Although the precise molecular mechanisms remain unclear, nevertheless observations over 15 years have revealed several facts. First, the mechanism by which bone is destroyed in myeloma occurs via the osteoclast, the normal bone-resorbing cell. Second, osteoclasts accumulate on bone-resorbing surfaces in myeloma adjacent to collections of myeloma cells. Thus, it appears that the mechanism by which osteoclasts are stimulated in myeloma is a local one. Third, it has been known for many years that cultures of human myeloma cells, in vitro, produce several osteoclast-activating factors, including lymphotoxin, interleukin-1 (IL-1), and interleukin-6 (IL-6). Fourth, hypercalcemia occurs in approximately one third of patients with myeloma at some point during the course of the disease. Hypercalcemia is always associated with markedly increased bone resorption, and frequently with the impairment in glomerular filtration. Fifth, the increase in osteoclastic bone resorption in myeloma is usually associated with a marked impairment in osteoblast function. Alkaline phosphatase activity in the serum is decreased or remains in the normal range, in contrast to patients with other types of osteolytic bone disease. Also, radionuclide scans do not show evidence of increased uptake, which indicates impaired osteoblast response to the increase in bone resorption.
Various mediators have been implicated in the stimulation of osteoclast activity in patients with multiple myeloma, including lymphotoxin (tumor necrosis factor-xcex2 (TNFxcex2)), interleukin-1-beta (IL-1xcex2), parathyroid hormone-related protein (PTHrP), and interleukin-6 (IL-6). However, reports of factors that are produced by myeloma cells have been wholly inconsistent. Some studies have been inconclusive due to the presence of other contaminating cell types including stromal cells and macrophages in the multiple myeloma cell population. IL-6 is a major myeloma growth factor that enhances the growth of several myeloma cell lines and those cells freshly isolated from myeloma patients (Bataille et al. J Clin Invest (1989) 84:2008). IL-6 production can be detected in about 40% of freshly isolated myeloma cells by PCR, but only 1 in 150 patients studied show detectable IL-6 production by immunocytochemistry or ELISA assays (Epstein J. Hematology/Oncology Clinics of North America (1992) 6:249-256. The IL-6 receptors were only detected in 6 of 13 samples from patients with multiple myeloma (Bataille et al. Hematology/Oncology Clinics of North America (1992) 6:285-295). Furthermore, mature myeloma cells have been reported to have a minimal proliferative response to interleukin-6. Interleukin-11 (IL-11) has an IL-6-like activity on plasmacytomas, but to date no one has demonstrated that myeloma cells produce IL-11. Bataille and coworkers (Bataille et al. Blood (1995) 86(2):685-91) have shown that the perfusion of 5 patients with refractory myeloma with an antibody of IL-6 decreased the size of the myeloma cell burden in only 2 of these patients.
In addition to IL-6 and IL-1xcex2, TNFxcex1 and lymphotoxin have been implicated as mediators of bone destruction in multiple myeloma. IL-6 is an extremely potent bone-resorbing agent that induces hypercalcemia in animal models in the absence of renal failure (Boyce et al. Endocrinology (1989) 125:2780-2783). In contrast, hypercalcemia rarely occurs in myeloma patients without renal failure. More importantly, in highly purified myeloma cells, no IL-1xcex2 and only rare TNFxcex1 production can be detected, suggesting that other contaminating cell types such as macrophages may be the source of the IL-1xcex2 and TNFxcex1 (Epstein (1992), supra). Similarly, lymphotoxin is produced by most human myeloma cell lines (Bataille et al. (1995), supra) but does not appear to be produced by myeloma cells in vivo (Alsina et al. Blood (1996) 87(4):1495-1501). In addition to IL-1xcex2, TNFxcex1, lymphotoxin and IL-6, myeloma cells produce a truncated form of M-CSF which is biologically active. However, M-CSF does not cause hypercalcemia or induce osteoclast formation by itself in human marrow cultures (MacDonald et al. J Bone Miner Res (1986) 1:227-233). Thus, the specific role played by many of these factors in osteolytic bone disease occurring in myeloma patients has not been definitively illustrated in vivo. Thus, the known cytokines do not entirely account for the bone resorption observed in these patients.
Furthermore, freshly isolated marrow supernatants from the affected bones in myeloma patients contain a bone-resorbing activity that comprises an unknown resorbing cytokine. These data suggest that myeloma cells produce factors in the marrow microenvironment that differ from those produced by the cells in vitro and that this factor(s) is not a cytokine previously known to be produced by myeloma cells.
NF-xcexaB is a transcription factor which regulates the expression of the kappa light chain gene in murine B lymphocytes, but is now known to be expressed ubiquitously. A number of different NF-xcexaB proteins have been identified and well-characterized (Siebenlist et al. Annu Rev Cell Biol (1994) 10:405-455; see also, Baeurele et al. Cell (1996) 87:13-20). NF-xcexaB in its active state is a heterodimer, which consists usually of two subunits. The most common subunits are known as P65 and P50; another common subunit is P52. Different combinations of these subunits may be involved in the observation of different target genes. In unstimulated cells, NF-xcexaB is both present in the cytoplasm and bound to other proteins known as IkBxcex1 and IkBxcex2 and prevent it from entering the nucleus. Upon stimulation of cells, specific enzymes lead to the phosphorylation of IkB, which in turn leads to its rapid degradation in the proteasomes. Upon degradation of IkB, NF-xcexaB is then available to translocate to the nucleus. In the nucleus, NF-xcexaB binds to promoter sequences of target genes and leads to their transcription. Proteasome activity is thus required for NF-xcexaB translocation.
The proteasome is a non-compartmentalized collection of unrelated proteases which form a common architecture in which proteolytic subunits are self-assembled to form barrel-shaped complexes (Baumeister et al. Cell (1998) 92:367-380). The proteasome contains an array of distinct proteolytic activities inside eukaryotic cells; among these are activities that assist in translocating NF-xcexaB to the nucleus where it exerts its effect. Compounds which inhibit proteasomal activity reduce NF-xcexaB activity by limiting its capacity to be translocated to the nucleus (Barnes et al. New Engl J Med (1997) 336:1066-1071).
It has recently been shown that mice lacking expression of the transcription factor NF-xcexaB develop abnormal bone conditions, such as osteopetrosisxe2x80x94the converse of osteoporosisxe2x80x94due to an absence of osteoclast formation (Franzoso et al. Genes and Dev (1997) 11:3482-3496). Osteopetrosis is characterized by absence of osteoclast function, along with the filling in of the marrow cavity with osteocartilagenous material. However, the mechanisms of osteoclast formation in normal mice as compared to such formation in myeloma are different; the cytokine pattern characterizing osteoclast formation in myeloma has not been characterized. As the mechanisms are different, it is unpredictable what the effect of NF-xcexaB gene depletion would be on myeloma bone disease.
Orlowski, R Z, et al, Cancer Res (1998) 58:4342-4348 have shown that lymphoma tumor growth is inhibited by a proteasome inhibitor. However, the etiologies of lymphoma and of myeloma are quite different, and it would not be predictable whether agents effective against one would or would not be effective against the other.
The present invention adds to the repertoire of agents which inhibit myeloma bone disease by providing drugs that will inhibit key proteins and enzymes involved in proteasomal activity and which decrease the activity of the nuclear transcription factor NF-xcexaB, and thus inhibit the bone disease associated with myeloma. In accordance with the present invention, inhibition of the functions of proteasomal proteins and of the transcription factor NF-xcexaB in myeloma cells leads to decreased myeloma bone disease. Thus, assessing a candidate compound for its ability to inhibit proteasomal proteins or NF-xcexaB provides a useful means to identify agents to treat myeloma bone disease.
Thus, in one aspect, the invention provides methods to identify compounds that are useful to treat myeloma bone disease by assessing their capacity to inhibit proteasome activity or to inhibit the activity of the transcription factor NF-xcexaB, or to inhibit production of these moieties. In another aspect the invention provides a method to treat myeloma bone disease by administering to a subject in need of such treatment a compound that inhibits proteasome activity, the activity of transcription factor NF-xcexaB, or the production of the proteasome enzymes or NF-xcexaB.
In accordance with the present invention, there are provided methods of treating bone disease associated with myeloma in subjects suffering therefrom. The method comprises administering to the subject, in a sufficient amount, a compound which inhibits proteasomal activity and function, or the activity of the nuclear transcription factor NF-xcexaB, or the production of these proteins.
As employed herein, the term xe2x80x9csubjectxe2x80x9d embraces human, as well as other animal species, such as, for example, canine, feline, bovine, porcine, rodent, and the like.
As used herein, the terms xe2x80x9ctreatxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d include a postponement of development of bone disease symptoms and/or a reduction in the severity of such symptoms that will, or are expected to develop. Thus, the terms denote that a beneficial result has been conferred on a vertebrate subject with myeloma bone disease.
The compositions of the invention may be administered systemically or locally. For systemic use, the compounds herein are formulated for parenteral (e.g., intravenous, subcutaneous, etc.) delivery according to conventional methods. Intravenous administration can be by a series of injections or by continuous infusion over an extended period of time. Treatment will continue until the desired outcome is achieved. In general, pharmaceutical formulations will include a compound of the present invention in combination with a pharmaceutically acceptable vehicle.
Parenteral preparations comprise particularly sterile or sterilized products. Injectable compositions may be provided containing the active compound and any of the well known injectable carriers. These may contain salts for regulating the osmotic pressure.
Within the present invention, an xe2x80x9ceffective amountxe2x80x9d of a composition is that amount which produces a statistically significant effect. For example, an xe2x80x9ceffective amountxe2x80x9d for therapeutic uses is the amount of the composition comprising an active compound herein required to provide a clinically significant decreases in the viability of human myeloma cells or reduces tumor markers in the sera obtained from the affected subjects. Such effective amounts will be determined using routine optimization techniques and are dependent on the particular condition to be treated, the condition of the patient, the route of administration, the formulation, and the judgment of the practitioner and other factors evident to those skilled in the art. The dosage required for the compounds of the invention is manifested as a statistically significant difference in tumor volume, delay of onset of limb paralysis or tumor marker indicia between treatment and control groups. General guidance for treatment regimens is obtained from experiments carried out in animal models of the disease of interest.
The dosage of the compounds of the invention will vary according to the extent and severity of the need for treatment, the activity of the administered compound, the general health of the subject, and other considerations well known to the skilled artisan.
The compounds useful in the methods and compositions of the invention are inhibitors of proteasomal activity or of the transcription factor NF-xcexaB. Known inhibitors of these activities can be ascertained from the literature and compounds can be tested for these activities using assays known in the art. In addition, inhibitors which lower the level of effective expression of the nucleotide sequence encoding the enzymes that have proteasomal activity or of the nucleotide sequence encoding NF-xcexaB can be assessed and used in the invention methods.
Examples of compounds useful in the invention are as follows:
See, for example, Vinitsky, A. et al. J Biol Chem (1994) 269:29860-29866; Figueiredo-Pereira, M. E. et al. J Neurochem (1994) 63:1578-1581; Wojcik, C. et al. Eur J Cell Biol (1996) 71:311-318.
In the foregoing list, lactacystin is known to be an irreversible inhibitor of proteasome activity. It binds to the xcex2 catalytic subunit and is a specific inhibitor of the 20S proteasome. It also irreversibly inhibits NF-xcexaB.
SN50 is the NLS (nuclear localization sequence) of p50 plus the hydrophobic region of K-FGF. It inhibits the translocation of the NF-xcexaB active complex to the nucleus.
Certain peptidyl epoxy ketones such as EST are irreversible inhibitors of the proteasomes. MG-132 shows activity against the chymotryptic activity of the 20S protein without affecting its ATPase or isopeptidase activity and reversibly inhibits NF-xcexaB activity. MG-115 and MG-341 show similar activities to MG-132. Various other inhibitors of NF-xcexaB are less active in the ABA assay. These include capsaicin, curcumin, and resiniferatoxin. Other compounds known to inhibit NF-xcexaB are gliotoxin and PDTC (1-pyrrolidine carbothiotic acid). Various other compounds such as BAY-11-7082 and BAY-11-7085 as well as calyculin-A inhibit phosphorylation of NF-xcexaB. Calpain inhibitor inhibits calpain 1 and the proteasome; other compounds such as olomoucine and roscovitine inhibit cdk2 and/or cdk5.
Compounds which inhibit the production of the enzymes having proteasomal activity or of NF-xcexaB can be assessed by measuring the level of production of these proteins in the presence and absence of candidate compounds. The levels of production can be readily measured in in vitro systems using, for example, immunoassays for the level of protein produced. The levels of such proteins can also be assessed by utilizing, for example, methionine labeling and size separation of proteins in the cells to be assessed. In order to effect a convenient level of protein production for measurement, it is advantageous to use recombinant expression systems for the relevant enzymes or the NF-xcexaB so that substantial amounts are produced.
Typical approaches to inhibiting the production of NF-xcexaB or proteasome enzymes include the use of antisense technology or the formation of triplexes with double-stranded forms of nucleotide sequences relevant in the expression of the genes. In addition, various small molecules may also inhibit this production.
Radl et al. (Am J Pathol (1988) 132:593-597) described a murine model of myeloma which occurred spontaneously in aging mice of the C57 BL/KaLwRij strain. This condition occurred upon aging in approximately one (1) mouse of this strain for every two-hundred (200), and led to a monoclonal gammopathy with all of the characteristic features of the human disease, including growth of malignant cells in the bone marrow and characteristic skeletal lesions. Id. By transplantation of the fresh or frozen myeloma cells by intravenous injection into recipients of the same strain, the disease can be produced more precisely. More recently, Manning et al. (Br J Cancer (1992) 66:1088-1093) described a cell line derived from one of these myelomas.
To develop a better animal model of human myeloma bone disease, a cell line was established and subcloned from this murine myeloma by Garrett et al. Bone (1997) 20(6):515-20. This cell line (ST33) causes osteolytic bone lesions in mice characteristic of human myeloma bone disease. Osteolytic lesions were determined by animal x-rays and quantified. The cell line produces IL-6, but grows independently of exogenous IL-6. Mice inoculated intravenously with the cultured cells predictably develop an identical disease to the mice injected intravenously with fresh bone marrow-derived myeloma cells, including monoclonal gammopathy and radiologic bone lesions. Some of the mice became hypercalcemic, and the bone lesions are characterized by increased osteoclast activity. Identical results were obtained in inoculated Nu/Bg/XID mice with cultured murine myeloma cells.
This model is used to determine the mechanisms by which the myeloma cells cause osteoclast activation, since mice can be inoculated with a precise numbers of cells and it can accurately be predicted when the mice will develop bone lesions, paraplesia, and become hypercalcemic.
It has been recently shown that transfer of cells derived from other 5T myelomas such as 5TGM-1 into inbred C57BL/KaLwRij strain of mice reliably produce myeloma bone disease with involvement of non-bone organs such as the liver and kidney. The animals have elevated serum levels of IgG2b. 5TGM-1 cells are IL-6 independent. More recently the role of adhesion molecules in the induction of bone-resorbing cytokines by these myeloma cells in vitro was demonstrated.
5TGM-1 myeloma cells were initially derived from a myeloma, designated 5TGM-1, which arose spontaneously in an aged C57BL/KaLwRij mouse, as reported by Dallas et al. (to be published in Blood (1998)). 5TGM-1 cells were propagated from the bone marrow of this mouse, maintained in Iscove""s Modified Dulbecco""s Medium(trademark) (xe2x80x9cIMDMxe2x80x9d, available at Life Tech. Inc, Gaithersburg, Md.), and supplemented with 10% Fetal Bovine Serum(trademark) (xe2x80x9cFBSxe2x80x9d, Summit, Fort Collins, Colo.) and 1% penicillin-streptomycin solution (GIBCO, Grand Island, N.Y.) at 37xc2x0 C. in 5% CO2 atmosphere. Bone marrow transfer of 5TGM-1 myeloma in the inbred C57BL/KaLwRij strain of mice also reliably produced myeloma disease exhibiting all the features of human myeloma, such as severe osteolysis and involvement of non-bone organs such as liver and kidney. Based on the histological examination of affected organs in the STGM-1-bearing mice and the increased serum level of monoclonal IgG2b confirmed by SDS-PAGE(trademark), 5TGM1 was defined as a murine myeloma.
Still another model of myeloma bone disease was developed by injecting the human myeloma cell line ARH77 into sublethally irradiated SCID(trademark) mice (Alsina et al. Blood (1996), supra). These animals developed hypercalcemia, lytic bone lesions and the histologic finding characteristic of human myeloma.

Treatment of myeloma bone disease with proteasomal and NF-xcexaB activity inhibitors


This invention is directed to stabilized antimicrobial compositions comprising an iodopropynyl compound, and a benzylidene camphor.

1. Field of the Invention
The present invention pertains to a stabilized biocidal composition, a paint containing the stabilized biocidal composition, and a method for protecting a substrate from fungal infestation with the stabilized biocidal composition. The stabilized biocidal composition comprises a halopropynyl compound and a benzylidene camphor.
2. Description of the Background
Both exterior and interior surfaces, substrates of all types and organic compositions and formulations, when exposed to common environmental conditions, e.g. moisture, are prone to attack, discoloration and various kinds of destruction by a variety of species of microorganisms, including fungi, algae, bacteria and protozoa. As a result, there has always been a great need for effective and economical means to protect, for extended periods of time, commercial compositions and formulations from the deterioration and destruction caused by such microorganisms.
The type of materials which need protection against such microorganisms include, for example, materials such as paints and other coating formulations, surfactants, proteins, starch-based compositions, inks, emulsions and resins, stucco, concrete, stone, and cementaceous surfaces, wood, caulking, sealants, leather, plastics, and textiles. Other important commercial materials such as polymer dispersions or aqueous latex paints containing polyvinyl alcohol, polyacrylates or vinylpolymers, thickener solutions containing cellulose derivatives, kaolin suspensions and metal working fluids, also are prone to degradation by the action of objectionable microorganisms which can significantly impair the usefulness of such compositions. Such degradation may produce, inter alia, changes in pH values, gas formation, discoloration, the formation of objectionable odors, and/or changes in rheological properties.
Wooden objects, for example, are subject to degradation from a wide variety of natural pests. Fungi are particularly prevalent and include brown rots, white rots and soft rots. Fortunately, a variety of compositions have been developed for treating wooden objects and other materials and surfaces to retard the destructive effect of such pests.
A great deal of effort has gone into developing a wide variety of materials which, to various degrees, are effective in retarding or preventing the growth of, and accompanying destruction caused by, such microbes in a variety of circumstances. Such biocidal compounds include halogenated compounds, organometallic compounds, quaternary ammonium compounds, phenolics, metallic salts, heterocyclic amines, formaldehyde donors, organosulfur compounds and the like.
One of the most effective and best known classes of biocides used in such compositions are those containing a halopropynyl moiety, and especially an iodopropynyl moiety. Such compounds are widely disclosed in the patent literature including U.S. Pat. Nos. 3,660,499; 3,923,870; 4,259,350; 4,592,773; 4,616,004 and 4,639,460 to name a few. Included within this class of compounds are the halopropynyl carbamates which are known primarily for their fungicidal activity. Among these is 3-iodo-2-propynyl butyl carbamate, also referred to as IPBC, which is one of the best known and probably the most widely used of the halopropynyl carbamate fungicides. It is a highly active broad spectrum fungicide and, in addition to its fungicidal activity, it has also been associated with algaecidal activity as disclosed in Great Britain Patent 2,138,292 and U.S. Pat. Nos. 4,915,909 and 5,082,722.
Despite their wide acceptance, the halopropynyl carbamate biocides have been reported to be prone to degradation under certain conditions, sometimes resulting in some discoloration and yellowing. In those instances where degradation does occur, and especially in those instances where this degradation results in discoloration and yellowing, the use of such halopropynyl carbamate biocides has been limited, especially in compositions where a white or clear color is desired such as in white caulks, white paints, paper coatings, plastics, plastic coatings and the like.
It has also been suggested that such products may be incompatible with the driers used in certain solvent based systems and that such driers and other potential additives may cause a slow degradation of the biocide.
Each application or system can present its own set of unique conditions and circumstances that may affect the performance of a particular substance and which in turn may require its own unique or specific remedy to insure that acceptable performance is maintained. There is, therefore, a constant need to find improved additives and conditions that will sufficiently inhibit the loss of activity whenever it is necessary to use the antimicrobial under conditions that may pose a threat to its integrity.
A number of attempts to mitigate such problems for a variety of applications have been reported. For example, see Gabriele et al., (U.S. Pat. No. 4,552,885, Journal of Coatings Technology, 56(712):33-48), Singer (U.S. Pat. No. 4,276,211) and Long (U.S. Pat. No. 4,297,258). While many of these have found some success in certain applications, none provides a sufficient remedy for all cases. Degradation remains a problem in many instances, therefore, and there is a constant need for new and better remedies.
The present invention provides a significantly more effective way to stabilize halopropynyl compounds, and particularly a halopropynyl carbamate fungicide such as IPBC (known in commerce as Troysan(copyright) Polyphase(copyright)), against the undesirable degradation and yellowing caused by exposure to UV radiation.
The present invention is directed to a stabilized antimicrobial composition comprising an iodopropynyl compound and a benzylidene camphor.
In another embodiment, the present invention is directed to a paint containing the antimicrobial composition comprising an iodopropynyl compound and a benzylidene camphor.
In yet another embodiment, the invention is directed to a method for protecting a substrate from fungal infestation and yellowing which comprises coating said substrate with an effective amount of a paint containing the antimicrobial composition comprising an iodopropynyl compound and a benzylidene camphor.
It has been found that the integrity of iodopropynyl antimicrobial compositions are significantly enhanced by the inclusion of a benzylidene camphor. The addition of the benzilidene camphor acts to retard any degradation of the iodopropynyl compound rendering the antimicrobial composition more stable and markedly less prone to yellowing.
The class of compounds which can be stabilized in accordance with the present invention are well known and can be generally identified by the following structural formula:
YCxe2x89xa1Cxe2x80x94CH2X
wherein Y is a halogen, preferably iodine and X can be (1) oxygen which is part of an organic functional group; (2) nitrogen which is part of an organic functional group; (3) sulfur which is part of an organic functional group; or (4) carbon which is part of an organic functional group.
The functional group of which oxygen is a part, is preferably an ether, an ester, or a carbamate group. The functional group of which nitrogen is a part is preferably an amine, an amide, or a carbamate group. The functional group of which sulfur is a part is preferably a thiol, a thiane, a sulfone, or a sulfoxide group. The organic functional group of which carbon is a part is preferably an ester, a carbamate or an alkyl group. Examples of active iodopropynyl derivatives are disclosed in U.S. Pat. Nos. 3,923,870; 4,259,350; 4,592,773; 4,616,004; 4,719,227 and 4,945,109, which are herein incorporated by reference. These iodopropynyl derivatives include compounds derived from propynyl or iodopropynyl alcohols such as the esters, acetals, carbamates and carbonates and the iodopropynyl derivatives of pyrimidines, thiazolinones, tetrazoles, triazinones, sulfamides, benzothiazoles, ammonium salts, carboxamides, hydroxamates, and ureas. Preferred among these compounds is the halopropynyl carbamate, 3-iodo-2-propynyl butyl carbamate. This compound is included within the useful class of compounds having the generic formula
wherein R may have one to three linkages corresponding to n and is selected from the group consisting of hydrogen, substituted and unsubstituted alkyl groups having from 1 to 20 carbon atoms, substituted and unsubstituted aryl, alkylaryl, and aralkyl of from 6 to 20 carbon atoms or cycloalkyl and cycloalkenyl groups of from 3 to 10 carbon atoms, and m and n are independently integers from 1 to 3, i.e., they are not necessarily the same.
Particularly preferred are formulations of such halopropynyl carbamates where m is 1 and n is 1 and which have the following formula:
Suitable R substituents include alkyls such as methyl, ethyl, propyl, n-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, and octadecyl; cycloalkyls such as cyclohexyl; aryls, alkary ms and aralkyls such as phenyl, benzyl, toly l, and cumyl; halogenated alkyls and aryls, such as chiorobenzyl and chilorophenyl; and alkoxy aryis such as ethoxyphenyl and the like.
Especially preferred are iodopropynyl carbamates such as 3-iodo-2-propynyl propyl carbamate, 3-iodo-2-propynyl butyl carbamate, 3-iodo-2-propynyl hexyl carbamate, 3-iodo-2-propynyl cyclohexyl carbamate, 3-iodo-2-propynyl phenyl carbamate, and mixtures thereof.
There are several criteria that a UV absorber must satisfy in order to provide an antimicrobial that will not degrade or discolor when exposed to sunlight. First it must be compatible with the active halopropynyl antimicrobial under conditions of use. Second, it should be colorless or nearly colorless so as not to impart a color itself. Third it must retain its UV absorbing properties over the period of time that would be required to provide suitable stability to the product in which the antimicrobial is to be used.
It might be expected that any UV absorber should offer some protection against degradation and yellowing caused by UV light. Apparently, however, the effectiveness of a UV absorber to prevent degradation cannot be correlated simply with its ability to absorb light. There must be other significant, though less understood criteria at work which must be satisfied in order to provide adequate protection against the deleterious effects of UV light as is evidenced by the test results provided in U.S. Pat. No. 5,938,825.
It has been found that the benzylidene camphor molecules are especially effective in providing protection against degradation and yellowing caused by U.V. light. While substituents on the aromatic ring can modestly affect the effectiveness of the benzylidene camphor to stabilize a halopropynyl compound, the benzylidene camphor molecules as a class all appear to be effective. The kinds of variations in effectiveness noted with other U.V. absorbers based on small structural changes were not seen here. See, for example, U.S. Pat. No. 5,938,825. Indeed, it is the surprising and unexpected finding of this invention that while in other classes of UV absorbers, only certain compounds can be used to provide stabilized antimicrobial compositions containing halopropynyl compounds, all members of the benzylidene camphor group appear to be able to provide this kind of stability.
While benzylidene camphor itself plus nearly all derivatives having substituents on the aromatic ring appear to provide good protection, those having an alkoxy group substituent in the four or para position on the aromatic ring appear to be the most effective and are preferred. Those wherein the alkyl of the alkoxy is a methy a, ethyl, propyl, butyl pentyl or hexyl are especially preferred, with methoxy and ethoxy being most preferred.
The addition of a benzylidene camphor of this invention stabilizes the halopropynyl compounds, particularly halopropynyl carbamate fungicides such as 3-iodo-2-propynyl butyl carbamate (IPBC), in lattices such as acrylic lattices, vinyl acetate acrylic lattices, polyvinyl acetate lattices, styrenated acrylic lattices and styrene butadiene lattices, silicone formulations used for paints and caulks, as well as in leather treatment fluids, other wood treatment formulations and metal working fluids.
In accordance with the invention, the halopropynyl compound can be included in a final formulation for use in such applications as paints, coatings, stucco, plastics, concrete, stone, cementaceous surfaces, wood, caulking, sealants, textiles, and the like, in a broad range from about 0.004% to 5.0% active concentration, more usually in a range from about 0.01% to 2%. Such compositions can be prepared from highly concentrated compositions of the active ingredients by appropriate dilution. The optimum useful range is normally about 0.1% to 1.0% of halopropynyl compound in the final formulations for such end use systems. With the use of such formulations in end use systems, it is possible to protect surfaces as well as other substrates for extended periods of time against microbial growth.
The UV component will normally be added in an amount of from about 5% to 400% by weight of the halopropynyl compound, and more usually from 10% to 300% by weight.
Compositions of the present invention will generally be formulated by mixing the UV components in a selected proportion relative to the halopropynyl compound in a liquid vehicle for dissolving or suspending the active components. The present invention specifically contemplates the preparation of a concentrate containing a liquid vehicle and the above noted constituents. The concentrate is useful for adding a halopropynyl compound into particular formulations in the form of a stabilized biocide. The vehicle may also contain a diluent, an emulsifier and a wefting-agent. As noted above, expected uses of the biocidal compositions include protection of wood, paint, coatings, adhesives, paper, textiles, plastics, cardboard, lubricants, caulking, and the like. An extensive list of potential industries and applications for the present invention can be found in U.S. Pat. No. 5,209,930 which is herein incorporated by reference.
Useful liquid vehicles for the halopropynyl compound, particularly the preferred iodopropynyl butyl carbamate are several glycol ethers and esters like propylene glycol n-butyl ether, propylene glycol tert-butyl ether, 2-(2-methoxymethylethoxy)-tripropylene glycol methyl ether, propylene glycol methyl ether, dipropyleneglycol methyl ether, tripropylene glycol methyl ether, propylene glycol n-butyl ether and the esters of the previously mentioned compounds. Other useful solvents are n-methyl pyrrolidone, n-pentyl propionate and dibasic esters of several dicarboxylic acids and mixtures thereof. Also applicable are ketones including ethyl methyl ketone, 2-octanone and the like.
In many applications, a preferred liquid vehicle for these products can be selected from n-methyl pyrrolidone, propylene glycol n-butyl ether, 1-methoxy-2-propanol, and the dibasic isobutyl ester blend of succinic, glutaric and adipic acids.
When preparing formulations of the present invention for specific applications, other adjuvants which are conventionally employed in compositions intended for such applications may also be added, such as organic binding agents, additional fungicides, auxiliary solvents, processing additives, fixatives, plasticizers, water soluble or water insoluble dyes, colors pigments, siccatives, corrosion inhibitors, antisettlement agents, anti-skinning agents and the like. Additional fungicides used in the composition are preferably soluble in the liquid vehicle.
According to the present invention, substrates are protected from infestation by fungal organisms without yellowing simply by treating said substrate with a composition of the present invention. Such treating may involve mixing the composition with the substrate, coating or otherwise contacting the substrate with the composition and the like.
The following examples are presented to illustrate and explain the invention. Unless otherwise indicated, all references to parts and percentages are based on weight.

Stabilized antimicrobial compositions containing halopropynyl compounds and benzylidene camphors


An economical process for creating decorative and/or functional finishes on chrome, involves formation of a polyurethane film on the chrome substrate, wherein a strong and durable adhesion between the polyurethane film and the metal substrate is achieved by employing a silane adhesion promoter. Specific embodiments involve the use of an aromatic amine functional silane-coupling agent and/or an epoxy functional silane-coupling agent to achieve excellent adhesion between the polyurethane film and a chrome surface.

This invention relates to a process for depositing a polymer film on a metal surface, and more particularly to a process for applying a durable urethane film to a metal surface.
Traditional chrome plating creates a smooth, bright chrome finish. It has long been desired to have other finishes, such as black chrome, gold-tinted chrome, and other tinted or colored metallic finishes for decorative purposes. More specifically, there is a desire for clear polymeric decorative coatings that allow the brightness and luster of chrome plating to be seen, while modifying the appearance by imparting a color or tint to the chrome plating.
Several methods have been used in an attempt to achieve colored metallic finishes. One method involves electroplating, wherein black chrome and bronze finishes can be created. A problem with the electroplating methods is that it is very difficult to consistently obtain a desired colored metallic finish. Another disadvantage with the electroplating techniques is that they are generally limited to black and bronze colors or combinations thereof.
Another method that has been used for obtaining colored metallic finishes involves physical vapor deposition (PVD). This method offers a wider variety of colors than the electroplating method. However, physical vapor deposition is very expensive, and therefore, its use for achieving a desired colored finish is extremely limited. Another problem with physical vapor deposition is that it is difficult to control the gloss of the finishes.
Another method that has been attempted for obtaining colored metallic finishes involves applying transparent organic polymer coating containing a dye, pigment or other colorant on a chrome-plated substrate. This method is convenient, and offers a very wide variety of color finishes. However, the use of organic coatings on chrome-plated substrates has been extremely limited due to poor adhesion between the organic coating and the chrome surface, especially after prolonged exposure to extreme temperature and/or humidity. Even organic polymer coating compositions which initially exhibit good adhesion have not exhibited adequate adhesive durability for most product applications. As a result, this technique has not been applied to automotive, electronic, or other durable consumer goods.
A process for adhering a relatively thick layer, e.g., 5 millimeters, of polyurethane elastomer to a metal, such as steel, iron or aluminum, is disclosed in U.S. Pat. No. 4,542,070. The process involves coating the surface of the metal with a primer composition containing a polyepoxy compound and a polyamine compound, further coating the surface with a composition containing an isocyanate compound having an isocyanate group concentration of 15-50% by weight, and casting a layer of polyurethane elastomer onto the double coated surface of the metal followed by hardening the whole system. A silane-coupling agent may be added to the primer composition to improve adhesive properties and water resistance. Disclosed examples of silane-coupling agents include gamma-glycidoxypropyltrimethoxysilane and gamma-aminopropyltriethoxysilane. Color pigments may be added to the composition. Solvents that may be used for the primer composition are those which dissolve both the polyamine compound and the polyepoxy compound, with examples including toluene, xylene, ethylbenzene, methylethylketone, methylcellosolve, ethylcellosolve and acetate esters of a cellosolve compound. The polyurethane elastomer is used to improve the durability of steel, iron and aluminum surfaces of metal articles.
In the present invention, a clear polyurethane film is adhered to a bright metal surface using a primer containing a silane-coupling agent. The polymer film may contain a coloring or tinting agent that modifies the perceived color of the underlying chrome surface.
The invention offers a process of creating unique surface finishes on chrome-plated substrates. More specifically, the process provides an economical way of creating surface finishes similar to black chrome, PVD finishes, and other colored metallic finishes, such as blue, red, green, yellow, etc. The colors and the gloss level can be varied as desired. The process employs an adhesion enhancer that can be applied as a primer or as an additive to a polyurethane composition. The adhesion performance between the chrome surface and the film is improved so that both the film and the adhesion between the film and the chrome plating are durable enough for practical applications such as in the automotive industry and in electronic devices such as cellular phones.
These and other features, advantages and objects of the present invention will be further understood and appreciated by those skilled in the art by reference to the following specification, claims and appended drawings.
In accordance with a preferred embodiment of the invention, a clear, hard polyurethane polymer film is deposited on a chrome plating by first applying an aqueous primer composition to the chrome plating, and applying a two part urethane composition over the primer composition. The primer composition is comprised, and more preferably consists essentially of, water, methanol, and a silane-coupling agent. The primer composition may be applied to a bright metal surface by spraying, dipping or wiping techniques. Preferably, the bright metal surface is cleaned prior to application of the primer composition. The applied primer composition is allowed to dry. After the primer composition has dried, a liquid urethane composition is applied over the dried primer composition, and is allowed to cure. The urethane composition can be applied by any of various techniques, including spraying, dipping or wiping techniques, with spraying being preferred. A suitable thermal cure can be achieved in about 60 minutes at 180xc2x0 F. (about 82xc2x0 C.).
The polyurethane films of this invention generally have a thickness of from about 5-200 microns, more typically from 10-100 microns, and preferably from 20-50 microns.
Although a desirable aesthetic finish can be achieved without pigments or dyes, the two-part urethane composition preferably includes a dye, pigment or other colorant or a mixture of colorants to create a desired tinted film.
The urethane composition may be either a one-component urethane system, or preferably a two-component urethane system. A two-component urethane system is a urethane system in which the isocyanate and polyol components are kept separate from one another until just prior to use at which time those components are mixed together and applied to a surface. Upon mixing the two components, a full urethane polymerization reaction occurs. Generally, any of a variety of two-component polyurethane systems that are suitable for forming continuous films may be used in this invention. However, preferred polyurethane systems include those comprising, as the polyol component, alpha,omega-polymethacrylate polyols. Suitable alpha,omega-polymethacrylate polyols are commercially available, or can be obtained by reacting terminally hydroxy-functional polymethacrylates, obtained by free-radical polymerization in the presence of a hydroxy-functional molecular weigh regulator, with polyols, with the addition of non-basic transesterification catalysts, in a molar ratio of polymethacrylate to polyol of from 1:1 to 1:10. Examples of monomers that may be used for forming the polymethacrylate sequence of the terminally hydroxy-functional polymethacrylate polyols include diols such as methylmethacrylate, ethylmethacrylate, propylmethacrylate, n-butylmethacrylate, isobutylmethacrylate, tert-butylmethacrylate, n-pentylmethacrylate, amylmethacrylate, n-hexylmethacrylate, n-octylmethacrylate, 2-ethylhexylmethacrylate, n-decylmethacrylate, cyclopentylmethacrylate, cyclohexylmethacrylate, 4-tert-butylcyclohexylmethacrylate, cyclooctylmethacrylate, phenylmethacrylate, isobornylmethacrylate or other acrylates or methacrylates. Examples of suitable diols for the transesterification reaction include ethylene glycol, propane-1,2-diol, propane-1,3-diol, butane-1,2-diol, butane-1,3-diol, butane-1,4-diol, neopentylglycol, hexane-1,6-diol, octane-1,8-diol, decane-1,10-diol, doceane-1,12-diol, cyclopentane-1,2-diol, cyclohexane-1,2-diol, cyclohexane-1,4-diol, diethylene glycol, triethylene glycol, polyethylene glycol, polypropylene glycol, polybutylene glycol, polyoxyethylene-polyoxypropylenediols, 2,3-butene-1,4-diol, 1,2-hydroxymethylbenzene, and 1,4-dihydroxymethylbenzene. However, polyols having three or more hydroxyl functional groups may be employed.
The polyol components of the two-component urethane system may have a number-average molecular weight of from about 1,000 to about 30,000 Daltons, a hydroxyl number of between 20 and 200 mg of KOH/g, and an acid number of between 5 and 150 mg of KOH/g.
In addition to the alpha,omega-polymethacrylate polyols, other polyols may be employed. For example, to increase the hardness of the cured polyurethane film, aliphatic, cycloaliphatic, arylaliphatic and/or aromatic diols and/or polyols, having a molecular weight of from about 60 to about 4,000 Daltons, may be employed. In order to increase flexibility of the cured urethane film, saturated and/or unsaturated polyester diols and/or polyester polyols and/or polyether diols and/or polyether polyols having a number-average molecular weight of from about 400 to about 5,000 Daltons may be employed. Polyester diols may be prepared by esterifying organic dicarboxylic acids or their anhydrides with organic diols, or from a hydroxy carboxylic acid or from a lactone. Branched polyester polyols may be prepared by employing polyols or polycarboxylic acids having a higher functionality.
Other suitable polyurethane compositions may comprise, as the polyol component, various polyether polyols generally derived from cyclic ethers, and various polyester polyols, such as those obtained from residues of terephthalic acid production or by transesterification of dimethyl terephthalate or poly(ethylene terephthalate) with glycols.
Examples of suitable polyisocyanate compounds that may be used in the two-component urethane systems include monomeric organic polyisocyanates having a molecular weight of from about 140 to 300 Daltons, lacquer polyisocyanates having a molecular weight of from about 300 to 1,000 Daltons, and isocyanate-functionalized prepolymers containing urethane groups and having a molecular weight above 1,000 Daltons, as well as mixtures thereof.
Examples of monomeric polyisocyanates include 1,4-diisocyanato-butane, 1,6-diisocyanatohexane, 1,5-diisocyanato-2,2-dimethyl-pentane, 2,2,4-trimethyl-1,6-diisocyanatohexane, 2,4,4-trimethyl-1,6-diisocyanatohexane, 1-isocyanato-3,3,5-trimethyl-5-isocyanatomethylcyclohexane, 1-isocyanato-1-methyl-4(3)-isocyanatomethylcyclohexane, bis-(4-isocyanatocyclohexyl)methane, 1,10-diisocyanatodecane, 1,12-diisocyanatododecane, cyclohexane-1,3-diisocyanate, cyclohexane-1,4-diisocyanate, xylylenediisocyanate isomers, 2,4-diisocyanatotoluene and mixtures thereof with 2,6-diisocyanatotoluene, 2,2xe2x80x2-diisocyanatodiphenylmethane, 2,4xe2x80x3-diisocyanatodiphenylmethane, 4,4xe2x80x3-diisocyanatodiphenylmethane, and mixtures of the preceding polyisocyanates. Lacquer polyisocyanates are obtained by oligomerizing monomeric diisocyanates to form carbodiimide, uretdione (dimers), isocyanurate (trimers), biuret, urea, urethane, allophanate and/or oxadiazine groups. Several of these groups may be formed simultaneously or successively during oligomerization.
Examples of isocyanate functionalized prepolymers containing urethane groups having a molecular weight of about 1,000 or above may be prepared by reacting monomeric diisocyanates and/or lacquer polyioscyanates with an organic polyhydroxyl compound having a molecular weight of about 300 or greater. The polyhydroxyl compounds typically used to prepare isocyanate functionalized prepolymers are those having a number average molecular weight that is preferably greater than 500 Daltons, and more preferably from about 500 Daltons to about 4,000 Daltons. These polyhydroxyl compounds typically have from 2 to 6, and more typically from about 2 to 3 hydroxyl groups from molecule, and are generally selected from ether, ester, thioether, carbonate and/or polyacrylate polyols.
To prepare a two-component coating composition for use in practicing this invention, one or more polyols, and one or more polyisocyanates are mixed together in amounts corresponding to an NCO:OH equivalent ratio of from about 0.5:1 to about 2.0:1, more typically from about 0.8:1 to about 1.5:1. Various ingredients conventionally employed in urethane coating compositions may be added. These ingredients include flow control agents, viscosity-controlling additives, pigments, fillers, flatting agents, UV stabilizers and anti-oxidants and catalysts for the cross-linking reaction.
Although two-component urethane systems are preferred, one-component urethane systems may also be used. One-component urethane systems are those in which a soluble or dispersible urethane prepolymer that is the reaction product of a polyol with a polyisocyanate is provided with moisture curable functionalities or air-drying functionalities that facilitate cross-linking and formation of a film after application to a chrome or other bright metal substrate. Examples of one-component urethane systems include air-curing urethanes systems such as those in which an oligomeric urethane prepolymer is cross-linked by oxidation of unsaturated carbon-carbon double bonds in a long chain aliphatic group. Other one-component urethane systems include moisture curable urethane systems that include silanol terminated urethane prepolymers that are cross-linked by hydrolysis and silane condensation reactions upon contact with moisture.
Generally, two-component urethane compositions are preferred because they usually exhibit better scratch resistance, and chemical resistance than one-component systems. However, the principals of this invention may be applied to other applications using a one-component urethane system when scratch-resistance and chemical resistance are not as important as it is with most automotive and electronic applications (e.g., cellular telephone housings).
The polyurethane films of this invention are preferably relatively hard and non-elastomeric, and exhibit a pencil hardness of from about 3H to about 6H.
Depending on the selection of polyisocyanates, polyols, and additives, the coating composition may be solventless, aqueous-based, or organic solvent-based.
The description is intended to provide examples of suitable polyols and polyisocyanates that may be employed in the practice of this invention. However, the invention is not limited to any particular two-component polyurethane systems. Two-component urethane systems containing acrylic polyols such as polymeric/oligomeric materials comprised of acrylates, methacrylates, acrylonitrile, methacrylonitrile, or combinations of these monomers etc. are suitable and/or preferred. However, other polyurethane compositions such as polyether based urethane systems are also believed to be suitable for various automotive, appliance and consumer electronics applications. It is believed that the principles of this invention may also be applied to various applications in which it is desirable to strongly adhere a polyurethane film to the surface of a metal. More specifically, it is believed that use of silane-coupling agent or adhesion enhancer, either in a primer that is applied to a metal and dried before application of a two-component urethane system, or added into a two-component urethane system, allows a strong, durable bond to be formed between the metal and a cured polyuretaane film. Generally any of a variety of commercially available two-component urethane compositions may be employed in accordance with this invention to provide an aesthetic or functional film that is strongly adhered to a metal surface.
The silane adhesion enhancer may be employed in a primer composition in an amount of from about 0.05 to about 5%, and more preferably from about 0.5 to about 2%, by weight of the primer composition, with an amount of 1% being most preferred. Preferably, the primer composition is an aqueous solution that is free, or at least substantially free, of environmentally undesirable volatile organic compounds. Preferably, the aqueous primer composition is comprised of, and more preferably consists essentially of, water, methanol, and one or more silane adhesion enhancers. The aqueous primer composition may contain from about 50% to about 95% water, and from about 5 to 50% methanol.
When the silane adhesion enhancer is added directly to a liquid two-component urethane composition, rather than to an aqueous primer composition, the silane adhesion enhancer may be employed in an amount from about 0.05% to about 5%, more preferably from about 0.5% to about 2%, and most preferably about 1%, by weight of the urethane composition. When the silane adhesion enhancer is added directly to the urethane composition, the urethane composition is applied directly to a clean, but otherwise untreated, surface of a chrome plate.
Examples of silane compounds that may be employed as adhesion enhancers include gamma-glycidoxypropyltrimethoxysilane, gamma-aminopropyltriethoxysilane, gamma-mercaptopropyltrimethoxysilane, and the like. However, preliminary testing has strongly suggested that epoxy functional silane-coupling agents (e.g., gamma-glycidoxypropyltrimethoxysilane) and aromatic amine functional silane-coupling agents, such as N-phenyl-gamma-aminopropyltrimethoxysilane are particularly useful for achieving strong, durable adhesion between a chrome plate and a cured polyurethane film. A variety of suitable silane adhesion promoters (coupling-agents), including the preferred aromatic amine functional silane-coupling agents and epoxy functional coupling-agents, are well known and commercially available. Examples of other suitable silanes include amine silanes such as N-beta(aminoethyl)-gamma-aminopropyltrimethoxysilane and gamma-aminopropyltriethoxysilane.
A particular use of this invention involves application of a tinted or colored decorative polymer film to a chrome plate to impart a desired hue or color to the chrome plate while also allowing the brightness and luster of the chrome plate to be seen through the film. Therefore, in accordance with this aspect of the invention, any of various dyes, pigments, or other colorants, or mixtures of colorants may be added in an amount effective to impart a desired color, tint or hue to a chrome plate. Suitable colorants and amounts thereof are well known and/or can be easily determined by routine experimentation. The tinted urethane compositions of this invention, when applied to a chrome plate or other metal surface, create a unique surface finish that is different from conventional paint or traditional chrome plated finishes. The tinted finishes can be generally any color in the spectrum, e.g., gray, gold, red, blue, etc.
Although the invention is expected to be used primarily on chrome surfaces, the principles of this invention may be used for adhering a polyurethane film to various other bright metal surface, such as nickel, nickel alloys, tin, tin alloys (e.g., tin-cobalt alloys) and stainless steel.
Preliminary testing has shown that urethane coatings applied to a chrome substrate in accordance with this invention demonstrate outstanding adhesion even after an extended period of time under a humid environment.

Method and composition for metallic finishes