The present invention relates to ether compounds and pharmaceutically acceptable salts thereof; methods for synthesizing the ether compounds; compositions comprising an ether compound or a pharmaceutically acceptable salt thereof; and methods for treating or preventing a disease or disorder selected from the group consisting of a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X, a peroxisome proliferator activated receptor-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, renal disease, cancer, inflammation, and impotence, comprising administering a therapeutically effective amount of a composition comprising an ether compound or a pharmaceutically acceptable salt thereof. The ether compounds and compositions of the invention may also be used to reduce the fat content of meat in livestock and reduce the cholesterol content of eggs.
Obesity, hyperlipidemia, and diabetes have been shown to play a casual role in atherosclerotic cardiovascular diseases, which currently account for a considerable proportion of morbidity in Western society. Further, one human disease, termed xe2x80x9cSyndrome Xxe2x80x9d or xe2x80x9cMetabolic Syndromexe2x80x9d, is manifested by defective glucose metabolism (insulin resistance), elevated blood pressure (hypertension), and a blood lipid imbalance (dyslipidemia). See e.g. Reaven, 1993, Annu. Rev. Med. 44:121-131.
The evidence linking elevated serum cholesterol to coronary heart disease is overwhelming. Circulating cholesterol is carried by plasma lipoproteins, which are particles of complex lipid and protein composition that transport lipids in the blood. Low density lipoprotein (LDL) and high density lipoprotein (HDL) are the major cholesterol-carrier proteins. LDL are believed to be responsible for the delivery of cholesterol from the liver, where it is synthesized or obtained from dietary sources, to extrahepatic tissues in the body. The term xe2x80x9creverse cholesterol transportxe2x80x9d describes the transport of cholesterol from extrahepatic tissues to the liver, where it is catabolized and eliminated. It is believed that plasma HDL particles play a major role in the reverse transport process, acting as scavengers of tissue cholesterol. HDL is also responsible for the removal non-cholesterol lipid, oxidized cholesterol and other oxidized products from the bloodstream.
Atherosclerosis, for example, is a slowly progressive disease characterized by the accumulation of cholesterol within the arterial wall. Compelling evidence supports the belief that lipids deposited in atherosclerotic lesions are derived primarily from plasma apolipoprotein B (apo B)-containing lipoproteins, which include chylomicrons, CLDL, IDL and LDL. The apo B-containing lipoprotein, and in particular LDL, has popularly become known as the xe2x80x9cbadxe2x80x9d cholesterol. In contrast, HDL serum levels correlate inversely with coronary heart disease. Indeed, high serum levels of HDL is regarded as a negative risk factor. It is hypothesized that high levels of plasma HDL is not only protective against coronary artery disease, but may actually induce regression of atherosclerotic plaque (e.g., see Badimon et al., 1992, Circulation 86:(Suppl. III)86-94; Dansky and Fisher, 1999, Circulation 100:1762-3.). Thus, HDL has popularly become known as the xe2x80x9cgoodxe2x80x9d cholesterol.
The fat-transport system can be divided into two pathways: an exogenous one for cholesterol and triglycerides absorbed from the intestine and an endogenous one for cholesterol and triglycerides entering the bloodstream from the liver and other non-hepatic tissue.
In the exogenous pathway, dietary fats are packaged into lipoprotein particles called chylomicrons, which enter the bloodstream and deliver their triglycerides to adipose tissue for storage and to muscle for oxidation to supply energy. The remnant of the chylomicron, which contains cholesteryl esters, is removed from the circulation by a specific receptor found only on liver cells. This cholesterol then becomes available again for cellular metabolism or for recycling to extrahepatic tissues as plasma lipoproteins.
In the endogenous pathway, the liver secretes a large, very-low-density lipoprotein particle (VLDL) into the bloodstream. The core of VLDL consists mostly of triglycerides synthesized in the liver, with a smaller amount of cholesteryl esters either synthesized in the liver or recycled from chylomicrons. Two predominant proteins are displayed on the surface of VLDL, apolipoprotein B-100 (apo B-100) and apolipoprotein E (apo E), although other apolipoproteins are present, such as apolipoprotein CIII (apo CIII) and apolipoprotein CII (apo CII). When a VLDL reaches the capillaries of adipose tissue or of muscle, its triglyceride is extracted. This results in the formation of a new kind of particle called intermediate-density lipoprotein (IDL) or VLDL remnant, decreased in size and enriched in cholesteryl esters relative to a VLDL, but retaining its two apoproteins.
In human beings, about half of the IDL particles are removed from the circulation quickly, generally within two to six hours of their formation. This is because IDL particles bind tightly to liver cells, which extract IDL cholesterol to make new VLDL and bile acids. The IDL not taken up by the liver is catabolized by the hepatic lipase, an enzyme bound to the proteoglycan on liver cells. Apo E dissociates from IDL as it is transformed to LDL. Apo B-100 is the sole protein of LDL.
Primarily, the liver takes up and degrades circulating cholesterol to bile acids, which are the end products of cholesterol metabolism. The uptake of cholesterol-containing particles is mediated by LDL receptors, which are present in high concentrations on hepatocytes. The LDL receptor binds both apo E and apo B-100 and is responsible for binding and removing both IDL and LDL from the circulation. IN addition, remnant receptors are responsible for clearing chylomicrons and VLDL remnants i.e., IDL). However, the affinity of apo E for the LDL receptor is greater than that of apo B-100. As a result, the LDL particles have a much longer circulating life span than IDL particles; LDL circulates for an average of two and a half days before binding to the LDL receptors in the liver and other tissues. High serum levels of LDL, the xe2x80x9cbadxe2x80x9d cholesterol, are positively associated with coronary heart disease. For example, in atherosclerosis, cholesterol derived from circulating LDL accumulates in the walls of arteries. This accumulation forms bulky plaques that inhibit the flow of blood until a clot eventually forms, obstructing an artery and causing a heart attack or stroke.
Ultimately, the amount of intracellular cholesterol liberated from the LDL controls cellular cholesterol metabolism. The accumulation of cellular cholesterol derived from VLDL and LDL controls three processes. First, it reduces the cell""s ability to make its own cholesterol by turning off the synthesis of HMGCoA reductase, a key enzyme in the cholesterol biosynthetic pathway. Second, the incoming LDL-derived cholesterol promotes storage of cholesterol by the action of ACAT, the cellular enzyme that converts cholesterol into cholesteryl esters that are deposited in storage droplets. Third, the accumulation of cholesterol within the cell drives a feedback mechanism that inhibits cellular synthesis of new LDL receptors. Cells, therefore, adjust their complement of LDL receptors so that enough cholesterol is brought in to meet their metabolic needs, without overloading (for a review, see Brown and Goldstein, In, The Pharmacological Basis Of Therapeutics, 8th Ed., Goodman and Gilman, Pergaman Press, NY, 1990, Ch. 36, pp. 874-896).
High levels of apo B-containing lipoproteins can be trapped in the subendothelial space of an artery and undergo oxidation. The oxidized lipoprotein is recognized by scavenger receptors on macrophages. Binding of oxidized lipoprotein to the scavenger receptors can enrich the macrophages with cholesterol and cholesteryl esters independently of the LDL receptor. Macrophages can also produce cholesteryl esters by the action of ACAT. LDL can also be complexed to a high molecular weight glycoprotein called apolipoprotein(a), also known as apo(a), through a disulfide bridge. The LDL-apo(a) complex is known as Lipoprotein(a) or Lp(a). Elevated levels of Lp(a) are detrimental, having been associated with atherosclerosis, coronary heart disease, myocardial infarcation, stroke, cerebral infarction, and restenosis following angioplasty.
Peripheral (non-hepatic) cells predominantly obtain their cholesterol from a combination of local synthesis and uptake of preformed sterol from VLDL and LDL. Cells expressing scavenger receptors, such as macrophages and smooth muscle cells, can also obtain cholesterol from oxidized apo B-containing lipoproteins. In contrast, reverse cholesterol transport (RCT) is the pathway by which peripheral cell cholesterol can be returned to the liver for recycling to extrahepatic tissues, hepatic storage, or excretion into the intestine in bile. The RCT pathway represents the only means of eliminating cholesterol from most extrahepatic tissues and is crucial to maintenance of the structure and function of most cells in the body.
The enzyme in blood involved in the RCT pathway, lecithin:cholesterol acyltransferase (LCAT), converts cell-derived cholesterol to cholesteryl esters, which are sequestered in HDL destined for removal. LCAT is produced mainly in the liver and circulates in plasma associated with the HDL fraction. Cholesterol ester transfer protein (CETP) and another lipid transfer protein, phospholipid transfer protein (PLTP), contribute to further remodeling the circulating HDL population (see for example Bruce et al., 1998, Annu. Rev. Nutr. 18:297-330). PLTP supplies lecithin to HDL, and CETP can move cholesteryl ester made by LCAT to other lipoproteins, particularly apoB-containing lipoproteins, such as VLDL. HDL triglyceride can be catabolized by the extracellular hepatic triglyceride lipase, and lipoprotein cholesterol is removed by the liver via several mechanisms.
Each HDL particle contains at least one molecule, and usually two to four molecules, of apolipoprotein (apo A-I). Apo A-I is synthesized by the liver and small intestine as preproapolipoprotein which is secreted as a proprotein that is rapidly cleaved to generate a mature polypeptide having 243 amino acid residues. Apo A-I consists mainly of a 22 amino acid repeating segment, spaced with helix-breaking proline residues. Apo A-I forms three types of stable structures with lipids: small, lipid-poor complexes referred to as pre-beta-1 HDL; flattened discoidal particles, referred to as pre-beta-2 HDL, which contain only polar lipids (e.g., phospholipid and cholesterol); and spherical particles containing both polar and nonpolar lipids, referred to as spherical or mature HDL (HDL3 and HDL2). Most HDL in the circulating population contains both apo A-I and apo A-II, a second major HDL protein. This apo A-I- and apo A-II-containing fraction is referred to herein as the AI/AII-HDL fraction of HDL. But the fraction of HDL containing only apo A-I, referred to herein as the AI-HDL fraction, appears to be more effective in RCT. Certain epidemiologic studies support the hypothesis that the AI-HDL fraction is antiartherogenic (Parra et al., 1992, Arterioscler. Thromb. 12:701-707; Decossin et al., 1997, Eur. J. Clin. Invest. 27:299-307).
Although the mechanism for cholesterol transfer from the cell surface is unknown, it is believed that the lipid-poor complex, pre-beta-1 HDL, is the preferred acceptor for cholesterol transferred from peripheral tissue involved in RCT. Cholesterol newly transferred to pre-beta-1 HDL from the cell surface rapidly appears in the discoidal pre-beta-2 HDL. PLTP may increase the rate of disc formation (Lagrost et al., 1996, J. Biol. Chem. 271:19058-19065), but data indicating a role for PLTP in RCT is lacking. LCAT reacts preferentially with discoidal and spherical HDL, transferring the 2-acyl group of lecithin or phosphatidylethanolamine to the free hydroxyl residue of fatty alcohols, particularly cholesterol, to generate cholesteryl esters (retained in the HDL) and lysolecithin. The LCAT reaction requires an apoliprotein such apo A-I or apo A-IV as an activator. ApoA-I is one of the natural cofactors for LCAT. The conversion of cholesterol to its HDL-sequestered ester prevents re-entry of cholesterol into the cell, resulting in the ultimate removal of cellular cholesterol. Cholesteryl esters in the mature HDL particles of the AI-HDL fraction are removed by the liver and processed into bile more effectively than those derived from the AI/AII-HDL fraction. This may be due, in part, to the more effective binding of AI-HDL to the hepatocyte membrane. Several HDL receptor receptors have been identified, the most well characterized of which is the scavenger receptor class B, type I (SR-BI) (Acton et al., 1996, Science 271:518-520). The SR-BI is expressed most abundantly in steroidogenic tissues (e.g., the adrenals), and in the liver (Landshulz et al., 1996, J. Clin. Invest. 98:984-995; Rigotti et al., 1996, J. Biol. Chem. 271:33545-33549). Other proposed HDL receptors include HB1 and HB2 (Hidaka and Fidge, 1992, Biochem J. 15:161-7; Kurata et al., 1998, J. Atherosclerosis and Thrombosis 4:112-7).
While there is a consensus that CETP is involved in the metabolism of VLDL- and LDL-derived lipids, its role in RCT remains controversial. However, changes in CETP activity or its acceptors, VLDL and LDL, play a role in xe2x80x9cremodelingxe2x80x9d the HDL population. For example, in the absence of CETP, the HDL becomes enlarged particles that are poorly removed from the circulation (for reviews on RCT and HDLs, see Fielding and Fielding, 1995, J. Lipid Res. 36:211-228; Barrans et al., 1996, Biochem. Biophys. Acta. 1300:73-85; Hirano et al., 1997, Arterioscler. Thromb. Vasc. Biol. 17:1053-1059).
HDL is not only involved in the reverse transport of cholesterol, but also plays a role in the reverse transport of other lipids, i.e., the transport of lipids from cells, organs, and tissues to the liver for catabolism and excretion. Such lipids include sphingomyelin, oxidized lipids, and lysophophatidylcholine. For example, Robins and Fasulo (1997, J. Clin. Invest. 99:380-384) have shown that HDL stimulates the transport of plant sterol by the liver into bile secretions.
Peroxisome proliferators are a structurally diverse group of compounds that, when administered to rodents, elicit dramatic increases in the size and number of hepatic and renal peroxisomes, as well as concomitant increases in the capacity of peroxisomes to metabolize fatty acids via increased expression of the enzymes required for the xcex2-oxidation cycle (Lazarow and Fujiki, 1985, Ann. Rev. Cell Biol. 1:489-530; Vamecq and Draye, 1989, Essays Biochem. 24:1115-225; and Nelali et al., 1988, Cancer Res. 48:5316-5324). Chemicals included in this group are the fibrate class of hypolipidermic drugs, herbicides, and phthalate plasticizers (Reddy and Lalwani, 1983, Crit. Rev. Toxicol. 12:1-58). Peroxisome proliferation can also be elicited by dietary or physiological factors, such as a us high-fat diet and cold acclimatization.
Insight into the mechanism whereby peroxisome proliferators exert their pleiotropic effects was provided by the identification of a member of the nuclear hormone receptor superfamily activated by these chemicals (Isseman and Green, 1990, Nature 347:645-650). This receptor, termed peroxisome proliferator activated receptor a (PPAR60 ), was subsequently shown to be activated by a variety of medium and long-chain fatty acids. PPARxcex1 activates transcription by binding to DNA sequence elements, termed peroxisome proliferator response elements (PPRE), in the form of a heterodimer with the retinoid X receptor (RXR). RXR is activated by 9-cis retinoic acid (see Kliewer et al., 1992, Nature 358:771-774; Gearing et al., 1993, Proc. Natl. Acad. Sci. USA 90:1440-1444, Keller et al., 1993, Proc. Natl. Acad. Sci. USA 90:2160-2164; Heyman et al., 1992, Cell 68:397-406, and Levin et al., 1992, Nature 355:359-361). Since the discovery of PPARxcex1, additional isoforms of PPAR have been identified, e.g., PPARxcex2, PPARxcex3 and PPARxcex4, which are have similar functions and are similarly regulated.
PPREs have been identified in the enhancers of a number of genes encoding proteins that regulate lipid metabolism. These proteins include the three enzymes required for peroxisomal xcex2-oxidation of fatty acids; apolipoprotein A-I; medium-chain acyl-CoA dehydrogenase, a key enzyme in mitochondrial xcex2-oxidation; and aP2, a lipid binding protein expressed exclusively in adipocytes (reviewed in Keller and Whali, 1993, TEM, 4:291-296; see also Staels and Auwerx, 1998, Atherosclerosis 137 Suppl:S19-23). The nature of the PPAR target genes coupled with the activation of PPARs by fatty acids and hypolipidemic drugs suggests a physiological role for the PPARs in lipid homeostasis.
Pioglitazone, an antidiabetic compound of the thiazolidinedione class, was reported to stimulate expression of a chimeric gene containing the enhancer/promoter of the lipid-binding protein aP2 upstream of the chloroamphenicol acetyl transferase reporter gene (Harris and Kletzien, 1994, Mol. Pharmacol 45:439-445). Deletion analysis led to the identification of an approximately 30 bp region responsible for pioglitazone responsiveness. In an independent study, this 30 bp fragment was shown to contain a PPRE (Tontonoz et al., 1994, Nucleic Acids Res. 22:5628-5634). Taken together, these studies suggested the possibility that the thiazolidinediones modulate gene expression at the transcriptional level through interactions with a PPAR and reinforce the concept of the interrelatedness of glucose and lipid metabolism.
In the past two decades or so, the segregation of cholesterolemic compounds into HDL and LDL regulators and recognition of the desirability of decreasing blood levels of the latter has led to the development of a number of drugs. However, many of these drugs have undesirable side effects and/or are contraindicated in certain patients, particularly when administered in combination with other drugs.
Bile-acid-binding resins are a class of drugs that interrupt the recycling of bile acids from the intestine to the liver. Examples of bile-acid-binding resins are cholestyramine (QUESTRAN LIGHT, Bristol-Myers Squibb), and colestipol hydrochloride (COLESTID, Pharmacia and Upjohn Company). When taken orally, these positively charged resins bind to negatively charged bile acids in the intestine. Because the resins cannot be absorbed from the intestine, they are excreted, carrying the bile acids with them. The use of such resins, however, at best only lowers serum cholesterol levels by about 20%. Moreover, their use is associated with gastrointestinal side-effects, including constipation and certain vitamin deficiencies. Moreover, since the resins bind to drugs, other oral medications must be taken at least one hour before or four to six hours subsequent to ingestion of the resin, complicating heart patients"" drug regimens.
The statins are inhibitors of cholesterol synthesis. Sometimes, the statins are used in combination therapy with bile-acid-binding resins. Lovastatin (MEVACOR, Merck and Co., Inc.), a natural product derived from a strain of Aspergillus; pravastatin (PRAVACHOL, Bristol-Myers Squibb Co.); and atorvastatin (LIPITOR, Warner Lambert) block cholesterol synthesis by inhibiting HMGCoA, the key enzyme involved in the cholesterol biosynthetic pathway. Lovastatin significantly reduces serum cholesterol and LDL-serum levels. It also slows progression of coronary atherosclerosis. However, serum HDL levels are only slightly increased following lovastatin administration. The mechanism of the LDL-lowering effect may involve both reduction of VLDL concentration and induction of cellular expression of LDL-receptor, leading to reduced production and/or increased catabolism of LDL. Side effects, including liver and kidney dysfunction are associated with the use of these drugs.
Niacin, also known as nicotinic acid, is a water-soluble vitamin B-complex used as a dietary supplement and antihyperlipidemic agent. Niacin diminishes production of VLDL and is effective at lowering LDL. It is used in combination with bile-acid-binding resins. Niacin can increase HDL when administered at therapeutically effective doses; however, its usefulness is limited by serious side effects.
Fibrates are a class of lipid-lowering drugs used to treat various forms of hyperlipidemia, elevated serum triglycerides, which may also be associated with hypercholesterolemia. Fibrates appear to reduce the VLDL fraction and modestly increase HDL; however, the effects of these drugs on serum cholesterol is variable. In the United States, fibrates have been approved for use as antilipidemic drugs, but have not received approval as hypercholesterolemia agents. For example, clofibrate (ATROMID-S, Wyeth-Ayerst Laboratories) is an antilipidemic agent that acts to lower serum triglycerides by reducing the VLDL fraction. Although ATROMID-S may reduce serum cholesterol levels in certain patient subpopulations, the biochemical response to the drug is variable, and is not always possible to predict which patients will obtain favorable results. ATROMID-S has not been shown to be effective for prevention of coronary heart disease. The chemically and pharmacologically related drug, gemfibrozil (LOPID, Parke-Davis), is a lipid regulating agent which moderately decreases serum triglycerides and VLDL cholesterol. LOPID also increases HDL cholesterol, particularly the HDL2 and HDL3 subfractions, as well as both the AI/AII-HDL fraction. However, the lipid response to LOPID is heterogeneous, especially among different patient populations. Moreover, while prevention of coronary heart disease was observed in male patients between the ages of 40 and 55 without history or symptoms of existing coronary heart disease, it is not clear to what extent these findings can be extrapolated to other patient populations (e.g., women, older and younger males). Indeed, no efficacy was observed in patients with established coronary heart disease. Serious side-effects are associated with the use of fibrates, including toxicity; malignancy, particularly malignancy of gastrointestinal cancer; gallbladder disease; and an increased incidence in non-coronary mortality. These drugs are not indicated for the treatment of patients with high LDL or low HDL as their only lipid abnormality.
Oral estrogen replacement therapy may be considered for moderate hypercholesterolemia in post-menopausal women. However, increases in HDL may be accompanied with an increase in triglycerides. Estrogen treatment is, of course, limited to a specific patient population, postmenopausal women, and is associated with serious side effects, including induction of malignant neoplasms; gall bladder disease; thromboembolic disease; hepatic adenoma; elevated blood pressure; glucose intolerance; and hypercalcemia.
Long chain carboxylic acids, particularly long chain xcex1,xcfx89-dicarboxylic acids with distinctive substitution patterns, and their simple derivatives and salts, have been disclosed for treating atherosclerosis, obesity, and diabetes (See, e.g., Bisgaier et al., 1998, J. Lipid Res. 39:17-30, and references cited therein; International Patent Publication WO 98/30530; U.S. Pat. No. 4,689,344; International Patent Publication WO 99/00116; and U.S. Pat. No. 5,756,344). However, some of these compounds, for example the xcex1,xcfx89-dicarboxylic acids substituted at their xcex1,xcex1xe2x80x2-carbons (U.S. Pat. No. 3,773,946), while having serum triglyceride and serum cholesterol-lowering activities, have no value for treatment of obesity and hypercholesterolemia (U.S. Pat. No. 4,689,344).
U.S. Pat. No. 4,689,344 discloses xcex2,xcex2,xcex2xe2x80x2,xcex2xe2x80x2-tetrasubstituted-xcex1,xcfx89-alkanedioic acids that are optionally substituted at their xcex1,xcex1,xcex1xe2x80x2,xcex1xe2x80x2 positions, and alleges that they are useful for treating obesity, hyperlipidemia, and diabetes. According to this reference, both triglycerides and cholesterol are lowered significantly by compounds such as 3,3,14,14-tetramethylhexadecane-1,16-dioic acid. U.S. Pat. No. 4,689,344 further discloses that the xcex2,xcex2,xcex2xe2x80x2,xcex2xe2x80x2-tetramethyl-alkanediols of U.S. Pat. No. 3,930,024 also are not useful for treating hypercholesterolemia or obesity.
Other compounds are disclosed in U.S. Pat. No. 4,711,896. In U.S. Pat. No. 5,756,544, xcex1,xcfx89-dicarboxylic acid-terminated dialkane ethers are disclosed to have activity in lowering certain plasma lipids, including Lp(a), triglycerides, VLDL-cholesterol, and LDL-cholesterol, in animals, and elevating others, such as HDL-cholesterol. The compounds are also stated to increase insulin sensitivity. In U.S. Pat. No. 4,613,593, phosphates of dolichol, a polyprenol isolated from swine liver, are stated to be useful in regenerating liver tissue, and in treating hyperuricuria, hyperlipemia, diabetes, and hepatic diseases in general.
U.S. Pat. No. 4,287,200 discloses azolidinedione derivatives with anti-diabetic, hypolipidemic, and anti-hypertensive properties. However, these administration of these compounds to patients can produce side effects such as bone marrow depression, and both liver and cardiac cytotoxicity. Further, the compounds disclosed by U.S. Pat. No. 4,287,200 stimulate weight gain in obese patients.
It is clear that none of the commercially available cholesterol management drugs has a general utility in regulating lipid, lipoprotein, insulin and glucose levels in the blood. Thus, compounds that have one or more of these utilities are clearly needed. Further, there is a clear need to develop safer drugs that are efficacious at lowering serum cholesterol, increasing HDL serum levels, preventing coronary heart disease, and/or treating existing disease such as atherosclerosis, obesity, diabetes, and other diseases that are affected by lipid metabolism and/or lipid levels. There is also is a clear need to develop drugs that may be used with other lipid-altering treatment regimens in a synergistic manner. There is still a further need to provide useful therapeutic agents whose solubility and Hydrophile/Lipophile Balance (HLB) can be readily varied.
Citation or identification of any reference in Section 2 of this application is not an admission that such reference is available as prior art to the present invention.
In one embodiment, the invention provides novel compounds having the general formula I:
and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H,
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5,
In another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H,
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5,
In yet another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 is selected from the group consisting of xe2x80x94CH2OH, xe2x80x94OC(O)R5, xe2x80x94CHO, xe2x80x94SO3H,
K2 is selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H,
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5,
In yet another embodiment, the invention provides novel compounds having the general formula I and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently selected from the group consisting of xe2x80x94CH2OH, xe2x80x94OC(O)R5, xe2x80x94CHO, xe2x80x94SO3H,
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
with the proviso that when n and m are both 1 or both 0, then K1 and K2 are not both X, wherein X is selected from the group consisting of xe2x80x94COOH, xe2x80x94C(O)OR5,
In still another embodiment, the invention provides novel compounds having the general formula I, and pharmaceutically acceptable salts thereof, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
n and m are independent integers ranging from 0 to 4;
K1 and K2 are independently xe2x80x94CH2OH or xe2x80x94OC(O)R5; and
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl.
The compounds of formula I and pharmaceutically acceptable salts thereof are useful for treating or preventing cardiovascular diseases, dyslipidemias, dyslipoproteinemias, disorders of glucose metabolism, Alzheimer""s Disease, Syndrome X, PPAR-associated disorders, septicemia, thrombotic disorders, obesity, pancreatitis, hypertension, renal diseases, cancer, inflammation, or impotence.
In another embodiment, the invention comprises a compound of the formula IV:
wherein:
n is an integer ranging from 1 to 4;
K1 selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H,
R1, and R2 are independently selected from the group consisting of (C1-C6)alkyl, C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
W is selected from the group consisting of H, (C1-C6)alkyl, and a hydroxy protecting group.
In another embodiment, the invention provides a compound of the formula V:
wherein:
n is an integer ranging from 1 to 4;
K1 selected from the group consisting of xe2x80x94CH2OH, xe2x80x94C(O)OH, xe2x80x94CHO, xe2x80x94C(O)OR5, xe2x80x94OC(O)R5, xe2x80x94SO3H,
R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
R5 is selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl;
each R6 is independently selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl;
R7 is selected from the group consisting of H, (C1-C6)alkyl, (C2-C6)alkenyl, and (C2-C6)alkynyl; and
Hal is selected from the group consisting of chloro, bromo, and iodo.
The compounds of formulas IV and V are useful as intermediates for synthesizing the compounds of formula I.
In still another embodiment, the invention provides a method for the synthesis of a compound of a formula II:
comprising (a) contacting in the presence of a base a compound of a formula XXIV:
with a compound of a formula XXVIII:
to provide a compound of a formula XXIX:
and (b) deprotecting the compound of the formula XXIX to provide the compound of the formula II, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH; and
PG is a hydroxy protecting group.
In still another embodiment, the invention provides a method for the synthesis of a compound of formula III:
comprising contacting a compound of a formula of formula VI:
with a reducing agent, wherein:
R1, R2, R3, and R4 are independently selected from the group consisting of (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, phenyl, and benzyl; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group; or R1, R2, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group and R3, R4, and the carbon to which they are attached are taken together to form a (C3-C7)cycloalkyl group, with the proviso that none of R1, R2, R3, or R4 is xe2x80x94(CH2)0-4Cxe2x89xa1CH;
each R10 is independently selected from the group consisting of xe2x80x94H, xe2x80x94OH, C1-C8)alkoxy, (C6)aryloxy, xe2x80x94O(C2-C6)alkenyl, xe2x80x94Oxe2x80x94(C2-C6)alkynyl, halo; and
n and m are independent integers ranging from 0 to 4.
The present invention further provides compositions comprising a compound of the formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle. These compositions are useful for treating or preventing a disease or disorder selected from the group consisting of a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X, a PPAR-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a renal disease, cancer, inflammation, and impotence. These composition are also useful for reducing the fat content of meat in livestock and reducing the cholesterol content of eggs.
The present invention provides a method for treating or preventing a cardiovascular disease, dyslipidemia, dyslipoproteinemia, a disorder of glucose metabolism, Alzheimer""s Disease, Syndrome X, a PPAR-associated disorder, septicemia, a thrombotic disorder, obesity, pancreatitis, hypertension, a renal disease, cancer, inflammation, and impotence, comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition comprising a compound of formula I, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention further provides a method for reducing the fat content of meat in livestock comprising administering to livestock in need of such fat-content reduction a therapeutically effective amount of a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention provides a method for reducing the cholesterol content of a fowl egg comprising administering to a fowl species a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable vehicle.
The present invention may be understood more fully by reference to the figures, detailed description, and examples, which are intended to exemplify non-limiting embodiments of the invention.


1. Field of the Invention
Embodiments of the present invention generally relate to call handling by sequenced applications, and, in particular, to a system and method for bypassing a sequenced application if inadequate system resources are available.
2. Description of Related Art
Session Initiation Protocol (SIP) is an open signaling protocol for establishing many kinds of real-time communication sessions. Examples of the types of communication sessions that may be established using SIP include voice, video, and/or instant messaging. These communication sessions may be carried out on any type of communication device such as a personal computer, laptop computer, Personal Digital Assistant, telephone, mobile phone, cellular phone, or the like. One key feature of SIP is its ability to use an end-user's Address of Record (AOR) as a single unifying public address for all communications. Thus, in a world of SIP-enhanced communications, a user's AOR becomes their single address that links the user to all of the communication devices associated with the user. Using the AOR, a caller can reach any one of the user's communication devices, also referred to as User Agents (UAs) without having to know each of the unique device addresses or phone numbers.
Many SIP communications are enhanced by virtue of the fact that an application is inserted or included into the communication session during the establishment of that session. The incorporation of applications into a communication session is typically referred to as application sequencing because the applications are sequentially invoked during the establishment of the communication session. In some instances the applications are owned and operated by an enterprise that is administering the SIP network. In some instances, the applications may be provided by third-party vendors. In either event, the traditional way in which applications were included in the communication session was during the communication session establishment stage so that these applications can insert themselves into the signaling and media path of the communication session.
Exemplary types of applications that may be utilized for a communication session include, without limitation, call recording applications, communication log services, conferencing applications, security applications, encryption applications, collaboration applications, whiteboard applications, mobility applications, presence applications, media applications, messaging applications, bridging applications, and any other type of application that can supplement or enhance communications.
Session managers such as Avaya Aura™ for enterprise telephony networks allow sequencing of network applications at session origination and termination phases, in order to affect the way the session is routed in the network. During the origination phase, the call is routed through the servers associated with the calling party's profile. During the termination phase, the call is routed through the servers associated with the called party's profile. The selection of network applications that are used during origination and termination sequencing phases is generally based on the identities of calling and called parties that are involved in a communication session. The list of servers (e.g., feature servers) that forms the sequence vector may be administered at user provisioning time. The calling party's provisioning profile provides the originating sequence vector whereas the called party's profile provides the terminating sequence vector. These two vectors combined provide a map of how a session initiation request travels from calling party to called party in the network.
Sequence vectors presently known in the art are static despite status changes that may occur in the applications that make up the sequence vector. For example, if an application that is in the sequence for a call were to fail, the call setup would fail even if the application is not critical for the completion of the call. However, if the session manager could skip over an application in distress or failure, or execute the application at a reduced level of performance, the call may be completed despite the application being in distress or failure. Currently, there is no easy way for applications that are in the sequence vector to inform a session manager about its current signaling and media status in order to influence the sequencing decision that a session manager makes as a session progresses through the network. Therefore, a need exists to provide dynamic adjustment to sequence vectors in order to provide more robust call handling when a noncritical application is in distress or failure.


The heart is a complicated organ. Stimulation by heart current causes myocardial contraction to pump out blood and makes the blood to circulate in the blood vessel. The heart current passes through the atrium and then the ventricle to cause myocardial contraction. The myocardium rhythmically contracts under the action of heart current. However, the advance in age or the change in pathological and physiological characteristics of the heart causes contraction disorder and abnormal rhythm of the heart. One of the methods to treat arrhythmia is septal ablation, that is, making the abnormal heart current loop open through an interventional surgery. To perform ablation, it is necessary to guide the catheter with an ablation electrode to reach the left atrium. This is usually performed by femoral artery puncture, whereby the electrophysiology catheter with an ablation electrode is delivered to the left atrium under X-ray image observation, the electrode is placed against the orifice of the pulmonary vein, the site of abnormal heart current loop that generates arrhythmia is determined by collecting electric signals, and the discharge energy or other energy generated by the ablation electrode brings about lesion degeneration or coagulative necrosis to the tissue near this site, to thereby cut off the abnormal heart current loop. The energy for use in ablation can be radio frequency current, direct current, microwave, ultrasonic wave or laser.
The key to electrophysiology ablation is positioning of the electrode, namely to determine the site to be ablated in a quick and precise manner. U.S. Pat. No. 6,837,886 B2 proposes an electrophysiology ablation device, whose positioning method is carried out by an openable meshed flat disk concealed in the catheter head. During the process of vein puncture, the disk is concealed in the catheter head, and after the catheter head is inserted into the orifice of the pulmonary vein, the disk is opened to abut against the orifice of the pulmonary vein. The disk is braided from a metal wire, which has electrically conductive function, and is itself an electrode that generates electric pulses once the power is on to carry out circumferential ablation on the orifice of the pulmonary vein. That invention is mainly defective in the following aspect: due to the difference in sizes and shapes of the orifices of the patients' pulmonary veins, it is very difficult in practical operation to abut the meshed flat disk completely against the orifice of the pulmonary vein, but instead usually only in a slanting or partial manner, so that it is impossible to carry out ideal circumferential ablation of the orifice of the pulmonary vein, and adversely affecting the therapeutic effect.


Fuel Cell
A fuel cell is an electrochemical device in which the energy of a chemical reaction is converted directly into electricity. Unlike an electric cell or battery, a fuel cell does not run down or require recharging; it operates as long as the fuel and an oxidizer are supplied continuously from outside the cell.
A fuel cell consists of an anode to which fuel, commonly hydrogen, or methanol, is supplied; and a cathode-to which an oxidant, commonly air or oxygen, is supplied. The two electrodes of a fuel cell are separated by an ionic conductor electrolyte. In the case of a hydrogen-oxygen fuel cell with an alkali metal hydroxide electrolyte, the anode reaction is 2H2+4OH−→4H2O+4e and the cathode reaction is O2+2H2O+4e→4OH−. The electrons generated at the anode move through an external circuit containing the load and pass to the cathode. The OH— ions generated at the cathode are conducted by the electrolyte to the anode, where they form water by combining with hydrogen. The water produced at the anode is removed continuously in order to avoid flooding the cell. Hydrogen-oxygen fuel cells using ion exchange membranes or immobilized phosphoric acid electrolytes found early use in the Gemini and Apollo space programs, respectively.
Hydrogen Fuel Cell
The hydrogen fuel cell is an attractive replacement alternative to the internal combustion engine for producing electricity because it is both highly efficient and weakly polluting. The hydrogen fuel cell has existed for a long time and could produce an estimated 40% of the total energy demand within the next fifty years.
A conventional hydrogen fuel cell identified with numeral reference 10 is shown in FIG. 1. As shown, a hydrogen fuel cell mainly consists of two electrodes, an anode (2) and a cathode (4), separated by an electrolyte (6). At the anode (2), gaseous hydrogen liberates an electron and a positively charged ion. The electron transits through an external circuit (8) producing an electrical current while the ion diffuses through the electrolyte. At the cathode (4), the electrons combine with the hydrogen ions and oxygen to form water a non-polluting waste product that can be reused. A catalyst is used in order to accelerate this oxidizing reaction.
Hydrogen fuel cells are classified according to operating temperature and electrolyte type. There are five different categories of hydrogen fuel cells according to the type of electrolyte used: phosphoric acid; molten carbonate; solid oxide; proton-exchange membrane; and alkaline.
In order to implement hydrogen fuel cells in a day-to-day life, two technological obstacles must be overcome. The first concerns the cell itself and the second concerns the production, storage and transport of the hydrogen that is the energy vector of the process. Up to now, the development of the hydrogen fuel cell has leaped ahead while the hydrogen storage technology lags behind. This technological delay could very well be a determining factor in the marketability of hydrogen fuel cells.
Although hydrogen is a relatively widely present element in nature, it rarely presents itself as a readily available molecularly free gas. Hydrogen is therefore not considered as a source of energy per se, but rather as an energy vector. Various methods are available in order to produce hydrogen. Among these, there is the electrolysis of water or pyrol. However, the only profitable method at the present time is the production of hydrogen from fossil fuels.
Once produced, hydrogen may be stored as a liquid at extremely low temperatures or alternatively, under extremely high pressure. However, the high cost of this storing approach favours the use of a technology where the hydrogen is produced in place and at a production rate governed by its consumption rate. Hence, instead of storing liquid hydrogen, a liquid fuel containing hydrogen, for instance liquid hydrocarbons, is transported in place to be transformed in a later stage, and as needed, into hydrogen.
The presently available hydrogen fuel cell technology typically uses a liquid fuel containing hydrogen, for example diesel, gasoline, methanol, natural gas, etc. Such liquid fuel is converted by a reformer into a gaseous mixture of hydrogen and carbon dioxide. Then, the hydrogen is extracted from the gaseous mixture and supplied to the hydrogen fuel cell.
Methanol, for example, which is in liquid form at room temperature, contains a large quantity of hydrogen that may be chemically extracted. The process used to convert hydrocarbons such as methanol into hydrogen and carbon is internal or external reforming. Partial oxidizing and autothermic reforming are other physico-chemical processes that allow for separation of hydrogen from hydrocarbons. Vapour reforming of hydrocarbons (crude or refined oil, natural gas or gasified coal) yields hydrogen-rich mixtures that must be treated further in order to remove carbon monoxide and carbon dioxide which hinder the operation of certain hydrogen fuel cells.
The vapour reforming of natural gas involves the catalysed endothermic conversion of light hydrocarbons (including methane through gasoline) with water vapour. The industrial process usually occurs at 850° C., under 2.5 mPa of pressure, according to the following equation:CnHm+nH2OnCO+(n+m/2)H2  (I)                where n is an integer equal or greater than 1;m=2n+2.
The catalyzed exothermic conversion (shift reaction) of the carbon monoxide by-product produces hydrogen according to the following equation:CO+H2OCO2+H2  (II)
The CO2 is separated from the gas mixture by absorption processes or membrane separation, and the hydrogen, before being transferred to the hydrogen fuel cell, is treated a second time in order to remove unwanted compounds. Presently, and despite the important costs linked to its extraction, the carbon dioxide is generally released into the atmosphere, thereby contributing to the increase of the greenhouse effect.
The partial oxidizing of heavy hydrocarbons involves the exothermic or autothermic conversion of heavy hydrocarbons in the presence of oxygen and water vapour. The following equation describes the phenomenon:CH1,4+0,3H2O+0,4O20,9CO+0,1CO2+H2  (III)
The partial oxidizing of coal, except for the initial preparation of coal, follows the same process as the one used for the gasification of heavy hydrocarbons. By-products also include CO2.
Although hydrogen fuel cell technologies presently pollute less than internal combustion engines, these systems when combined with hydrocarbon reforming for example, still produce CO2, the greatest contributor in terms of volume to the greenhouse effect. The growing concerns over climatic changes add to the pressures aimed at reducing such emissions which contribute to the greenhouse effect. The aforementioned need for decarbonization of hydrocarbons during reforming is but one example that warrants the use of a carbon dioxide separation and sequestration technology in order to avoid CO2 dumping into the environment. Also, the presence of all the non-hydrogenated contaminants in the fuel decreases the hydrogen fuel cell's power and efficiency.
There already exists, in the prior art, a large number of processes for the production of electricity which are based on the hydrogen fuel cell concept. Among these, many rely on a typically less polluting process than the internal combustion engine but still dump gaseous CO2 back into the atmosphere (JP2001-229946; JP11-229167; WO 01/23302; U.S. Pat. Nos. 6,299,744; 5,746,985) or into the water (U.S. Pat. No. 5,141,823).
Literature abounds with a substantial number of systems integrating a treatment intended to reduce CO2 emissions by these types of cells. The United States government already uses this technology for certain space applications and intends of providing such a system for a future Mars mission (U.S. Pat. No. 5,005,787). The carbon dioxide produced by the crew and the hydrogen fuel cell would be introduced into a greenhouse and in return, the oxygen-charged air would be recirculated back into the living quarters and cabins. Japanese documents JP2000-287546, JP11-275965, and JP06-333589 also propose a similar solution in order to definitely remedy the CO2 emission problem stemming from hydrogen fuel cell operation.
CO2 recycling is also proposed in other applications, often depending on the type of cell used. CA 2,326,024 and JP2001-219271, for example, suggest the recycling of CO2 and its use as a shielding gas during an arc welding process. The molten carbonate cells are a particular case in which CO2 is used in order to enrich the oxidant at the cathode. A number of these technologies aim to convert CO into CO2 first (JP2000-340247; JP2000-302405; JP2000-251918; JP11-199202; TW 432,741), and then to recycle this CO2 toward the hydrogen fuel cell's cathode (JP2000-331698; JP2000-260446; JP11-162488; JP11-067251; JP06-275291; JP02-301968; CA 2,002,227/Absorption).
Some designers wager on a slightly different know-how, namely the methanation of CO2 (JP04-190831; JP08-069808; WO 01/04045; U.S. Pat. Nos. 5,997,594; 6,221,117). Thus reconversion of carbon dioxide into CH4 permits the recycling of carbon and hydrogen by conventional hydrogen fuel cells. U.S. Pat. No. 6,187,465 puts forward a means for recirculating CO2 for a hydrogen fuel cell without any unwanted emissions.
Adsorption is a <<classic>> which invariably sustains interest. Zeolites (JP08-069808; EP 0 700 107) occupy a substantial part of this consideration, but other systems also attract attention such as JP09-204925 which uses an ionic resin. The separation of gaseous hydrogen by way of a porous membrane or surface (JP2001-139304/zirconate; CA 2,322,871) allows for the extraction of CO2 which may then be stocked (WO 01/83364), recycled or discarded (U.S. Pat. No. 5,759,712). There is also the PSA (Pressure Swing Adsorption) described for example in JP10-027621; JP62-274561; and U.S. Pat. No. 6,299,994.
Obviously, the separation and sequestration of CO2 remain a largely explored area covering a realm of possibilities. In view of the fact that carbon dioxide reduces the performance of hydrogen fuel cells, numerous processes include either a CO2 <<separation unit>> (JP62-170171; U.S. Pat. No. 5,248,567; CA 2,332,079), a CO2 <<separation apparatus>> (JP06-044993; JP07-169482; JP04-337252; WO 00/03126), or what is known as a <<scrubbing device>> (WO 01/25140; EP 0 677 883; U.S. Pat. No. 4,537,839; JP59-184468). Finally, JP11-162495 refers to a <<decarbonation system>>.
Absorption of exhaust fumes is another method which sustains keen interest among many inventors as a number of patents/patent applications demonstrate (JP02-206689; JP60-035470; JP60-241673; JP2001-106503/aqueous sodium hydroxide; JP2001-023677/water or alkaline solution; EP 0 376 219) (JP2000-297656; JP04-190831; JP04-051464; WO 01/04045; WO 01/17896; WO 01/23302; WO 01/65621; CA 1,291,787). Although different means have been employed, the cornerstone of innovation in this field remains the improvement of the solubilization of the gas in question.
Also known in the prior art, there are processes aiming at reducing CO2 emissions in general. Examples of those processes are given in U.S. Pat. Nos. 5,514,378; 6,143,556; CA 2,222,030; 6,258,335; and EP 0 991 462.
U.S. Pat. No. 5,514,378 discloses a process for the reduction of CO2 emissions in an enzymatic photobioreactor using carbonic anhydrase. Carbonic anhydrase is a very reactive enzyme that is common to most animal and plant species and hence, readily available. Trachtenberg (U.S. Pat. No. 6,143,556; CA 2,222,030) describes a system for the treatment of exhaust fumes with an enzyme that may be carbonic anhydrase, but does not suggest any specific application with respect to hydrogen fuel cells. The University of Michigan presents a photobioreactor for the treatment of CO2 with carbonic anhydrase for a medical application as an artificial lung (WO 92/00380; U.S. Pat. No. 5,614,378).
U.S. Pat. No. 6,258,335 discloses a catalytic process for the removal of exhaust CO2 through chemical fixation. This process comprises the optional use of carbonic anhydrase without any particular consideration for reforming exhaust. Materials Technology Corporation (U.S. Pat. No. 4,743,545) presents a bioreactor with a catalyst, that may be carbonic anhydrase, included inside of a hollow bead.
EP 0 991 462 in the name of the applicant discloses a counter-current-packed-column for CO2 treatment. In this process, carbonic anhydrase is used in free or immobilized states.
U.S. Pat. No. 6,110,370 discloses a process where carbonic anhydrase is used to treat water and U.S. Pat. Nos. 4,602,987; 4,761,209; CA 1,294,758 in the name of Aquanautics Technology Corporation disclose a method for extracting and using oxygen from fluids. This system includes a step for the separation of CO2 by using the carbonic anhydrase enzyme and an electrochemical cell.
Although a lot of efforts have been put forward in the development and improvement of hydrogen fuel cell in terms of production and storage of the hydrogen fuel, and in terms of reduction of CO2 emissions, there is still place for improvements in this field. More particularly, there is still a need for a process or an apparatus that would provide a simple and affordable way of producing the required fuel, hydrogen; and that without further polluting the atmosphere with CO2 emissions.


Trench excavation for purposes of installing an underground utility infrastructure is an essential and common activity of any ground development work. The common applications are for various kinds of piping, communications, energy etc. There are different types of digging equipment, and each has its advantages and disadvantages. The common denominator with all equipment manufacturers of mechanical digging equipment is the search for solutions that enable more efficient digging and reduction of the limitations connected with ground hardness.
There are two types of equipment in use today, excavators and trenchers. Excavators have a jointed arm powered hydraulically, with a digging tool at one end. The advantage of these machines lies in the fact that they are universal and flexible in the type of digging they can achieve. However, they are not efficient as they do not operate continuousiy, and require three movements, a first movement for digging, a second for removing the soil from the trench and dumping it along the sides of the trench, and a third for returning to the trench for digging. Thus, the effective digging time is approximately only 30% of working time.
Additionally, these machines do not move while digging. At the end of a digging cycle, depending on the length of the arm, they must be re-positioned. For this reason, the total effective digging time is reduced below 30% of the working time.
An additional limitation of these machines is the ground cutting speed of the digging tool. The speed is very low and thus the digging tool requires a large force to split the ground, and must be very heavy. For these reasons, these machines have difficulty digging into hard and rocky ground.
It is possible to equip excavators with a hydraulic hammer to break the rocks, after which another pass is required to clean the trench. Clearly, these extra operations greatly increase the excavation cost.
Trenchers operate in continuous fashion, thus saving valuable working time. The major disadvantages of these machines are that the digging systems are assembled from a large number of moving parts and chains including a separate soil removal system. Multiplication of systems and moving parts reduces the efficiency and technical reliability, while increasing the price. Further, since trenchers have a large contact area with the ground, and cut on a diagonal, they require large amounts of power, force and weight for digging operations.
Other types of trenchers include those having a large digging wheel with cutting teeth. These machines are limited in their cutting depth which is always less than the wheel radius. This type of trencher also has a large contact area with the ground, and since the wheel is driven from its center, large amounts of power and large moments of force are required for digging operations. An additional soil removal system is required.
Examples of patents disclosing trench excavation equipment include Japanese Patent No. 60-25-129 to Miwa, in which a drum-shaped cutter is pivotally supported on the front of a traveler with a conveyer to carry excavated soil to the rear.
Russian Patent 457777 to Kudra discloses a trench excavator device having inclined knives attached to a screw conveyor, facing the spiral direction to improve operation.
French Patent 2,566,024 to Corneille discloses a narrow trench digger with vertical rotating auger, with a parallel partition behind, equipped with soil loosening tools, such as vibrating vertical toothed bars, teeth on the auger spirals, or vertical rotary cutters.
Belgian Patent 902104 to Durieux discloses a trench cutting machine having a rotating tool comprising a pipe on which a flat is spiral wound or threaded with cutting or abrasive pieces. The trench cutting machine propels itself along the ground via a winch. Belgian Patent 1005788 to Durieux discloses a rotary trench cutter with a detachable vertical partition, to produce trenches of different sizes.
Therefore, it would be desirable to provide a trencher for excavating various size trenches, which operates at a high speed with increased capability for use on hard and rocky ground.


High-k materials (k>5.0) are used as insulating spacer materials in semiconductor devices. It is desirable to modify the k-value to improve device performance. In addition, device performance suffers when dopants diffuse into the channel region from the source/drain regions of a semiconductor device. It is desirable to prevent dopant diffusion into the channel region.


A client device may access remotely an application running on a remote server. However, a remote application may be designed for a desktop environment for a large screen, which can make it very difficult for a user at a client device having a small screen to interact with the remote application.
Instead of remotely accessing a desktop application from a client device, the application may be rewritten to run on the client device. However, client devices are typically slower and have limited resources compared with servers (e.g., desktop computer). As a result, rewriting an application on a server to run on a client device can be a huge undertaking requiring a large investment and long development time. For example, it can be very difficult to port existing code from an operating system of a server to a client device (e.g., smartphone). In many cases it is not practical to rewrite an application from scratch to match the native functionality and user interface of a client device.
Accordingly, there is a need for systems and methods that facilitate user interaction with an application running on a server from a client device and provide an improved experience for users at the client device.


Ion implantation is a technology widely used in semiconductor device manufacturing. In an ion implantation apparatus, an ion beam is generated and directed at a semiconductor wafer to implant ions therein, thereby forming ion implanted regions having desired conductivity. For different types of ion implanted regions, different ion beam properties, such as beam current and/or beam energy, are used. Various types of ion implantation apparatuses are developed to provide ion beams of different properties. Examples of such ion implantation apparatuses include medium current implanters (MCI), high current implanters (HCI), and high energy implanters (HEI). Ion implantation apparatuses of different types, e.g., MCI and HCI, are often provided as separate tools.


Power switching devices are routinely used in a number of applications; commonly, a power switching device is implemented by means of a transistor—for example, an Insulated Gate Bipolar Transistor (IGBT)—capable of sustaining high voltages (such as up to 100-1,000V) and of driving large currents (such as up to 0.1-10 A). A typical example of an application of the IGBT is in the automotive field, wherein the IGBT can be used to control the ignition sparks of plugs in an internal-combustion engine.
Particularly, in such application the IGBT is coupled with a primary winding of a transformer; the transformer has a plurality of secondary windings, each one coupled with a respective spark plug. The IGBT is firstly turned on by applying a suitable voltage to its gate terminal. As a result, the IGBT passes from an off (blocking) state—wherein a collector-emitter voltage thereof is about equal to a voltage provided by an automotive battery (typically 12V, with respect to a reference or ground voltage)—to an on state—wherein the same collector-emitter voltage reaches a saturation voltage (such as lower than 1V). In this way, a voltage across the primary winding passes from the ground voltage (i.e., 0V) to approximately the battery voltage (i.e., 12V). This causes the charging of the primary winding with a current having a linear-like pattern. The peak value of this charging current is determined by the length of a time interval, during which the IGBT is kept on. At this point, when the shooting of an ignition spark is required the IGBT is turned off so as to cause an abrupt cut of the charging current. Consequently, an extra-voltage appears across the primary winding; this generates a very high voltage at each secondary winding (of the order of some thousands of volts), which high voltage causes the generation of the ignition spark.
When the IGBT turns on in order to charge the primary winding, the voltage across the primary winding undergoes a sharp variation, having a duration corresponding to a turn-on transient period of the IGBT (while switching from the off state to the on state). Typically, by applying a step voltage to the gate terminal of the IGBT, the duration of the turn-on transient period is of the order of hundreds of nanoseconds. However, this results in a very high incremental ratio ΔV/Δt of the voltage across the primary winding, which generates an overshoot that may cause an undesired ignition spark.
In order to solve this problem, the IGBT is generally controlled to obtain a so-called soft turn-on thereof, wherein the collector-emitter voltage of the IGBT is gradually decreased (from 12V to 1V). For this purpose, it is possible to apply a direct turn-on current to the gate terminal of the IGBT; the turn-on current charges corresponding stray capacitors, so as to increase the gate voltage relatively slowly until the IGBT turns on. In this way, the incremental ratio ΔV/Δt of the voltage across the primary winding of the transformer is greatly reduced (thereby avoiding any undesired ignition sparks).
Unfortunately, the above described soft turn-on procedure may increase a turn-on delay between the application of the signal required to turn-on the IGBT and its actual switching. The turn-on delay may cause a corresponding reduction of the maximum charging current that is reached when the IBGT is turned off to generate the ignition spark, and consequently a reduction of the energy stored in the transformer (for the same time available); this may cause a poor ignition spark when the turn-on delay is too long.
A solution known in the art for reducing the length of the turn-on delay (without causing any overshoots) consists of pre-charging the gate terminal of the IGBT—to a pre-charging voltage lower than its threshold voltage—before the application of the above-described turn-on current. However, the threshold voltage of the IGBT is strictly related to manufacturing process spreads and to temperature variations. Therefore, the pre-charging voltage takes a worst-case value sufficiently low to ensure that the IGBT is kept off (before applying the turn-on current) in any condition. Accordingly, such solution may not be completely satisfactory, since in most practical situations the length of the turn-on delay remains significantly high.
In any case, the length of the turn-on delay varies according to the actual operative conditions. Therefore, it may be impossible to control the generation of the ignition sparks accurately.


Periodic signals are used in a variety of electronic devices. One type of periodic signal are clock signals that can be used to establish the timing of a signal or the timing at which an operation is performed on a signal. For example, data signals are typically coupled to and from memory, such as synchronous dynamic random access memory (“SDRAM”), in synchronism with a clock or data strobe signal. More specifically, read data signals are typically coupled from a memory in synchronism with a read data strobe signal. The read data strobe signal typically has the same phase as the read data signals, and it is normally generated by the same memory device that is outputting the read data signals. Write data signals are typically latched into a memory device in synchronism with a write data strobe signal. The write data strobe signal typically has a phase relative to the write data signals so that a write data strobe signal transitions during a “data eye” occurring at the center of the period in which the write data signals are valid.
Internal clock signals generated in electronic devices, for example, memory devices or memory controllers, are often synchronized or have some other controlled phase relationships relative to external or internal clock signals. For example, with reference to a memory, a clock signal used for both latching write data and outputting read data may be generated in the memory to which the data are being written. The clock signal is typically generated in the memory device from an internal clock signal that is also derived from the system clock signal.
Various techniques can be used to generate a clock signals or read/write data strobe signal. FIG. 1 illustrates a conventional clock circuit 100 providing an output clock signal ICLK to a clock tree circuit 140. When enabled by an active CkEn signal, the clock tree circuit 140 distributes the ICLK signal as a DCLK signal to various circuitry that operate according to the DCLK signal. In FIG. 1, the DCLK signal is provided to data output circuitry 150. In particular, the DCLK signal clocks a data register 154 which provides data to an output buffer 158 to generate a data output signal DQ. The clock circuit 100 generates an ICLK signal that when delayed through the clock tree circuit 140 results in a DCLK signal that is synchronized with a reference clock signal RCLK (and its complement RCLK/). The clock generator includes a delay-locked loop (DLL) 102 and a duty cycle correction (DCC) circuit and output buffer 116. The DLL includes an input buffer 104 that provides a buffered reference clock CLKS to a DLL delay line 108. The delayed buffered reference clock signal is output to the DCC and output buffer 116 for correction of the duty cycle and buffering before being output as the ICLK signal. The ICLK signal is also provided to a model delay 120. The model delay 120 models propagation delay through the output buffer and the clock tree circuit 140. A feedback clock signal FBCLK is output from the model delay 120 and provided through model delay 124 to a phase detector circuit 128 as the DLLFB signal. The model delay 124 models the propagation delay of the input buffer 104. The phase detector circuit 128 detects a phase difference between the CLKS and DLLFB signals. A phase difference signal indicative of the phase difference between the CLKS and DLLFB signals is provided to shift logic 132 that generates a control signal based on the phase difference signal to adjust the delay of the DLL delay line 108. The delay is increased or decreased in order to synchronize the CLKS and DLLFB signals. When synchronized, the clock circuit 100 is said to be “locked.”
Although the timing of the ICLK signal relative to the RCLK (and RCLK/signal) is set by the clock circuit 100 so that the DQ signal output by the clock tree circuit 140 is synchronized with the RCLK signal, there may be a “jitter” in the DQ signal. The clock jitter may be caused by the resolution of adjustment in the DLL delay line 108, and also the resolution of the phase detection by the phase detector circuit 128. Clock jitter may also be caused by varying operating conditions, such as varying power, voltage, and temperature. For example, the ICLK signal may need to be driven over a relatively long signal line to be input in the clock tree circuit 140. Although the propagation delay to the clock tree circuit 140 and through the clock tree circuit 140 is modeled by the feedback model delay 120, the actual propagation delay due to the signal line may vary under changing operating conditions, thus, resulting in clock jitter.


Stack molding is well known in the injection molding art and provides various advantages. In particular, stack molding enables the output of an injection molding machine to be at least doubled without significantly increasing its size or clamping tonnage. Stack molds are typically double or quadruple-level, although there could be any number of stacks in a molding machine. For example, some rubber molds use up to ten levels.
A double level stack mold generally comprises a stationary first platen, a movable center platen and a movable second platen, with two single face mold plates mounted back to back. A first mold (single cavity or multi-cavity) is defined by one of a mold cavity or core plate which is located on the face of the movable center platen adjacent the stationary first platen and the other of the mold cavity or core plate which is located on the stationary first platen. A second mold is defined by one of a mold cavity or core plate which is located on the other face of the moveable center platen adjacent to the movable second platen and the other of the mold cavity or core plate located on the moveable second platen. The molds are opened and closed by a single machine force actuator (generally a hydraulic ram) applied to the moveable second platen and transferred from the second platen to the center platen by a suitable linkage. In a quadruple stack mold, an additional two moveable platens are provided and mold cavity plates and/or mold core plates are located thereon to define additional molds.
To supply molten resin to the cavities of the closed molds, conventional stack molds employ a sprue bar which runs from the machine through the stationary platen to the center platen and which serves as a direct channel between the extruder nozzle of the injection molding machine and the mold's hot runner distributor, which is mounted in the center platen of the stack mold. Alternatively, a movable sprue bar located outside of the mold stack can convey the resin to the center section, as described by Bertschi in U.S. Pat. No. 5,011,646. Sprue bars generally include heaters along their length to maintain the molten state of the resin traveling therethrough and must cope with the relatively high pressure at which the molten resin passes through them.
For injection molding applications where there are more than two levels in the stack mold, multiple sprue bars can be used for delivering a split stream of molten resin to the hot runner distributors in the multi-level injection mold. In this case, after the resin stream is split, the sprue bars carry the resin to the hot runner distributors in their respective mold sections comprising the injection mold. With multi-sprue bar applications, a single source injection unit channel is typically used with a machine nozzle that divides the single source channel into a plurality of channels aligned with the individual sprue bars, as described in U.S. Pat. No. 5,522,720 to one of the present inventors, and assigned to the assignee of the present invention.
In such cases, the sprue bars are normally attached to the respective mold section to which the molding resin is being delivered. Because injection mold sections in a multi-level stack mold generally move in the longitudinal or vertical direction when the mold is open and closed, the sprue bars must be displaced with the mold sections. Accordingly, the sprue bars are not rigidly attached to their source of resin, i.e.--the machine nozzle or the channel splitting device. Consequently, the sprue bar arrangement must be designed so that the sprue bars will return to their sources of resin and reform a seal therewith at the beginning of each molding cycle.
In particular, several design problems are typical for stack molds with more than two levels where resin must flow from a single source injection unit to multiple levels spaced progressively farther from the stationery platen. For example, in a four level stack mold, a sprue bar will feed the first and second level via channels in the mold plate between the two levels and a second sprue bar will feed the third and fourth levels via channels in the mold plate between these two levels. It is desired that sprue bars be as short as possible to reduce pressure losses and to minimize the manufacturing expense of the sprue bars. A further difficulty occurs as, due to the progressive arrangement, the two sprue bars will necessarily be of different lengths and thus the pressure drop that occurs between the inlet end of the sprue bar adjacent to the injection nozzle and the outlet end of the bar is much larger in the longer sprue bar than in the shorter.
When molding shallow parts, and thus opening the mold to a relatively small degree, the length of the sprue bars is generally not large, and the difference in the sprue bar length is relatively small. Consequently, the pressure drop is of minor consequence, generally on the order of 3 to 5 MPa. However, a relatively large pressure drop, on the order of 25 MPa, can occur when molding tall parts because the sprue bars are necessarily longer. This large pressure drop must be compensated for at the injection molding machine and, more importantly, the differential in the pressure drop between the sprue bars can cause insufficient mold packing in the molds furthermost from the injection nozzle.
Another difficulty with sprue bars is that variations in their length occur due to thermal expansion effects, as the sprue bars are heated to allow resin to flow through them. Accordingly, when the mold is closed, the position of the end of each sprue bar relative to the stationery platen and the channel splitting nozzle on the injection molding machine will vary, due to these thermal variations and due to variations in the position in which the mold plates close at the various levels. The combination of these variables makes it very difficult to predict the location of the two sprue bar ends each time the mold is closed and the sprue bar is returned to the channel splitting nozzle. Therefore, some resin leakage from the joint between the nozzle and the sprue bars is inevitable. Resin also tends to leak or "drool" from the nozzle gates or the open channel of the sprue bars when the mold is opened. This drool cannot be tolerated at any of the parting lines of the mold cavity and core sections. At best, such drool prevents complete mold closing and allows flashing to occur and, at worst, can cause permanent damage that requires expensive repairs.
U.S. Pat. No. 5,522,720 to one of the present inventors, and assigned to the assignee of the present invention, discloses a nozzle that tolerates misalignment with the two sprue bars while still forming a tight and repeatable seal between the sprue and the nozzle. Although this design overcomes the problem of drool between the nozzle and sprue bar during injection (mold closed), it does not solve the problem of drool from the gates when the mold opens, or the substantial pressure drops to the lengths of the two sprue bars.
U.S. Pat. No. 4,207,051 to one of the present inventors and assigned to the assignee of the present invention shows a stack mold wherein molten resin is supplied to a center platen through a telescoping tube assembly which is mounted externally to the mold. Essentially, the two tubes form an expandable single sprue bar to deliver molten resin to the mold hot runner and the sprue bar thus need not be detached from the injection nozzle. However, it has proven difficult to construct and operate such a telescoping tube system to accommodate the very high injection pressures (exceeding 20,000 psi) experienced at the nozzle in a multi-cavity, multi-level stack arrangement.
U.S. Pat. No. 5,458,843 discloses a four level stack mold that utilizes a single sprue bar with feed connectors extending through mold components. Drool is reduced via a valveless anti-drool arrangement whereby a spring-activated extension of an outwardly tapered piston into the manifold flow passage reduces its internal pressure and thereby minimizes backflow and resin drool from the feed connector. However, no provision is made for the possibility of drool in the central distributor side of the feed connector. Therefore, the risk of leakage at the mold parting line still exists.
U.S. Pat. No. 4,212,626 to Gellert dispenses with sprue bars entirely and instead uses a combination of control valve units abutted together to transfer the pressurized melt through mechanically operated valve gates from the stationary platen, where the machine nozzle resides, to the moving platen, where the hot runner manifold resides. Several problems are inherent in this approach. First, drool at the parting lines is likely to occur over time, as the valve gates must remain aligned at the parting mold faces with extreme precision over millions of injection cycles. Second, melt channel capacity is limited by the size of the valve gates through which the melt must pass through. Therefore, large parts cannot be successfully molded using this arrangement. Third, the mold shut height is much greater to accommodate the arrangement of the valve gate construction, leading to slower cycle times and greater material expense (the platens are thicker and therefore have greater mass).
U.S. Pat. No. 4,611,983 to Bielfeldt discloses a transfer molding system for fiber-reinforced thermoset resins whereby the molten resin is transferred to an injection cylinder via a feed bore. The injection piston is connected to a telescoping sleeve, so that as the piston moves up inside the injection cylinder to fill the mold cavity with resin, the sleeve also rises and seals off the feed bore. Also, the inner diameter of the sleeve is larger than the root diameter of the injection piston, so that any resin drool flows out of the annular clearance. However, this technique suffers from various disadvantages and does not work if applied to a high injection pressure, multi-cavity, multi-level stack mold arrangement with at least two hot runner systems.
U.S. Pat. No. 4,586,887 to Gellert shows two opposed hot tip bushings meeting at a stack mold parting line. Each hot tip bushing has a first, inner heating element and a second, outer heating element, each running along the length of the hot tip. A temperature difference is created by heating the inner heating element of the first nozzle and the outer heating element of the second nozzle, which, when combined with the taper of the gates, is intended to reduce tip drool, as the tips freeze off each time the mold faces separate. Excess melt is intended to be absorbed into the system when the mold is opened. However, this arrangement has been less than satisfactory in eliminating tip drool.
U.S. Pat. No. 4,891,001 to Gellert was directed to overcome some of the drooling problems of U.S. Pat. No. 4,586,887 discussed above. This reference teaches an arrangement wherein, rather than heating the tip with two coaxial heaters running the length of the tips, localized heat control is provided on the tip directly at the orifice in the mold face. The first tip has a heating element proximate the mold face, while the second tip had a heating element that is distal the mold face. A similar principal of creating unequal temperatures of the tips at mold separation is intended to result in freezing. However, this arrangement has also been found to experience unacceptable drool.
Accordingly, it is desired to have a stack mold and a sprue bar assembly therefor which does not suffer from the above-mentioned or other disadvantages.


1. Field of the Invention
The present invention relates to a thin-film patterning method for a magnetoresistive device.
2. Related Background Art
Conventional thin-film patterning methods for thin-film magnetic heads and the like having magnetoresistive devices, for example, are described in Japanese Patent Application Laid-Open Nos. 2002-175606, 2003-17353, 2003-512941, 2000-76618, 2001-110663, and 5-342527, for example. These methods can perform thin-film patterning of thin-film magnetic heads and the like.


Presently available are devices which generate short laser pulses including a laser oscillator which generates a first laser pulse, an element to compress the pulse by reflecting the first laser pulse by stimulated Brillouin scattering into a laser pulse of a shorter temporal duration, and a primary ray path that includes the laser oscillator and the pulse compressing element and along which the first laser pulse travels from the laser oscillator to the pulse compressing element.
Such devices, known from prior art, normally make use of laser oscillators generating the first laser pulse with the temporal duration in the range of nanoseconds, most preferably in the range between approximately a few and and some tens of nanoseconds. Laser pulses generated in that way are shortened by one reflection cycle inside a pulse compressing element.
The shortcomings of these devices are that the temporal duration of the shortened or compressed pulse depends on the refractive medium inside the pulse compressing element and--in particular--the fact that there is no possibility to generate laser pulses of a predefined time duration.
Therefore, this invention has the underlying task to create a device and a process that opens up the possibility of generating laser pulses with a predefined time duration.


1. Field of the Invention
The present invention relates generally to ferromagnetic memory and more specifically to ferromagnetic memory utilizing giant magnetoresistance and spin polarization.
2. Description of the Background Art
For many years, random access memory for computers was constructed from magnetic elements. This memory had the advantage of very high reliability, nonvolatility in the event of power loss and infinite lifetime under use. Since this memory was hand assembled from three-dimensional ferrite elements, it was eventually supplanted by planar arrays of semiconductor elements. Planar arrays of semiconductors can be fabricated by lithography at a much lower cost than the cost of fabricating prior art magnetic ferrite memory elements. Additionally, these semiconductor arrays are more compact and faster than prior art ferrite magnetic memory elements. Future benefits of increasingly smaller scale in semiconductor memory are now jeopardized by the concern of loss of reliability, since very small scale semiconductor elements are not electrically robust.
Non-volatile magnetic memory elements that are read by measuring resistance have been previously demonstrated by Honeywell Corporation. These systems operate on the basis of the classical anisotropic magneto-resistance phenomena, which results in resistance differences when the magnetization is oriented perpendicular versus parallel to the current. Previous work by others has shown that a 2% change in resistance is sufficient to permit the fabrication of memory arrays compatible with existing CMOS computer electronics. Unfortunately, scaling of these elements down from the current 1 .mu.m size has proved challenging.


A Personal Data Vault (PDV) is a cloud, or network, based data storage where a user, or an agent acting on behalf of the user, can store data, such as files, documents, photos, medical journals, music, contact lists, presence information, and so forth. The stored data can subsequently be accessed by authorized clients, i.e., clients which have been granted access to the stored data. The clients may be other users of the data storage, a network operator, or a service provider of, e.g., a personalized service, or a data sharing service.
It is known to use policy languages, such as the eXtensible Access Control Markup Language (XACML), to describe how resources, e.g., data or information, are to be treated. Before a resource can be accessed by a client, it is checked if access is allowed by the policy.
In situations where the data storage provider, or an associated PEP, is not fully trusted to enforce access policy, encryption is a common solution. However, encryption has the disadvantage that the owner of the data has to be online in order to provide a client requesting access with a decryption key for the encrypted data. If the owner wants to grant offline access, the key has to be provided to the requesting client by some other means than storing the key in the data storage, since storing keys in the data storage defeats the trust model. Regardless how access to the key is implemented, the owner does not have full control and anyone being in possession of the key can access the stored data. Thus, confidentiality of data is not guaranteed anymore.
A known solution for controlling access to stored data is to employ split keys, e.g., in situations where several clients are available and at least a few of them are trusted. The owner of the stored data may then apply so-called secret sharing of the keys, or possibly of the data, in such a way that only several clients, i.e., more than one client, jointly can retrieve the encrypted data. For example, the owner may split the key among n clients in such a way that at least n/2+1 clients, i.e., a majority of the clients, are required to co-operate in order to obtain the key or the stored data. Several schemes for secret sharing are known in the art
While splitting of keys provides an improved protection, straight-forward usage of this technique implies that a group of clients holding parts of the key can reconstruct the complete key without involving the owner of the data. Also, existing schemes for policy and access control do not provide security if non-malicious mistakes are made. For example, a data storage provider may by mistake grant access to clients not authorized by the owner, e.g., due to misconfiguration of access policies.


1. Field of the Invention
This invention relates to the field of electric transformers, and in particular to transformers that are used in ballast circuits of lamp assemblies.
2. Description of Related Art
Ballasts are commonly used in lamp assemblies to provide a preferred, or optimal, current and voltage to the lamp device. Most lamp ballasts employ a transformer to effect the required transformation of supply voltage to this preferred voltage. The reliability, or expected time-to-failure, of a transformer is inversely proportional to its operating temperature. Electric current flowing through the coils of the transformer generates heat, and this heat causes an increase in the operating temperature of the transformer, thereby reducing its reliability. The amount of heat generated can be reduced by using larger sized wires in each coil, but would result in a larger sized and more costly transformer. Alternatively, the operating temperature can be reduced by efficiently removing the generated heat from the transformer. A variety of techniques are currently available for increasing the efficiency of heat transfer from the coils of a transformer. Thermally conductive potting compounds have been used to conduct the heat from the transformer coils to an enclosure containing the transformer. These semi-fluid compounds, however, are somewhat difficult to handle, compared to solid devices and components, and often introduce reliability problems to other devices, for example, by flowing into the moving parts of switches, relays, connectors, and the like.
European Patent Application EP 0 254 132, filed Jul. 8, 1987, discloses fastening a metal shell about a transformer, wherein the shell preferably contacts the exterior layer of the coil windings, via a thin insulating layer. This shell is preferably connected to the ballast enclosure, to transfer the heat generated by the coils to the enclosure, both the shell and the enclosure being made of heat-conductive material. This exterior shell must be configured to allow air to circulate within the enclosure, else the thermal efficiency gained by providing the shell will be reduced by the reduction in radiant heat dissipation. Also, the wires that are connected to the coils must be routed through openings in the shell. To assure an efficient thermal contact between the shell and the coil, both the coil dimensions and the shell dimensions must be controlled. A loose fitting shell will be thermally inefficient, and a tight fitting shell may be difficult to fit onto the transformer.
It is an object of this invention to provide a method of manufacturing a transformer that provides for efficient heat-transfer from the coils of the transformer. It is a further object of this invention to provide a method of manufacturing a transformer that provides an efficient heat transfer without introducing additional manufacturing constraints. It is a further object of this invention to provide a transformer that includes an efficient heat transfer arrangement.
These objects and others are achieved by providing one or more heat-conducting devices coincident with the plastic bobbin that is typically used to form the coils of the transformer. The coil wire is subsequently wrapped around the bobbin and adjacent heat-conducting device assembly, using conventional coil winding techniques. The heat-conducting device is preferably configured to extend beyond the transformer so as to contact a heat-conducting surface, such as a ballast enclosure, when the transformer is appropriately mounted. Because the heat-conducting device is located adjacent the inner windings of the coil, which is typically the locale of the highest temperature build-up in a transformer, a highly efficient heat-transfer is achieved. Preferably, the heat-conducting device is a thick copper conductor having a thin layer of insulating tape separating it from the coil windings.