This invention relates to a process for the preparation of a key intermediate using an chiral additive to effect an asymmetric conjugate addition.

The present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of formula I.
The compound possessing a high affinity for at least one of two receptor subtypes, are responsible for the dilation of smooth muscle, such as blood vessels or in the trachea. The endothelin antagonist compounds provide a potentially new therapeutic target, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.
Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 411-415 (1988)).
Three endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which resemble one another in structure, exist in the bodies of animals including human, and these peptides have vasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86, 2863-2867 (1989)).
As reported, the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (Japan, J. Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990)).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)), an improved renal function by the endothelin antibody in an acute renal failure model (J. Clin, invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer, 50 (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).
Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A.sub.2, prostacyclin, noradrenaline, angiotensin II and substance P (Biochem. Biophys, Res. Commun., 157, 1164-1168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., 13, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184 (1989)). Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res. Commun., 159, 317-323 (1989)). Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276-279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)).
Internal hyperplastic response was induced by rat carotid artery balloon endothelial denudation. Endothelin causes a significant worsening of the internal hyperplasia (J. Cardiovasc. Pharmacol., 22, 355-359 & 371-373(1993)). These data support a role of endothelin in the phathogenesis of vascular restenosis. Recently, it has been reported that both ET.sub.A and ET.sub.B receptors exist in the human prostate and endothelin produces a potent contraction of it. These results suggest the possibility that endothelin is involved in the pathophysiology of benign prostatic hyperplasia (J. Urology, 151, 763-766(1994), Molecular Pharmocol., 45, 306-311(1994)).
On the other hand, endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively. These findings suggest that endothelin is an important mediator for endotoxin-induced diseases (Biochem. Biophys. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989)).
Further, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-inducea renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.
Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)).
It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7), S119-SI21 (1991)). One of the endothelin receptors is ET.sub.A receptor Selective to ET-1 rather than ET-3, and the other is ET.sub.B receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348, 730-735 (1990)).
These two subtypes of endothelin receptors are differently distributed in tissues. It is known that the ET.sub.A receptor is present mainly in cardiovascular tissues, whereas the ET.sub.B receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.
Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ET.sub.A receptor but also the ET.sub.B receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.
Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. Further, it is suggested that endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension.
Two endothelin receptors ET.sub.A and ET.sub.B are known so far and antagonists of these receptors have been shown to be potential drug induced targets. EP 0526708 A1 and WO 93/08799 A1 are representative examples of patent applications disclosing non-peptidic compounds with alleged activity as endothelin receptor antagonists.
The present invention discloses an asymmetric conjugate addition for preparing the compound of Formula I, ##STR1## a key intermediate in the synthesis of endothelin antagonists of the following structure: ##STR2## wherein ##STR3## represents: 5- or 6-membered heterocyclyl, 5- or 6-membered carbocyclyl, and aryl;
R.sup.1 is: C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, aryl, or heteroaryl; PA1 R.sup.2 is OR.sup.4 and N(R.sup.5).sub.2 ; PA1 R.sup.3b is aryl, or heteroaryl; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; and PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl. PA1 b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 c) aryl, wherein aryl is as defined below, PA1 C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with with one, two or three substituents selected from the group consisting of: H, OH, CO.sub.2 R.sup.6, Br, Cl, F, I, CF.sub.3, N(R.sup.7).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.1 is: PA1 a) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, PA1 b) aryl, or PA1 c) heteroaryl; PA1 heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.2 is: OR.sup.4 or N(R.sup.5).sub.2 ; PA1 R.sup.3 is: PA1 a) H, PA1 b) C.sub.1 -C.sub.8 alkyl, PA1 c) C.sub.1 -C.sub.8 alkenyl, PA1 d) C.sub.1 -C.sub.8 alkynyl, PA1 e) C.sub.1 -C.sub.8 alkoxyl, PA1 f) C.sub.3 -C.sub.7 cycloalkyl, PA1 g) S(O).sub.t R.sup.5, PA1 h) Br, Cl, F, I, PA1 i) aryl, PA1 j) heteroaryl, PA1 k) N(R.sup.5).sub.2, PA1 l) NH.sub.2, PA1 m) CHO, PA1 n) --CO--C.sub.1 -C.sub.8 alkyl, PA1 o) --CO-aryl, PA1 p) --CO-heteroaryl, PA1 q) --CO.sub.2 R.sup.4, or PA1 r) protected aldehyde; PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 n is: 0 to 5; PA1 t is: 0, 1 or 2; PA1 R.sup.4 is: C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; PA1 R.sup.6, is: H, C.sub.1 -C.sub.8 alkyl, or aryl; PA1 R.sup.7 is: H, C.sub.1 -C.sub.8 alkyl, aryl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; or when two R.sup.7 substutients are on the same nitrogen they can join to form a ring of 3 to 6 atom; PA1 b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 c) aryl, wherein aryl is as defined below, PA1 C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO.sub.2 R.sup.6, Br, Cl, F, I, CF.sub.3, N(R.sup.7).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.1 is: PA1 a) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, PA1 b) aryl, or PA1 c) heteroaryl; PA1 heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2,C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; PA1 R.sup.3 is PA1 a) H, PA1 b) C.sub.1 -C.sub.8 alkyl, PA1 c) C.sub.1 -C.sub.8 alkenyl, PA1 d) C.sub.1 -C.sub.8 alkynyl, PA1 e) C.sub.1 -C.sub.8 alkoxyl, PA1 f) C.sub.3 -C.sub.7 cycloalkyl, PA1 g) S(O).sub.t R.sup.5, PA1 h) Br, Cl, F, I, PA1 i) aryl, PA1 j) heteroaryl, PA1 k) N(R.sup.5).sub.2, PA1 I) NH.sub.2, PA1 m) CHO, PA1 n) --CO--C.sub.1 -C.sub.8 alkyl, PA1 o) --CO-aryl, PA1 p) --CO-heteroaryl, PA1 q) --CO.sub.2 R.sup.4, or PA1 r) protected aldehyde; PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 n is:0 to 5; PA1 t is: 0, 1 or 2; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; and PA1 R.sup.6 is: H, C.sub.1 -C.sub.8 alkyl, and aryl; and PA1 R.sup.7 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, when there are two R.sup.7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; PA1 a) (-)-sparteine, PA1 b) N,N,N',N'-tetra(C.sub.1 -C.sub.6)-alkyltrans-1,2-diamino-cyclohexane, or PA1 c) ##STR10## wherein R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl, except that R.sup.8 and R.sup.9 cannot simultaneously be H; and R.sup.10 is C.sub.1 -C.sub.6 alkyl or aryl, PA1 b) 5- or 6-membered carbocyclyl containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 c) aryl, wherein aryl is as defined below, PA1 C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO.sub.2 R.sup.6, Br, Cl, F, I, CF.sub.3, N(R.sup.7).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.1 is: PA1 a) C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, C.sub.3 -C.sub.8 cycloalkyl, PA1 b) aryl, or PA1 c) heteroaryl; PA1 heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, and CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2, PA1 R.sup.2 is OR.sup.4 or N(R.sup.5).sub.2 ; PA1 R.sub.3 is PA1 a) CHO, PA1 b) CH(OR.sup.4).sub.2 ; PA1 n is: 0 to 5, PA1 t is: 0, 1 or 2; PA1 X and Y are independently: O, S, or NR.sup.5 ; PA1 R.sup.4 is C.sub.1 -C.sub.8 alkyl; PA1 R.sup.5 is: C.sub.1 -C.sub.8 alkyl, or aryl; PA1 R.sup.6 is: H, C.sub.1 -C.sub.8 alkyl, and aryl; PA1 R.sup.7 are independently: H, C.sub.1 -C.sub.8 alkyl, and aryl, when there are two R.sup.7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO.sub.2 R.sup.4, Br, Cl, F, I, CF.sub.3, N(R.sup.5).sub.2, C.sub.1 -C.sub.8 alkoxy, C.sub.1 -C.sub.8 alkyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, or C.sub.3 -C.sub.8 cycloalkyl, CO(CH.sub.2).sub.n CH.sub.3, CO(CH.sub.2).sub.n CH.sub.2 N(R.sup.5).sub.2 ; PA1 1) reacting an .alpha.,.beta.-unsaturated ester or amide ##STR13## where R.sup.3 is CH(OR.sup.4).sub.2 ; with an organolithium compound, R.sup.1 Li, in the presence of a chiral additive and an aprotic solvent at a temperature range of about -78.degree. C. to about 0.degree. C. to give the conjugate adduct; and PA1 2) removing the aldehyde protecting group with an acid to give the compound of Formula I, where R.sup.3 is CHO. PA1 a) (-)-sparteine, PA1 b) N,N,N',N'-tetra(C.sub.1 -C.sub.6)-alkyltrans-1,2-diamino-cyclohexane, or PA1 c) ##STR14## wherein R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl, except that R.sub.8 and R.sup.9 cannot simultaneously be H; and R.sup.10 is C.sub.1 -C.sub.6 alkyl or aryl, PA1 a) (-)-sparteine, PA1 b) N,N,N',N'-tetra(C.sub.1 -C.sub.6)-alkyltrans-1,2-diamino-cyclohexane, or PA1 c) ##STR18## wherein R.sup.8 and R.sup.9 are independently: H, C.sub.1 -C.sub.6 alkyl, C.sub.3 -C.sub.7 cycloalkyl or aryl, except that R.sup.8 and R.sup.9 cannot simultaneously be H; and R.sup.10 is C.sub.1 -C.sub.6 alkyl or aryl, PA1 2) the conversion of the aldehyde (R.sup.3 is CHO) to the desired protected aldehyde (R.sup.3 is CH(OR.sup.4).sub.2 and R.sup.4 is C.sub.1 -C.sub.8 alkyl).

Asymmetric conjugate addition reaction using a chiral additive


A process for production of a chain metal powder, which comprises the steps of reducing metal ions contained in an aqueous solution, while applying a magnetic filed to the solution, in the presence of both a reducing agent capable of generating a gas during the reduction of metal ions and a foamable water soluble compound, through the generation of a gas, a bubble layer on the surface of the aqueous solution to form a chain metal powder, separating the bubble layer formed on the surface of the aqueous solution from the solution, and collecting the chain metal powder contained in the bubble layer.

An anisotropic conductive film is used in one of processes for mounting electronic components whereby a semiconductor package is mounted on a printed wiring board, or conductor circuits formed on the surfaces of two printed wiring boards are electrically connected with each other and the two printed wiring boards are secured with respect to each other.
In the case of mounting a semiconductor package, for example, a semiconductor package having a connection section where a plurality of electrodes called bumps are disposed on a surface thereof which is to be placed on a printed wiring board for mounting thereon, and a printed wiring board having a connection section where a plurality of electrodes are disposed in the same pitch as the bumps are prepared. The semiconductor package and the printed wiring board are disposed so that the connection sections thereof face each other, with the corresponding electrodes on both connection sections being aligned to overlap one-on-one in the plane direction of the film, and are bonded together by thermal bonding with an anisotropic conductive film interposed therebetween, thereby mounting the semiconductor package on the printed wiring board.
In the case of connecting two printed wiring boards, two printed wiring boards each having a connection section where a plurality of electrodes are disposed in the same pitch are prepared. The two printed wiring boards are disposed so that both connection sections thereof face each other, with the corresponding electrodes on both connection sections being aligned to overlap one-on-one in the plane direction of the film, and are bonded together by thermal bonding with an anisotropic conductive film interposed therebetween, thereby connecting the conductor circuits on both sides and securing the two printed wiring boards with respect to each other.
The anisotropic conductive film used in mounting of electronic components typically has such a structure as a powdered conductive component is dispersed in a film containing a binder of various resins and has heat sensitive adhesion property. The content ratio of the conductive component in the anisotropic conductive film is controlled so as to have higher conductive resistance (referred to as "insulation resistance") in the plane direction, in order to prevent short circuiting in the plane direction of the film, namely to prevent each pair of opposing electrodes facing each other with interposing the film therebetween from short circuiting with an other pair of adjacent electrodes within the surface.
When the anisotropic conductive film is used in thermal bonding, since the anisotropic conductive film is compressed in the thickness direction by heat and pressure applied thereto, content ratio of the conductive component in the thickness direction increases so that the electrically conductive powders are brought closer to or into contact with each other to form a network of electrical conductivity. As a result, conductive resistance (referred to as "connection resistance") of the anisotropic conductive film in the thickness direction decreases. However, since the content ratio of the conductive component in the plane direction of the anisotropic conductive film does not increase, the initial state that the insulation resistance is high and electrical conductivity is low is maintained in the plane direction.
Thus the anisotropic conductive film has a property of anisotropic electrical conductivity, namely connection resistance is low in the thickness direction and insulation resistance is high in the plane direction. This property of anisotropic electrical conductivity enables the followings:
[A] while maintaining each pair of opposing electrodes independent from others by preventing the electrodes from short circuiting in the plane direction of the film;
[B] to establish good electrical conductive connection between each pair of opposing electrodes that face each other via the film. At the same time, it is also possible to secure a semiconductor package on a printed wiring board by thermal bonding or secure printed wiring boards with respect to each other by thermal bonding, by the heat sensitive adhesion property of the anisotropic conductive film itself. As a result, use of the anisotropic conductive film makes the operation simpler to mount electronic components.
Various metal powders have been put into practical use as the conductive component contained in the anisotropic conductive film, such as those consisting of powders of a shape such as granule, sphere, or lamella (scale, flake) having an average particle diameter ranging from several micrometers to several tens of micrometers. Particularly in recent years attention is drawn to a chain metal powder having a shape in which fine metal particles are bonded in a chain form.
Since the chain metal powder has large specific surface area than a granular ones, it has an excellent dispersibility to the binder. And it has lager aspect ratio, adjacent chain metal powders tend to connect with each other so as to easily form a network of good electrical conductivity while being dispersed in the film. Accordingly, the chain metal powder used as an conductive component makes it possible to form an anisotropic conductive film having better electrical conductivity in the thickness direction with smaller amount of filling than in the case of conventional powders.
Also in case the chain metal powder contains a ferromagnetic metal as described hereinafter, upon application of a magnetic field, the chain metal powder are oriented in a certain direction accordingly. For example, it is also made possible to further improve the anisotropic electrical conductivity of the anisotropic conductive film by applying a magnetic field in the process for the production of the anisotropic conductive film thereby orienting the chain metal powder in the thickness direction of the film. In order to have the chain metal powder oriented in the direction of film thickness, for example, such a process may be employed as to produce the anisotropic conductive film by applying a liquid mixture containing a chain metal powder and a binder onto a flat surface and solidifying the mixture by drying or other means, while applying a magnetic field to the mixture that has been spread over the flat surface and has not yet solidified, thereby solidifying the mixture in the state where the chain metal powder is oriented in the thickness direction so that the direction of orientation of the chain metal powder is fixed.
Use of the chain metal powder also makes it possible to produce an electrically conductive paste that enables to form an electrically conductive film having better electrical conductivity, an electrically conductive sheet having higher electrical conductivity or an active material compound for a battery having excellent collecting ability, while using a smaller amount of filling than in the case of conventional ones. Unprecedented applications may also be opened up by making use of the peculiar particle shape of the chain metal powder in such fields as capacitor, catalyst, electromagnetic shielding material, etc.
A chain metal powder containing a ferromagnetic metal such as Ni, Fe or Co, or an alloy thereof can be produced by the reduction deposition method, according to which, a lot of the fine metal particles are deposited by the action of a reducing agent in an aqueous solution containing ions of these metals. The submicron-sized fine metal particles made of the ferromagnetic metal or alloy in the early stage of deposition have a single magnetic domain structure or a similar structure, and are therefore simply polarized into bipolar state so as to exhibit magnetism. A lot of metal particles that exhibit magnetism are bonded in a chain form through the magnetism, thereby to form the chain metal powder. When the metal further deposits so as to cover the lot of metal particles that are bonded in the chain form, a chain metal powder is formed that the metal particles bond more firmly with each other.
However, the chain metal powder of the conventional reduction deposition method only produces a configuration such as a branching shape that many chains are branched out or, even when there are few branches, a bending shape that the chains are significantly bent or bent several times. The chain metal powders may be nonetheless useful, for example, in forming a good network of electrical conductivity in a binder. In order to make better use of the peculiar configuration of chain, however, it is preferable to produce a chain metal powder that has not only fewer branches but also has a linear shape or close to it. It is also important that the chain metal powder consisting of linear shape has small distribution of the chain length, in order to equalize properties when orienting a lot of chain metal powders in the same direction.
For example, the anisotropic conductive film is rendered the anisotropic electrical conductivity thereof by orienting the lot of chain metal powders in the thickness direction. With respect to the anisotropic conductive film having such a structure in order to reliably prevent short circuiting between adjacent electrodes which are arranged at very narrow pitch in the connection sections of the electronic component and the printed wiring board, it is required that:
[C] adjacent chain metal powders contained in the film do not form a network of electrical conductivity due to branching, namely the powders have as few branches as possible; and
[D] the chain metal powders oriented in the thickness direction do not cause short circuiting between adjacent electrodes even when the powders fall down in the plane direction of the film when a printed wiring board and an electronic component or two printed wiring boards are pressed so as to be bonded together with the anisotropic conductive film interposed therebetween, namely lengths of the powders are controlled to be less than the distance between the adjacent electrodes.
In order to meet the requirements described above, it has been proposed to carry out a reduction deposition method while applying a magnetic field to an aqueous solution. With this method, since a number of fine metal particles deposited in the aqueous solution can be bonded in a chain form while being oriented in the direction of magnetic field through the magnetism of the particles themselves, it is made possible to produce a chain metal powder that have fewer branches than in the case where magnetic field is not applied, and have linear shape.
For example, Non-Patent Document 1 describes that a chain metal powder consisting of linear shape can be obtained when Fe or Fe—Co is deposited while applying a magnetic field to an aqueous solution in a reduction deposition reaction conducted in the aqueous solution by using boron hydride as a reducing agent and that, in the case of Fe, it is necessary to apply a magnetic field of at least 10 mT, preferably 100 mT or more intensity in order to make the chain metal powder consisting of linear shape.
Non-Patent Document 2 describes that a chain metal powder can be obtained when Ni, Co or Fe is deposited in a reduction deposition reaction in an aqueous solution by using a trivalent Ti compound as a reducing agent, and that the chain metal powder consisting of linear shape of Ni can be obtained by applying a magnetic field of 100 mT during the reaction.
However, the chain metal powders produced by these processes include powders having some branches which can not be completely eliminated. Also since the above-described processes are not capable of controlling the chain length, the chain metal powder produced thereby is varying in length from very short to extremely long.
When the chain metal powder that have some branches and varies in length is used as a conductive component of the anisotropic conductive film, for example, the anisotropic conductive film may not have sufficiently high insulation resistance in the plane direction of the film even when the chain metal powder is oriented in the thickness direction of the film. Moreover, as the pitch between the adjacent electrodes becomes smaller, there increases a possibility that long particles of the chain metal powder to fall down in the plane direction of the film and cause short circuiting during pressure bonding.    Non-Patent Document 1: "Magnetic Properties of Single-Domain Iron and Iron-Cobalt Particles Prepared by Boronhydride Reduction", A. L. Oppegard, F. J. Darnell and H. C. Miller, The Journal of Applied Physics, 32 (1961) 184s    Non-Patent Document 2: "Use of Ti(III) complexes To reduce Ni Co and Fe in Water Solutions", V. V. Sviridov, G. P. Shevchenko, A. S. Susha and N. A. Diab, The Journal of Physical Chemistry, 100 (1996) 19632

Process for production of chain metal powders, chain metal powers produced thereby, and anisotropic conductive film formed by using the powders


An active damper for an L-C filter suppresses transients that appear on the DC link from a power supply. The damper suppresses the transients by filtering the line voltage to obtain its steady-state component and comparing the steady-state voltage to the instantaneous voltage on the DC link. When the two voltages differ, the active damper cancels the transient by dissipating the energy on the DC link and the energy stored in the filter's inductor.

This invention relates in general to power supplies and in particular to a damping system for EMI filters.
All electromechanical equipment create electromagnetic interference or "noise" on their power lines. The noise can be generated by load transients, switching power supplies or PWM inverters. Such noise can adversely affect the performance of other equipment that receive power from same power lines.
Typically, the noise is removed from the power lines by an EMI filter. As shown in FIG. 1, the EMI filter 2 includes an inductor L and capacitor C coupled between an input voltage bus 4a, 4b and a DC link 6a, 6b. This filter has a resonant frequency of 1/(2.pi..sqroot.LC). The EMI filter 2 passes all signals having frequencies above the resonant frequency and attenuates all signals having frequencies below the resonant frequency. However, it amplifies signals having frequencies at or near the resonant frequency. As a result, the peak voltage at the resonant frequency exceeds the voltage on the bus 4a, 4b. For an undamped EMI filter 2 having an inductance of 1 mH and a capacitance of 22 microfarads, the peak at the resonant frequency of 1 kHz is 18dB, which is 180% of the DC link voltage (see FIG. 2). Consequently, the ratings of the components, including the filter capacitor C, on the DC link 6a,6b must be increased above the maximum peak voltage.
The EMI filter 2 can be equipped with a damping circuit which limits peak voltage and ringing caused by load and line transients. Typically, this damping circuit includes a resistor in series with a capacitor. The damping resistor dissipates the energy stored in the filter 2 and the damping capacitor blocks the DC component of the input voltage, thereby reducing dissipation by the damping resistor. The size of the damping capacitor depends upon the maximum tolerable peak voltage. A maximum overshoot of 5-6 dB requires the damping capacitor to have a capacitance of approximately three times the filter capacitance. Further reduction in peaking requires an even larger damping capacitance, typically provided by a multilayer ceramic (MLC) capacitor.
The damping capacitor tends to be heavy and expensive. Further, MLC capacitors are only offered in discrete voltages (e.g., 100 vdc, 200 vdc, 400 vdc). Consequently, a power line voltage of 110 vdc requires an MLC capacitor of 200 vdc. Still further, link voltage peaking caused by moderate damping can force the use of bigger capacitors connected to the DC link.
The cost, size and weight of the capacitance increases with the power rating of the power supply system.


The present invention relates to novel cationic lipids, transfection agents, microparticles, nanoparticles, and short interfering nucleic acid (siNA) molecules. The invention also features compositions, and methods of use for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of gene expression and/or activity in a subject or organism. Specifically, the invention relates to novel cationic lipids, microparticles, nanoparticles and transfection agents that effectively transfect or deliver biologically active molecules, such as antibodies (e.g., monoclonal, chimeric, humanized etc.), cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, dsRNA, allozymes, aptamers, decoys and analogs thereof, and small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules, to relevant cells and/or tissues, such as in a subject or organism. Such novel cationic lipids, microparticles, nanoparticles and transfection agents are useful, for example, in providing compositions to prevent, inhibit, or treat diseases, conditions, or traits in a cell, subject or organism. The compositions described herein are generally referred to as formulated molecular compositions (FMC) or lipid nanoparticles (LNP).

The present invention relates to the delivery of biologically active molecules to cells. Specifically, the invention relates to compounds, compositions and methods for delivering nucleic acids, polynucleotides, and oligonucleotides such RNA, DNA and analogs thereof, peptides, polypeptides, proteins, antibodies, hormones and small molecules, to cells by facilitating transport across cellular membranes in, for example, epithelial tissues and endothelial tissues. The compounds, compositions and methods of the invention are useful in therapeutic, research, and diagnostic applications that rely upon the efficient transfer of biologically active molecules into cells, tissues, and organs. The discussion is provided only for understanding of the invention that follows. This summary is not an admission that any of the work described below is prior art to the claimed invention.
The cellular delivery of various therapeutic compounds, such as antiviral and chemotherapeutic agents, is usually compromised by two limitations. First the selectivity of a number of therapeutic agents is often low, resulting in high toxicity to normal tissues. Secondly, the trafficking of many compounds into living cells is highly restricted by the complex membrane systems of the cell. Specific transporters allow the selective entry of nutrients or regulatory molecules, while excluding most exogenous molecules such as nucleic acids and proteins. Various strategies can be used to improve transport of compounds into cells, including the use of lipid carriers, biodegradable polymers, and various conjugate systems.
The most well studied approaches for improving the transport of foreign nucleic acids into cells involve the use of viral vectors or cationic lipids and related cytofectins. Viral vectors can be used to transfer genes efficiently into some cell types, but they generally cannot be used to introduce chemically synthesized molecules into cells. An alternative approach is to use delivery formulations incorporating cationic lipids, which interact with nucleic acids through one end and lipids or membrane systems through another (for a review see Felgner, 1990, Advanced Drug Delivery Reviews, 5, 162-187; Felgner 1993, J. Liposome Res., 3, 3-16). Synthetic nucleic acids as well as plasmids can be delivered using the cytofectins, although the utility of such compounds is often limited by cell-type specificity, requirement for low serum during transfection, and toxicity.
Another approach to delivering biologically active molecules involves the use of conjugates. Conjugates are often selected based on the ability of certain molecules to be selectively transported into specific cells, for example via receptor-mediated endocytosis. By attaching a compound of interest to molecules that are actively transported across the cellular membranes, the effective transfer of that compound into cells or specific cellular organelles can be realized. Alternately, molecules that are able to penetrate cellular membranes without active transport mechanisms, for example, various lipophilic molecules, can be used to deliver compounds of interest. Examples of molecules that can be utilized as conjugates include but are not limited to peptides, hormones, fatty acids, vitamins, flavonoids, sugars, reporter molecules, reporter enzymes, chelators, porphyrins, intercalcators, and other molecules that are capable of penetrating cellular membranes, either by active transport or passive transport.
The delivery of compounds to specific cell types, for example, cancer cells or cells specific to particular tissues and organs, can be accomplished by utilizing receptors associated with specific cell types. Particular receptors are overexpressed in certain cancerous cells, including the high affinity folic acid receptor. For example, the high affinity folate receptor is a tumor marker that is overexpressed in a variety of neoplastic tissues, including breast, ovarian, cervical, colorectal, renal, and nasoparyngeal tumors, but is expressed to a very limited extent in normal tissues. The use of folic acid based conjugates to transport exogenous compounds across cell membranes can provide a targeted delivery approach to the treatment and diagnosis of disease and can provide a reduction in the required dose of therapeutic compounds. Furthermore, therapeutic bioavailability, pharmacodynamics, and pharmacokinetic parameters can be modulated through the use of bioconjugates, including folate bioconjugates. Godwin et al., 1972, J. Biol. Chem., 247, 2266-2271, report the synthesis of biologically active pteroyloligo-L-glutamates. Habus et al., 1998, Bioconjugate Chem., 9, 283-291, describe a method for the solid phase synthesis of certain oligonucleotide-folate conjugates. Cook, U.S. Pat. No. 6,721,208, describes certain oligonucleotides modified with specific conjugate groups. The use of biotin and folate conjugates to enhance transmembrane transport of exogenous molecules, including specific oligonucleotides has been reported by Low et al., U.S. Pat. Nos. 5,416,016, 5,108,921, and International PCT publication No. WO 90/12096. Manoharan et al., International PCT publication No. WO 99/66063 describe certain folate conjugates, including specific nucleic acid folate conjugates with a phosphoramidite moiety attached to the nucleic acid component of the conjugate, and methods for the synthesis of these folate conjugates. Nomura et al., 2000, J. Org. Chem., 65, 5016-5021, describe the synthesis of an intermediate, alpha-[2-(trimethylsilyl)ethoxycarbonyl]folic acid, useful in the synthesis of ceratin types of folate-nucleoside conjugates. Guzaev et al., U.S. Pat. No. 6,335,434, describes the synthesis of certain folate oligonucleotide conjugates. Vargeese et al., International PCT Publication No. WO 02/094185 and U.S. Patent Application Publication Nos. 20030130186 and 20040110296 describe certain nucleic acid conjugates.
The delivery of compounds to other cell types can be accomplished by utilizing receptors associated with a certain type of cell, such as hepatocytes. For example, drug delivery systems utilizing receptor-mediated endocytosis have been employed to achieve drug targeting as well as drug-uptake enhancement. The asialoglycoprotein receptor (ASGPr) (see for example Wu and Wu, 1987, J. Biol. Chem. 262, 4429-4432) is unique to hepatocytes and binds branched galactose-terminal glycoproteins, such as asialoorosomucoid (ASOR). Binding of such glycoproteins or synthetic glycoconjugates to the receptor takes place with an affinity that strongly depends on the degree of branching of the oligosaccharide chain, for example, triatennary structures are bound with greater affinity than biatenarry or monoatennary chains (Baenziger and Fiete, 1980, Cell, 22, 611-620; Connolly et al., 1982, J. Biol. Chem., 257, 939-945). Lee and Lee, 1987, Glycoconjugate J., 4, 317-328, obtained this high specificity through the use of N-acetyl-D-galactosamine as the carbohydrate moiety, which has higher affinity for the receptor, compared to galactose. This "clustering effect" has also been described for the binding and uptake of mannosyl-terminating glycoproteins or glycoconjugates (Ponpipom et al., 1981, J. Med. Chem., 24, 1388-1395). The use of galactose and galactosamine based conjugates to transport exogenous compounds across cell membranes can provide a targeted delivery approach to the treatment of liver disease such as HBV and HCV infection or hepatocellular carcinoma. The use of bioconjugates can also provide a reduction in the required dose of therapeutic compounds required for treatment. Furthermore, therapeutic bioavailability, pharmacodynamics, and pharmacokinetic parameters can be modulated through the use of bioconjugates.
A number of peptide based cellular transporters have been developed by several research groups. These peptides are capable of crossing cellular membranes in vitro and in vivo with high efficiency. Examples of such fusogenic peptides include a 16-amino acid fragment of the homeodomain of ANTENNAPEDIA, a Drosophila transcription factor (Wang et al., 1995, PNAS USA., 92, 3318-3322); a 17-mer fragment representing the hydrophobic region of the signal sequence of Kaposi fibroblast growth factor with or without NLS domain (Antopolsky et al., 1999, Bioconj. Chem., 10, 598-606); a 17-mer signal peptide sequence of caiman crocodylus Ig(5) light chain (Chaloin et al., 1997, Biochem. Biophys. Res. Comm., 243, 601-608); a 17-amino acid fusion sequence of HIV envelope glycoprotein gp4114, (Morris et al., 1997, Nucleic Acids Res., 25, 2730-2736); the HIV-1 Tat49-57 fragment (Schwarze et al., 1999, Science, 285, 1569-1572); a transportan A—achimeric 27-mer consisting of N-terminal fragment of neuropeptide galanine and membrane interacting wasp venom peptide mastoporan (Lindgren et al., 2000, Bioconjugate Chem., 11, 619-626); and a 24-mer derived from influenza virus hemagglutinin envelop glycoprotein (Bongartz et al., 1994, Nucleic Acids Res., 22, 4681-4688). These peptides were successfully used as part of an antisense oligodeoxyribonucleotide-peptide conjugate for cell culture transfection without lipids. In a number of cases, such conjugates demonstrated better cell culture efficacy then parent oligonucleotides transfected using lipid delivery. In addition, use of phage display techniques has identified several organ targeting and tumor targeting peptides in vivo (Ruoslahti, 1996, Ann. Rev. Cell Dev. Biol., 12, 697-715). Conjugation of tumor targeting peptides to doxorubicin has been shown to significantly improve the toxicity profile and has demonstrated enhanced efficacy of doxorubicin in the in vivo murine cancer model MDA-MB-435 breast carcinoma (Arap et al., 1998, Science, 279, 377-380).
Another approach to the intracellular delivery of biologically active molecules involves the use of cationic polymers. For example, Ryser et al., International PCT Publication No. WO 79/00515 describes the use of high molecular weight lysine polymers for increasing the transport of various molecules across cellular membranes. Rothbard et al., International PCT Publication No. WO 98/52614, describes certain methods and compositions for transporting drugs and macromolecules across biological membranes in which the drug or macromolecule is covalently attached to a transport polymer consisting of from 6 to 25 subunits, at least 50% of which contain a guanidino or amidino side chain. The transport polymers are preferably polyarginine peptides composed of all D-, all L- or mixtures of D- and L-arginine. Rothbard et al., U.S. Patent Application Publication No. 20030082356, describes certain poly-lysine and poly-arginine compounds for the delivery of drugs and other agents across epithelial tissues, including the skin, gastrointestinal tract, pulmonary epithelium and blood brain barrier. Wendel et al., U.S. Patent Application Publication No. 20030032593, describes certain polyarginine compounds. Rothbard et al., U.S. Patent Application Publication No. 20030022831, describes certain poly-lysine and poly-arginine compounds for intra-ocular delivery of drugs. Kosak, U.S. Patent Application Publication No. 20010034333, describes certain cyclodextran polymers compositions that include a cross-linked cationic polymer component. Beigelman et al., U.S. Pat. No. 6,395,713; Reynolds et al., International PCT Publication No. WO 99/04819; Beigelman et al., International PCT Publication No. WO 99/05094; and Beigelman et al., U.S. Patent Application Publication No. 20030073640 describe certain lipid based formulations.
Another approach to the intracellular delivery of biologically active molecules involves the use of liposomes or other particle forming compositions. Since the first description of liposomes in 1965, by Bangham (J. Mol. Biol. 13, 238-252), there has been a sustained interest and effort in the area of developing lipid-based carrier systems for the delivery of pharmaceutically active compounds. Liposomes are attractive drug carriers since they protect biological molecules from degradation while improving their cellular uptake. One of the most commonly used classes of liposome formulations for delivering polyanions (e.g., DNA) is that which contains cationic lipids. Lipid aggregates can be formed with macromolecules using cationic lipids alone or including other lipids and amphiphiles such as phosphatidylethanolamine. It is well known in the art that both the composition of the lipid formulation as well as its method of preparation have effect on the structure and size of the resultant anionic macromolecule-cationic lipid aggregate. These factors can be modulated to optimize delivery of polyanions to specific cell types in vitro and in vivo. The use of cationic lipids for cellular delivery of biologically active molecules has several advantages. The encapsulation of anionic compounds using cationic lipids is essentially quantitative due to electrostatic interaction. In addition, it is believed that the cationic lipids interact with the negatively charged cell membranes initiating cellular membrane transport (Akhtar et al., 1992, Trends Cell Bio., 2, 139; Xu et al., 1996, Biochemistry 35, 5616).
Experiments have shown that plasmid DNA can be encapsulated in small particles that consist of a single plasmid encapsulated within a bilayer lipid vesicle (Wheeler, et al., 1999, Gene Therapy 6, 271-281). These particles typically contain the fusogenic lipid dioleoylphosphatidylethanolamine (DOPE), low levels of a cationic lipid, and can be stabilized in aqueous media by the presence of a poly(ethylene glycol) (PEG) coating. These particles have systemic applications as they exhibit extended circulation lifetimes following intravenous (i.v.) injection, can accumulate preferentially in various tissues and organs or tumors due to the enhanced vascular permeability in such regions, and can be designed to escape the lyosomic pathway of endocytosis by disruption of endosomal membranes. These properties can be useful in delivering biologically active molecules to various cell types for experimental and therapeutic applications. For example, the effective use of nucleic acid technologies such as short interfering RNA (siRNA), antisense, ribozymes, decoys, triplex forming oligonucleotides, 2-5A oligonucleotides, and aptamers in vitro and in vivo may benefit from efficient delivery of these compounds across cellular membranes. Lewis et al., U.S. Patent Application Publication No. 20030125281, describes certain compositions consisting of the combination of siRNA, certain amphipathic compounds, and certain polycations. MacLachlan, U.S. Patent Application Publication No. 20030077829, describes certain lipid based formulations. MacLachlan, International PCT Publication No. WO 05/007196, describes certain lipid encapsulated interfering RNA formulations. Vargeese et al., International PCT Publication No. WO2005007854 describes certain polycationic compositions for the cellular delivery of polynucleotides. McSwiggen et al., International PCT Publication Nos. WO 05/019453, WO 03/70918, WO 03/74654 and U.S. Patent Application Publication Nos. 20050020525 and 20050032733, describes short interfering nucleic acid molecules (siNA) and various technologies for the delivery of siNA molecules and other polynucleotides.
In addition, recent work involving cationic lipid particles demonstrated the formation of two structurally different complexes comprising nucleic acid (or other polyanionic compound) and cationic lipid (Safinya et al., Science, 281: 78-81 (1998). One structure comprises a multilamellar structure with nucleic acid monolayers sandwiched between cationic lipid bilayers ("lamellar structure") (FIG. 7). A second structure comprises a two dimensional hexagonal columnar phase structure ("inverted hexagonal structure") in which nucleic acid molecules are encircled by cationic lipid in the formation of a hexagonal structure (FIG. 7). Safinya et al. demonstrated that the inverted hexagonal structure transfects mammalian cells more efficiently than the lamellar structure. Further, optical microscopy studies showed that the complexes comprising the lamellar structure bind stably to anionic vesicles without fusing to the vesicles, whereas the complexes comprising the inverted hexagonal structure are unstable and rapidly fuse to the anionic vesicles, releasing the nucleic acid upon fusion.
The structural transformation from lamellar phase to inverted hexagonal phase complexes is achieved either by incorporating a suitable helper lipid that assists in the adoption of an inverted hexagonal structure or by using a co-surfactant, such as hexanol. However, neither of these transformation conditions are suitable for delivery in biological systems. Furthermore, while the inverted hexagonal complex exhibits greater transfection efficiency, it has very poor serum stability compared to the lamellar complex. Thus, there remains a need to design delivery agents that are serum stable, i.e. stable in circulation, that can undergo structural transformation, for example from lamellar phase to inverse hexagonal phase, under biological conditions.
The present application provides compounds, compositions and methods for significantly improving the efficiency of systemic and local delivery of biologically active molecules. Among other things, the present application provides compounds, compositions and methods for making and using novel delivery agents that are stable in circulation and undergo structural changes under appropriate physiological conditions (e.g., pH) which increase the efficiency of delivery of biologically active molecules.

Lipid nanoparticle based compositions and methods for the delivery of biologically active molecules


A device and method are provided for locating faults in a paired line. The fault locating device has a transmitting unit connectable to the conductors of a paired line containing the fault. The device also has a portable receiving unit to track the path of the paired line. The transmitting unit contains circuits for creating and transmitting a locator signal and a carrier signal including synchronization through the conductors toward the receiving unit. The receiving unit contains a pickup coil positioned proximal to the paired line, inducing induced locator and carrier signals in the pickup coil. The receiving unit also contains circuits for processing the induced locator and carrier signals and for producing a synchronization signal used to detect and segregate a component of the induced locator signal which is indicative of a fault. The presence or absence of the indicative component is communicated to an operator by means of an audible or visual fault indicator.

A paired line is a conventional means of carrying telecommunications transmissions. A paired line is typically two balanced conductors individually insulated and twisted together along their length. A plurality of paired lines are usually bundled together to form a paired cable containing up to one hundred or more paired lines surrounded by a shield, wherein each paired line of the paired cable is capable of independently carrying a signal. The paired lines of a telecommunications cable are typically spiraled together in groups, having a characteristic spiral pattern termed the lay. A paired line is generally an effective telecommunications carrier, however, a fault can occasionally occur in a paired line limiting the effectiveness thereof. For example, a resistance fault can occur in a paired line when water invades the outer protective covering of a paired cable. The resulting resistance fault is a resistive contact between the two conductors of a paired line within the paired cable. The resistance fault is also often accompanied by a resistance from one of the two conductors of the paired line to ground or to another conductor of the paired cable. Another type of fault can occur when there is a discontinuity or break in the shield of the paired cable. The fault allows an increased coupling of extraneous voltages into one or more enclosed paired lines of the paired cable from nearby sources, such as power transmission cables. An open conductor fault or an underdesired bridged tap is a fault which interrupts current flow through a paired line or unbalances the paired line, diminishing the effectiveness of the paired line for telecommunications applications.
Such faults typically cause noise in the affected paired line that is extremely disruptive to the clarity of the telecommunications signal sent over the paired line. A disruptive to the clarity of the telecommunications signal sent over the paired line. A fault in a paired line can also cause other problems such as circuit failure, arc-over and corrosion. Therefore, it is desirable to locate and repair faults in a paired line, particularly a paired line in a telecommunications cable
Since telecommunications cables are not always readily accessible, often being buried below ground, noninvasive methods are preferred for locating faults in a paired line of a telecommunications cable. Tone location methods are conventional noninvasive means for locating a short fault in a paired line of a telecommunications cable using an audible tone as a locator signal. However, tone location methods are often ineffective for locating most resistance faults in a paired line. One reason for such ineffectiveness is a phenomenon termed carry-by. Carry-by occurs at faults that exceed a threshold resistance typically above about 2000 ohms. Most resistance faults have a resistance in a range between about 5000 to about 50,000 ohms. When a resistance exceeding the threshold resistance for carry-by is encountered at the resistance fault in a paired line, the current of the audible tone produces a voltage across the conductors of the paired line past the fault. This voltage causes a corresponding tone current to flow into pair capacitance beyond the fault. Thus, a tone will be audible beyond the resistance fault defeating the tone location method. The problem of carry-by is particularly acute when a high-frequency tone is present in the paired line because the magnitude of tone current flow past the fault is directly related to the frequency of the tone.
It is further noted that less tone current is typically driven through the paired line as the level of fault resistance increases. At relatively high levels of resistance, such as encountered in resistance faults, the level of tone current available for detection can drop below the background noise level present on a paired cable. Consequently, the background noise masks the location of the fault.
Alternate tone location methods have been developed in the telephone industry for detecting resistance faults, which overcome the above-described limitations caused by carry-by. For example, one alternate tone location method uses a 600-volt, breakdown test set to weld the conductors of the paired line together at the fault, which reduces fault resistance to zero in the paired line, thereby allowing effective tone location of the resistance fault. This tone location method, however, can cause extensive cable and equipment damage, particularly to plastic insulated cable and electronic central offices due to the high breakdown voltages used. Accordingly, this tone location method for overcoming fault resistance is disfavored.
Another alternate tone location method for locating resistance faults is disclosed in U.S. Pat. No. 4,291,204, wherein a tone locating device temporarily reduces the fault resistance to a low value by establishing a transient arc at the fault. Passing the fault locating tone through the low-resistance arc at the fault reduces tone carry-by, but does not entirely eliminate it. In addition, the conductors and equipment are susceptible to damage caused by formation of the transient arc, albeit to a lesser degree than the damage potential of the previously described tone location method.
Accordingly, it is an object of the present invention to provide a device and method for effectively locating faults in a paired line using a locator signal. In particular, it is an object of the present invention to provide a device and method for effectively locating resistance faults in a paired line using a locator signal. It is another object of the present invention to provide a device for effectively locating open faults or bridged taps in a paired line using a locator signal. It is yet another object of the present invention to provide a device and method for effectively locating shield break faults in a paired cable. It is another object of the present invention to provide a device and method for effectively locating faults in a paired line using a locator signal, wherein background noise is overcome. It is still another object of the present invention to provide a device and method for effectively locating faults using a locator signal, wherein the impact of carry-by is minimized. It is a further object of the present invention to provide a device and method for effectively locating faults in a paired line using a locator signal, wherein the device is fully portable in the field for expeditiously tracking relatively long lengths of the paired line. These objects and others are accomplished in accordance with the invention described hereafter.

Tone location device for locating faults in a paired line


An audio visual system has a housing with a video display and one or more speakers. The speakers are housed in cavities which limit dispersion of the sound generated, and the video display is preferably a directional LCD display. The housing is preferably mounted to a base by an adjustable arm having passages to accommodate enclosed wiring. One adjustable arm has segments joined by dual-pivot joints, while another has segments joined by single pivot joints. In both types of arms, the frictional resistance of the joints can be adjusted. Preferably, the elements of the arm are strung onto the wiring prior to assembly. The housing can also contain a light source to provide a reading light.

Multimedia presentation devices that have both audio and visual output are frequently used to provide both entertainment and information to users. While these devices have been well suited to providing output for multiple users or to a single isolated user, they have had limited ability to provide output to a single user who is not isolated. Typically, the sound generated from the speakers and light generated by the video display are broadcast and not limited to a region in close proximity of the intended user. The broadcasting of the sound and the light can have two disadvantages. On one hand, it limits the ability of the intended user to receive output which they do not want others to receive, and on the other hand, the broadcasting of the sound and light may distract and/or disturb others near the user. These problems also make it difficult for multiple users to receive individual outputs from independent devices.
Classically, cathode ray tube (CRT) television receivers have been used for audio visual systems. These receivers are not only energy inefficient, using CRT's to provide the visual output, but are frequently large and heavy, which makes repositioning of the television difficult. As a result, the user is frequently required to adjust his/her position in order to view the television. Small, portable televisions and other audio visual systems have been developed using LCD screens for the visual display; however, these devices typically broadcast the sound. Furthermore, these portable devices are designed to be held by the user or to rest on a horizontal surface, which again may require the user to assume a viewing position which is not comfortable to hold for long periods of time.
The issues of focusing the output to a particular user and allowing the user to view from an arbitrary position are particularly important to users in a hospital setting, where the audio visual device may be needed to provide entertainment for a patient who may need to view the audio visual device while in bed without disturbing another patient in the same room who either requires rest or does not wish to be disturbed by the audio visual presentations being viewed by others in the room.
A somewhat similar problem can occur in computer laboratories and dormitory rooms where there are likely to be multiple computers which, today, frequently have multimedia output including speakers. An attempt to address the problem of providing an audio output to a single user is addressed in U.S. Pat. Nos. 5,742,690 and 5,956,411. These patents teach a personal multimedia speaker system for a personal computer. The multimedia speakers have a linear array of speakers to direct sound to the location of the user. A folded waveguide coupled to the speaker array acts to cancel sound in other directions and improve sound quality. The system of the '690 and '411 patents is designed for use with a desktop computer and the depth of the speakers is not a concern, since it is designed to run the full depth of the computer monitor which can typically be 11 inches to 14 inches. These patents also do not address the issue of limiting the visual output to a single user.
Acoustic waveguides have also been employed to provide improved sound quality for large, traditional televisions, as taught in U.S. Pat. Nos. 5,274,709 and 5,524,062. However, here again the depth of the speakers is not a concern. Similarly, these patents do not address the ability to limit the visual output of the system.
For smaller portable computers, which in part overcome the size problem, the efforts to date have been devoted to improving the stereo bass response, such as taught in U.S. Pat. Nos. 5,550,921 and 5,668,882. These patents have not addressed the issue of directional sound, let alone of providing visual output for only a single user.
The issue of user comfort has been addressed by U.S. Pat. No. 6,104,443, which teaches a suspended television receiver or video monitor. The television receiver of the '443 patent is mounted to a positioning mechanism that allows the user to place the television receiver at a desired location and angle for comfortable viewing. The '443 patent discloses both a flexible gooseneck and a parallel arm structure where the parallel arms are connected to provide a scissor type action as they are adjusted to position the television receiver. While the '443 patent addresses the issue of user comfort, it does not address the issue of providing audio visual output to a single user. A gooseneck makes precisely positioning the television receiver difficult for a user, since the gooseneck can have a large elastic component when bent, which will relax once the user releases the television receiver. Alternatively, the gooseneck may be subject to drooping under the weight of the television receiver as the distance from the base increases. Additionally, a gooseneck is not well suited for readily moving the television receiver between viewing and storage positions. The alternative positioning mechanism taught, using parallel arms, can pinch the user as he/she adjusts the position of the television receiver.
Thus, there is a need for a device which can provide an audio visual output to a single user without such output being readily apparent to others in the vicinity of the user, and particularly for such a device which can be readily positioned to allow the user to receive the audio visual output while assuming a comfortable position.


A low cost array antenna (10) employs U-dipole elements (30) inserted into slots in a printed circuit board (18). Board (18), supported in spaced relation directly by back reflector (12), bears a feed network (22) connected to an input/output port (24). The dipole element (30) is a dual-dipole single-feed element, including parallel coextensive dipole segments (32, 34) attached at one end, with a sole signal feed path via feed segment (36). Feed segment (36) is inserted into board (18) and soldered to a feed point of feed network (22). One or more mounting tabs (38) are also inserted into slots in board (18) and may be fixed in place by soldering to an isolated conductor portion provided on board (18) for this purpose. A dual array antenna (50) includes dipoles (51-54) for left slant polarization reception and dipoles (61-64) for right slant polarization reception. Receive diversity is thus provided for cellular communications, with vertical polarization for transmission via parallel use of both arrays (51-54, 61-64).

This invention relates to antennas and, more particularly, to economical forms of antennas employing U-dipole radiating elements of unitary sheet metal construction.
For a variety of reasons it is desirable to provide highly reliable, low cost antennas suitable for meeting the requirements of cellular communication applications. Prior types of antennas suitable for such applications have typically required a significant number of components, some of which may involve costly fabrication techniques, and involve relatively complex and expensive construction and assembly.
A new type of radiating element of U-dipole form, which is capable of fabrication by one piece stamping from conductive sheet stock, is disclosed and described in copending application Ser. No. 08/803,658, filed Feb. 21, 1997, titled U-Dipole Radiating Elements and Antennas and commonly assigned with the present application. The U-dipole form of radiating element provides the potential for use in new forms of antennas providing advantages of simplicity of construction and low cost fabrication.
Objects of the present invention are to provide new and improved antennas utilizing U-dipole elements and such antennas having one or more of the following characteristics or features:
plug-in construction with U-dipole elements inserted into a printed circuit board; PA1 electrical connection by soldering U-dipole element feed segments to a feed network on a printed circuit board; PA1 U-dipole element structural support by insertion into a printed circuit board; PA1 feed network/structural printed circuit board supported directly by back reflector; PA1 U-dipoles supported by a printed circuit board in single or dual array configuration; PA1 array polarization determined by slant alignment of U-dipoles in an array; and PA1 diplexer arrangements for configurations such as 45 degree polarization for signal reception and vertical polarization for signal transmission.


The invention provides an efficient method and apparatus for exchanging data between two entities, such as two application programs or a resource library and an application program. The invention provides a mechanism for populating a complex object model implementation in accordance with the particular data format preferred by the receiving entity from one or more external data formats on the fly responsive to a request for data. The method and apparatus allow the registration of resource factories which can produce resources through mechanisms other than the traditional parsing of a file. One implementation of this is using the URL scheme to identify the factory to handle a request, and allowing that factory to create a specialized Java package resource.

It often is necessary for two application programs to exchange data with each other or for application data used by an application program to be stored in a resource library separate from the application program. For instance, certain data may be used by many different application programs. Therefore, it is efficient to store data in discrete data units (e.g., objects) in a database or other resource library that is accessible to each of the plurality of application programs that may need access to that data. Accordingly, mechanisms have been devised for efficiently transporting data between two computing entities. The two computing entities, for example, may be two application programs or a resource library and an application program or even two different resource libraries. A front-end software module, such as an Application Program Interface (API) module, may be designed to intercept the transport mechanism before it reaches the second application program, parse the data from the transport mechanism to extract the application data and deliver it to the second application program.
XML (eXtensible Markup Language) is a platform-independent programming language that is commonly used in connection with transporting data between two application programs and/or between an application program and a resource factory. It provides a flexible way to create common information formats and share both the format and the information with or amongst a plurality of application programs, particularly on distributed networks like the Internet. Like HTML (HyperText Markup Language), XML code comprises mark-up symbols that describe the content of a file (often termed a page in HTML lingo or a document in XML lingo). Unlike HTML, which only describes how to display and interact with the document or the data within the document, XML describes the content of the document in terms of what data is being described.
Further, unlike HTML, XML is extensible, i.e., the mark-up symbols allowed in XML are unlimited and self-defining. That is, XML programmers are not limited to a standard set of defined mark-up symbols and tags and can create custom mark-up symbols and tags. In this specification, a basic familiarity with XML is assumed in the reader.
An XML document, therefore, can be processed purely as data by a program. Accordingly, one of the transport mechanisms commonly used for exchanging data between two software applications, e.g., an application server and a client, or between a resource library and an application program, is to embed the data in XML documents that can be transferred between two application programs or from a resource library to an application program (such as over a network using well known transfer protocols). In essence, XML provides a system for placing structured data in a document in a way that it can be exchanged between application programs over a network.
An XML parser software module runs at the front end of the application program and parses the XML document to extract the data from the document.
Java is an object-oriented, platform-independent programming language specifically designed for use in distributed network environments, such as the Internet, that is well known and is commonly used in connection with transporting data between two application programs. In this specification, a basic familiarity with Java and Enterprise JavaBeans also is assumed in the reader.
Java code can define classes, objects, attributes, packages, etc., all as well known in the art. Java code can be embedded within an XML document as content of the document. Java classes provide a way to structure data that can be readily exchanged between application programs using, for example, Java Development Kit (JDK) APIs and Java.lang.reflection APIs. Accordingly, it is well known in the prior art to define Java classes, populate the Java class model with application data, and store the information in XML format in an XML document for exchange between application programs or between a resource library and an application program. Put simply, the data is represented in a Java class model data structure and that data structure is stored as content in an XML document for transfer between application programs. An object in Java is an instance of a class.
The receiving application program is front ended by an XML parser program that can parse XML documents and extract Java objects therefrom. Merely one of many possible examples in which application data is transported as described above is in software application modeling and development, where the application data is often referred to as metadata. The complete set of XML documents and Java code to express an application program's metadata can be extremely large and complex.
In modern times, in which distributed networks (of which the Internet is merely one example) are ubiquitous, it is common for one application program that uses the same data as a second application program to require the data to be in a different format. For instance, two different vendors may provide software that a customer may wish to integrate into a larger computing system in which the software from one of the vendors generates data that will then be passed to the software of the other vendor for further processing. However, these two vendors may use different formats for data. Accordingly, many transport mechanisms are platform and/or format independent in order to provide a mechanism by which data can be transported between two computing entities that may use different platforms and/or data formats. Accordingly, data generated by one application program in a first format can be embedded in one of these platform and format independent transport mechanisms for transport.
The receiving application program typically will have a front-end software module, e.g., an API, designed to, not only intercept the transport mechanism and parse the data therefrom before it reaches the actual application program tools, but that also determines the format of the received data and, if it is in an external format (i.e., a format other than the internal format used by the application program tools of the receiving entity), converts it to the internal format used by the application program tools.
Generally, metamodel data classes have been tightly coupled to an XML format or to an external format. Accordingly, in order to enable an application program to use application data received from application programs in different formats, application programmers had to write an implementation for each different format. Alternately, the application program that generates and/or transmits the data to another application program would need to have different implementations of the Java classes for each different format employed by an application program to which it transmits application data.
FIG. 1 is a flow chart illustrating operation of an API in accordance with the above-discussed, prior art approach. In this example, all data that an application program tool (hereinafter tool) might need to retrieve is stored in a data repository and is transported between modules as Java constructs (e.g., objects) embedded in XMI documents.
The process starts at step 101. In step 102, the user of a tool performs an operation that causes the application program to seek data. The tool is aware of a naming protocol for resources that may be stored in a resource repository database and thus generates a request for a specific XMI document and Java object within that document. The tools typically maintain caches of data (e.g., objects, classes, etc.) used recently. Accordingly, in step 103, it first checks if the resource to which the requested object corresponds is already cached, since, if it is already cached, there is no need to perform all of the steps alluded to above to retrieve and parse data from an XMI document and convert to the internal data format.
Thus, if that resource is cached, flow proceeds from step 103 to step 108 where the object is identified in the cache. In step 109, the object is retrieved from the cache and returned to the tool (or, if the object is null in the cache, the tool instead is informed of that fact). The process would then end at step 111.
However, if the corresponding resource has not been cached, flow proceeds to step 104 in order to load the object in the manner summarized above. Specifically, in step 104, the resource repository calls a resource factory that uses a URI converter that takes the URI specified in the request and returns the contents of that URI. In step 105, the URI converter attempts to open the input stream from the document and return the resulting input stream, as is well known in the art. In step 106, it is determined if the stream has been successfully retrieved and converted. If not, the process has failed and flow proceeds to step 110, in which null data is returned to the tool. The process then terminates at step 111.
Assuming the stream is successfully retrieved and converted in step 106, flow will proceed to step 107. In step 107, the input stream is parsed into the individual objects and the resource containing the objects is written to the cache. Flow then proceeds to steps 108 and 109, where the particular one of the objects in the parsed document that was requested is located in the resource and returned to the tool. The process ends at step 111.
In this routine, the entire XMI document within which the requested object is contained is retrieved, converted, parsed and written to the cache, even though only a single object was requested.
Further, the complete set of XML documents and Java code to express an application program's metadata can be extremely large and complex. When there are multiple formats for expressing the metadata, the size and complexity of the system is further increased and, particularly, there is much more data that must be retrieved, converted, parsed, and stored.
It would be desirable to reduce the processing overhead needed for an application program to interface to application data in different formats.
XMI (eXtensible Metadata Interchange) is a relatively recent standard adopted by the Object Management Group (OMG). XMI is an open industry standard that combines the benefits of the XML standard for defining, validating and sharing document formats with the benefits of the object-oriented Unified Modeling Language (UML). The XMI format specifies an open information interchange model intended to provide developers working in object technology with the ability to exchange programming data over a network in a standardized way. It is specifically aimed at providing a standard XML document format for object models built to the Meta Object Facility (MOF) specification. Accordingly, it provides a standard way to serialize model objects. It provides only a single format and does not address other sources of model objects.

Method and apparatus for efficiently reflecting complex systems of objects in XML documents

Abstract: The method and apparatus allow the registration of reflection adapter factories, and specialized model classes which work with those adapters, for the purpose of computing object attributes and populating the Java package resource with them. One implementation of this mechanism is a set of Java Reflection adapters which compute the properties of JavaClass model objects from the JDK reflection API'S.

International Business Machines Corporation


Systems for spinal stabilization and fixation replace, reconstruct or augment the spinal ligamentous and/or bony tissues resected during surgical procedures. The spinal stabilization system includes at least an implant configured to span the intervertebral disc space with at least one of its ends attached to a respective vertebral body by at least one anchor. The system has a low profile conformable to the spinal anatomy.

The present invention is directed devices and methods for use in spinal surgery, and more particularly to devices and methods for stabilizing the spine.
Various spinal surgical procedures require access of a subject disc space or vertebral body, such as for the repair of a herniated disc or vertebral body, the insertion of one or more interbody fusion devices, interbody spacers, or artificial discs. In order to access a spinal column, one or more spinal ligaments and bony tissue may have to be severed or at least partially resected to allow insertion of devices and/or surgical instruments into or to the disc space or vertebral body. It also may be desirable to augment or replace existing spinal ligaments and bony tissue. Posterior or anterior rigid metal constructs can also be used to stabilize the spinal column after these techniques are completed.
Rigid metal plates or rods on the anterior, antero-lateral, lateral or posterior portions of the spinal column segment are in close contact with and exposed to the adjacent vasculature and tissue. It is desirable that the potential for screw back out, loosening, bending of the construct, and stress shielding be reduced or eliminated in view of this close contact with the vasculature and the surrounding tissue.

Flexible systems for spinal stabilization and fixation


In one embodiment, a punching machine having a tool bearing, a drive spindle coupled to the tool bearing, and a drive system configured to move the tool bearing axially along a lifting axis and to rotate the tool bearing about the lifting axis, the drive system having a motor system having a stator and a rotor internally coupled to the stator and a spindle nut coupled to the rotor and cooperating with the drive spindle, wherein the spindle nut is at least partially disposed within the stator.

As those of ordinary skill in the art will appreciate, punching machines may be employed to punch holes or other cut-outs from a workpiece (e.g., a metal sheet). Typically, punching machines include a tool bearing for a punching tool and a rotary/lifting drive, which moves the tool bearing back and forth along a lifting axis to a working area of the punching machine. Also, the tool bearing is rotatably adjustable about the lifting axis. The punching machine may also include a motor-driven spindle transmission provided with a drive control system. Typically, a rotary/lifting drive having two electric drive motors is provided for the tool bearing of a punching machine. Both drive motors may be arranged laterally next to a drive spindle, which in turn runs in the direction of a lifting axis of the tool bearing. One of the drive motors serves for workpiece punching and for that purpose is connected via a belt drive to a lifting spindle nut disposed on the drive spindle. By driving this spindle transmission in one direction of rotation, the tool bearing (and hence the attached punching tool) is moved with working strokes towards the workpiece to be processed and then by reversing the motor, the tool bearing is moved in the opposite direction. The second drive motor in a conventional punching machine is intended for rotary adjustment of the tool bearing and the punching tool. This drive motor is connected via another belt drive to enable rotation of the punching tool relative to the lifting axis. A more efficient punching tool would be desirable.


Pumped laser crystals for use in an imaging apparatus are designed and housed so as to minimize variation in dot size across the spectrum of duty cycles ranging generally from 1% to 100%--that is, from print densities ranging from every hundredth pixel to every consecutive pixel.

1. Field of the Invention
The present invention relates to digital printing apparatus and methods, and more particularly to a system for imaging lithographic printing members on- or off-press using digitally controlled laser output.
2. Description of the Related Art
In offset lithography, a printable image is present on a printing member as a pattern of ink-accepting (oleophilic) and ink-repellent (oleophobic) surface areas. Once applied to these areas, ink can be efficiently transferred to a recording medium in the imagewise pattern with substantial fidelity. Dry printing systems utilize printing members whose ink-repellent portions are sufficiently phobic to ink as to permit its direct application. Ink applied uniformly to the printing member is transferred to the recording medium only in the imagewise pattern. Typically, the printing member first makes contact with a compliant intermediate surface called a blanket cylinder which, in turn, applies the image to the paper or other recording medium. In typical sheet-fed press systems, the recording medium is pinned to an impression cylinder, which brings it into contact with the blanket cylinder.
In a wet lithographic system, the non-image areas are hydrophilic, and the necessary ink-repellency is provided by an initial application of a dampening (or "fountain") solution to the plate prior to inking. The ink-abhesive fountain solution prevents ink from adhering to the non-image areas, but does not affect the oleophilic character of the image areas.
If a press is to print in more than one color, a separate printing member corresponding to each color is required. The original image is decomposed into a series of imagewise patterns, or "separations," that each reflect the contribution of the corresponding printable color. The positions of the printing members are coordinated so that the color components printed by the different members will be in register on the printed copies. Each printing member ordinarily is mounted on (or integral with) a "plate" cylinder, and the set of cylinders associated with a particular color on a press is usually referred to as a printing station.
To circumvent the cumbersome photographic development, plate-mounting and plate-registration operations that typify traditional printing technologies, practitioners have developed electronic alternatives that store the imagewise pattern in digital form and impress the pattern directly onto the plate. Plate-imaging devices amenable to computer control include various forms of lasers. For example, U.S. Pat. Nos. 5,351,617 and 5,385,092 disclose ablative recording systems that use low-power laser discharges to remove, in an imagewise pattern, one or more layers of a lithographic printing blank, thereby creating a ready-to-ink printing member without the need for photographic development. In accordance with those systems, laser output is guided from the diode to the printing surface and focused onto that surface (or, desirably, onto the layer most susceptible to laser ablation, which will generally lie beneath the surface layer). Other systems use laser energy to cause transfer of material from a donor to an acceptor sheet, to record non-ablatively, or as a pointwise alternative to overall exposure through a photomask or negative.
As discussed in the '617 and '092 patents, laser output can be generated remotely and brought to the recording blank by means of optical fibers and focusing lens assemblies. It is important, when focusing radiation onto the recording blank, to maintain satisfactory depth-of-focus--that is, the tolerable deviation from perfect focus on the recording surface. Adequate depth-of-focus is important to construction and use of the imaging apparatus; the smaller the working depth-of-focus, the greater will be the need for fine mechanical adjustments and vulnerability to performance degradation due to the alignment shifts that can accompany normal use. Depth-of-focus is maximized by keeping output beam divergence to a minimum.
Unfortunately, optical efforts to reduce beam divergence also diminish power density, since a lens cannot alter the brightness of the radiation it corrects; a lens can only change the optical path. Thus, optical correction presents an inherent tradeoff between depth-of-focus and power loss. U.S. Ser. No. 08/676,470, filed on Jul. 8, 1996 and entitled DIODE-PUMPED LASER SYSTEM AND METHOD, discloses an approach that utilizes the divergent output of a semiconductor or diode laser to optically pump a laser crystal, which itself emits laser radiation with substantially less beam divergence but comparable power density; the laser crystal converts divergent incoming radiation into a single-mode output with higher brightness.
The output of the laser crystal is focused onto the surface of a recording medium to perform the imaging function. In ablation-type systems, the beam is focused on the "ablation layer" of the recording material, which is designed to volatilize in response to laser radiation; again, the depth-of-focus of the laser beam provides a degree of tolerable deviation. In transfer-type systems, the beam is focused on the transfer layer. As used herein, the term "plate" or "member" refers to any type of printing member or surface capable of recording an image defined by regions exhibiting differential affinities for ink and/or fountain solution; suitable configurations include the traditional planar or curved lithographic plates that are mounted on the plate cylinder of a printing press, but can also include seamless cylinders (e.g., the roll surface of a plate cylinder), an endless belt, or other arrangement.
Practical imaging equipment requires lasers that respond nearly instantaneously to high-frequency square-wave power pulses so that imaging dots--that is, the spots produced by the laser beam on the recording material--appear as sharp, discrete, and ordinarily round shapes of consistent size. Dots must also be printed, or recording space left blank, at very closely spaced intervals to achieve typical print resolutions. Although the '470 application discloses the ability to control image-dot size by varying the pulse width within certain limits, it has been found that dot size can also change with the density at which dots are printed. The term "duty cycle" refers to the percentage of pixel locations in an imaged field that actually receive laser radiation (that is, the frequency with which the laser crystal is activated). The larger the duty cycle, the darker will be the resulting color, since in digital printing systems gray-scale densities or tints are achieved by varying pixel densities.
If dot size varies with the duty cycle, it will be impossible to establish consistent calibrations for color densities, since dot size also affects density. For example, if dots are smaller at low duty cycles, areas imaged at low pixel densities will print lighter than would be expected. And since documents typically contain regions of varying densities that may be interwoven in complex patterns, the problem cannot be corrected simply by altering the pixel density to correct for varying dot sizes.

Diode-pumped system and method for producing image spots of constant size