Post-construction materials, including concrete, containing water insoluble polymers are disclosed herein. The water insoluble polymers are formed beneath the surface of the post-construction material using a first composition comprising a blend of fatty acid salts and a second composition comprising alkaline earth metal halides or alkaline earth metal carbonates.

The cost of corrosion and other structural defects in materials is devastating with respect to damage and deterioration to structures as well as the potential for human injury. From a financial perspective, the cost of corrosion alone is estimated to be over $300 billion each year in the United States. The problem of preventing corrosion and addressing other potential structural defects remains a challenge confronting the construction and maintenance industries.
Commonly, structures are made of concrete materials. Because conventional concrete has very low tensile strength, it is common practice to reinforce concrete with steel bars in applications where the concrete is subjected to substantial loads. In such implementations, the concrete has at least two functions. One function is to protect the reinforcing steel bars against corrosion. Another prominent function is to improve resistance from shear and compressive stresses. As a general matter, the protective effect of hardened concrete against climatic and environmental conditions on reinforcing steel depends, for example, on the amount and type of cement, water/cement factor and concrete integrity. However, since concrete is also a permeable absorptive material, concrete is often subject to undesirable intrusion of moisture and other substances, each of which can lead to corrosion of the reinforcing steel.
Indeed, concrete is widely known to be a porous material with a vast network of interconnected pores. When the pores of concrete are occupied by water and the relative humidity of the ambient atmosphere is unsaturated, moisture vapor will be emitted from the concrete. In many circumstances, the moisture vapor emissions from concrete simply become part of the humidity of the air. However, in some circumstances, especially involving concrete slabs that accommodate flooring overlay materials, the moisture vapor emission from the concrete causes negative consequences, such as degradation of the flooring glue and delamination of the flooring material. For at least the foregoing reasons, it is advantageous to reduce or eliminate the moisture vapor emission from concrete.
There are numerous methods in practice for reducing moisture vapor emission from concrete systems. Particular methods are frequently employed based at least in part on the source of the moisture-at-issue. In the case of free mix water or surface rain water potentially emerging from a concrete structure/system, various sealant systems and drying techniques have been used to reduce the rate of moisture vapor emission to acceptable levels. These methods are expensive and labor intensive to apply. In the case of groundwater wicking through a concrete slab and emerging as moisture vapor, various polymer sheet vapor barriers have been used to prevent or reduce the degree to which the groundwater contacts the concrete and wicks therethrough. Such sheets involve additional cost/labor and are susceptible to various levels of unreliability due to seams and punctures.
It is noted that efforts have been made to solve the premature deterioration of concrete structures. For example, U.S. Pat. No. 4,869,752 to Jaklin describes the use of modified inorganic silicates, e.g., modified alkali silicates, as a concrete additive to prevent corrosion of steel structures or reinforcing steel. U.S. Pat. No. 6,277,450 to Katoot describes the use of a coating process to coat metal surfaces which are modified to an active moiety of metal hydroxide receptive to a fully cross-linked polymer of various thickness. Other processes that have been used have included precoating surfaces of metals used in the building and construction industry. However, such methods are generally costly, ineffective and inefficient/impractical.
Previous efforts have also relied on treatments that react with the divalent metals in the material. Although this has been effective in filling some of the voids, some types of post-construction materials lack divalent metals. Further, the relatively low amounts of divalent metals limit the ability to fill voids in a consistent and reliable manner.
Despite efforts to date, a need remains for treatments, materials and processes that can reduce and/or eliminate vapor transmission, e.g., moisture transmission, through porous structures such as concrete-containing structures in an efficient, reliable and cost-effective manner. These and other needs are advantageously satisfied by the disclosed Water insoluble polymers and methods.

Chemically reactive surface-applied waterproofing for post-construction materials


The invention provides a chemokine designated Beta R1, whose production in T cells, astrocytes, a fibroblasts is preferentially induced by IFN-.beta. as compared to IFN-.alpha.. A cDNA encoding the Beta R1 polypeptide and comprising the endogenous Beta R1 promoter is described. When coupled to a reporter gene, the promoter sequence may be used to screen for mimics of IFN-.beta. activity.

Interferon (IFNs) are a family of cytokines with diverse biological functions, including antitumor, immunomodulatory, antiviral and antiparasitic actions. At present, the IFN family includes more than 20 different proteins. Initially, IFN's were classified by source as leucocyte, fibroblast, or immune IFNs. Initially, IFNs were also grouped into two types with Type 1 comprising fibroblast and leucocyte IFNs and type II comprising immune IFNs. Based on their genetic similarities and differences, the type I IFNs are currently divided into the following three classes: IFN-.alpha., IFN-.beta., and IFN-.omega.. The type II IFNs are classified as IFN-.gamma..
IFNs act by binding to specific cell receptors, which are found on the surface of most cells, and causing the translocation to the nucleus of cytoplasmic transcription factors that enhance or suppress the expression of specific genes. The products of these interferon-stimulated genes (hereinafter referred to as ISGs) are primarily polypeptides that act as mediators of the biological activities associated with the respective IFN. IFN-.alpha. and IFN-.beta. bind to the same receptor and activate transcription of ISGs through the assembly and translocation from the cytoplasm to the nucleus of ISGF3, a multisubunit transcription factor that interacts with a cis-acting DNA regulatory element termed the interferon-stimulated response element or ISRE. Transcription of the ISGs stimulated by IFN-.alpha. and IFN-.beta. occurs in the absence of ongoing protein synthesis, and is therefore mediated directly by the interaction of either IFN-.alpha. or IFN-.beta. with their common receptor.
IFN-.beta. is a particularly useful cytokine which has been shown to be effective in decreasing the relapse rate, relapse severity, progression of neurological disability and development of new brain lesions, as observed with brain magnetic resonance imaging, in relapsing-remitting multiple sclerosis patients. Unfortunately, IFN-.beta. can cause side effects in such patients. Moreover, a substantial number of the patients treated with IFN-.beta. develop neutralizing antibodies. In addition, IFN-.beta. must be administered by injection. There are also concerns that IFN-.beta. may not penetrate certain tissue compartments Accordingly, efforts are currently underway to identify other compounds, particularly small molecular weight molecules, that induce an IFN-.beta. type response, hereinafter referred to as "IFN-.beta. mimics". These efforts are directed at identifying IFN-.beta. mimics that can be administered orally and that freely permeate tissues. The efforts are also directed at identifying IFN-.beta. mimics that are less toxic than naturally-occurring or recombinant forms of IFN-.beta..
In certain instances, such as autoimmune diseases, IFN-.alpha. or IFN-.beta. can induce a deleterious inflammatory reaction in an individual. Accordingly efforts are also underway to identify compounds, hereinafter referred to as "IFN-.beta. inhibitors", that block the IFN-.beta. type components of this reaction.
The efforts to identify IFN-.beta. mimics and IFN-.beta. inhibitors have been hampered by the fact that there are no known ISG products whose synthesis is selectively induced by IFN-.beta. as compared to IFN-.alpha. and thus can be used to give the full measure of an IFN-.beta. type response. Accordingly, it is desirable to have an ISG product whose synthesis is selectively induced by IFN-.beta. as compared to IFN-.alpha.. It is also desirable to have a system that can be used to identify compounds that selectively induce an IFN-.beta. type response as compared to an IFN-.alpha. type response. An in vitro system that can be used to screen IFN-.beta. mimics and that can be used to assess the potency of the IFN-.beta. mimics is especially desirable. It is also desirable to have a system that can be used to screen IFN-.beta. inhibitors.

DNA encoding a chemokine, Beta R1, comprising the Beta R1 promoter


An integrated and modular coupling module for coupling light between optical devices, such as an optical fiber connector and optoelectronic device, is presented. In this invention, beam-shaping elements and alignment elements are integrated on a single alignment plate in such a way that they maintain a precise physical relationship. The relative physical arrangement between the beam-shaping elements and the alignment elements are configured such that once the alignment elements are engaged with the peripheral devices, accurate optical alignment between the peripheral devices and the coupling module is also attained. The optical coupling module of the present invention enables it to withstand temperatures of 220xc2x0 C. or higher while maintaining its integrity and performance. The principle of the present invention can also be extended to constructing coupling modules for coupling other types of electromagnetic radiation.

The present invention relates generally to fiber-optic systems for telecommunication and data-communication applications. More specifically, it relates to a novel type of coupling modules for interconnecting fiber-optic components.
The explosive growth of Internet traffic has imposed an unprecedented demand on the existing communications backbone-fiber-optic networks. As the demand for ever greater bandwidth grows, a particular challenge to fiber-optic equipment makers is to increase the bandwidth capacity of fiber-optic transceivers without increasing their overall physical dimensions, so that the users of the fiber-optic transceivers can attain higher bandwidth without increasing the sizes of their network switch boxes.
A crucial step in achieving greater bandwidth capacity while shrinking the package size lies in a simple and reliable way of coupling light between optoelectronic devices (e.g., lasers, light-emitting diodes, and photo-detectors) and optical fibers. This is a difficult task in a system where one or more optical fibers are brought into the proximity of optoelectronic devices by a fiber connector, for the fiber connector is typically aligned using passive alignment means which requires high precision and stringent tolerance. The task becomes more formidable when a fiber ribbon-connector is used to bring a plurality of optical fibers to an array of optoelectronic devices in a parallel fashion.
An effective way of coupling optical fibers in a fiber connector to their corresponding optoelectronic devices is to use an optical coupler that is embedded with optical lenses. The use of lenses to couple light has additional advantages of increasing the working distance and easing the mechanical tolerance imposed on the assembled components. This way of optical coupling, however, requires an accurate and reliable alignment amongst optical fibers in the fiber connector, optical lenses in the coupler, and optoelectronic devices that is to be maintained over a wide range of operating temperatures. In addition, such an optical coupler should be simple in assembly, therefore more reliable in alignment and lower in cost.
Furthermore, as the bandwidth increases, fiber-optic transceivers run at increasingly faster speeds. Accordingly, the manufacturing process for the fiber-optic transceivers has evolved from using electrical pins by way of wave solder processing to Ball Grid Array (BGA) by way of reflow processing. The latter is a surface mount technology. Given that the reflow processing typically occurs at a temperature around 220xc2x0 C., the optical coupling devices along with other optical components in a high-speed fiber-optic transceiver must be able to withstand this high-temperature treatment, while maintaining their integrity and performance.
Various devices for the interconnections of optical fibers and for the coupling of optical fibers to optoelectronic components have been devised in the art. For instance, U.S. Pat. Nos. 5,574,814, 5,671,311, and 5,781,682 disclose several optical couplers. No optical lenses, however, are incorporated in these prior art coupling devices. Although optical lenses are implemented in an optical coupler disclosed by U.S. Pat. Nos. 5,002,357, the assembly housing of this coupler also contains a fiber connector and an electronic light pulse communication device among other things, thus making it bulky and less modular.
Depicted in FIG. 1 is another prior art optical coupler that incorporates optical lenses. Optical coupler 100 comprises a transparent plastic plate 11 molded with a plurality of plastic lenses 12. Since optical coupler 100 is entirely made of transparent plastic, it will not be able to withstand the high-temperature reflow processing for BGA described above, thus rendering it not applicable to high-bandwidth fiber-optic transceivers. Moreover, given that optical coupler 100 is not equipped with any alignment features, it would be difficult to optically align optical coupler 100 with other optical elements in an accurate and secure fashion.
As fiber-optic systems rapidly grow in modern communications networks, there exists a need for simple, effective, modular, versatile, and low-cost optical coupling devices for high-bandwidth fiber-optic transceivers.
The aforementioned need in the art is provided by a coupling module for coupling light between two optical devices, such as an optical fiber connector and an optoelectronic device. In one embodiment of the present invention, a coupling module of the present invention comprises an alignment plate, one or more beam-shaping elements, and one or more alignment elements. The beam-shaping elements are embedded in one or more precision slots on the alignment plate, typically by way of press-fitting, such that their respective positions are secured within the alignment plate. The alignment elements, typically in the form of alignment pins and holes, are produced on the alignment plate in such a way that they effectively become an integral part of the alignment plate. The positions of the alignment elements are so chosen that they correspond to the alignment features on peripheral devices, such as a fiber connector and an optoelectronic device. The precision slots and alignment elements can be created in a single manufacturing process, thereby enabling the beam-shaping elements and alignment elements to be aligned in a simple, precise and secure way. Moreover, the relative physical arrangement between the beam-shaping elements and the alignment elements are configured such that once the alignment elements are engaged with the peripheral devices, accurate optical alignment between the peripheral devices and the coupling module is also attained. A coupling module thus constructed maintains a precise optical alignment that is less susceptible to change with temperature variations (e.g., during the high-temperature treatment described above) and other extraneous effects.
In an alternative embodiment of the present invention, the beam-shaping elements are embedded into the precision slots at an elevated temperature, whereby the precision slots expand and/or the alignment plate softens to allow the beam-shaping elements to be press-fit with relative ease. The use of a soft metal like copper for the alignment plate facilitates the press-fitting process. Subsequent cooling to a normal operating temperature then causes the beam-shaping elements to be compressed in their respective positions within the alignment plate. In the coupling module thus constructed, the beam-shaping elements are more firmly embedded in the alignment plate during the normal operation, thereby rendering a more enduring optical alignment.
In another embodiment of the present invention, the alignment plate is made to contain one or more xe2x80x9cplungersxe2x80x9d, comprising one or more foreign materials. The plungers are configured such that one or more gaps form between the embedded plungers and the remaining of the alignment plate, thereby providing one or more precision slots. The incorporation of the plungers in an alignment plate renders a variety of utilities and advantages. For instance, it is easier to create the precision slots by way of embedding the plungers in the alignment plate than having the precision slots directly machined out of the alignment plate, for a combined (and hence larger) area occupied by a plunger and the corresponding precision slot can be readily produced by way of stamping, or other suitable techniques. The plungers can also be of xe2x80x9cthermalxe2x80x9d type, namely, they are made of materials whose coefficients of thermal expansion are markedly different from that of the alignment plate. In this case, the alignment plate with the embedded xe2x80x9cthermal plungersxe2x80x9d are heated (or cooled) to an elevated (or lower) temperature, such that the precision slots expand to allow the beam-shaping elements to be press-fit into the precision slots with relative ease. Subsequently cooling (or warming) to a normal operating temperature causes the beam-shaping elements to be firmly compressed in their respective positions within the alignment plate. The incorporation of the xe2x80x9cthermal plungersxe2x80x9d in an alignment plate advantageously exploits the difference in coefficient of thermal expansion between different materials and thereby enables the beam-shaping elements to be more securely embedded in the alignment plate. Furthermore, the plungers can be of xe2x80x9ccompressionxe2x80x9d type, that is, they are made of a soft metal such as copper, thereby allowing the alignment plate to be made of a hard metal, such as stainless steel. An important advantage of using a hard metal for the alignment plate is that the alignment elements (e.g., alignment pins) are more firmly secured in the alignment plate and hence their respective positions are less susceptible to shift. The use of the xe2x80x9ccompression plungersxe2x80x9d permits the beam-shaping elements to be embedded in the precision slots by way of press-fitting. All in all, the use of plungers facilitate the embedding of the beam-shaping elements and enhances the overall stability of optical alignment of the coupling module thus constructed.
In the present invention, the alignment plate is typically made of a metal, such as copper, aluminum, or stainless steel. An advantage of using copper or stainless steel is that the coefficients of thermal expansion of these materials match that of the commonly used materials for making PC boards (e.g., FR4) more closely than the coefficient of thermal expansion of transparent plastic (used in the prior art optical coupler of FIG. 1) does. The alignment plate can also be made of other types of metal (e.g., brass), machinable ceramic, or high-temperature plastic (e.g., opaque plastic) The alignment elements, such as alignment pins and holes, are generally produced by means of machining, casting and stamping, such that they effectively become an integral part of the alignment plate. And the alignment elements and the precision slots can be created in a single manufacturing process. The alignment pins are typically made of metal, such as brass or stainless steel. A beam-shaping element generally refers to an optical assembly having beam-focusing and beam-shaping capabilities. It can be, for instance, a single refractive or diffractive lens, a ball lens, a GRIN lens, or other beam-focusing and beam-shaping means known in the art. It can also comprise an assembly of refractive lenses, diffractive lenses, ball lenses, and GRIN lenses arranged or molded in an array. The use of relatively simple and inexpensive lenses, e.g., glass ball lenses, eases the manufacture process and lowers the cost of the coupling module of the present invention.
It should be noted that various exemplary embodiments in this specification are provided for illustrative purposes, to elucidate the principle and the scope of the present invention. In general, an alignment plate may contain alignment elements in the form of a combination of alignment pins and alignment holes. It may also contain only alignment pins or alignment holes. There can also be situations where an alignment plate does not contain any alignment elements in the form of alignment pins or holes, but is embedded with alignment features in its body and along its edges. Those skilled in the art will know how to design an alignment plate along with appropriate alignment elements and features in accordance with the present invention, for a given application.
In yet another embodiment of the present invention, the coupling module of the present invention further contains one or more transparent windows that cover the beam-shaping elements embedded in the alignment plate. The primary function of the transparent windows is to prevent dust, moisture, and other environmental factors from degrading the performance of the embedded optics. The sealing between the transparent windows and the alignment plate need not necessarily be hermetic. The windows may further contain an optical coating (such as an anti-reflection coating) on their respective outer surfaces, or be placed with a slight tilt to reduce the optical reflection, since optical back-reflection can adversely affect the performance of a fiber-optic transceiver. If so desired, the windows can also be shaped such that they serve as auxiliary optical lenses (or the windows carry appropriate types of optical coating), so as to complement the performance of the beam-shaping elements in the coupling module of the present invention.
The coupling module of the present invention can be employed to optically couple fiber connectors and optoelectronic devices in a passive alignment, an active alignment, or a combination of both. In the passive alignment, the coupling module is equipped with alignment pins and holes designed to mate the corresponding alignment features on the peripheral devices, which may include a fiber connector on one side and an optoelectronic device on the other. In the active alignment, the coupling module is first sandwiched between first and second peripheral devices. After the optical alignment amongst the three devices is obtained, the position of the coupling module is then secured by use of an adhesive agent, such as epoxy or solder. In general, the optical alignment between a fiber connector and a coupling module is engaged in a passive manner by way of alignment pins and holes; whereas the optical alignment between a coupling module and an optoelectronic device may be adjusted actively and then secured by use of an adhesive agent. The passive alignment is generally more secure and less susceptible to extraneous effects. The active alignment, by comparison, imposes fewer physical restrictions on the coupling module and peripheral devices.
All in all, the coupling module of the present invention provides a significant simplification, size and cost reduction in the packaging of optoelectronic devices, while maintaining a more accurate and reliable optical alignment between optical fibers and optoelectronic devices. The unique design of the optical coupling module of the present invention enables it to readily withstand temperature of 220xc2x0 C. or higher while maintaining its integrity and performance, hence rendering it a desirable candidate for high-speed fiber-optic transceivers. Another advantage of the coupling module of the present invention is that it permits the use of relatively simple and inexpensive lenses, such as glass ball lenses, thereby easing the manufacture process and lowering the overall cost. A further advantage of the present invention is that the coefficient of thermal expansion of the alignment plate can be made to match that of the commonly used materials for making PC boards (e.g., FR4) more closely than the prior art optical coupler (shown in FIG. 1) is able to do. Moreover, being capable of carrying a plurality of beam-shaping elements such as an array of optical lenses, the coupling module of the present invention is particularly suited for coupling multiple optical fibers in a fiber connector to arrayed optoelectronic devices.
It should be noted that other types of optical elements, such as optical switches, filters, isolators and polarization rotators, can be embedded in a coupling module of the present invention, either in addition to or in replacement of the beam-shaping elements discussed above. Moreover, the general principle of the present invention can be applied to constructing coupling modules for coupling other types of electromagnetic radiationxe2x80x94extending beyond the optical regime of the spectrum. For instance, by incorporating appropriate beam-shaping and beam-coupling elements, a coupling module according to the present invention can be used to couple infrared, or microwave radiation.
The novel features of this invention, as well as the invention itself, will be best understood from the following drawings and detailed description.

Integrated coupling modules for high-bandwidth fiber-optic systems


Compounds of the formula

The invention relates to antibiotics. Novel xcex2-lactams of the invention and compositions containing them inhibit or prevent bacterial growth and/or attachment to host tissue.
xcex2-Lactam antibiotics, such as the penicillins, are known in the art. As use of these and other antibiotics has become more prevalent, resistant strains of bacteria have emerged and the need to develop new antibiotics has become apparent. The present invention is directed to a novel class of xcex2-lactam compounds which are effective against bacterial infection, colonization and/or growth in any environment in which such prevention or inhibition is desirable.
Periplasmic chaperones are required for assembly of virulence associated pili in pathogenic, gram-negative bacteria. Pili occur on the surface of these bacteria and allow the bacteria to colonize host tissue and give rise to infections. The pili are protein fibers that present adhesions that attach to receptors that are found in the host.
The development of compounds that interfere with bacterial protein secretions constitutes an attractive approach to overcome wide-spread bacterial resistance to existing antibiotics.
The contents of all publications and U.S. patents and patent applications referred to hereinafter are hereby incorporated by reference to the extent necessary to understand or complete the disclosure of the present invention and to the same extent as though each were individually so incorporated.
The invention is directed generally to compounds of the formula
and the salts, esters and amides thereof
wherein Z
is S, SO, SO2 or O;
each of R1, R2 and R3 is independently h or substituted or unsubstituted alkyl (1-10C), substituted or unsubstituted acyl (2-11C), substituted or unsubstituted aryl (6-14C), substituted or unsubstituted arylcarbonyl (7-15C), substituted or unsubstituted arylalkyl (7-15C) wherein substituents on any alkyl or acyl moiety are selected from the group consisting of halo and RO, wherein R is H or alkyl (1-6C), and any substituents on any aryl moiety are selected from the group consisting of halo, xe2x80x94CN, CF3 and RO, where R is H or alkyl with the proviso that R1 cannot be H and R1 and R3 are not identical
wherein in formula (1), the B ring may contain one double bond that is located between positions 2 and 3, in formula (2), the B ring may contain one double bond that can be located between positions 2 and 3 or positions 3 and 4.
The A and B rings have been numbered for the purpose of this application. This numbering may vary from that of IUPAC. The named compounds employ numbering consistent with IUPAC which may vary from the internal numbering scheme for the A and B rings.
In additional aspects, the invention is directed to methods to inhibit or prevent bacterial growth using the compounds of the invention, to antibodies specific for them and to antimicrobial compositions, including pharmaceutical compositions containing these compounds.
Further, the compounds of the invention are useful as scaffolds for the generation of libraries using combinatorial techniques. The libraries would be screened for desirable prospects using assays, those for antichaperone activity or antimicrobial activity.
The present invention provides novel class of xcex2-lactams which are effective in treating or preventing bacterial infections. Without intending to be bound by any theory, applicants believe that the compounds of the invention exert their effects by interfering with the function of chaperones required for the assembly of pili from pilus subunits in diverse Gram-negative bacteria. Such interference is particularly effective since the formation of pili is essential to bacterial pathogenicity and since the production of pilus subunits in the absence of chaperones is known to be directly toxic.
The novel compounds of the invention comprise (1S,2R,5S)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid and its derivatives, the corresponding compounds where S is replaced by O or by SO or SO2, and their six-membered ring analogs.
The active forms of the compounds of the invention are those wherein the chirality of the nitrogen at position 1 is xe2x80x9cSxe2x80x9d, the chirality of the carbon at position 2 is xe2x80x9cRxe2x80x9d, the chirality of the carbon at position 5 is xe2x80x9cSxe2x80x9d, and the chirality of the carbon at position 6 is xe2x80x9cRxe2x80x9d in the specific parent compound described above. The same stereochemistry is retained in the analogous compounds and derivatives although the designation of the chirality at each position may be different depending on the specific substitutions made. Accordingly, the appropriate stereoisomer can be determined by referring to formula (1). As long as this stereochemical form is present, the formulation will be active. The invention, of course, includes racemic mixtures which include this stereoisomer as well as mixtures of the various diastereomers, as long as this particular form is included.
Included in such derivatives are the salts, especially pharmaceutically acceptable salts.
Salts of carboxylic acids include those derived from inorganic bases such as the sodium, potassium, lithium, ammonium, calcium, magnesium, zinc, aluminum, and iron salts and the like, as well as those derived from organic, especially nontoxic, bases such as the primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion-exchange resins. Examples of such compounds capable of forming salts are isopropyl amine, trimethyl amine, triethyl amine, 2-dimethyl aminoethanol, dicyclohexyl amine, amino acids such as lysine, arginine and histidine, caffeine, procaine, betaene, theobromine, purines, piperazines, and the like.
As the compounds of the invention may themselves contain amino groups, the acid addition salts are also included in the scope of the invention. Such acid addition salts can be formed from inorganic acids such as hydrochloric, sulfuric, and phosphoric acid or from organic acids such as acetic, propionic, glutamic, glutaric, as well as acid ion-exchange resins.
The compounds of formula (1) including (1a) and (1b) may also be in esterified form. Typically, the esters are prepared from a hydrocarbyl alcohol. By xe2x80x9chydrocarbylxe2x80x9d is meant a monovalent substituent containing only carbon and hydrogen which may be straight or branched chain, saturated or unsaturated, aromatic or nonaromatic or both and can be cyclic or noncyclic. Thus, hydrocarbyl alcohol of 1-10C could include cyclopentyl ethyl alcohol, 2-pentanyl alcohol, 3-butynyl alcohol, 2,4-dimethyl hexyl alcohol, benzyl alcohol and the like. Particularly preferred are alkyl alcohols. xe2x80x9cAlkylxe2x80x9d refers to a saturated straight or branched chain hydrocarbon which may, if it contains a sufficient number of carbon atoms, be cyclic or contain a cyclic portion. Typical examples include methyl, ethyl, t-butyl, cyclohexyl and the like. The alkyl esters of the compounds of formula are particularly preferred, especially alkyl esters wherein the alcohol contains 1-4C.
Suitable embodiments of R1, R2 and R3 include substituted or unsubstituted alkyl (1-10C), substituted or unsubstituted acyl (2-11C), substituted or unsubstituted aryl (6-14C), substituted or unsubstituted pyridyl, substituted or unsubstituted arylcarbonyl (7-15C), substituted or unsubstituted arylalkyl (7-15C) wherein substituents on any alkyl moiety are selected from the group consisting of halo, and RO, wherein R is H or alkyl (1-6C) and substituents on any aryl moiety are selected from the group consisting of halo, RO, where R is H or alkyl, and xe2x80x94CN and CF3. Particularly preferred are embodiments wherein R1 is unsubstituted phenyl carbonyl or substituted phenyl carbonyl wherein said substituents are selected from the group consisting of lower alkyl (1-4C) and halo.
Embodiments wherein R2 is alkyl (1-6C) or H are also preferred.
Also preferred are embodiments having formula (1a) wherein Z is S.
Also preferred are embodiments having formula (1a) wherein Z is S or SO2; R1 is naphthylmethyl carbonyl or phenyl carbonyl, R2 is hydrogen, benzyl, phenyl, hydroxyphenyl or pyridyl and R3 is hydrogen or phenyl.
Thus, preferred among the compounds of the invention are those wherein W is selected from the group consisting of:
phenyl-CO,
4-chlorophenyl-CO,
2,4-dinitrophenyl-CO,
3-ethoxyphenyl-CO,
phenyl, and
4-ethoxyphenyl.
In the foregoing, preferred embodiments include the alkyl esters, the embodiments wherein R2 is methyl or hydrogen, and Z is S.
Compositions Containing the xcex2-Lactams and Methods of Use
The compounds of the invention are effective in inactivating a wide range of gram-negative bacteria. Accordingly, they can be used in compositions and as for materials such as foodstuffs, cosmetics, medicaments, or other materials containing nutrients for organisms. For use in such contexts, the compounds of the invention are supplied either as a single compound, in admixture with several other compounds of the invention or in admixture with additional agents. In general, as these active ingredients are preservatives in this context, they are usually present in relatively low amounts, of less than 5%, by weight of the total composition, more preferably less than 1%, still more preferably less than 0.1%.
The compounds of the invention are also useful as standards in and in used to practice these assays.
For use as antimicrobials for treatment of animal subjects, the compounds of the invention can be formulated as pharmaceutical or veterinary compositions. Depending on the subject to be treated, the mode of administration, and the type of treatment desired, e.g., prevention, prophylaxis, therapy; the compounds are formulated in ways consonant with these parameters. A summary of such techniques is found in Remington""s Pharmaceutical Sciences, latest edition, Mack Publishing Co., Easton, Pa.
As used herein, xe2x80x9ctreatmentxe2x80x9d includes both prophylaxis and therapy. Thus, in treating an animal subject, the compounds of the invention may be administered to a subject already harboring a bacterial infection or in order to prevent such infection from occurring.
In general, for use in treatment, the compounds of the invention may be used alone or in combination with other antibiotics such as erythromycin, tetracycline, macrolides, for example azithromycin and the cephalosporins. Depending on the mode of administration, the compounds will be formulated into suitable compositions to permit facile delivery to the affected areas.
Formulations may be prepared in a manner suitable for systemic administration or topical or local administration. Systemic formulations include those designed for injection (e.g., intramuscular, intravenous or subcutaneous injection) or may be prepared for transdermal, transmucosal, or oral administration. The formulation will generally include a diluent as well as, in some cases, adjuvants, buffers, preservatives and the like. The compounds can be administered also in liposomal compositions or as microemulsions.
For injection, formulations can be prepared in conventional forms as liquid solutions or suspensions or as solid forms suitable for solution or suspension in liquid prior to injection or as emulsions. Suitable excipients include, for example, water, saline, dextrose, glycerol and the like. Such compositions may also contain amounts of nontoxic auxiliary substances such as wetting or emulsifing agents, pH buffering agents and the like, such as, for example, sodium acetate, sorbitan monolaurate, and so forth.
Various sustained release systems for drugs have also been devised. See, for example, U.S. Pat. No. 5,624,677.
Systemic administration may also include relatively noninvasive methods such as the use of suppositories, transdermal patches, transmucosal delivery and intranasal administration. Oral administration is also suitable for compounds of the invention. Suitable forms include syrups, capsules, tablets, as is understood in the art.
For administration to animal or human subjects, the dosage of the compounds of the invention is typically 0.1-100 mg/kg. However, dosage levels are highly dependent on the nature of the infection, the condition of the patient, the judgment of the practitioner, and the frequency and mode of administration.
Antibodies
Antibodies to the compounds of the invention may also be produced using standard immunological techniques for production of polyclonal antisera and, if desired, immortalizing the antibody-producing cells of the immunized host for sources of monoclonal antibody production. Techniques for producing antibodies to any substance of interest are well known. It may be necessary to enhance the immunogenicity of the substance, particularly as here, where the material is a small molecule, by coupling the hapten to a carrier. Suitable carriers for this purpose include substances which do not themselves produce an immune response in the mammal to be administered the hapten-carrier conjugate. Common carriers used include keyhole limpet hemocyanin (KLH), diphtheria toxoid, serum albumin, and the viral coat protein of rotavirus, VP6. Coupling of the hapten to the carrier is effected by standard techniques such as contacting the carrier with the peptide in the presence of a dehydrating agent such as dicyclohexylcarbodiimide or through the use of linkers such as those available through Pierce Chemical Company, Chicago, Ill.
The compounds of the invention in immunogenic form are then injected into a suitable mammalian host and antibody titers in the serum are monitored.
Polyclonal antisera may be harvested when titers are sufficiently high. Alternatively, antibody-producing cells of the host such as spleen cells or peripheral blood lymphocytes may be harvested and immortalized. The immortalized cells are then cloned as individual colonies and screened for the production of the desired monoclonal antibodies. The genes encoding monoclonal antibodies secreted by selected hybridomas or other cells may be recovered, manipulated if desired, for example, to provide multiple epitope specificity or to encode a single-chain form and may be engineered for expression in alternative host cells, such as CHO cells.
Thus, as used herein, xe2x80x9cantibodiesxe2x80x9d also includes any immunologically reactive fragment of the immunoglobulins such as Fab, Fabxe2x80x2 and F(abxe2x80x2)2 fragments as well as modified immunoreactive forms such as Fv regions, which are produced by manipulation of the relevant genes (isolable, for example, from the appropriate hybridoma) including humanization of the antibody.
The antibodies of the invention are, of course, useful in immunoassays for determining the amount or presence of the invention compounds. Such assays are essential in quality controlled production of compositions containing the compounds of the invention. They may also be used as affinity ligands for purifying and/or isolating the invention compounds. Such assays may also be useful in identifying prospective compounds from libraries generated by combinatorial techniques wherein the compounds of the invention or derivatives thereof are employed as scaffolds.
Synthesis of the Invention Compounds
The compounds of the invention can conveniently be prepared using an approach illustrated by Reaction Scheme 1.
As shown in Reaction Scheme 1, the Meldrum""s acid derivative of formula (3) is coupled with the thiazolidine of formula (2) to obtain the illustrative xcex2-lactam of the invention compound 1A.
The Meldrum""s acid derivative as set forth in formula (3) is obtained by condensation of a suitable carboxylic acid chloride with Meldrum""s acid as illustrated in Reaction Scheme 2.
Similarly, the Meldrum""s acid derivative of formula 4 is prepared as in Reaction Scheme 3, wherein the carboxylic acid, preactivated with 1,1xe2x80x2-carbonyldiimidazole, is condensed with Meldrum""s acid.
The thiazolidine derivative is prepared as shown in Reaction Scheme 4.
The corresponding compounds where Z is O can be prepared in an analogous manner by substituting the amino alcohol for the amino thiol.
The mono- and bi-oxidation products, Z is SO or SO2, respectively, can be prepared in an analogous manner to the compounds where Z is S with the additional oxidation reactions shown in Reaction Scheme 5 (R1, R2 and R3 are as defined above; P is a solid phase, e.g. Merrifield resin, Wang resin). See Ernesto Mata, xe2x80x9cxcex2-Lactams on Solid Support: Mild and Efficient Removal of Penicillin Derivatives from Merrifield Resin using Aluminum Chloride.xe2x80x9d
B-Lactams on Solid Support: Mild and Efficient Removal of Penicillin Derivatives from Merrifield Resin using Aluminum Chloride,xe2x80x9d Tetrahedron Letters (1997) Vol. 38, No. 36, pp. 6335-6338. The oxidation can alternatively be performed in solution. A chiral center occurs when Z is SO.
In somewhat more detail, in Reaction Scheme 1, the Meldrum""s acid derivative 3 is prepared as described by Yamamoto, Y. et al. Chem Pharm Bull (1987) 35:1871-1879, the contents of which are incorporated herein by reference. In particular, the conditions set forth on page 1876 are employed. Briefly, gaseous HCl was passed into an ice cold solution of the Meldrum""s acid derivative 3 (5 mM) containing the thiazolidine derivative 2 (5 mM) in 50 ml of dry benzene until saturation. The mixture was refluxed for 1 hr and then washed with water (2xc3x9730 ml). The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was then purified using silica gel column chromatography with hexane ether (1:1) as eluent to give the xcex2-lactam product 1A. Further elution with ether provides the side-product residue of the Meldrum""s acid derivative.
The Meldrum""s acid derivative 3 is prepared as shown in Reaction Scheme 2 using chloroform as solvent and 4-dimethylamino pyridine as base at a temperature of 0xc2x0 C. to room temperature as described in Yamamoto, Y. et al. Chem Pharm Bull (1987) 35:1860-1870.
Reaction Scheme 1 may also be conducted as described above but substituting for the Meldrum""s acid 3, the 2-naphthylacetyl Meldrum""s acid 4 prepared as set forth in Reaction Scheme 3 using methylene chloride as solvent as described in Hamilakis, S. et al. J Heterocyclic Chem (1996) 33:825-829, the procedure described at page 828 being incorporated herein by reference. This procedure was followed except that cold 2% KHSO4 (aqueous) was used in the workup rather than 10% HCl (aq.).
The thiazoline derivative 2 used in Reaction Scheme 1 was prepared as set forth in Reaction Scheme 4. This preparation is described by Almqvist, F. et al., Tet Lett (1998) 39:2293-2294. Optically pure L-ethyl cysteinate was reacted with acetyl formate to provide the formyl derivative which was then cyclized with a Dean-Stark reaction using benzene and a catalytic amount of TsOH.
Screening Assays
Antichaperone binding activity can be measured by any number of direct methods such as monitoring spectral changes in the compound and/or the chaperone, or determining the extent of compound binding to immobilized chaperone or vice versa, or by indirect methods such as competition assays to determine the extent to which these compounds inhibit chaperone binding to target pilus subunits and/or derivatives (Soto, et al., EMBO J (1998) 17:6155-6167) and/or synthetic peptides corresponding to subunit fragments known to bind chaperones (Kuehn, et al., Science (1993) 262:1234-1241; Karlsson, et al., Bioorg Med Chem (1998) 6:2085-2101).
Assays to determine the extent of pilus expression in the presence of these compounds would be performed as described in Soto, et al., op cit. and/or by haemagglutination assays as described in Striker, et al., Mol Microbiol (1995) 16:1021-1029.
Assays of inhibition of bacterial binding to target tissues in the presence of these compounds would be performed as described in Striker, et al., op cit.
Conventional techniques, e.g. radial diffusion method against E. coli ML-35P, L. monocytogenes Strain EGD and yeast phase C. albican, would be used to evaluate the spectra of the antimicrobial activity for the novel xcex2-lactams of the invention.
Experimentally, the antimicrobial activity of the novel xcex2-lactams are compared with that of the known antimicrobials against Listeria monocytogenes and E. coli by a classical colony counting technique. The antimicrobial agents were mixed with midlogarithmic phase bacteria in a sterile solution of 10 mM sodium phosphate buffer, pH 6.5 containing 0.3 mg/ml of trypticase soy broth powder. Approximately 50-100 (1 of the mixtures were incubated in a 37xc2x0 C. shaking water bath and 10 (1 aliquots removed at intervals and either plated directly or diluted with a Spiral Plater (Spiral Systems Instruments, Bethesda, Md.) as described by Gilchrist, J. E. et al., J Assoc Anal Chem (1977) 60:807. The colonies were counted after overnight incubation.

Abstract: Compounds of the formula

Abstract: wherein

Abstract: Z is S, SO, SO2 or O;

Abstract: each of R1, R2 and R3 is independently H or substituted or unsubstituted alkyl (1-10C), substituted or unsubstituted alkenyl, substituted or unsubstituted acyl (2-11C), substituted or unsubstituted aryl (6-14C), substituted or unsubstituted arylcarbonyl (7-15C), substituted or unsubstituted arylalkyl (7-15C), substituted or unsubstituted pyridyl wherein substituents on any alkyl, alkenyl, or acyl moiety are selected from the group consisting of halo, and RO, wherein R is H or alkyl (1-6C), and substituents on any aryl or pyridyl moiety are selected from the group consisting of halo, and RO, where R is H or alkyl (1-6C), xe2x80x94CN and xe2x80x94CF3; with the proviso that R1 is not H and R1 and R3 are not identical and

Abstract: with the proviso that in formula (1), the B ring may contain one double bond that is located between positions 2 and 3, and in formula (2), the B ring may contain one double bond that can be located between positions 2 and 3 or positions 3 and 4

Abstract: are useful as antibacterial agents.


A relatively non-toxic desazadesferrithiocin analog having the formula:

Humans have evolved a highly efficient iron management system in which we absorb and excrete only about 1 mg of the metal daily; there is no mechanism for the excretion of excess iron [Brittenham, G. M. Disorders of Iron Metabolism: Iron Deficiency and Overload. In Hematology: Basic Principles and Practice; 3rd ed.; Hoffman, R., Benz, E. J., Shattil, S. J., Furie, B., Cohen, H. J. et al., Eds.; Churchill Livingstone: New York, 2000; pp 397-428]. Whether derived from transfused red blood cells [Olivieri, N. F. and Brittenham, G. M. Iron-chelating Therapy and the Treatment of Thalassemia. Blood 1997, 89, 739-761; Vichinsky, E. P. Current Issues with Blood Transfusions in Sickle Cell Disease. Semin. Hematol. 2001, 38, 14-22; Kersten, M. J., Lange, R., Smeets, M. E., Vreugdenhil, G., Roozendaal, K. J., Lameijer, W. and Goudsmit, R. Long-Term Treatment of Transfusional Iron Overload with the Oral Iron Chelator Deferiprone (L1): A Dutch Multicenter Trial. Ann. Hematol. 1996, 73, 247-252] or from increased absorption of dietary iron [Conrad, M. E.; Umbreit, J. N.; Moore, E. G. Iron Absorption and Transport. Am. J. Med. Sci. 1999, 318, 213-229; Lieu, P. T.; Heiskala, M.; Peterson, P. A; Yang, Y. The Roles of Iron in Health and Disease, Mol. Aspects. Med. 2001, 22, 1-87], without effective treatment, body iron progressively increases with deposition in the liver, heart, pancreas, and elsewhere. Iron accumulation eventually produces (i) liver disease that may progress to cirrhosis [Angelucci, E.; Brittenham, G. M.; McLaren, C. E.; Ripalti, M.; Baronciani, D.; Giardini, C.; Galimberti, M.; Polchi, P.; Lucarelli, G. Hepatic Iron Concentration and Total Body Iron Stores in Thalassemia Major. N. Engl. J. Med. 2000, 343, 327-331; Bonkovsky, H. L.; Lambrecht, R. W. Iron-Induced Liver Injury. Clin. Liver Dis. 2000, 4, 409429, vi-vii; Pietrangelo, A Mechanism of Iron Toxicity. Adv. Exp. Med. Biol. 2002, 509, 19-43], (ii) diabetes related both to iron-induced decreases in pancreatic β-cell secretion and to increases in hepatic insulin resistance [Cario, H.; Holl, R. W.; Debatin, K. M.; Kohne, E. Insulin Sensitivity and p-Cell Secretion in Thalassaemia Major with Secondary Haemochromatosis: Assessment by Oral Glucose Tolerance Test. Eur. J. Pediatr. 2003, 162, 139-146; Wojcik, J. P.; Speechley, M. R.; Kertesz, A E.; Chakrabarti, S.; Adams, P. C. Natural History of C282Y Homozygotes for Hemochromatosis. Can. J. Gastroenterol. 2002, 16, 297-302], and (iii) heart disease, still the leading cause of death in thalassemia major and related forms of transfusional iron overload [Brittenham, G. M. Disorders of Iron Metabolism Iron Deficiency and Overload. In Hematology: Basic Principles and Practice; 3rd ed.; Hoffman, R., Benz, E. J., Shattil, S. J., Furie, B., Cohen, H. J. et al., Eds.; Churchill Livingstone: New York, 2000; pp 397-428; Brittenham, G. M.; Griffith, P. M.; Nienhuis, A W.; McLaren, C. E.; Young, N. S.; Tucker, E. E.; Allen, C. J.; Farrell, D. E.; Harris, J. W. Efficacy of Deferoxamine in Preventing Complications of Iron Overload in Patients with Thalassemia Major. N. Engl. J. Med. 1994, 331, 567-573; Zurlo, M. G.; De Stefano, P.; Borgna-Pignatti, C.; Di Palma, A.; Piga, A.; Melevendi, C.; Di Gregorio, F.; Burattini, M. G.; Terzoli, S. Survival and Causes of Death in Thalassaemia Major. Lancet 1989, 2, 27-30].
Although iron comprises 5% of the earth's crust, living systems have great difficulty in accessing and managing this vital micronutrient. The low solubility of Fe(III) hydroxide (Ksp=1×10−39) [Raymond, K. N.; Carrano, C. J. Coordination Chemistry and Microbial Iron Transport. Ace. Chem. Res. 1979, 12, 183-190], the predominant form of the metal in the biosphere, has led to the development of sophisticated iron storage and transport systems in nature. Microorganisms utilize low molecular weight, virtually ferric ion-specific ligands, siderophores [Byers, B. R; Arceneaux, J. E. Microbial Iron Transport: Iron Acquisition by Pathogenic Microorganisms. Met. Ions Biol. Syst. 1998, 35, 37-66; Kalinowski, D. S.; Richardson, D. R. The Evolution of Iron Chelators for the Treatment of Iron Overload Disease and Cancer. Pharmacol Rev. 2005, 57, 547-583.]; higher eukaryotes tend to employ proteins to transport and store iron (e.g., transferrin and ferritin, respectively) [Bergeron, R. J. Iron: A Controlling Nutrient in Proliferative Processes. Trends Biochem. Sci. 1986, 11, 133-136; Theil, E. c.; Huynh, B. H. Ferritin Mineralization: Ferroxidation and Beyond. J. Inorg. Biochem. 1997, 67, 30; Ponka, P.; Beaumont, c.; Richardson, D. R. Function and Regulation of Transferrin and Ferritin, Semin. Hematol. 1998, 35, 35-54]. In humans, nontransferrin-bound plasma iron, a heterogeneous pool of the metal in the circulation, unmanaged iron, seems to be a principal source of iron-mediated organ damage.
The toxicity associated with excess iron, whether a systemic or a focal problem, derives from its interaction with reactive oxygen species, for instance, endogenous hydrogen peroxide (H2O2) [Graf, E.; Mahoney, J. R; Bryant, R. G.; Eaton, J. W. Iron-Catalyzed Hydroxyl Radical Formation. Stringent Requirement for Free Iron Coordination Site. J. Biol. Chem. 1984, 259, 36203624; Halliwell, B. Free Radicals and Antioxidants: A Personal View. Nutr. Rev. 1994, 52, 253-265; Halliwell, B. Iron, Oxidative Damage, and Chelating Agents. In The Development of Iron Chelators for Clinical Use; Bergeron, R. J., Brittenham, G. M., Eds.; CRC: Boca Raton, 1994; pp 3356; Koppenolo, W. Kinetics and Mechanism of the Fenton Reaction: Implications for Iron Toxicity. In Iron Chelators: New Development Strategies; Badman, D. G., Bergeron, R. J., Brittenham, G. M., Eds.; Saratoga: Ponte Vedra Beach, Fla., 2000; pp 3-10]. In the presence of Fe(II), H2O2 is reduced to the hydroxyl radical (HU), a very reactive species, and HO−, a process known as the Fenton reaction. The Fe(III) liberated can be reduced back to Fe(II) via a variety of biological reductants (e.g., ascorbate), a problematic cycle. The hydroxyl radical reacts very quickly with a variety of cellular constituents and can initiate free radicals and radical-mediated chain processes that damage DNA and membranes, as well as produce carcinogens [Halliwell, B. Free Radicals and Antioxidants: A Personal View. Nutr. Rev. 1994, 52, 253-265; Babbs, C. F. Oxygen Radicals in Ulcerative Colitis. Free Radic. Biol. Med. 1992, 13, 169-181; Hazen, S. L.; d'Avignon, A; Anderson, M. M.; Hsu, F. F.; Heinecke, J. W. Human Neutrophils Employ the Myeloperoxidase-Hydrogen Peroxide-Chloride System to Oxidize a-Amino Acids to a Family of Reactive Aldehydes. Mechanistic Studies Identifying Labile Intermediates along the Reaction Pathway. J. Biol. Chem. 1998, 273, 4997-5005]. The solution to the problem is to remove excess unmanaged iron [Bergeron, R. J.; McManis, J. S.; Weimar, W. R; Wiegand, J.; Eiler-McManis, E. Iron Chelators and Therapeutic Uses. In Burger's Medicinal Chemistry; 6th ed.; Abraham, D. A, Ed.; Wiley: New York, 2003; pp 479-561].
In the majority of patients with thalassemia major or other transfusion-dependent refractory anemias, the severity of the anemia precludes phlebotomy therapy as a means of removing toxic accumulations of iron. Treatment with a chelating agent capable of sequestering iron and permitting its excretion from the body is then the only therapeutic approach available. The iron-chelating agents now in use or under clinical evaluation [Brittenham, G. M. Iron Chelators and Iron Toxicity. Alcohol 2003, 30, 151-158] include desferrioxamine B mesylate (DFOa), 1,2-dimethyl-3-hydroxypyridin-4-one (deferiprone, L1), 4-[3,5-bis(2-hydroxyphenyl)-1,2,4-triazol-1-yl]benzoic acid (deferasirox, ICL670A), and the desferrithiocin (DFT) analogue, (S)-2-(2,4-dihydroxyphenyl)-4,5-dihydro-4-methyl-4-thiazolecarboxylic acid [deferitrin, (S)-4′-(HO)-DADFT, 1; Table 1]. Subcutaneous (sc) infusion of desferrioxamine B (DFO), a hexacoordinate hydroxamate iron chelator produced by Streptomyces pilosus [Bickel, H., Hall, G. E., Keller-Schierlein, W., Prelog, V., Vischer, E. and Wettstein, A. Metabolic Products of Actinomycetes. XXVII. Constitutional Formula of Ferrioxamine B. Helv. Chim. Acta 1960, 43, 2129-2138], is still regarded as a credible treatment for handling transfusional iron overload [Olivieri, N. F. and Brittenham, G. M. Iron-chelating Therapy and the Treatment of Thalassemia. Blood 1997, 89, 739-761; Giardina, P. J. and Grady, R. W. Chelation Therapy in β-Thalassemia: An Optimistic Update. Semin. Hematol. 2001, 38, 360-366]. DFO is not orally active, and when administered sc, has a very short half-life in the body and must therefore be given by continuous infusion over long periods of time [Olivieri, N. F. and Brittenham, G. M. Iron-chelating Therapy and the Treatment of Thalassemia. Blood 1997, 89, 739-761; Pippard, M. J. Desferrioxamine-Induced Iron Excretion in Humans. Bailliere's Clin. Haematol. 1989, 2, 323-343]. For these reasons, patient compliance is a serious problem [Olivieri, N. F. and Brittenham, G. M. Iron-chelating Therapy and the Treatment of Thalassemia. Blood 1997, 89, 739-761; Giardina, P. J. and Grady, R. W. Chelation Therapy in β-Thalassemia: An Optimistic Update. Semin. Hematol. 2001, 38, 360-366]. The orally active bidentate chelator, deferiprone, is licensed in Europe and some other countries as second-line therapy to DFO [Hoffbrand, A V.; Al-Refaie, F.; Davis, B.; Siritanakatkul, N.; Jackson, B. F. A; Cochrane, J.; Prescott, E.; Wonke, B. Long-term Trial of Deferiprone in 51 Transfusion-Dependent Iron Overloaded Patients. Blood 1998, 91, 295-300; Olivieri, N. F. Long-term Therapy with Deferiprone. Acta Haematoi. 1996, 95, 37-48; Olivieri, N. F.; Brittenham, G. M.; McLaren, C. E.; Templeton, D. M.; Cameron, R. G.; McClelland, R. A; Burt, A D.; Fleming, K. A Long-Term Safety and Effectiveness of Iron-Chelation Therapy with Deferiprone for Thalassemia Major. N. Engi. J. Med. 1998, 339, 417-423; Richardson, D. R. The Controversial Role of Deferiprone in the Treatment of Thalassemia. J. Lab. Clin. Med. 2001, 137, 324-329]. Unfortunately, although it is orally active, it is less efficient than sc DFO at removing iron. Whereas the orally active tridentate chelator deferasirox has now been approved by the FDA, it did not demonstrate non-inferiority to DFO. Furthermore, it apparently has a somewhat narrow therapeutic window, owing to potential nephrotoxicity, noted in animals during the preclinical toxicity studies [Nisbet-Brown, E.; Olivieri, N. F.; Giardina, P. J.; Grady, R. W.; Neufeld, E. J.; Sechaud, R; Krebs-Brown, A J.; Anderson, J. R; Alberti, D.; Sizer, K. c.; Nathan, D. G. Effectiveness and Safety of ICL670 in Iron-Loaded Patients with Thalassaemia: a Randomised, Double-Blind, Placebo-Controlled, Dose-Escalation Trial. Lancet 2003, 361, 1597-1602; Galanello, R; Piga, A; Alberti, D.; Rouan, M.-C.; Bigler, H.; Sechaud, R. Safety, Tolerability, and Pharmacokinetics of ICL670, a New Orally Active lron-Chelating Agent in Patients with Transfusion-Dependent Iron Overload Due to Thalassemia. J. Clin. Pharmacol. 2003, 43, 565-572; Cappellini, M. D. Iron-chelating therapy with the new oral agent ICL670 (Exjade). Best Pract Res Clin Haematol 2005, 18, 289-298]. In addition, Novartis has recently (April, 2007) updated the prescribing information for deferasirox: "Cases of acute renal failure, some with a fatal outcome, have been reported following the postmarketing use of Exjade® (deferasirox). Most of the fatalities occurred in patients with multiple co-morbidities and who were in advanced stages of their hematological disorders" [Exjade Prescribing Information, www.pharma.us.novartis.com/product/pi/pdf/exjade.pdf (accessed May 2007)]. Finally, ligand 1 is an orally active tridentate DFT analogue now in phase I/II trials in patients. Although the preclinical toxicity profile of 1 was relatively benign, that is, no geno- or reproductive toxicity and only mild nephrotoxicity at high doses, the clinical results remain to be elucidated.
It is an object of the present invention to provide novel desferrithiocin analogues useful for the treatment of iron overload in mammals and the diseases associated therewith.

This patent is subject to a terminal disclaimer.

Abstract: wherein: R1, R2, R4 and R5 may be the same or different and may be H, straight or branched chain alkyl having up to 14 carbon atoms, e.g., methyl, ethyl, propyl and butyl, or arylalkyl wherein the aryl portion is hydrocarbyl and the alkyl portion is straight or branched chain, the arylalkyl group having up to 14 carbon atoms, R2 optionally being alkoxy having up to 14 carbon atoms;                    R3 is [(CH2)n—O]x—[(CH2)n—O]y-alkyl;            n is, independently, an integer from 1 to 8;            x is an integer from 1 to 8;            y is an integer from 0 to 8, and            R3O may occupy any position on the phenyl ring except the 4-position, or                        a salt, hydrate or solvate thereof; and methods and compositions for treating the effects of trivalent metal, i.e., iron, overload.

University of Florida Research Foundation, Inc.


An apparatus and method for treatment of benign prostatic hyperplasia is disclosed wherein the apparatus includes an applicator having a probe having proximal and distal probe sections wherein the proximal and distal probe sections each define an axis and wherein the axes are not collinear.

1. Field of the Invention
The present invention relates generally to methods and apparatus for the electroporation of tissues and more specifically to such methods and apparatus for the treatment of benign prostatic hyperplasia.
2. Description of the Related Art
Though greater detail will follow in the discussion below, succinctly stated, the present invention provides apparatus and methods of providing treatment for the undesirable proliferation of cells in the prostate by killing the cells with electric field pulses of selected duration and strength to take advantage of a cellular event known as "electroporation."
Electroporation
The biophysical phenomenon known as electroporation refers to the use of electric field pulses to induce microscopic pores—"electropores"—in the lipid cell membranes. Depending on the parameters of the electric pulses, an electroporated cell can survive the pulsing or die. The cause of death of an electroporated cell is believed to be a chemical imbalance in the cell, resulting from the fluid communication with the extra-cellular environment through the pores. For a given cell size, geometry, and orientation, the number of electropores—and their size—created in the cell by the applied electric field pulses depends on both the amplitude E of the electric field pulses and the duration t of the pulses. That is, for a given pulse duration t, no pores will be induced in the cell until the amplitude E reaches a certain lower limit. This limit is different for different cells, particularly, for cells of different sizes. The smaller the size of a cell, the higher the electric field required to induce pores and thus the higher the lower limit is. Above the lower amplitude E limit the number of pores and their effective diameter increases proportionally with both increasing field amplitude E and pulse duration t. Electroporation is observed for pulse durations in the range from tens of microseconds to hundreds of milliseconds.
Until the upper limit of electroporation is achieved, an electroporated cell can survive the pulsing and restore its viability thereafter. Above the upper limit the pore diameters and number of induced pores become too large for a cell to survive. The irreversibly chemically imbalanced cell cannot repair itself by any spontaneous or biological process and dies. To kill a cell a potential in the range of 2 to 4 V should be applied along the cell. The cell killing by electroporation is a probabilistic process. That is, increasing the number of applied pulses of duration t leads to an increased probability of cell killing, a probability increase that is approximately equal to the percentage increase in the total time duration of the applied electric pulses.
The survivability of electroporated cells depends significantly on their temperature. At higher temperature cells are more vulnerable to cell death by electroporation. Thus, the amplitude and duration of the electric pulses required for cell killing are lower. It is believed that this observation is explained by two underlying phenomena: at higher temperatures cells are less stable biochemically because of more intense metabolic activity; and, secondly, at elevated temperatures the strength of lipid membranes decreases, which facilitates creating larger pores or irreversible rupture of the cell membrane. At lower temperatures (about 10 to about 20 degrees Celsius) cells are more resistant to electroporation and can survive two to three times higher voltages than they can at body temperature.
The Prostate Gland and Benign Prostatic Hyperplasia
The prostate gland forms part of the male reproductive system. The prostate gland is located between the bladder and the rectum and wraps around the urethra, the tube that carries urine out from the bladder through the penis. The gland consists a dense fibrous capsule enclosing several lobes or regions. The prostate gland is generally composed of smooth muscles and glandular epithelial tissue. The glandular epithelial tissue produces prostatic fluid. The smooth muscles contract during sexual climax and squeeze the prostatic fluid into the urethra as the sperm passes through the ejaculatory ducts and urethra. Prostatic fluid secreted by the prostate gland provides nutrition for ejaculated spermatozoids increasing their mobility and improves the spermatozoids chances for survival after ejaculation by making the environment in the vaginal canal less acidic.
Anatomically, the prostate gland is usually described as including three glandular zones: the central, peripheral and transitional zones. The transitional zone is located right behind the place where the seminal vesicles merge with the urethra. This transitional zone tends to be predisposed to benign enlargement in later life.
The prostate reaches its normal size and weight (about 20 grams) soon after puberty. The size and weight of the prostate typically remain stable until the individual reaches his mid-forties. At this age, the prostate gland—typically in the transitional zone—begins to enlarge through a process of excessive cell proliferation known as benign prostatic hyperplasia (BPH). This overgrowth can occur in both smooth muscle and glandular epithelial tissues and has been attributed to a number of different causes, including hormones and growth factors as well as generally to the aging process.
Benign prostate hyperplasia can cause distressing urination symptoms. As the disease progresses the dense capsule surrounding the enlarging prostate prevents it from further expansion outward and forces the prostate to press against the urethra, partially obstructing the urine flow. The tension in the smooth muscles of the prostate also increases which causes further compression of the urethra and reduction of the urine flow. Some symptoms of BPH stem from the gradual loss of bladder function leading to an incomplete emptying of the bladder. The symptoms can include straining to urinate, a weak or intermittent stream, an increased frequency of urination, pain during urination, and incontinence—the involuntary loss of urine following an uncontrollable sense of urgency. These symptoms alone can negatively affect the quality of life of affected men. Left untreated, BPH can cause even more severe complications, such as urinary tract infection, acute urinary retention, and uremia.
Before age 40, only 10% of men have benign prostatic hyperplasia; but by age 80, about 80% have signs of this condition. Benign prostatic hyperplasia is the most common non-cancerous form of cell growth in men. About 14 million men in US have BPH, and about 375,000 new patients are diagnosed every year.
For many years, researchers have tried to find medications to shrink the prostate or at least stop its growth. Between 1992 and 1997, the FDA approved four drugs for treatment of BPH: finasteride, terazosin, tamsulosin, and doxazosin.
Finasteride inhibits production of hormone DHT. DHT is one of the hormones that have been found to be involved in prostate enlargement. Treatment with Finasteride has been shown to shrink the prostate in some men.
Terazosin, doxazosin, and tamsulosin belong to the class of drugs known as alpha-blockers. Alpha-blockers act by relaxing the smooth muscle of the prostate and bladder to improve urine flow and reduce bladder outlet obstruction. In men with severe symptoms, though, these medications are palliative only. They can delay but not prevent the eventual need for surgery.
Regardless of the efficacy of any drug treatment, the long term exposure to xenobiotic compounds may produce additional unwanted side effects that are not realized until years after treatment. Accordingly, a need exists for an apparatus and method for the treatment of BPH that does not require the introduction of xenobiotic compounds.
For men with the most severe symptoms, surgery is generally considered to be the best long-term solution. There are several surgical procedures that have been developed for relieving symptoms of BPH. Each of these procedures, however, suffers from one or more of the following deficiencies: high morbidity, long hospital stays, the use of general anesthesia, significant side effects such as impotence, and possible complications such as infection and inflammation.
In recent years, a number of procedures have been introduced that are less invasive than surgery. One such procedure is transurethral microwave thermal therapy. In transurethral microwave thermal therapy, a Foley-type catheter containing a microwave antenna is placed within the urethra. The microwave antenna is positioned adjacent to the transitional zone of the prostate, where BPH occurs, and allows selective heating of the prostate. Maintaining the temperature of the BPH tissue above 45 degrees C. during about a one hour session leads to necrosis of the tissues and subsequent reabsorption of necrotic tissue by the body.
Another recently developed non-invasive technique is transurethral needle ablation (TUNA). TUNA uses low level radio frequency (RF) energy to heat the prostate. Using TUNA, two separate needles are inserted into prostate through the urethra. Several watts of RF energy is applied to each needle to cause thermal necrosis of the prostate cells around the needles. Application of this treatment to several sites of the prostate typically results in sufficient necrosis to relieve symptoms of the BPH.
While generally successful, the microwave and RF therapies are relatively long procedures. Also, because of the poor temperature control of the heated volume, the volume of removed tissue is often not sufficient for the long term relief of the symptoms and/or the healthy tissue of the urethra is damaged. A damaged urethra is capable of restoring itself, but the healing is a long morbid process accompanied by sloughing of the necrotic tissue into urethra and excretion of it during urination.
Therefore, a need exists for a minimally invasive therapy for treatment of BPH that requires shorter treatment times and is less morbid than existing therapies.

Apparatus and method for the treatment of benign prostatic hyperplasia


A method for processing a roll includes providing a roll comprising an axis of rotation, providing at least one pulling device, and bending the roll in a direction opposite to a curvature of the roll via the at least one pulling device. The at least one pulling device is disposed at a radial distance from the axis of rotation of the roll.

Such methods and rolls are in the prior art. DE 19819663 A1, for example, describes such a roll. The drawback here is that the roll and the method are complex.
A grinder is described in DE 699 12 162 T2 which has a grinding mechanism and a measuring system that is associated and displaceable with the mechanism. This grinder is provided for grinding an outer surface of a roll, for example, a paper machine roll, and in particular a tissue cylinder or a machine glazing cylinder.
JP 6328850 A describes a grinding method in which a shaft body is ground at its operating temperature so that the concentricity of the shaft body during later operation is improved and its deflection eliminated.
A method for eliminating the radial run-out of a peripherally drilled, heated roll at the operating temperature is described in U.S. Pat. No. 4,250,606. By way of a tie bolt that is inserted into one of the peripheral holes, the roll is given the same curvature at room temperature as that which was previously measured at the operating temperature. At room temperature, the roll is then ground cylindrically so that it assumes a curvature in the opposite direction at room temperature as the curvature which was present previously at the operating temperature after the tie bolt is removed. After subsequent heating to the operating temperature, the roll then has no significant deflection.
EP 1 217 123 A1 describes a paper processing roll which can be exposed to an elevated temperature during operation. For the roll to assume an optimal shape quality and concentric running quality for the process under production conditions in the machines, the roll has a heat-treated surface. For example, it is hot ground and/or hot balanced, or the previously determined profile of the roll in the hot state is subsequently transferred as a negative profile onto the roll by grinding in the cold state, after the roll has cooled.

Roller and methods for production and operation


In a rotary cutter, a contact pressure profile can be adjusted by judging or detecting a contact pressure profile of a knife in its longitudinal direction and heating or cooling respective portions of the knife or plain rotor according to the judged or detected contact pressure profile.

1. Field of the Invention
The present invention relates to a rotary cutter for cutting consecutively such sheet material as paper strip, paper board, synthetic resin film, etc. into pieces with desired length, in particular, to a contact pressure control method for this kind of rotary cutter and a device therefor.
2. Description of the Prior Art
The sheet product such as paper, film, etc., includes a group of flat product and another group of roll product. The flat product is formed by cutting the product supplied from a sheet manufacturing line or the roll product in the feeding direction and the width direction of the product with a slitter and a fly knife in a cutter or a sheeter.
Regarding the cutting method, a slitter employing the type of thin upper and lower blades produces little paper dust even in cutting the paper of 600 g/m2. But there are some problems in cutting with a fly knife. In the type with one fixed blade shown in FIG. 12 of attached drawings, for example, a paper sheet 1 is cut by a fixed blade 2 and a rotating blade 3, but this type has not enough power for cutting a thick paper. To cut the thick paper, a twin rotor type with upper and lower rotating blades 4 and 5 shown in FIG. 13 has been developed and is in main use at present. In this twin rotor type, however, an adjusting operation for matching relative positions of the upper and the lower rotating blades is so difficult that even a skilled worker needs six to eight hours for the blade position matching in some cases.
To solve these problems, a rotary cutter with a structure shown in FIG. 14 has been developed. The details of the structure and the operation of this rotary cutter are disclosed in the Japanese Patent Laid-Open Publication Number 6-304895/1994. Briefly described, the rotary cutter comprises a knife rotor 6, a plain rotor 7, and a feed roller 8. The knife rotor 6 has knives 9a, 9b which are mounted on the two portions of outer surface of said knife rotor and arranged in the longitudinal direction of the knife rotor. In this rotary cutter, the paper sheet 1 which is sandwiched between and fed from the plain rotor 7 driven by a variable speed motor and the feed roller 8 is cut by the knife 9a attached to the outer surface of the knife rotor 6 driven by a servo motor while the paper 1 is pressed against the plain rotor 7. The knife rotor 6 is controlled and driven so as to rotate at the same speed with that of the fed paper 1 only when the attached knives 9a, 9b contact the paper 1 to be cut.
The structure and operation of this rotary cutter have been described above and a holding mechanism of the respective knives 9a, 9b in the knife rotor 6 is, for example, as shown in an enlarged partial sectional view of FIG. 15. As shown in FIG. 15, the knife 9a is attached to the knife rotor 6 as follows. At first, a knife holder 12 equipped with a permanent magnet 11 is fixed by a bolt 13 into a groove 10 formed in the longitudinal direction of the knife rotor 6, and then, into an insertion groove 14 formed consequently, the knife 9a is simply inserted, and, as a result, the knife can be fixed to the knife rotor 6 due to the magnetic effect. Accordingly, the knife replacement service can be carried out within a few seconds and the period for knife replacement has surprisingly been reduced.
But in such material as film where a cut section is expected to be a similar one cut by a guillotine, even a rotary cutter as described above needs the blade position matching, that is, the clearance between the plain rotor 7 and the position of knife rotor 6 in FIG. 14 and FIG. 15 must be adjusted. Traditionally, the clearance is adjusted in a manner that the relative position of the upper and lower blades is adjusted by carefully examining the cut section of a sheet or carefully listening to the sound at the cutting, and therefore, the adjusting operation is still a difficult work.
Furthermore, the contact pressure, even if once adjusted, changes in the long hour running due to the knife wear itself or to the variation in size resulting from the expansion and contraction of the knife and surrounding machine components. It is very difficult to compensate these factors.
The object of the present invention is to provide a contact pressure control method and a device for a rotary cutter which solves the problems of the conventional technology as described above.

Contact pressure control method and device for rotary cutter


This invention relates to reconstructed polypeptides which have properties of inducing apoptosis of nucleated blood cells having Integrin Associated Protein (IAP) and causing no hemagglutination. The reconstructed polypeptides comprise two or more H chain V regions and two or more L chain V regions of a monoclonal antibody which induces apoptosis of nucleated blood cells having IAP. The reconstructed polypeptides are useful as a therapeutic agent for blood dyscrasia such as leukemia.

Japanese Patent Application 9-67499 discloses the preparation of a specific monoclonal antibody using a splenic stromal cell line as a sensitizing antigen aiming at developing specific antibodies that can recognize the aforementioned splenic stromal cells and the preparation of novel monoclonal antibodies that recognize mouse Integrin Associated Protein (mouse IAP) as an antigen. JP-Appl. 9-67499 also discloses that the monoclonal antibodies are capable of inducing apoptosis of myeloid cells.
WO99/12973 discloses monoclonal antibodies whose antigen is human Integrin Associated Protein (hereinafter referred to as human IAP; amino acid sequence and nucleotide sequence thereof are described in J. Cell Biol., 123, 485-496, 1993; see also Journal of Cell Science, 108, 3419-3425, 1995) and which are capable of inducing apotosis of human nucleated blood cells (myeloid cell and lymphocyte) having said human IAP. These monoclonal antibodies are referred to antibody MABL-1 and antibody MABL-2, and hybridomas producing these antibodies are also referred to MABL-1 (FERM BP-6100) and MABL-2 (FERM BP-6101), respectively.
Japanese Patent Application 11-63557 describes the preparation of single-chain Fvs having single chain Fv regions from the monoclonal antibodies whose antigen is human IAP. The single-chain Fvs are capable of inducing apoptosis of nucleated blood cells having human IAP.
The monoclonal antibody recognizing IAP as an antigen induces apoptosis of nucleated blood cells having human IAP, but it also causes hemagglutination in vitro. It indicates that the administration of a large amount of the monoclonal antibody recognizing IAP as an antigen may result in a side effect such as hemagglutination.


A memory has an array of k-level cells, organized into pages of words, each storing a string of bits. The memory device includes a coding circuit input with strings of N bits, and generates corresponding k-level strings. A program circuit is input with the k-level strings to stores in groups of c cells with k levels. A read circuit reads data stored in groups of c cells with k levels and generates k-level strings. A read decoding circuit is input with k-level strings read from groups of c cells with k levels to generate strings of N bits. The words of each page are grouped in groups of words, each word including groups of c cells with k levels, and at least one remaining bit of the word being stored, with corresponding remaining bits of other words of the page, in a group of c cells with k levels.

In a multi-level memory device cells generally assume more than two logic states and thus may store information of more than one bit. A multi-level memory device that occupies a silicon area slightly larger than that of a four-level memory device of the same storage capacity is described in the Italian patent application VA2006A000065, assigned to the current assignee. It employs three-level cells whereby each pair of cells is to store a string of three bits and comprises a coding circuit and a decoding circuit for converting, in a write operation, the strings of three bits to be stored, in strings of two ternary values to be written in respective pairs of three-level cells, and vice versa during a read operation.
There may be three possible states of each cell, thus the relative distributions of the three different read thresholds can be relatively farther away from the voltage levels at which the known "read disturb" and "retention" phenomena (discussed in the above cited prior Italian patent application) are more severe.
A method of managing a multi-level memory device that addresses the issues caused by an accidental interruption or supply voltage drop of a magnitude capable of stopping an ongoing program operation that could take place during programming and that may render the memory device usable as if it were a two-bit memory device, is also disclosed in the above cited prior Italian patent application.
According to the three-level memory device disclosed in the prior application, each cell may assume one of three possible logic values, with the advantage of an area occupation significantly smaller than that of a common one-bit-per-cell memory device, though with a reduced number of threshold voltage distributions than a two-bit-per-cell memory device. This may make unnecessary error correction code techniques, that may otherwise be indispensable with present day technology two-bit per cell devices for ensuring an acceptable reliability, and thus the consequent limitations in terms of "bit manipulation" that the use of ECC technique may impose.
An architecture of the memory device according to the cited prior application is schematically depicted in FIG. 1.

Method of managing a multilevel memory device and related device


A removable battery tray for an electric bunker rake. The battery tray fits on the frame of the bunker rake during operation, and can be easily removed by a hoist or other method so that the bunker rake can continue to operate with another charged set of batteries. The battery tray also has a central power connector that is used for charging and is the only electrical disconnect required when changing the battery tray.

1. Field of the Invention
This invention relates in general to electrically powered vehicles and relates specifically to an electrically powered bunker rake with a removable, rechargeable battery tray system.
2. Prior Art
One application for the present invention is in electrically powered bunker rakes that are used on golf courses, particularly for conditioning sand bunkers. Conventional electrically powered bunker rakes utilize six 6-volt lead-acid deep cycle batteries. Generally, one battery set of six 6-volt or six 8-volt batteries powers the bunker rake for about three to five hours. Once the battery set has discharged, if more bunker conditioning is required, the operator must either re-charge the battery set, which may take eight to twelve hours, or replace the battery set with a fully charged, alternate battery set. The batteries in the battery set are anchored to the bunker rake frame with metal or plastic hold-down brackets. To remove the batteries, the hold-down brackets as well as wiring to each battery must be removed. The process of exchanging the batteries is time consuming and is not conducive to efficiently conditioning all of the bunkers on a golf course.

Removable battery tray system for an electrically powered bunker rake


A tire comprises a tread portion provided with two circumferential grooves disposed one each side of the tire equator and extending continuously in the tire circumferential direction, and a crown land region between the two circumferential grooves. The crown land region is provided with first crown sipes extending from one of the circumferential grooves and terminating within the crown land region, and second crown sipes extending from the other circumferential groove and terminating within the crown land region.

The following patent document 1 discloses a tire whose running performance during circuit running is improved, while securing wet performance. This tire is provided with two circumferential grooves one on each side of the tire equator, and oblique grooves disposed axially outside the circumferential grooves. Between the two circumferential grooves, there is formed a land region extending in the tire circumferential direction on the tire equator. Such tire has a problem such that the temperature of the land region of the tread portion is hard to increase and thereby the tire has low grip performance initially after starting to run.


A vehicle having an air pre-cleaner coupled with an engine enclosure such that the air inlet to the air pre-cleaner is positioned beneath the top wall of the engine enclosure and receives air from a duct within the enclosure, and the debris outlet of the air pre-cleaner is located above the top wall of the engine enclosure.

This invention relates to off road vehicles having air cleaners or pre-cleaners coupled with the vehicle""s internal combustion engine.
It is known to provide off road work vehicles such as loader backhoes with large air intake pipes that extend upwardly from the vehicle hood. These vehicles generate a large amount of dust and airborne debris as the wheels contact the ground. The air proximate the ground and tires tends to contain large quantities of dirt and debris. Also, the engine cooling fan located proximate the engine within the engine enclosure tends to generate dust and airborne debris. The pipes extend high above the hood so that relatively clean air can be pulled into the pipe. These pipes often have the disadvantage of being positioned directly in front of the vehicle operator station, and therefore can block or obstruct the operator""s forward view from the operator station.
It is also known to provide off road work vehicles with an air intake pipe having a pre-cleaner mounted to the top of the pipe. One type of pre-cleaner includes propeller blades that rotate as air is drawn through the pre-cleaner for use by the engine. Rotation of the blades imparts a centrifugal force to the air and debris. The airborne debris is heavier than the surrounding air, and the centrifugal force imparted to the debris propels the debris outwardly through a debris outlet. The air is thereby cleaned of heavy debris and airborne dirt, and the air remaining within the pre-cleaner is pulled downwardly through the intake pipe for use by the internal combustion engine. Air intake pipes having pre-cleaners mounted on the top of the intake pipe also have the disadvantage of blocking the seated operator""s view from within the operator station.
It would therefore be desirable to provide an air intake mechanism that would generally not obstruct the view of the operator during operation of an off road work vehicle. It would also be desirable for such a mechanism to direct relatively clean air toward the vehicle""s internal combustion engine.
The preferred embodiment of the present invention provides an off road work vehicle having an internal combustion engine positioned within an engine enclosure. An air pre-cleaner is fixed with the engine enclosure and serves to direct cleaned air to the engine to facilitate combustion within the engine. The air pre-cleaner includes fan blades which rotate to propel airborne debris radially outwardly with centrifugal force so that relatively heavy airborne debris is expelled from the pre-cleaner through a debris outlet near the upper portion of the air cleaner. The debris outlet is formed in a cap of the pre-cleaner and is located above a top surface of the engine enclosure. The pre-cleaner includes an air inlet positioned beneath the debris outlet and located within the engine enclosure. The air pre-cleaner defines a clean air outlet through which cleaned air from the air pre-cleaner passes to the engine. Ducts positioned within the engine enclosure direct air toward the air inlet of the air pre-cleaner. A duct inlet is formed in the engine enclosure for directing air from the exterior of the engine enclosure into the duct.

Air cleaner and hood ducting arrangement