Benzimidazole compounds having the generic structure:

The subject invention is directed to certain substituted benzimidazole compounds that have improved resistance to metabolism in primates. The subject compounds are alpha adrenoceptor agonists and are useful in treating alpha agonist associated disorders.
Alpha adrenergic receptors, agonists, antagonists, and compounds related in structure to those of this invention are disclosed in the following references: Timmermans, P. B. M. W. M., A. T. Chiu and M. J. M. C. Thoolen, xe2x80x9c12.1xcex1-Adrenergic Receptorsxe2x80x9d, Comprehensive Medicinal Chemistry, Vol. 3, Membranes and Receptors, P. G. Sammes and J. B. Taylor, eds., Pergamon Press (1990), pp. 133-185; Timmermans, P. B. M. W. M. and P. A. van Zwieten, xe2x80x9cxcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Drugs of the Future, Vol. 9, No. 1, (January, 1984), pp. 41-55; Megens, A. A. H. P., J. E. Leysen, F. H. L. Awouters and C. J. E. Niemegeers, xe2x80x9cFurther Validation of in vivo and in vitro Pharmacological Procedures for Assessing the xcex11 and xcex12-Selectivity of Test Compounds: (2) xcex1-Adrenoceptor Agonistsxe2x80x9d, European Journal of Pharmacology, Vol. 129 (1986), pp. 57-64; Timmermans, P. B. M. W. M., A. de Jonge, M. J. M. C. Thoolen, B. Wilffert, H. Batink and P. A. van Zwieten, xe2x80x9cQuantitative Relationships between xcex1-Adrenergic Activity and Binding Affinity of xcex1-Adrenoceptor Agonists and Antagonistsxe2x80x9d, Journal of Medicinal Chemistry, Vol. 27 (1984) pp. 495-503; van Meel, J. C. A., A. de Jonge, P. B. M. W. M. Timmermans and P. A. van Zwieten, xe2x80x9cSelectivity of Some Alpha Adrenoceptor Agonists for Peripheral Alpha-1 and Alpha-2 Adrenoceptors in the Normotensive Ratxe2x80x9d, The Journal of Pharmacology and Experimental Therapeutics, Vol. 219, No. 3 (1981), pp. 760-767; Chapleo, C. B., J. C. Doxey, P. L. Myers, M. Myers, C. F. C. Smith and M. R. Stillings, xe2x80x9cEffect of 1,4-Dioxanyl Substitution on the Adrenergic Activity of Some Standard xcex1-Adrenoreceptor Agentsxe2x80x9d, European Journal of Medicinal Chemistry, Vol. 24 (1989), pp. 619-622; Chapleo, C. B., R. C. M. Butler, D. C. England, P. L. Myers, A. G. Roach, C. F. C. Smith, M. R. Stillings and I. F. Tulloch, xe2x80x9cHeteroaromatic Analogues of the xcex12-Adrenoreceptor Partial Agonist Clonidinexe2x80x9d, J. Med. Chem., Vol. 32 (1989), pp. 1627-1630; Clare, K. A., M. C. Scrutton and N. T. Thompson, xe2x80x9cEffects of xcex12-Adrenoceptor Agonists and of Related Compounds on Aggregation of, and on Adenylate Cyclase Activity in, Human Plateletsxe2x80x9d, Br. J. Pharmac., Vol. 82 (1984), pp. 467-476; U.S. Pat. No. 3,890,319 issued to Danielewicz, Snarey and Thomas on Jun. 17, 1975; and U.S. Pat. No. 5,091,528 issued to Gluchowski on Feb. 25, 1992.
Alpha-2 adrenergic agonists are useful for treating a variety of disorders including: respiratory disorders (e.g., asthma, nasal congestion, COPD, cough, cystic fibrosis), gastrointestinal disorders (e.g., diahrrea, irritable bowel syndrome), ocular disorders (e.g., glaucoma), cardiovascular disorders (e.g., myocardial ischemia, shock, arrhythmias, angina, congestive heart failure), benign prostatic hypertrophy and migraine. However, many compounds disclosed in the art and related in structure to those of this invention are not alpha-2 adrenoceptor selective (e.g., they interact with other alpha receptors such as alpha-1 adrenoceptors). Alpha-2 adrenoceptor selectivity is desirable when treating alpha-2 associated or alpha-2 mediated disorders. For example, alpha-2 adrenergic agonists that possess significant alpha-1 adrenergic effects are known to cause cardiovascular side effects such as hypertension. In addition, many compounds disclosed in the art and related in structure to those of this invention possess significant central nervous system (CNS) activity which may lead to undesirable side effects such as severe sedation.
It has also been observed that some alpha adrenergic agonists are subject to extensive metabolic transformation in primates. Such metabolic transformation results in inactivation of the parent compound or in the formation of an active metabolite with a different pharmacological profile from the parent compound. Of particular importance to the present invention is the metabolic transformation that occurs to some alpha adrenergic benzimidazoles that are peripherally acting alpha-2-adrenoceptor selective agonists. Metabolic N-methylation at the benzimidazole ring may result in compounds that (1) are inactive; (2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activity at other undesired receptors, such as at alpha-1 adrenoceptors; and/or (4) have an increased potential for CNS activity. Thus, there is a continuing need for peripherally acting selective alpha-2 adrenergic compounds that have lower CNS activity and that resist metabolic transformation into undesirable compounds.
The present invention is directed to compounds having a structure according to the following formula:
wherein:
(a) R1 is alkyl;
(b) R2 is selected from the group consisting of: hydrogen, alkyl, methoxy, cyano, and halo;
(c) R3 is selected from the group consisting of: hydrogen, methyl, hydroxy, cyano and halo;
(d) R4 is selected from the group consisting of: hydrogen, methyl, ethyl and isopropyl;
(e) R5 is selected from the group consisting of: hydrogen, methyl, amino, methoxy, hydroxy, cyano and halo;
(f) provided that at least one of R2, R3, R4 or R5 is other than hydrogen or fluorine;
(g) provided that when R1 is methyl and both R2 and R5 are hydrogen, R3 is other than methyl or halo;
(h) provided that when R3 is cyano, R1 is methyl; and
any tautomer of the above structure or a pharmaceutically acceptable salt, or biohydrolyzable ester, amide, or imide thereof.
The compounds of the present invention are useful in treating many medical disorders, including for example, respiratory disorders, ocular disorders, gastrointestinal disorders, disorders associated with sympathetic nervous system activity, migraine, peripheral pain, and disorders where vasoconstriction would provide a benefit. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment using these compounds or the compositions containing them.
xe2x80x9cAlkylxe2x80x9d is an unsubstituted saturated or unsaturated hydrocarbon chain having 1 to 3 carbon atoms. Alkyl chains may be straight, branched or cyclized. Preferred alkyl groups are methyl, ethyl, and cyclopropyl.
xe2x80x9cBiohydrolyzable amidexe2x80x9d refers to an amide of a compound of the invention that is readily converted in vivo by a subject to yield an active compound of the invention.
xe2x80x9cBiohydrolyzable esterxe2x80x9d refers to an ester of a compound of the invention that is readily converted by a subject to yield an active compound of the invention.
xe2x80x9cHaloxe2x80x9d, xe2x80x9chalogenxe2x80x9d, or xe2x80x9chalidexe2x80x9d is a chloro, bromo, fluoro or iodo. Preferred halo are chloro, bromo, and iodo. More preferred halo are chloro and bromo.
xe2x80x9cPharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., carboxyl) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987, incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include halides, sulfonates, carboxylates, phosphates, and the like. Clearly contemplated in such salts are addition salts that may provide an optical center, where once there was none. For example, a chiral tartrate salt may be prepared from the compounds of the invention, and this definition includes such chiral salts.
xe2x80x9cPrimatexe2x80x9d includes humans.
The present invention involves compounds having the following structure:
In the above structure, R1 is alkyl. Preferred R1 is methyl, ethyl or cyclopropyl.
In the above structure, R2 is hydrogen, alkyl, methoxy, cyano, or halo. Preferred R2 is hydrogen, alkyl, or cyano. More preferred R2 is methyl or halo.
In the above structure, R3 is hydrogen, methyl, hydroxy, cyano or halo. Preferred R3 is cyano or hydroxy when R1 is methyl. Most preferred R3 is cyano when R1 is methyl. Preferred R3 is methyl or halo when R1 is other than methyl.
In the above structure, R4 is hydrogen, methyl, ethyl or isopropyl. Preferred R4 is hydrogen or methyl, more preferably hydrogen.
In the above structure, R5 is hydrogen, methyl, amino, methoxy, hydroxy, cyano or halo. Preferred R5 is hydrogen, methyl, or halo.
In the above structure, at least one of R2, R3, R4, and R5 is other than hydrogen or fluorine. In addition, when R1 is methyl and both R2 and R5 are hydrogen, then R3 is other than methyl or halo. Finally, when R3 is cyano, R1 is methyl.
The invention includes tautomers of the above structure. For example, when tautomer D of a molecule is shown (see below), it is understood to include tautomer E. Thus, the disclosure of one tautomeric form discloses each and all of the tautomers.
The invention also includes pharmaceutically acceptable acid addition salts, biohydrolyzable esters, amides, and imides of the above structure.
The compounds of the invention are sufficiently basic to form acid-addition salts. The compounds are useful both in the free base form and the form of acid-addition salts, and both forms are within the purview of the invention. The acid-addition salts are in some cases a more convenient form for use. In practice, the use of the salt form inherently amounts to the use of the base form of the active. Acids used to prepare acid-addition salts include preferably those which produce, when combined with the free base, medicinally acceptable salts. These salts have anions that are relatively innocuous to the animal organism, such as a mammal, in medicinal doses of the salts so that the beneficial property inherent in the free base are not vitiated by any side effects ascribable to the acid""s anions.
Examples of appropriate acid-addition salts include, but at not limited to hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogensulfate, acetate, trifluoroacetate, nitrate, maleate, citrate, fumarate, formate, stearate, succinate, mallate, malonate, adipate, glutarate, lactate, propionate, butyrate, tartrate, methanesulfonate, trifluoromethanesulfonate, p-toluenesulfonate, dodecyl sulfate, cyclohexanesulfamate, and the like. However, other appropriate medicinally acceptable salts within the scope of the invention are those derived from other mineral acids and organic acids. The acid-addition salts of the basic compounds are prepared by several methods. For example the free base can be dissolved in an aqueous alcohol solution containing the appropriate acid and the salt is isolated by evaporation of the solution. Alternatively, they may be prepared by reacting the free base with an acid in an organic solvent so that the salt separates directly. Where separation of the salt is difficult, it can be precipitated with a second organic solvent, or can be obtained by concentration of the solution.
Although medicinally acceptable salts of the basic compounds are preferred, all acid-addition salts are within the scope of the present invention. All acid-addition salts are useful as sources of the free base form, even if the particular salt per se is desired only as an intermediate product. For example, when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a medicinally acceptable salt by ion exchange procedures, these salts are clearly contemplated to be a part of this invention.
The compounds of the invention are useful for the treatment of a variety of diseases, disorders, and conditions that are modulated by alpha-2 adrenoceptors or by alpha-2 adrenoceptor activity. As used herein, the terms xe2x80x9cdisease,xe2x80x9d xe2x80x9cdisorderxe2x80x9d and xe2x80x9cconditionxe2x80x9d are used interchangeably. As used herein, a disorder described by the terms xe2x80x9cmodulated by alpha-2 adrenoceptors,xe2x80x9d or xe2x80x9cmodulated by alpha-2 adrenoceptor activityxe2x80x9d refers to a disorder, condition or disease where alpha-2 adrenoceptor activity is an effective means of alleviating the disorder or one or more of the biological manifestations of the disease or disorder; or interferes with one or more points in the biological cascade either leading to the disorder or responsible for the underlying disorder; or alleviates one or more symptoms of the disorder. Thus, disorders subject to xe2x80x9cmodulationxe2x80x9d include those for which:
The lack of alpha-2 activity is a xe2x80x9ccausexe2x80x9d of the disorder or one or more of the biological manifestations, whether the activity was altered genetically, by infection, by irritation, by internal stimulus or by some other cause;
The disease or disorder or the observable manifestation or manifestations of the disease or disorder are alleviated by alpha-2 activity. The lack of alpha-2 activity need not be causally related to the disease or disorder or the observable manifestations thereof;
Alpha-2 activity interferes with part of the biochemical or cellular cascade that results in or relates to the disease or disorder. In this respect, the alpha-2 activity alters the cascade, and thus controls the disease, condition or disorder.
The compounds of the invention are peripherally-selective alpha-2 adrenoceptor agonists. Alpha-2 adrenoceptors are distributed both inside and outside of the central nervous system. Thus, for example, a compound which displays a higher degree of central nervous system activity is preferred, but not limited to, use in central nervous system indications such as certain cardiovascular disorders (e.g., hypertension), pain, substance abuse and/or withdrawal. By centrally acting it is meant that they have some action on the alpha-2 adrenoceptors in the central nervous system in addition to their action at peripheral alpha-2 adrenoceptors.
Peripherally-acting compounds are preferred for, but not limited to, the treatment of respiratory disorders, ocular disorders, migraine, certain cardiovascular disorders, and certain gastrointestinal disorders. By peripherally acting, it is meant is that these compounds do not readily cross the blood-brain barrier and thus act primarily on alpha-2 adrenoceptors in the periphery. In addition, further specificity of action of these compounds can be achieved by delivering the agent to the region where activity is desired (for example, topical administration to the eye, nasal mucosa or respiratory tract), thereby reducing systemic exposure. Such peripherally-selective compounds have reduced CNS side effect potentials, particularly with respect to sedation. Methods are available in the art to determine which compounds are less centrally-acting than others.
The compounds of the subject invention have no or only weak alpha-1 agonist activity and have little or no effect on the central nervous system, even when dosed systemically.
Thus, the compounds of the invention are particularly useful for the treatment of respiratory disorders including nasal congestion associated with allergies, colds, and other nasal disorders, (as well as the sequelae of congestion of the mucous membranes, for example, sinusitis and otitis media), cough, chronic obstructive pulmonary disease and asthma. At effective doses, it has been found that undesired side effects can be avoided.
The compounds of the invention are also useful for the treatment of ocular disorders such as ocular hypertension, glaucoma, hyperemia, conjunctivitis, and uveitis.
The compounds of the invention are also useful for controlling gastrointestinal disorders, such as diarrhea, irritable bowel syndrome, hyperchlorhydria and peptic ulcer.
The compounds of the invention are also useful for diseases and disorders associated with sympathetic nervous system activity, including hypertension, myocardial ischemia, cardiac reperfusion injury, angina, cardiac arrhythmia, heart failure and benign prostatic hypertrophy.
The compounds of the invention are also useful for the prophylactic or acute treatment of migraine.
The compounds of the invention are also useful for the treatment of peripheral pain states associated with various disorders (for example, peripheral neuralgia).
The compounds of the invention are also useful for other diseases and disorders where vasoconstriction, particularly of veins, would provide a benefit, including septic or cardiogenic shock, elevated intracranial pressure, hemmorhoids, venous insufficiency, varicose veins, and menopausal flushing.
The pharmacological activity and selectivity of these compounds can be determined using published test procedures. The alpha-2 selectivity of the compounds is determined by measuring receptor binding affinities and in vitro functional potencies in a variety of tissues known to possess alpha-2 and/or alpha-1 receptors. (See, e.g., The Alpha-2 Adrenergic Receptors, L. E. Limbird, ed., Humana Press, Clifton, N.J.) The following in vivo assays are typically conducted in rodents or other species. Central nervous system activity is determined by measuring locomotor activity as an index of sedation. (See, e.g., Spyraki, C. and H. Fibiger, xe2x80x9cClonidine-induced Sedation in Rats: Evidence for Mediation by Postsynaptic Alpha-2 Adrenoreceptorsxe2x80x9d, Journal of Neural Transmission, Vol. 54 (1982), pp. 153-163). Nasal decongestant activity is measured using rhinomanometry as an estimate of nasal airway resistance. (See, e.g., Salem, S. and E. Clemente, xe2x80x9cA New Experimental Method for Evaluating Drugs in the Nasal Cavityxe2x80x9d, Archives of Otolaryngology, Vol. 96 (1972), pp. 524-529). Antiglaucoma activity is determined by measuring intraocular pressure. (See, e.g., Potter, D., xe2x80x9cAdrenergic Pharmacology of Aqueous Human Dynamicsxe2x80x9d, Pharmacological Reviews, Vol. 13 (1981), pp. 133-153). Antidiarrheal activity is determined by measuring the ability of the compounds to inhibit prostaglandin-induced diarrhea. (See, e.g., Thollander, M., P. Hellstrom and T. Svensson, xe2x80x9cSuppression of Castor Oil-Induced Diarrhea by Alpha-2 Adrenoceptor Agonistsxe2x80x9d, Alimentary Pharmacology and Therapeutics, Vol. 5 (1991), pp. 255-262). Efficacy in treating irritable bowel syndrome is determined by measuring the ability of compounds to reduce the stress-induced increase in fecal output. (See, e.g., Barone, F., J. Deegan, W. Price, P. Fowler, J. Fondacaro and H. Ormsbee III, xe2x80x9cCold-restraint stress increases rat fecal pellet output and colonic transitxe2x80x9d, American Journal of Physiology, Vol. 258 (1990), pp. G329-G337). Antiulcer and reduction of hyperchlorhydria efficacy is determined by measuring the reduction in gastric acid secretion produced by these compounds (See, e.g., Tazi-Saad, K., J. Chariot, M. Del Tacca and C. Roze, xe2x80x9cEffect of xcex12-adrenoceptor agonists on gastric pepsin and acid secretion in the ratxe2x80x9d, British Journal of Pharmacology, Vol. 106 (1992), pp. 790-796). Antiasthma activity is determined by measuring the effect of the compound on bronchoconstriction associated with pulmonary challenges such as inhaled antigens. (See, e.g., Chang, J. J. Musser and J. Hand, xe2x80x9cEffects of a Novel Leukotriene D4 Antagonist with 5-Lipoxygenase and Cyclooxygenase Inhibitory Activity, Wy-45,911, on Leukotriene-D4- and Antigen-Induced Bronchoconstriction in Guinea Pigxe2x80x9d, International Archives of Allergy and Applied Immunology, Vol. 86 (1988), pp. 48-54; and Delehunt, J., A. Perruchound, L. Yerger, B. Marchette, J. Stevenson and W. Abraham, xe2x80x9cThe Role of Slow-Reacting Substance of Anaphylaxis in the Late Bronchial Response After Antigen Challenge in Allergic Sheepxe2x80x9d, American Reviews of Respiratory Disease, Vol. 130 (1984), pp. 748-754). Activity in cough is determined by measuring the number and latency of the cough response to respiratory challenges such as inhaled citric acid. (See, e.g., Callaway, J. and R. King, xe2x80x9cEffects of Inhaled xcex12-Adrenoceptor and GABAB Receptor Agonists on Citric Acid-Induced Cough and Tidal Volume Changes in Guinea Pigsxe2x80x9d, European Journal of Pharmacology, Vol. 220 (1992), pp. 187-195). The sympatholytic activity of these compounds is determined by measuring the reduction of plasma catecholamines (See, e.g., R. Urban, B. Szabo and K. Starke xe2x80x9cInvolvement of peripheral presynaptic inhibition in the reduction of sympathetic tone by moxonidine, rilmenidine and UK 14,304xe2x80x9d, European Journal of Pharmacology, Vol. 282 (1995), pp. 29-37) or the reduction in renal sympathetic nerve activity (See, e.g., Feng, Q., S. Carlsson, P. Thoren and T. Hedner, xe2x80x9cEffects of clonidine on renal sympathetic nerve -activity, natriuresis and diuresis in chronic congestive heart failure ratsxe2x80x9d, Journal of Pharmacology and Experimental Therapeutics, Vol. 261 (1992), pp. 1129-1135), providing the basis for their benefit in heart failure and benign prostatic hypertrophy. The hypotensive effect of these compounds is measured directly as a reduction in mean blood pressure (See, e.g., Timmermans, P. and P. Van Zwieten, xe2x80x9cCentral and peripheral xcex1-adrenergic effects of some imidazolidinesxe2x80x9d, European Journal of Pharmacology, Vol. 45 (1977), pp. 229-236). Clinical studies have demonstrated the beneficial effect of alpha-2 agonists in the prevention of myocardial ischemia during surgery (See, e.g., Talke, P., J. Li, U. Jain, J. Leung, K. Drasner, M. Hollenberg and D. Mangano, xe2x80x9cEffects of Perioperative Dexmedetomidine Infusion in Patients Undergoing Vascular Surgeryxe2x80x9d, Anesthesiology, Vol. 82 (1995), pp. 620-633) and in the prevention of angina (See, e.g., Wright, R. A., P. Decroly, T. Kharkevitch and M. Oliver, xe2x80x9cExercise Tolerance in Angina is Improved by Mivazerolxe2x80x94an xcex12-Adrenoceptor Agonistxe2x80x9d, Cardiovascular Drugs and Therapy, Vol. 7 (1993), pp. 929-934). The efficacy of these compounds in cardiac reperfusion injury is demonstrated by measuring the reduction of cardiac necrosis and neutrophil infiltration (See, e.g., Weyrich, A., X. Ma, and A. Lefer, xe2x80x9cThe Role of L-Arginine in Ameliorating Reperfusion Injury After Myocardial Ischemia in the Catxe2x80x9d, Circulation, Vol. 86 (1992), pp. 279-288). The cardiac antiarrhythmic effect of these compounds is demonstrated by measuring the inhibition of ouabain induced arrhythmias (See, e.g., Thomas, G. and P. Stephen, xe2x80x9cEffects of Two Imidazolines (ST-91 and ST-93) on the Cardiac Arrhythmias and Lethality Induced by Ouabain in Guinea-Pigxe2x80x9d, Asia-Pacific Journal of Pharmacology, Vol. 8 (1993), pp.109-113; and Samson, R., J. Cai, E. Shibata, J. Martins and H. Lee, xe2x80x9cElectrophysiological effects of xcex12-adrenergic stimulation in canine cardiac Purkinje fibersxe2x80x9d, American Journal of Physiology, Vol. 268 (1995), pp. H2024-H2035). The vasoconstrictor activity of these compounds is demonstrated by measuring the contractile properties on isolated arteries and veins in vitro (See, e.g., Flavahan, N., T. Rimele, J. Cooke and M. Vanhoutte, xe2x80x9cCharacterization of Postjunctional Alpha-1 and Alpha-2 Adrenoceptors Activated by Exogenous or Nerve-Released Norepinephrine in the Canine Saphenous Veinxe2x80x9d, Journal of Pharmacology and Experimental Therapeutics, Vol. 230 (1984), pp. 699-705). The effectiveness of these compounds at reducing intracranial pressure is demonstrated by measurement of this property in a canine model of subarachnoid hemorrhage (See, e.g., McCormick, J., P. McCormick, J. Zabramski and R. Spetzier, xe2x80x9cIntracranial pressure reduction by a central alpha-2 adrenoreceptor agonist after subarachnoid hemorrhagexe2x80x9d, Neurosurgery, Vol. 32 (1993), pp. 974-979). The inhibition of menopausal flushing is demonstrated by measuring the reduction of facial blood flow in the rat (See, e.g., Escott, K., D. Beattie, H. Connor and S. Brain, xe2x80x9cThe modulation of the increase in rat facial skin blood flow observed after trigeminal ganglion stimulationxe2x80x9d, European Journal of Pharmacology, Vol. 284 (1995), pp. 69-76) as demonstrated for alpha-2 adrenergic agonists on cutaneous blood flow in the tail (See, e.g., Redfern, W., M. MacLean, R. Clague and J. McGrath, xe2x80x9cThe role of alpha-2 adrenoceptors in the vasculature of the rat tailxe2x80x9d, British Journal of Pharmacology, Vol. 114 (1995), pp. 1724-1730). The antimigraine effect of these compounds is demonstrated by measuring the reduction of dural neurogenic inflammation to trigeminal ganglion stimulation in the rat (See, e.g., Matsubara, T., M. Moskowitz and Z. Huang, xe2x80x9cUK-14,304, R(xe2x88x92)-alpha-methyl-histamine and SMS 201-995 block plasma protein leakage within dura mater by prejunctional mechanismsxe2x80x9d, European Journal of Pharmacology, Vol. 224 (1992), pp. 145-150).
It has been observed that some peripherally acting, alpha-2-selective adrenergic agonist benzimidazoles which appear metabolically stable in vitro and in vivo in rodents, are subject to metabolic transformation in primates (i.e., monkeys and humans) via N-methylation at the benzimidazole ring. Such metabolic transformation has been shown to alter the profile of these benzimidazoles such that they may be metabolized into compounds that (1) are inactive; (2) are alpha-2 adrenoceptor antagonists; (3) possess enhanced activity at other undesired receptors, such as at alpha-1 adrenoceptors; and/or (4) have an increased potential for CNS activity. The compounds of the present invention are peripherally acting selective alpha-2 adrenergic compounds that have lower CNS activity and that resist metabolic transformation into such undesirable compounds.
Metabolic stability of the compounds described above is evaluated in vitro in a precision cut liver slice assay and in vivo in pharmacokinetic studies in primates. The precision cut liver slice assay is a well recognized, validated in vitro model to study xenobiotic metabolism in animal species and humans. (See Ekins, S. xe2x80x9cPast, present, and future applications of precision-cut liver slices for in vitro xenobiotic metabolism.xe2x80x9d (Department of Medicine and Therapeutics, University of Aberdeen, UK.) Drug-Metab-Rev. (November, 1996) Vol. 28, No. 4: pp. 591-623). This assay is used to evaluate the metabolic activity of alpha-2 adrenergic agonists. The assay provides data on the biotransformations taking place within intact hepatocytes of the species of interest. Thus the full compliment of phase I and phase II metabolic enzymes are available to metabolize the drug as is the case in vivo.
For the pharmacokinetic studies, the compounds are administered orally to cynomolgus monkeys and measurements of administered benzimidazole compounds and corresponding N-methyl metabolites are made using 100 xcexcL aliquots of urine collected over various time-periods post-dose. Typically, a chemical homolog or stable-isotope-labeled internal standard is added to each sample and then diluted 100xc3x97 in water. Ten xcexcL of prepared sample is then analyzed by gradient HPLC, with tandem mass spectrometry detection. Single ion reaction monitoring schemes are employed to selectively detect the test compound, its N-methyl metabolite (if present), and the internal standard.
The compounds of the present invention show little to no metabolic N-methylation in these assays. In contrast, N-methyl metabolites were found for other alpha-2 selective benzimidazole compounds such as 5-(2-Imidazolinylamino)-4-methylbenzimidazole and 4-ethyl-5-(2-imidazolinylamino)benzimidazole. 5-(2-Imidazolinylamino)-4-methylbenzimidazole provides a very similar pharmacological profile to 7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole (see Example 1 below). That is, both compounds are very potent and selective alpha-2 adrenergic agonists, with very low CNS activity. In the precision cut liver slice assay, there is no evidence of the methyl metabolite for 7-cyano-5-(2-imidazolinylamino)-4-methylbenzimidazole. However, 5-(2-imidazolinylamino)-4-methylbenzimidazole, is rapidly metabolized in this assay and it was found that its metabolite is an alpha-2 adrenergic agonist with a significantly higher potential for CNS activity than the parent compound. 4-ethyl-5-(2-imidazolinylamino)benzimidazole, another selective alpha-2 adrenergic agonist, is rapidly and extensively N-methylated in primates. Its metabolite is a very potent alpha-2 antagonist, rather than an alpha-2 agonist.
The results indicate that the metabolic transformation of benzimidazoles through N-methylation can lead to rapid formation of undesired metabolites that have different pharmacological effects relative to the parent compound and that these effects are not easily predictable. Without being bound by theory it is contemplated that the factor favorably affecting the metabolic stability of the benzimidazole compounds of this invention is the sterical hindrance provided by substituents in close proximity to the benzimidazole nitrogens.
The compounds of this invention can be made using conventional organic syntheses. Particularly preferred syntheses are carried out using the following general schemes, Schemes 1-5. In the following general reaction schemes, R1, R2, R3, R4, and R5 are as defined above. For clarity, R1, R2, R3, R4, and/or R5 do not appear on the intermediates within a specific scheme unless they are prepared or needed in that specific scheme. Preferably, R1 is part of the starting material (see Scheme 1). R2 can be part of the starting material or introduced via amination or bromination followed by functional group manipulation (see Scheme 2). R3 can be part of the starting material (see Scheme 1) or obtained by manipulation of a carboxylic acid (see Scheme 3). R4 is introduced by alkylation of an aniline substrate prior to the benzimidazole ring formation (see Scheme 1). R5 or a direct precursor to R5 is introduced during the benzimidazole ring formation (see Scheme 4). Finally, the 5-(2-imidazolinylamino) group is conveniently obtained from the aminobenzimidazoles prepared according to Schemes 1-4 (see Scheme 5).
The starting materials depicted within the schemes are commercially available or are made from commercially available starting materials and methods known to one of ordinary skill in the art. The skilled artisan may change temperature, pressure, atmosphere, solvents, or the order of reactions as appropriate. Additionally, the skilled artisan may use protecting groups to block side reactions or increase yields as appropriate. All such modifications can be readily be carried out by the skilled artisan in the art of organic chemistry, and thus are within the scope of the invention.

5-(2-imidazolinylamino)-benzimidazole derivatives, their preparation and their use as .alpha.-adrenoceptor agonists with improved metabolic stability

Abstract: are used to treat alpha-2 mediated disorders, including nasal congestion, glaucoma, asthma, migraine, and diarrhea.


The present invention relates to systems, apparatus, and methods of intercepting commands at an application presentation layer. The method includes intercepting, at a proxy client, a command issued by an application to a network resource before the command is converted into a corresponding protocol command. The method further includes forwarding a simplified command of the corresponding protocol command to a proxy server, and converting, at the proxy server, the simplified command into the corresponding protocol command. Further, the method includes transmitting the corresponding protocol command to the network resource and receiving a response from the network resource, such that, the response corresponds to the protocol. The method further includes transmitting a confirmation message to the proxy client upon completion of the corresponding protocol command and transmitting the confirmation message to the application.

Presently, in order to optimize network traffic, the individual commands being transmitted must be captured and an attempt to predict the user's action must be made. Unfortunately, often times a single command made by the user can show up across the network as many individual commands. For example, if the user clicks on a folder stored on a file server and deletes that folder, even though the user only executed one command, the network traffic would include a delete command for each file within the folder. Therefore, because of the delete commands for each file, it is difficult to determine that the user was simply deleting a folder. Hence, improvements in the art are needed.

Methods and systems for presentation layer redirection for network optimization


A low-cost, current sensor suitable for mass production and a manufacturing method thereof are provided. The current sensor is small with high sensitivity and can be packaged in a standard assembly line which is normally used when an integrated circuit is manufactured. Further, it is possible to obtain a sufficient shielding effect against a disturbance flux without degrading the detecting sensitivity of a flux. A first magnetic material 50 is bonded to the lower part of a current conductor 22C. The first magnetic material 50 has the function of converging and amplifying a flux 3 generated by the current to be measured. A second magnetic material 51 is bonded above a magnetic sensor chip 20. The second magnetic material 51 has a shielding function against a disturbance flux entering from the outside.

1. Field of the Invention
The present invention relates to a current sensor and a method of manufacturing the current sensor.
To be specific, the present invention relates to a current sensor of magnetoelectric conversion type, which measures the intensity of a current by detecting a flux generated by the current to be measured with a magnetic field detection element, and a manufacturing method thereof.
2. Description of the Related Art
A Hall sensor using the Hall effect, a magnetoresistive element, a magnetic transistor, etc (or these including an ASIC for amplifying function or adjusting function) are widely known as magnetic sensors. Capturing a magnetic flux created around a current to be measured and measuring its current intensity can be done by using such magnetic field sensors.
For this purpose, a current sensor structure shown in FIG. 1 is widely used conventionally.
However, the current sensor having the configuration of FIG. 1 is not suitable for miniaturization because the sensor requires a magnetic core 4 surrounding a current conductor 2 fed with current. Further, since the magnetic core 4 and a Hall element 6 need to be separately manufactured and then assembled into one, the sensor has not been suitable for mass production and the cost is not low.
In order to solve such an inconvenience, "a magnetic field sensor with a terminal for detecting current" containing a chip with a magnetoelectric conversion element sealed with plastics has been proposed in Japanese Patent Application Laid-Open No. 61-80074 (1986). This publication discloses "a magnetic field sensor with a terminal for detecting current. This magnetic field sensor comprises a current conductor, a magnetoelectric conversion element chip placed on a part of the above current conductor (except both sides of the conductor), lead frames (each side of which are connected to the chip) and a sealing part (for integrally sealing the end of the lead frame, the magnetoelectric conversion element chip, and the part of the chip located on a current conductor). This magnetic field sensor is characterized in that the sensor has both ends of the current conductor as external terminals for current detection".
However, the invention disclosed in Japanese Patent Application Laid-Open No. 61-80074 (1986) has the following problems:
In the invention disclosed in Japanese Patent Application Laid-Open No. 61-80074 (1986), when current flows in the current conductor, a flux appearing concentrically around the current conductor is detected by a magnetic field sensor chip which is placed closely to a surface of the current conductor. And the magnetic field sensor chip mainly has sensitivity only to a flux which is perpendicular to the surface of the chip. The sensor has extremely low sensitivity to a flux in a horizontal direction. For this reason, it is difficult to detect current with high sensitivity.
The magnetic field sensor chip is sensitive to a flux which is perpendicular to the surface of the chip. It is rotated by 90°, and further, the magnetic field sensor chip is placed on a current conductor to detect the current flux in such a way that a flux generated by the current goes through the chip surface perpendicularly.
However, the invention is not practical and lacks mass productivity, considering complexity of a method of fixing the magnetic field sensor chip on the current conductor and a wire bonding method between a sensor chip terminal and a lead frame.
(2) There may be a current which is not a current to be measured around the current sensor. In such an environment, the invention disclosed in Japanese Patent Application Laid-Open No. 61-80074 (1986) is susceptible to an external flux generated by surrounding current. Thus, it is difficult to detect accurately a flux generated by the current to be measured.
(3) In the invention disclosed in Japanese Patent Application Laid-Open No. 61-80074 (1986), the current conductor and the surface of the lead frame (which is connected to the terminal of the magnetic field sensor chip) are not formed on the same height of a plane. Thus, it is difficult to form the lead frame and a current conductor in the process of packaging. And then, at the same time, the invention is not suitable for mass production.
(4) Proper shielding has not been sufficiently performed in the case where a flux generated by disturbance or an external interference magnetic field exists around the magnetic field sensor. In other words, it is desirable to guiding a magnetic flux to be measured by a magnetic detection element while suppressing a disturbance flux to be eliminated. If this is done effectively, a current sensor will contain a smaller measurement error and hold enough magnetic shield. In an actual one-chip current sensor, it has not been achieved efficiently yet.
Therefore, the present invention provides a low-cost current sensor suitable for mass production and a manufacturing method, the current sensor is small with high sensitivity and can be packaged in a standard assembly line which is normally used for manufacturing an integrated circuit.
Another object of the present invention is to provide a current sensor which is packaged in a standard assembly line with sufficient shielding effect against a disturbance flux, and to provide a manufacturing method thereof.

Current sensor and current sensor manufacturing method


Provided is a MLCC module used as a direct current (DC) link capacitor that is included in an inverter of a hybrid vehicle. The MLCC module includes: a plurality of first ceramic sheets 10, each including a plurality of first internal electrode portions 20; a plurality of second ceramic sheets 30, each being disposed between the plurality of first ceramic sheets 10 respectively to include a plurality of second internal electrode portions 40; a plurality of external electrode portions 50 being connected to the plurality of first internal electrode portions 20, respectively; a plurality of clamp lead electrode portions 60 being connected to the plurality of external electrode portions 50 to input and output electrical signals, respectively; and an epoxy molding compound (EMC) molding member sealing the plurality of first ceramic sheets 10, the plurality of second ceramic sheets 30, and the plurality of external electrode portions 50 to expose one ends of the plurality of clamp lead electrode portions 50, respectively.

1. Field
The present invention relates to a MLCC module, and more particularly, to a MLCC(multi layer ceramic capacitor) module used as a direct current (DC) link capacitor that is included in an inverter of a hybrid vehicle.
2. Background
A hybrid vehicle is driven by an engine and a power of a battery. A force distribution apparatus of the hybrid vehicle includes a fuel battery, a motor, an inverter, a motor control unit (MCU), and a direct current (DC)-to-DC (DC/DC) converter.
The fuel battery generates electricity, and the motor is driven by the force of the generated electricity. The MCU controls the inverter with a pulse width modulation (PWM). The DC/DC converter converts the power generated in the fuel battery to supply the converted power as power of various types of electric field loads. The inverter switches DC voltage output from the fuel battery according to control of the MCU to convert the DC voltage to three-phase alternative current (AC) and supply the same as drive power of the motor.
A DC link capacitor is applied to the inverter that supplies the drive power to the motor. A MLCC (multi layer ceramic capacitor) module may be applied as the conventional DC link capacitor. The conventional MLCC module uses a plurality of aluminum electrolytic capacitors.
The above references are incorporated by reference herein where appropriate for appropriate teachings of additional or alternative details, features and/or technical background.
When a plurality of aluminum electrolytic capacitors is used as a conventional MLCC module, electrolyte is used and thus unique resistance is high, decreasing equivalent series resistance (ESR) characteristic and insulation resistance (IR) characteristic. Since the IR characteristic is decreased, impedance characteristic is also deteriorated.
The present invention is conceived to solve the above-described problems and thus an aspect of the present invention provides a MLCC module that can use, as a dielectric substance, ceramic with a high dielectric constant and thereby can enhance the high capacity regardless of a small size and also can obtain low ESR characteristic and low IR characteristic and also can improve heat-dissipation characteristic.
Another aspect of the present invention also provides a MLCC module that can extend the horizontal length of a MLCC module with respect to the vertical length thereof and thereby can improve ESL characteristic.
According to an aspect of the present invention, there is provided a MLCC module including: a plurality of first ceramic sheets, each including a plurality of first internal electrode portions; a plurality of second ceramic sheets, each being disposed between the plurality of first ceramic sheets respectively to include a plurality of second internal electrode portions; a plurality of external electrode portions being connected to the plurality of first internal electrode portions, respectively; a plurality of clamp lead electrode portions being connected to the plurality of external electrode portions to input and output electrical signals, respectively; and an epoxy molding compound (EMC) molding member sealing the plurality of first ceramic sheets, the plurality of second ceramic sheets, and the plurality of external electrode portions to expose one ends of the plurality of clamp lead electrode portions, respectively.


A computing device with an expansion module that may be removed and replaced in an expansion slot is disclosed. The computing device includes computer circuitry to which the expansion module may be electrically connected by means of electrical connectors. The expansion module is coupled to a removable portion of the housing so that when said portion is swung open with assistance of mechanical force, the expansion module is simultaneously disengaged from the computer circuitry. Thereafter, the expansion module can be further removed from said portion.

This invention relates to a computing device with an expansion module.
It is well known that the performance of a computer may be enhanced by the use of expansion modules. Known expansion modules, or boards, may, for example, increase the memory or improve the sound or video capabilities of a computer. The computer will typically receive and accommodate the expansion module in one or more available expansion slots. However, it is also common, as in the case of memory expansion, for an existing module in an expansion slot to be replaced by an expansion module with improved performance. Memory expansion can include both increasing the size of Random Access Memory (RAM) and upgrading information or program code on Read Only Memory (ROM).
Desktop computers typically have expansion slots located within the main casing of the computer. In general, the computer casing has to be opened up before a new expansion module can be added. Portable computers tend to be less expandable than their desktop counterparts. This is usually due to the limited space available within the computer casing.
A known laptop computer, the OmniBook(copyright) 5500CT (available from Hewlett-Packard, USA), includes two memory slots that accommodate two memory expansion boards. To add a new memory board, a user initially removes a cover portion of the housing from the memory expansion slot. If a memory expansion board is already present, then it may be pulled out by the user. The user then positions the new memory board over the two connectors in the slot and presses down on the board until it seats fully.
A drawback with the expansion slot in the OmniBook(copyright) computer is that the expansion module is prone to damage. Firstly, the memory board contains memory chips that can be damaged by electrostatic discharge caused by manual handling. Secondly, applying manual pressure directly on the memory board when it is pushed into place can cause the board to crack. The user may not realize that the memory board is seated fully and may further increase pressure on the board in an attempt to position it properly. Thirdly, a user may attempt to position the new memory board in an incorrect orientation in the expansion slot that can result in damage to the connectors and the memory chips.
A known handheld computer, the HP 340LX (available from Hewlett-Packard, USA), uses a ROM chip to store the operating system code. When it is desired to upgrade the operating system, the user simply removes a cover portion from the front of the computer, slides out a circuit board module with the old ROM chip, and replaces it by sliding in a new expansion module with an upgraded ROM chip. Like the OmniBook(copyright) expansion module, the expansion module for the HP 340LX is also prone to damage from manual handling during insertion.
A solution to the preceding problems is provided in a pending US patent application entitled xe2x80x9cExpansion Modulexe2x80x9d with the serial number of 09/354,235, assigned to the current assignee. According to this patent application, the expansion module is coupled to a removable portion of the housing so that when the housing portion is replaced, the expansion module is simultaneously received in the expansion slot. The housing portion may then be slid laterally to a locking position. Nonetheless, in this patent application, the user needs to remove the keyboard and unfasten three screws that secure the keyboard located at the bottom of the case in order to get access to the expansion mode. This procedure makes the replacement inconvenient.
Therefore, there exists a need for a more convenient way to realize the replacement of expansion modules without enhancing the risk of damage to the module.
In a preferred embodiment, the invention provides a computing device with an expansion module that may be removed and replaced by a user with ease and with less risk of damage to the module. The computing device includes computer circuitry to which the expansion module may be electrically connected. Both the computer circuitry and the expansion module include electrical connectors, which when mated provide the electrical connection.
An embodiment of a computing device includes a computer circuitry, an expansion module, and a housing substantially enclosing the computer circuitry. Both the computer circuitry and the expansion module have a respective electrical connector for electrically connecting to each other. The housing has a housing cover that is removable from and replaceable on the reminder of the housing. The housing cover is coupled to the expansion module so that removal of the housing cover simultaneously separates the expansion module from the computer circuit, and replacement of the housing cover connects the two respective electrical connectors. With assistance of mechanical force, the housing cover can be swung open. This action causes the two electrical connectors to separate from each other. Thereafter, the expansion module can be further removed from the housing cover.
Preferably, friction between the two electrical connectors keeps them connected. The mating of the two connectors may further prevent movement of the expansion module. The housing cover is also restricted from movement when the expansion module is secured to the housing cover.
In a preferred embodiment of the invention, the computer device also has a locking means to provide the mechanical assistance for the removal and replacement of the housing cover. The locking means has a rear portion and a front portion, and is removable in a predetermined direction relative to the housing. A part of the housing cover is locked between the two portions. Furthermore, the locking means has a driven means through which the locking means is driven to move in the predetermined direction. When the locking means moves in a removal direction, the rear portion pushes the housing cover so that the housing cover is swung open. This action causes the two electrical connectors to separate from each other, either in partial or complete disengagement. The expansion module can be further detached from the computer circuitry by simply lifting the housing cover up. When the user wants to secure the expansion module, the locking means is driven in a replacement direction opposite to the removal direction. The front portion pushes the housing cover and the housing cover is driven back so that the two electrical connectors are connected and the expansion module is secured. Moreover, the locking means restricts the housing cover from movement when the expansion module is secured.


A digital-to-analog (D/A) converter used for a digital audio equipment, comprises a binary D/A converting circuit and a calculation processing circuit for receiving an analog signal derived from the binary D/A converting circuit. This D/A converter is capable of considerably reducing a load given to an LPF (low-pass filter) or, of omitting such an LPF. The binary D/A converting circuit outputs an analog signal value corresponding to each sampling point of a digital signal as a first analog output value, and also outputs an analog output signal value delayed by only 1 sampling period as a second analog output value. A difference calculating unit of the calculation processing circuit calculates a difference value between the first analog output value as a first analog input value, and the second analog output value as a second analog input value. The resultant difference value is integrated by an integrating unit and the integrated difference value is outputted as an analog output value from the calculation processing circuit. A portion of the output value of the integrating unit is returned to the input side of the difference calculating unit to be added to the second analog input signal value.

(1) Field of the Invention
The present invention relates to a digital-to-analog (D/A) converter connected at a poststage of a digital signal processing circuit in a digital audio appliance.
(2) Description of the Prior Art
Generally speaking, in such a sort of digital-to-analog converter (will be referred to a "D/A converter"), it is so arranged that a digital signal value outputted at each sampling point of a digital signal processing circuit is converted into an analog signal value (analog stepped wave) by way of a ladder type D/A convertering circuit, and then the resultant analog signal value is filtered by an LPF (low-pass filter to remove a high frequency signal component therefrom.
Then, the load given to the LPF is reduced by employing such a technique as over sampling operation, so that deterioration of audient sound (tone) quality caused by the LPF may be mitigated.
However, since the output signal wave of the above-described conventional D/A converter has a shape of a stepped waveform, the low-pass filter (LPF) is necessarily required. Accordingly, the phase characteristic is deteriorated and the lengthy delay time occurs due to an employment of such an LPF. It is therefore difficult to improve the audient sound quality at a satisfactory level.

Digital-to-analog converter capable of reducing load of low-pass filter


A disposable pull-on diaper having a wearer-facing surface and a garment-facing surface; a longitudinal centerline and a lateral centerline; a front waist region, a back waist region, and a crotch region disposed between the front and back waist regions. The front waist region and back waist region of the pull-on diaper interconnect to form a waist opening and leg openings. The pull-on diaper includes an absorbent assembly and an elastic belt. The absorbent assembly includes a liquid pervious topsheet, a liquid impervious backsheet, and an absorbent core disposed between the topsheet and backsheet. The elastic belt may exhibit less than about 80% of the maximum force after 15 seconds as measured by the Percent Release Test.

It has long been known that absorbent articles such as conventional taped diapers, pull-on diapers, training pants, sanitary napkins, pantiliners, incontinence briefs, and the like, offer the benefit of receiving and containing urine and/or other bodily exudates. To effectively contain exudates, the articles should provide a snug fit around the waist and legs of a wearer. Articles such as conventional diapers generally include a front and a rear waist section releasably connected by a fastening means. Application of a conventional diaper is usually performed by a caregiver with the wearer in a supine position. Such diapers may allow for easy application by the caregiver but generally make self-application by the wearer very difficult. Furthermore, conventional diapers may be difficult to apply when the wearer is in a standing position.
Disposable pull-on diapers were developed, in part, to address the problem associated with conventional diapers such as difficulties related to self-application and standing application. Pull-on diapers are designed to effectively contain exudates while allowing for self-application. Pull-on diapers generally include a front waist region, a back waist region, and a crotch region therebetween. The front waist region and back waist region may be attached to form a waist opening and pair of leg openings. Generally, pull-on diapers are manufactured in a prejoined configuration such that the front and rear waist sections do not need to be attached by a wearer or caregiver prior to wear. In one particular facet, pull-on diapers have become popular for use on children who are able to walk and who may be engaged in toilet training. Pull-on diapers may serve as an intermediary product for the child between a conventional diaper and underwear. The pull-on provides a milestone for the child who may be toilet training and developing independence from the caregiver. However, to be an effective advance over a conventional diaper, the pull-on should not only allow for self-application but should also provide a mechanism for easier self-application.
Unfortunately, current pull-on diapers may be difficult for self-application by a child. Many pull-on diapers have elastic elements in the portion of the pull-on diaper that encircles the waist of the child during wear. The elastic elements allow the pull-on diaper to achieve a snug, conforming fit about the waist of the child. The elastic elements also allow the pull-on diaper to fit a range of shapes and sizes thereby enabling the pull-on diaper to exhibit a degree of customized fit. While the elastic elements are beneficial once applied, the elastic elements may inhibit the process of application and, particularly, self-application. During application, the waist opening of a pull-on diaper may be enlarged from its relaxed dimensions. Enlargement of the waist opening is often necessary given the geometry of a child wearer. As the pull-on diaper is pulled from a child's feet to the child's buttocks, the circumference of the child generally increases. Ideally, the pull-on diaper will maintain an enlarged waist opening during the application process. Specifically, throughout the application process, the waist opening circumference should stay larger than the circumference of the child over which the waist opening must pass. Child studies have shown that self-application of a garment (e.g., underwear or pull-on diaper) may take anywhere from about 12 seconds to about 2 minutes depending upon factors such as the child's size, dexterity, strength, and attention span. Typically, self-application may take from about 15 seconds to about 30 seconds.
However, existing pull-on diapers do not maintain an enlarged waist opening once elongated. Elastic elements within the pull-on diaper may exert a force that constricts the waist opening. The child or caregiver may need to exert a lateral force either to increase the size of the waist opening of the pull-on diaper or to maintain the size of the waist opening. The need to exert a lateral force may exist if the waist opening of the pull-on diaper constricts to a circumference smaller than a circumference of the child over which the diaper must pass at some given time of application. For example, the region of the buttocks typically is the greatest circumference over which pull-on diaper must pass. A lateral force may need to be applied to the pull-on diaper if the diaper's waist opening is smaller than the circumference around the child's buttocks when the diaper passes over the buttocks during application.
It should also be appreciated that any constrictive force pressing against the body of the wearer results in friction that must be overcome in the application process. If the pull-on diaper is in contact with wearer's body as the diaper is applied, the waist opening must continue to expand which results in increased strain upon the elastic elements. Increased strain often results in increased normal forces which further increases the friction that must be overcome by the child. Given a child's limited dexterity and strength, an increase in friction may make successful application of the pull-on diaper impossible.
Furthermore, as the pull-on diaper is advanced up the legs, the anatomy of the wearer may serve as a geometric barrier to application. The buttocks may serve as barrier that can catch the waist edge of the pull-on diaper and effectively prevent further upward advancement of the pull-on diaper. The waist opening may need to be enlarged to a circumference generally greater than that of the buttocks. The forces exhibited by elastic elements in current products may make enlargement of the waist circumference difficult for the applicator and impossible for a child.
Another factor making application of a pull-on diaper difficult is waist opening deformation. Ideally, the shape of waist opening of the pull-on diaper should mirror the shape of the wearer and, particularly the shape of the child at the point of greatest circumference. Generally, a circular or elliptical (e.g., an ellipse having an aspect ratio of approximately 1:1 to 1:2) shaped waist opening are preferred. However, if the waist opening must be enlarged, this preferred waist opening shape can be deformed. For example, in enlarging the waist opening, the applicator typically grasps the pull-on diaper at two points evenly spaced around the waist edge. Applying a lateral force creates a line of force traveling between the grasp points. As the waist opening elongates along this line of force, the waist opening may draw in or neck in a direction perpendicular to the lateral line of force. Since the applicator often grasps the sides of the pull-on diaper that are proximate to the hips of the wearer, the pull-on diaper may neck between the front and the back of the diaper. Necking of the diaper in the front and the back may further hinder application since the waist opening is being necked in at the point where the wearer's geometry protrudes, the buttocks.
Even if a caregiver wishes to aid the wearer in self-application, current pull-on diapers may frustrate such efforts. A caregiver may enlarge the size of the waist opening of a pull-on diaper before providing the pull-on diaper to the wearer for application. Ideally, the caregiver may stretch the waist opening to a circumference greater than that of the lower torso of the wearer. However, if the elongating force is not maintained, the pull-on diaper will typically "snap back" to substantially its original, relaxed dimension due to the force exerted by the elongated elastic elements. The elastic elements of current pull-on diaper construction are aggressive in that they contract rapidly and exert relatively high forces. As a result, if the pull-on diaper is expanded by a caregiver and then provided to a child, the child is left with a pull-on diaper that may require application of a continuous elongating force or else the product returns to its original, relaxed dimension.
In light of the problems described above, it is desirable to provide a disposable pull-on diaper that is tailored for ease of application and, especially, ease of self-application by a child. It would be beneficial to provide a disposable pull-on diaper having a waist circumference that retains its elongated state for some period of time after release of the elongating force. It would be particularly beneficial if this period of time approximates the average time necessary for the application process. It would also be beneficial to provide a disposable pull-on diaper requiring only minimal force to maintain elongation or to re-elongate the pull-on diaper. It would also be beneficial if the pull-on diaper exerted a gradual increase in force upon recovery.

Disposable pull-on diaper having a low force, slow recovery elastic waist


A multicast traffic transmission method includes: detecting (S201) whether a transmission link between a designed forwarder (DF) and a traffic reception device is abnormal; and when the transmission link between the DF and the traffic reception device is abnormal, sending (S202) a first request to a backup designed forwarder (BDF). A packet of the first request includes a protection mark and address information about the traffic reception device, and the first request is used for requesting the BDF to forward traffic to the traffic reception device.

With the development of communication technologies, the multicast technology has been widely used in current Internet services. For example, the multicast technology can be applied to network conference, live broadcast of sports events or concerts, live broadcast teaching of network or medical operation and the like.
In the application of the multicast technology, two or more traffic forwarders are generally configured, and the traffic forwarders are configured to forward multicast traffic to a traffic reception device. In some cases, when a traffic transmission link between one of the traffic forwarders and the traffic reception device is abnormal, traffic reception by the traffic reception device is affected by the abnormal transmission link, so that the efficiency of receiving multicast traffic by the traffic reception device is low.

Multicast traffic transmission method, related device and computer-readable storage medium


A multi-container transfer and delivery device configured to allow multiple containers to transfer and mix their respective materials and for receiving of the mixed materials to a delivery device. The transfer device comprises a plurality of flow conduits for fluid flow between the multiple containers and the delivery device. Methods of mixing using the device and methods of sterilizing the device are described. A drug mixing kit comprising a multi-container housing with a plurality of flow conduits and a plurality of compartments for receiving containers and a transfer device is also described.

Lyophilized and similar liquid drugs are typically provided in medicament vials with standard elastomeric closure sizes, such as 20 mm and 13 mm diameter closures. Injections of these drugs, if administered to patients intramuscularly, intravenously, subcutaneously, and the like, require syringes with needles for delivery to the patient. Needles used to administer a drug to a patient are often different from the needle or access device used to access the medicament vials. Certain needle types are special for drug vials—such as anti-coring needles—and would be inappropriate for use when injecting a patient. For instance, a pharmacy technician may use a high flow rate needle to withdraw diluent from one source, and inject it into a lyophilized drug vial. The drug is then mixed accordingly and drawn back into the syringe—or perhaps a new, sterile syringe. Oftentimes the drug preparation needle is removed, disposed of and replaced by an alternate sterile needle appropriate for the specific type of patient injection e.g. deltoid intramuscular. Because prescribed mixing and preparation of drugs vary, certain drugs need to be mixed carefully, or flow through specific sized needles; or the drug is extremely expensive so residual drug left in the vial is undesirable. This is difficult to resolve due, in part, to vial closure design and varying materials. So it may become important to pair the appropriate needle or access device with the medicament vial. Furthermore, the resultant injection process varies—the location and type of injection. Someone other than the prescriber, typically a technician or nurse, often completes the preparation and may not even be the administrator of the medication. So, there are multiple steps that can be done in error. The time of preparation can be significant, adding cost and complexity to the process. By switching needles so often and using them for drug preparation, the likelihood of needle-stick injuries increases, causing pain and concern for healthcare providers, at a minimum, and leading to potential transmission of blood borne pathogens and potentially serious diseases. The necessary aseptic preparation of a drug and its delivery is also a challenge to the caregiver and presents a safety concern for the patient if not performed well.

Multi-container transfer and delivery device


A glitch filter identifies and eliminates positive edge and negative edge glitches without utilizing a high frequency sampling clock. The glitch filter comprises a programmable delay buffer string, two multiple input AND gates and a latch. The buffer string provides a plurality of incrementally delayed signals and utilizes them as signal samples thus simulating a high frequency sampling clock. The two multiple input AND gates serve to eliminate positive or negative edge glitches. The latch outputs the accurate filtered data without any positive or negative edge glitches.

In bus application circuits a common problem exists called the "wired OR phenomena". This phenomena may become evident when a plurality of pull-down transistors 10a-10i are configured in parallel with each other as seen in FIG. 1. When one or more transistors 10a-i stop conducting, the remainder of the transistors in the parallel path must conduct the total current. During the brief period of time when the current is being redistributed through the remaining conducting transistors, the node voltage, V.sub.0, may glitch high. The magnitude of the glitch is proportional to the percentage of pull-down transistors 10a-i that discontinue conduction.
After redistribution of current in remaining conducting pulldown transistors 10a-i, the positive edge glitch goes away and the proper node voltage, V.sub.0, is established. The "wired OR" phenomena may cause an error in logic operation if, during sampling, the glitch causes internal logic to change states.
Checking for "wired OR" type glitches often requires clocks with frequencies as high as several hundred megahertz to assure that all glitches are identified and eliminated. Providing a high frequency clock requires another clock circuit to be designed and built thus increasing die area on a semiconductor chip or requires another discrete clock (such as a crystal oscillator) to be put on the circuit board which increases system cost and increases board complexity. Further, the existence of a high frequency clock has detrimental effects on performance of the semiconductor chip by increasing the chip's power dissipation. In CMOS integrated circuits (which are overwhelmingly used in digital integrated circuit applications) power dissipation is directly proportional to frequency of operation. Therefore, the high frequency circuitry, whether internal or external to the semiconductor die, increases the chip power dissipation which often is a critical design constraint and therefore unacceptable.
It is an object of this invention to provide a digital glitch filter that identifies and eliminates high frequency glitches without the addition of a high frequency sampling clock.
It is another object of this invention to provide a programmable glitch filter so that a user may manually dictate the specific duration of the sampling window desired to filter glitches.
Other objects and advantages of the invention will become apparent to those of ordinary skill in the art having reference to the following specification together with the drawings herein.


A valve actuator is disclosed for use with short throw valves. The actuator includes a plate perpendicular to the valve stem that has a slot formed of regions having different radii of curvature centered on the valve stem. An eccentric cam is attached to a handle mounted on the valve stem. The cam extends through the slot and is rotatable for positioning at a radius corresponding to the radius of the different slot regions. When the cam is rotated so that it may traverse a slot region, the handle can be turned to move the valve closing member through an angle subtended by the slot region. This permits the valve to be opened or closed in a step-wise fashion and prevents rapid opening and closing of the valve that can cause a water hammer effect.

Piping systems, such as those used to deliver water to fire suppression sprinkler systems, handle large liquid flow rates under significant pressure. The flow to the sprinkler system is controlled by one or more shut-off valves which may be, for example, slow closing gate valves each operated by a hand wheel turning a jackscrew. Slow closing valves are mandated for sprinkler applications by various specifications, such as those promulgated by Underwriters' Laboratories (UL) or Factory Mutual (FM) to prevent damage upstream of the valve due to the water hammer effect which will occur if a valve is closed rapidly. In pipes carrying high flow rates under significant pressure, the change in momentum caused by a sudden valve closing will generate high transient forces on the pipes which can cause their mountings to fail and the pipe to leak or rupture, thereby rendering the sprinkler system inoperative.
It is desirable to use short throw valves such as quarter-turn ball valves and butterfly valves to control water flow to a sprinkler system due to the simplicity and reliability of such valves. However, these valves are capable of very rapid closing and may cause significant damage to the piping system due to the water hammer effect when manually operated without constraint. To use short throw valves and avoid the water hammer problem, the valves have been modified, for example, by the addition of a multi-turn handle coupled with reduction gearing to prevent quick closing. Such modifications defeat the purpose of using simple quarter turn valves, however, as the modifications render the valves more complicated, more expensive and less reliable. There is clearly a need for a short throw valve that is operable in a manner that avoids the water hammer effect but maintains the simplicity and reliability inherent in such valves.


Methods, apparatus, and articles of manufacture to extend a leading-edge vortex of a highly-swept wing aircraft wing are disclosed. An example apparatus includes a shoulder wing coupled to a fuselage of an aircraft above a highly-swept wing of the aircraft, the shoulder wing operative in a first position to extend a leading-edge vortex spanwise along the highly-swept wing of the aircraft.

Aircraft have become increasingly specialized to meet a growing number of mission profiles for a wide variety of commercial and military applications. Aircraft are being customized due to various parameter constraints impacting efficiency, maneuverability, and speed of the aircraft. In the commercial aircraft industry, a heavy emphasis is placed on the fuel economy of an aircraft. This emphasis results in driving many design parameters towards increasing the fuel economy of the aircraft. However, in military and reconnaissance flight applications, emphasis areas include payload capacity, stealth ability as well as landing on and taking-off from a range of runway sizes.
The main wings of an aircraft are painstakingly designed to meet a myriad of in-flight parameters that include generating a required amount of lift while exposing the aircraft to a minimal amount of drag. The main wings are also designed dependent upon whether the aircraft has a tail assembly. An aircraft with a tail assembly uses both the main wings and the tail surfaces to assist with aerodynamic control and stabilization. An aircraft without a tail assembly, commonly called a tailless aircraft, incorporates the pitch and roll aerodynamic control and stabilization functions into the main wings of the aircraft.
A tailless aircraft can be further customized with swept main wings. A swept wing is angled (i.e., swept) either forward or backward from the root of the wing. An angle or degree to which the main wings are swept can vary. The angle at which the wing is swept is referred to as the sweep angle. The sweep angle for wings on a subsonic aircraft (e.g., a commercial transport aircraft, a general aviation aircraft, etc.) may range from approximately 0-40 degrees, while the sweep angle for wings on a high-speed aircraft (e.g., a fighter jet) can be 45 degrees or more. Aircraft wings that have a sweep angle of approximately 45 degrees or more are referred to as highly-swept aircraft wings. Highly-swept wings may be classified as either subsonic highly-swept wings or supersonic highly-swept wings. For example, highly-swept wings with a larger leading edge radius may be better suited for subsonic flight (e.g., flight below speed of sound), while highly-swept wings with a smaller leading edge radius may be better suited for supersonic flight (e.g., flight at or above speed of sound). Consequently, an aircraft that has main wings where the sweep angles are more than 45 degrees are referred to as highly-swept wing aircraft, or highly swept aircraft. Highly-swept wings allow an aircraft to reach higher speeds during cruise and make maneuvers at high-angles of attack. However, utilizing highly-swept wings in a tailless aircraft design may cause the aircraft to become uncontrollable at low speed. For example, the tailless aircraft design may produce lift at low speed (e.g., a speed at which the aircraft is landing, a speed at which the aircraft is taking off, etc.) at an expense of reduced control due to an absence of a tail to trim out an induced pitching moment.

Methods and apparatus to extend a leading-edge vortex of a highly-swept aircraft wing


Methods and compositions for transporting drugs and macromolecules across biological membranes are disclosed. In one embodiment, the invention includes a method for enhancing transport of a selected compound across a biological membrane, wherein a biological membrane is contacted with a conjugate containing a biologically active agent that is covalently attached to a transport polymer. In one embodiment, the polymer consists of from 6 to 25 subunits, at least 50% of which contain a guanidino or amidino sidechain moiety. The polymer is effective to impart to the attached agent a rate of trans-membrane transport across a biological membrane that is greater than the rate of trans-membrane transport of the agent in non-conjugated form.

The present invention is directed to methods and compositions that are effective to enhance transport of biologically active agents, such as organic compounds, polypeptides, oligosaccharides, nucleic acids, and metal ions, across biological membranes.
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All references cited within this application are incorporated herein by references.
The plasma membranes of cells present a barrier to passage of many useful therapeutic agents. In general, a drug must be freely soluble in both the aqueous compartments of the body and the lipid layers through which it must pass, in order to enter cells. Highly charged molecules in particular experience difficulty in passing across membranes. Many therapeutic macromolecules such as peptides and oligonucleotides are also particularly intractable to transmembrane transport. Thus, while biotechnology has made available a greater number of potentially valuable therapeutics, bioavailability considerations often hinder their medicinal utility. There is therefore a need for reliable means of transporting drugs, and particularly macromolecules, into cells.
Heretofore, a number of transporter molecules have been proposed to escort molecules across biological membranes. Ryser et al. (1979) teaches the use of high molecular weight polymers of lysine for increasing transport of various molecules across cellular membranes, with very high molecular weights being preferred. Although the authors contemplated polymers of other positively charged residues such as ornithine and arginine, operativity of such polymers was not shown.
Barsoum et al. (1994) and Fawell et al. (1994) proposed using shorter fragments of the tat protein containing the tat basic region (residues 49-57 having the sequence RKKRRQRRR (SEQ ID NO: 1). Barsoum et al. noted that moderately long polyarginine polymers (MW 5000-15000 datons) failed to enable transport of .beta.-galactosidase across cell membranes (e.g., Barsourm on page 3), contrary to the suggestion of Ryser et al. (supra).
Other studies have shown that a 16 amino acid peptide-cholesterol conjugate derived from the Antennapedia homeodomain is rapidly internalized by cultured neurons (Brugidou et al., 1995). However, slightly shorter versions of this peptide (is residues) are not effectively taken up by cells (Derossi et al., 1996).
The present invention is based in part on the applicants"" discovery that conjugation of certain polymers composed of contiguous, highly basic subunits, particularly subunits containing guanidyl or amidinyl moieties, to small molecules or macromolecules is effective to significantly enhance transport of the attached molecule across biological membranes. Moreover, transport occurs at a rate significantly greater than the transport rate provided by a basic HIV tat peptide consisting of residues 49-57 (SEQ ID NO: 1).
The present invention includes, in one aspect, a method for enhancing transport of a selected compound across a biological membrane. In the method, a biological membrane is contacted with a conjugate containing a biologically active agent that is covalently attached to at least one transport polymer. The conjugate is effective to promote transport of the agent across the biological membrane at a rate that is greater than the trans-membrane transport rate of the biological agent in non-conjugated form.
In one embodiment, the polymer consists of from 6 to 25 subunits, at least 50% of which contain a guanidino or amidino sidechain moiety, wherein the polymer contains at least 6, and more preferably, at least 7 guanidino or amidino sidechain moieties. In another embodiment, the polymer consists of from 6 to 20, 7 to 20, or 7 to 15 subunits. More preferably, at least 70% of the subunits in the polymer contain guanidino or amidino sidechain moiety, and more preferably still, 90%. Preferably, no guanidino or amidino sidechain moiety is separated from another such moiety by more than one non-guanidino or non-amidino subunit. In a more specific embodiment, the polymer contains at least 6 contiguous subunits each containing either a guanidino or amidino group, and preferably at least 6 or 7 contiguous guanidino sidechain moieties.
In another embodiment, the transport polymer contains from 6 to 25 contiguous subunits, from 7 to 25, from 6 to 20, or preferably from 7 to 20 contiguous subunits, each of which contains a guanidino or amidino sidechain moiety, and with the optional proviso that one of the contiguous subunits can contain a non-arginine residue to which the agent is attached.
In one embodiment, each contiguous subunit contains a guanidino moiety, as exemplified by a polymer containing at least six contiguous arginine residues.
Preferably, each transport polymer is linear. In a preferred embodiment, the agent is attached to a terminal end of the transport polymer.
In another specific embodiment, the conjugate contains a single transport polymer.
The transport-enhancing polymers are exemplified, in a preferred embodiment, by peptides in which arginine residues constitute the subunits. Such a polyarginine peptide may be composed of either all D-, all L- or mixed D- and L-arginines, and may include additional amino acids. More preferably, at least one, and preferably all of the subunits are D-arginine residues, to enhance biological stability of the polymer during transit of the conjugate to its biological target.
The method may be used to enhance transport of selected therapeutic agents across any of a number of biological membranes including, but not limited to, eukaryotic cell membranes, prokaryotic cell membranes, and cell walls. Exemplary prokaryotic cell membranes include bacterial membranes. Exemplary eukaryotic cell membranes of interest include, but are not limited to membranes of dendritic cells, epithelial cells, endothelial cells, keratinocytes, muscle cells, fungal cells, bacterial cells, plant cells, and the like.
According to a preferred embodiment of the invention, the transport polymer of the invention has an apparent affinity (Km) that is at least 10-fold greater, and preferably at least 100-fold greater, than the affinity measured for tat(49-75) peptide by the procedure of Example 6 when measured at room temperature (23xc2x0 C.) or 37xc2x0 C.
Biologically active agents (which encompass therapeutic agents) include, but are not limited to metal ions, which are typically delivered as metal chelates; small organic molecules, such anticancer (e.g., taxane) and antimicrobial molecules (e.g., against bacteria or fungi such as yeast); and macromolecules such as nucleic acids, peptides, proteins, and analogs thereof. In one preferred embodiment, the agent is a nucleic acid or nucleic acid analog, such as a ribozyme which optionally contains one or more 2xe2x80x2-deoxy nucleotide subunits for enhanced stability. Alternatively, the agent is a peptide nucleic acid (PNA). In another preferred embodiment, the agent is a polypeptide, such as a protein antigen, and the biological membrane is a cell membrane of an antigen-presenting cell (APC). In another embodiment, the agent is selected to promote or elicit an immune response against a selected tumor antigen. In another preferred embodiment, the agent is a taxane or taxoid anticancer compound. In another embodiment, the agent is a non-polypeptide agent, preferably a non-polypeptide therapeutic agent. In a more general embodiment, the agent preferably has a molecular weight less than 10 kDa.
The agent may be linked to the polymer by a linking moiety, which may impart conformational flexibility within the conjugate and facilitate interactions between the agent and its biological target. In one embodiment, the linking moiety is a cleavable linker, e.g., containing a linker group that is cleavable by an enzyme or by solvent-mediated cleavage, such as an ester, amide, or disulfide group. In another embodiment, the cleavable linker contains a photocleavable group.
In a more specific embodiment, the cleavable linker contains a first cleavable group that is distal to the biologically active agent, and a second cleavable group that is proximal to the agent, such that cleavage of the first cleavable group yields a linker-agent conjugate containing a nucleophilic moiety capable of reacting intramolecularly to cleave the second cleavable group, thereby releasing the agent from the linker and polymer.
In another embodiment, the invention can be used to screen a plurality of conjugates for a selected biological activity, wherein the conjugates are formed from a plurality of candidate agents. The conjugates are contacted with a cell that exhibits a detectable signal upon uptake of the conjugate into the cell, such that the magnitude of the signal is indicative of the efficacy of the conjugate with respect to the selected biological activity. This method is particularly useful for testing the activities of agents that by themselves are unable, or poorly able, to enter cells to manifest biological activity. In one embodiment, the candidate agents are selected from a combinatorial library.
The invention also includes a conjugate library which is useful for screening in the above method.
In another aspect, the invention includes a pharmaceutical composition for delivering a biologically active agent across a biological membrane. The composition comprises a conjugate containing a biologically active agent covalently attached to at least one transport polymer as described above, and a pharmaceutically acceptable excipient. The polymer is effective to impart to the agent a rate of trans-membrane transport that is greater than the trans-membrane transport rate of the agent in non-conjugated form. The composition may additionally be packaged with instructions for using it.
In another aspect, the invention includes a therapeutic method for treating a mammalian subject, particularly a human subject, with a pharmaceutical composition as above.
These and other objects and features of the invention will become more fully apparent when the following detailed description of the invention is read in conjunction with the accompanying drawings.

Method and composition for enhancing transport across biological membranes

The Board of Trustees of the Leland Stanford Junior University


A recording paper including a color varying layer which normally exhibits a predetermined color and a substrate layer having a color different from that of the color varying layer, wherein the predetermined color disappears when a beam of specific wavelength is incident thereon.

1. Field of the Invention
The present invention relates to a recording paper on which an image, such as letters, can be directly recorded by beam scanning. The invention further relates to a recording apparatus, such as a printer or copier, etc., for recording information on the recording paper.
2. Description of related Art
It is known to use a coloring agent having a predetermined color which disappears when a specific wavelength is made incident thereon as a copying toner. Namely, if the coloring agent is used as a copying toner, information recorded on a copying paper is erased when the copying paper receives a beam of specific wavelength incident thereon, thereby restoring the copying paper so that it may be reused. An article entitled "Trends" in "NIKKEI MECHANICAL" dated Jul. 22, 1991 discloses such a toner.
The known coloring agent is made of a mixture of IR820B which is a blue cyanine dye and ammonium salt of organic boron compound. When a wavelength of 820 nm (near-infrared radiation) is incident on the coloring agent, the blue color disappears, so that the coloring agent becomes transparent. It is assumed that this phenomenon occurs due to an irreversible reaction which occurs when the IR820B absorbs the wavelength of 820 nm in the presence of ammonium salt of organic boron compound, which functions as a catalyst.
However, the applicability of such a coloring agent has been limited to a copying toner to make copying papers reusable. Namely, the conventional concept of the application of the coloring agent is addressed only to reusable copying paper.
In a conventional laser printer, a laser beam is on-off modulated in accordance with printing data output from a computer to form a latent image on a photosensitive drum. The latent image is then transferred to the recording paper through a toner. This type of laser printer is accordingly complex.
Furthermore, in a conventional copying machine, an image is formed on a photosensitive drum by light reflected from an original document (manuscript, etc.) to be copied and the image is then transferred to the recording paper through a toner, again, resulting in a complex construction.

Recording paper and recording apparatus using same


A reactive matrix infiltration process is described herein, which includes contacting a surface of a preform comprising reinforcement material particles with a molten infiltrant comprising a matrix material, the matrix material comprising an Al—Ce alloy, whereby the infiltrant at least partially fills spaces between the reinforcement material particles by capillary action and reacts with the reinforcement material particles to form a composite material form, the composite material comprising the matrix material, at least one intermetallic phase, and, optionally, reinforcement material particles. A composite material form also is described, which includes a plurality of reinforcement material particles comprising a metal alloy or a ceramic, a matrix material at least partially filling spaces between the reinforcement material particles; and at least one intermetallic phase surrounding at least some of the reinforcement material particles. The reinforcement material particles and intermetallic phase together may form a gradient core-shell structure.

Powder preform parts may be manufactured through an additive manufacturing technique such as binder jetting, slurry vat photopolymerization, or slurry extrusion or traditional powder processing techniques such as die pressing or powder injection molding. The binder jet technique forms layered builds through depositing a liquid binder onto a flat powder bed layer by layer loosely bonding the powder together into the desired shape. At least one disadvantage to these additive manufacturing processes is that the final step in such processes —that is, binder burn-off and powder sintering—leads to less geometrically accurate parts compared to parts produced by powder bed fusion additive manufacturing techniques. In other words, shrinkage of the sintered parts can be anywhere from 20-40% and is often uneven and unpredictable. Processes that can avoid these drawbacks and provide parts with lower or no distortion and suitable mechanical strength are needed in the art.

Reactive matrix infiltration of powder preforms

University of Tennessee Research Foundation


A convertible hunting utility cart including a frame portion. A pair of wheels are rotatably coupled with the frame portion. A U-shaped handle is pivotally and removably coupled with the frame portion. A hitch portion is couplable to the frame portion. A sled portion is couplable to the frame portion between the pair of wheels.

1. Field of the Invention
The present invention relates to a convertible hunting utility cart and more particularly pertains to transporting game and gear while hunting with a convertible hunting utility cart.
2. Description of the Prior Art
The use of hunter carts is known in the prior art. More specifically, hunter carts heretofore devised and utilized for the purpose of aiding a hunter while hunting are known to consist basically of familiar, expected and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which have been developed for the fulfillment of countless objectives and requirements.
By way of example, U.S. Pat. No. 5,295,556 to Mullin discloses a multipurpose hunting cart.
U.S. Pat. No. 5,004,263 to Hubbard discloses a utility cart.
U.S. Pat. No. Des. 333,370 to Monk discloses the ornamental design for a hunter's cart.
U.S. Pat. No. Des. 327,968 to Wright discloses the ornamental design for a hunter's carrying cart.
U.S. Pat. No. Des. 312,716 to Stephens, III discloses the ornamental design for a hunters cart.
U.S. Pat. No. 5,351,976 to Penson discloses an equipment cart.
While these devices fulfill their respective, particular objective and requirements, the aforementioned patents do not describe a convertible hunting utility cart for transporting game and gear while hunting.
In this respect, the convertible hunting utility cart according to the present invention substantially departs from the conventional concepts and designs of the prior art, and in doing so provides an apparatus primarily developed for the purpose of transporting game and gear while hunting.
Therefore, it can be appreciated that there exists a continuing need for new and improved convertible hunting utility cart which can be used for transporting game and gear while hunting. In this regard, the present invention substantially fulfills this need.