Disclosed are compounds which inhibit .beta.-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease. Also disclosed are pharmaceutical compositions comprising a compound which inhibits .beta.-amyloid peptide release and/or its synthesis.

1. Field of the Invention
This invention relates to compounds and pharmaceutical compositions comprising such compounds which inhibit cellular .beta.-amyloid peptide release and/or its synthesis, and, accordingly, have utility in treating Alzheimer's disease.
2. References
The following publications, patents and patent applications are cited in this application as superscript numbers:
1 Glenner, et al., "Alzheimer's Disease: Initial Report of the Purification and Characterization of a Novel Cerebrovascular Amyloid Protein", Biochem. Biophys. Res. Commun., 120:885-890 (1984). PA1 2 Glenner, et al., "Polypeptide Marker for Alzheimer's Disease and its Use for Diagnosis", U.S. Pat. No. 4,666,829 issued May 19, 1987. PA1 3 Selkoe, "The Molecular Pathology of Alzheimer's Disease", Neuron, 487-498 (1991). PA1 4 Goate, et al., "Segregation of a Missense Mutation in the Aryloid Precursor Protein Gene with Familial Alzheimer's Disease", Nature, 342:704-706 (1990). PA1 5 Chartier-Harlan, et al., "Early-Onset Alzheimer's Disease Caused by Mutations at Codon 717 of the .beta.-Amyloid Precursor Proteing Gene", Nature, 353:844-846 (1989). PA1 6 Murrell, et al., "A Mutation in the Amyloid Precursor Protein Associated with Hereditary Alzheimer's Disease", Science, 254:97-99(1991). PA1 7 Mullan, et al., "A Pathogenic Mutation for Probable Alzheimer's Disease in the APP Gene at the N-Terminus of .beta.-Aryloid, Nature Genet., 1:345-347 (1992). PA1 8 Schenk, et al., "Methods and Compositions for the Detection of Soluble .beta.-Amyloid Peptide", International Patent Application Publication No. WO 94110569, published May 11, 1994. PA1 9 Selkoe, "Amyloid Protein and Alzheimer's Disease", Scientific American, pp. 2-8, November, 1991. PA1 10 Losse, et al., Tetrahedron, 27:1423-1434 (1971). PA1 11 Citron, et al., "Mutation of the .beta.-Amyloid Precursor Protein in Familial Alzheimer's Disease Increases .beta.-Protein Production, Nature, 360:672-674 (1992). PA1 12 Hansen, et al., "Reexamination and Further Development of a Precise and Rapid Dye Method for Measuring Cell Growth/Cell Kill", J. Immun. Meth., 119:203-210 (1989). PA1 13 P. Seubert, Nature (1992) 359:325-327 PA1 14 Johnson-Wood et al., PNAS USA (1997) 94:1550-1555 PA1 15 Tetrahedron Letters, 34(48), 7685 (1993)) PA1 wherein R.sup.1 is selected from the group consisting of: PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, substituted alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; PA1 with the proviso excluding the following known compound: PA1 R.sup.2 is selected from the group consisting of PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthaliimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alyl, substituted alkyl, cycloakyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; ##STR3## PA1 wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.4 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl provided that at least one R.sup.4 is selected to be: PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is --C(O)Y or --C(S)Y where Y is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, alkoxy, substituted alkoxy, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of hydroxyl, amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; and ##STR4## PA1 wherein R.sup.1 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkenyl, substituted alkynyl, aryl, heteroaryl and heterocyclic; PA1 R.sup.2 is selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclic; PA1 each R.sup.4 is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heteroaryl, heterocyclic, substituted alkyl, substituted alkenyl and substituted alkynyl; PA1 each R.sup.5 is selected from hydrogen and methyl or together with R.sup.4 forms a cycloalkyl group of from 3 to 6 carbon atoms; PA1 X is selected from the group consisting of PA1 X can also be --CR.sup.6 R.sup.6 Y' where each R.sup.6 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic and Y' is selected from the group consisting of amino, thiol, alkoxy, phthalimido, --OC(O)R.sup.7, --SSR.sup.7, --SSC(O)R.sup.7 where R.sup.7 is selected from the group consisting of alkyl, substituted alkyl, cycloalkyl, aryl, heteroaryl and heterocyclic, PA1 provided that R' and R" are not both independently selected from hydrogen, alkyl, phenyl, benzyl and phenethyl; PA1 X' is hydrogen, hydroxy or fluoro; PA1 X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and PA1 n is an integer equal to 1 or 2; PA1 with the proviso that: PA1 with the additional provisos that in compounds selected from formulas I-IV: PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-histidine methyl ester PA1 N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-( S)-2-aminohexanamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino hexanamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylalaninamide PA1 N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-(3-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-(4-pyridyl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amin ohexanamide PA1 N[-N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanoate tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-[3-(N,N-dimethylamino)propo xy]phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl-L-4-[(tert-butyloxycarbonyl)meth oxy]phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tyrosine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl-L-4-(carboxymethoxy)phenylalanin e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morpholinoethoxy)phenyla lanine methyl ester PA1 N-N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-6-(N,N-dimethylamino )hexanoate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-pyridyl)propio nate methyl ester PA1 N[-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(3-pyridyl)propiona te methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3(4-pyridyl)propion ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-methoxypropionate methyl ester PA1 N-[N-(3,5-difluorphenylacetyl)-L-alaninyl]-2-amino-3-morpholinopropionate methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(2-morp holinoethoxy)phenylalaninamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-m ethoxypropionamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-( 4-pyridyl)propionamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-( 2-pyridyl)propionamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)pro pionate methyl ester PA1 N-(3-methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylal aninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propi onate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-naphthyl)propi onate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(2-thienyl)propio nate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine benzyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-bromo-propyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine 3-iodopropyl ester PA1 N-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-N.sub..epsilon. -(tert-butoxycarbonyl)-L-lysine methyl ester PA1 methyl N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-4-phenylbutanoate PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 2-phenylethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine 3-phenylpropyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetamide PA1 N-[N-(3,5 difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-pyridyl)acetate ethyl ester PA1 N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexanamide PA1 N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohexana mide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-anion-2-(3-methoxyphenyl)acet ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-methoxyphenyl)acet ate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-pyridyl)acetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-pyridyl)acetate ethyl ester PA1 N-[N-(cyclohex-1-enylacetyl)-L-alaninyl]-L-phenylalanine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-1-aminocyclopropane-1-carboxyla te methyl ester PA1 N-2-(N,N-dimethylamino)ethyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-al aninyl]-L-alaninanide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]glycine benzyl ester PA1 N-hydroxy-N'-[N-(3-nitrophenylacetyl)-L-alaninyl]-D,L-threoninarmide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanine ethyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-methoxy-N-methyl-N'-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninamide PA1 N-iso-butyl-N'[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N,N-di-n-propyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valinamide PA1 N'-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanine methyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninamide PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylala ninamide PA1 N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-(4-nitrophenyl)-N'-[N-[N-(isovaleryl)-L-phenylglycinyl]-L-alaninyl]-L-ala ninamide PA1 N-(4-nitrophenyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-benzyl-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-(3,5-difluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alani namide PA1 N-(3-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-(4-nitrobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-tryptophan methyl ester PA1 N-(4-methoxybenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalaninyl]-L-phenylgl ycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine methyl ester PA1 N-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl3-L-phenylglycine methyl ester PA1 N-(2-phenylethyl)-N'-[N-(3,5-difluoropbenylacetyl)-L-alaninyl]-L-alaninamid e PA1 N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-tryptophanamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-cyclohexylpropion ate methyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino -3-(4-nitrophenyl)propionamide PA1 N-[(R)-.alpha.-methylbenzyl]-N'-N-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide PA1 N-[(S)-.alpha.-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -alaninamide PA1 N-(4-fluorobenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninami de PA1 N-(4-pyridylmethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N-(4-trifluoromethylbenzyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L- alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-phenylpropionate ethyl ester PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-phenylalanine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-methylpropionate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-cyclohexylacetate ethyl ester PA1 N-(2-methoxyethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgly cinamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylglycinamide PA1 N-(2-pyridylmethyl)-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgl ycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4-fluorophenyl)aceta te ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-fluorophenyl)aceta te ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-alanine ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-3-phthalimidopropionate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine neopentyl ester PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-valinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminopentanoate methyl ester PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-(S)-2-amino-3-tert-butoxybutyryl] morpholine PA1 4-[N-[N-(3-nitrophenylacetyl)-L-alaninyl]-L-isoleucinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-leucine methyl ester PA1 N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-2-(N,N-dimethylamino)ethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -alaninamide PA1 N-cyclohexyl-N'-[N-3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alanina mide PA1 N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamid e PA1 3-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]thazolidine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobutanoate methyl ester PA1 N-(R)-sec-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 1-[N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninyl]pyrrolidine PA1 N-(S)-sec-butyl-N o[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-valine methyl ester PA1 N-2-fluoroethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninamide PA1 N-[(S)-6-methyl-3-oxohept-2-yl]-N'(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-4-nitrobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminobut yramide PA1 N-4-nitrobenzyl-N'-[N-(3,5-difluorophenyacetyl)-L-alaninyl]-(S)-2-aminopent anamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-fluorophenyl)aceta te methyl ester PA1 N'-[N-(3,5-diuorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophe n-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-2-yl)a cetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-3-yl)a cetate methyl ester PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-thienyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(benzothiophen-5-yl)a cetate ethyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetat e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetat e tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-thienyl)acetic acid PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(1H-tetrazol-5-yl)ace tate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(6-methoxy-2-naph thyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(3-trifluoromethylphe nyl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(4,5,6,7-tetrahydrobe nzothiophen-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(thieno[2,3-b]thiophe n-2-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(2-methylthiazol-4-yl )acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-aminohex-4-enoate methyl ester PA1 N-tert-butyl-N'-[N-(3,5-Difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(4- phenylphenyl)acetamide PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-aminobutanoyl]-L-phenylglycine tert-Butyl Ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-methionyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-leucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylalaninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine methyl ester PA1 N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-lysine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-glutamide PA1 N-[(S)-3-hydroxy-6-methylhept-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(S)-2-hydroxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam ide PA1 N-[N-(3,5-difluorophenyl-.alpha.-fluoroacetyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-2-(S)-aminocyclohexylacetyl]-L-phenylglycin e methyl ester PA1 N-[(1 R,2S)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(1R,2S)-1-hydroxy-1,2-diphenyleth-2-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide PA1 N-[(1S,2R)-1-hydroxy-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-ala ninamide PA1 N-2-methoxyethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamide PA1 N-[(S)-2-hydroxy-1,2-diphenylethyl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[(S)-1-hydroxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[.alpha.-hydroxy-.alpha.'-(4-hydroxyphenyl)-iso-propyl]-N'-(3,5-difluorop henylacetyl)-L-alaninamide PA1 N-2-pyridylmethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalan inamide PA1 N-[.alpha.-hydroxy-.alpha.'-pyrid-2-yl-iso-propyl]-N'-(3,5-difluorophenylac etyl)-L-alaninamide PA1 N-[.alpha.-hydroxy-.alpha.'-pyrid-4-yl-iso-propyl]-N'-(3,5-difluorophenylac etyl)-L-alaninamide PA1 N-[(S)-1-hydroxy-4-methylpent-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanina mide PA1 N-[.alpha.-methoxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-hydroxy-3-methyl-but-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-2-amino-2-(6-aminopyrid-2-yl)ac etate methyl ester PA1 N-[1-hydroxy-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[(S)-2-methoxy-1-phenyleth-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninam ide PA1 N-[(S)-1-methoxy-2-phenyl-prop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alanin amide PA1 N-[(S)-1-acetoxyhex-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[(S)-1-(tert-butylcarbonyloxy)-hex-2-yl]-N'-(3,5-difluorophenylacetyl)-L- alaninamide PA1 N-[2-hydroxy-1-(thien-2-yl)ethyl]-N'-(3,5-difluorophenylacetyl)-L-alaninami de PA1 N-[(S)-2-hydroxy-2-methyl-1-phenylprop-1-yl]-N'-(3,5-difluorophenylacetyl)- L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-(thien-2-yl)glycinyl]-L-phenylalanine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinol PA1 N-[N-(3,5-difluorophenylacetyl)-D,L-phenylglycinyl]-D,L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-D,L-valinyl]-D,L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-norleucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-norvalinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-tert-leucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-isoleucinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-cyclohexylalaninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(cyclopropyl)acetyl]-L-phenyl glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-3-yl)acetyl]-L-phenylg lycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-(S)-2-amino-2-(thien-2-yl)acetyl]-L-phenylg lycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-D-(4-fluorophenyl)glycinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(4-methoxyphenyl)glycinyl]-L-phenylglycin e methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycine tert-butyl ester PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(5-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(5-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-bromothien-2 -yl)glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-2-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(thien-3-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-3-yl)gly cinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinami de PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinami de PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(5-chlorothie n-2-yl)glycinamide PA1 N-Cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-4-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-L-3-(phenoxy)phenyl glycinamide PA1 N-(S)-(-)-.alpha.-methylbenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl] -D,L-phenylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-3-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(ethyl)phenyl glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(phenyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-(benzyl)pheny lglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-bromophenyl glycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(cyclohexyl)p henylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(4-ethylpheny l)phenylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-4-(tert-butyl)p henylglycinamide PA1 N-tert-butyl-N'-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-3-(4-chlorophen oxy)phenylglycinamide PA1 N-cyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-(phenyl)pheny lglycinamide PA1 N-[N-(3,5-difluorophenyl-.alpha.,.alpha.-hydroxyacetyl)-L-alaninyl]-L-pheny lglycine tert-butyl ester PA1 N-tert-butyl-N '[N-(3,5-difluorophenyl-a,.alpha.-difluoroacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine tert-butyl ester PA1 N-[(S)-1-oxo-1-phenylprop-2-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-fluorophenylacetyl)-L-alaninyl]-D,L-(pyrid-3-yl)glycine tert-butyl ester PA1 [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]morpholine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-(2-methoxy)phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butoxycarbonyl(hydroxyl amine) ester PA1 N-neopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinam ide PA1 N-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-methoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinamid e PA1 [N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinyl]azetidine PA1 N-iso-butyl-N'-[N(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinami de PA1 N-cyclopropanemethyl-N'-[N-(3,5-difluorophenylacetyl) L-alaninyl]-D,L-phenylglycinamnide PA1 N-methoxy-N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylg lycinamide PA1 N-2-methylprop-2-enyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phen ylglycinamide PA1 N-(pyrid-3-yl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-(pyrid-4yl)methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenyl glycinamide PA1 N-furfuryl-N'-[N-(3,5-difluorhenylacetyl)-L-alaninyl]-D,L-phenylglycinamide PA1 N-cyclopentyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycin amide PA1 N-1-benylpiperidin-4-yl-N'-[N-(3,5-difluorophenylactyl)-L-alaninyl]-D,L-phe nylglycinamide PA1 N,N-dimethyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycina mide PA1 N-2,2,6,6-tetramethylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alan inyl]-D,L-phenylglycinamide PA1 N-2-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-4-methylcyclohexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-pheny lglycinamide PA1 N-1-ethoxycarbonylpiperidin-4-yl-N'-[N-(3,5-difluorophenylacetyl)-L-alaniny l]-D,L-phenylglycinamide PA1 N-methyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-tert-butoxy-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycin amide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycine N-tert-butyl(hydroxylamine) ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine hydrazide PA1 N-(1-ethoxyethen-1-yl)-[N'-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylg lycine hydrazide PA1 N-4-(phenyl)butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N-3-(4-iodophenoxy)propyl-N N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-6-(amino)hexyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylgly cinamide Hydrochloride PA1 N-1-(phthalimido)pent-2-yl-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-(3,5-difluorophenyl)glycinyl]-L-(3,5-difl uorophenyl)glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-norleucine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine iso-propyl ester PA1 N-(isopropyl) N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycine iso-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine methyl ester PA1 N-[N-(3,5-difluoropbenylacetyl)-L-alaninyl]-2-amino-2-(5-chlorobenzothiophe n-3-yl)acetate methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-3-(thiazol-4-yl)pro pionate tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-(thien-2-yl)glycinamide PA1 N-[N-(3-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N-[N-(4-fluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycine PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-(S)-2-amino-2-(2-furanyl)aceta mide PA1 N'-[N-(3,5-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,4-difluorophenylacetyl)-D-alaninyl]-D-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylalanin-N-methylsulfona mide PA1 N"-methyl-N"-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamid e PA1 N"-methyl-N"-phenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-alaninam ide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-phenylglycinamide PA1 N"-methyl-N"-benzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-glycinamid e PA1 N"-4-fluorobenzyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(4-fluoro)phenylglycine neopentyl ester PA1 N-[N-(2,3,4,5,6-pentafluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-(pyrid-3-yl)glycine tert-butyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)serinyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-(O-benzyl)threoninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-tbreoninyl]-L-phenylglycine methyl ester PA1 N-[N-(3,5-difluorophenylacetyl)-L-serinyl]-L-phenylglycine methyl ester PA1 N"-4-methylphenyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglyc inamide PA1 N"-tetrahydrofurfuryl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenyl glycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenyl-glycinamide PA1 N'-[N-(3,5-difluorophenylacetyl-L-methionyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-2-aminobutanoyl]-L-phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-phenylglycinyl]-L-phenylglycinamide PA1 N-[N-(3,5-difluorophenylacetyl)-L-valinyl]-L-phenylglycinamide PA1 N-[(R)-.alpha.-methylbenzyl]-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L -phenylglycinamide PA1 N-[1-phenyl-2-oxo-3-methylbutan-1-yl]-N'(3,5-difluorophenylacetyl)-L-alanin amide PA1 N-[1-phenyl-2-oxo-propan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-pentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-ala ninamide PA1 N-[1-phenyl-2-oxo-butan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-4-methylpentan-1-yl]-N'-(3,5-difluorophenyl-acetyl)-L-ala ninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-.alpha.-hydroxyphenylalanine methyl ester PA1 N"-[4-((2-hydroxy-4azido)-phenyl)NHC(O)-)butyl] N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylglycinamide PA1 N-[(S)-1-phenyl-2-oxo-2-phenyl-ethan-1-yl]-N'(3,5-difluorophenyl-acetyl)-L- alaninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-fluorophenylglycine tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-phenylphenylglycine tert-butyl ester PA1 N"-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-4-n-butylpheny lglycinamide PA1 N"-tert-butyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-4-(phenylace tenyl)phenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-phenylglycinthioamide PA1 N-[1,3-diphenyl-2-oxo-propan-1-yl]-N'(3,5-difluorophenylacetyl)-L-alaninami de PA1 N-[1-phenyl-2-oxo-2-cyclopentylethan-1-yl]-N'(3,5-difluorophenylacetyl)-L-a laninamide PA1 N-[1-phenyl-2-oxo-hexan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alaninamide PA1 N-[1-phenyl-2-oxo-3-methylpentan-1-yl]-N'-(3,5-difluorophenylacetyl)-L-alan inamide PA1 N"-n-hexyl-6-biotinamidyl-N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L- phenylglycinthioamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-methioninyl]-L-methionine PA1 N'-[N-(2-tert-BOC-amino)propionyl)-L-alaninyl]-L-phenylglycine methyl ester PA1 N"-tert-butyl N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-L-2-fluorophenylglycinamide PA1 N'-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D,L-2-phenylglycine methyl ester PA1 N-[(S)-1-phenyl-2-oxo-3-phenylpropan-1-yl]-N'(3,5-difluorophenylacetyl)-L-a laninamide PA1 N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycin e PA1 N'-[N-(3,5-difluorophenylacetyl)-D,L-thien-3-ylglycinyl]-D,L-2-phenylglycin e tert-butyl ester PA1 N'-[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine PA1 N'-N[N-(3,5-difluorophenylacetyl)-L-thien-3-ylglycinyl]-L-2-phenylglycine tert-butyl ester PA1 N-[2-hydroxy-1-(S)phenyleth-1-yl]-N'-[(3,5-difluorophenylacetyl)-L-phenylgl ycinyl]-L-alaninamide PA1 N-[2-hydroxyeth-1-yl-N'-[(3,5-difluorophenylacetyl)-L-alaninyl]-L-phenylgly cinamide PA1 N'-[N-(3,5-difluorophenyl-2-oxo-acetyl)-L-alaninyl]-L-2-phenylglycine ten-butyl ester PA1 [N-(3-amioproprionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 [N-3-tert-butoxycarbonylamio)propionyl)-L-alaninyl]-L-phenylglycine tert-butyl ester PA1 N-cyclohexyl-N-methyl-N-[N-(3,5-difluorophenylacetyl)-L-alaninyl]-D, L-phenylglycinamide PA1 N-cyclohexyl-N-methyl-N-[N-(3,5-difluorophenyl-.alpha.-hydroxyacetyl)-L-ala ninyl]-D,L-phenylglycinamide PA1 N-cyclohexyl-N'-[N-3,5-difluoropbenyl-.alpha.-hydroxyacetyl)-L-alaninyl]-D, L-phenylglycinamide.
All of the above publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.
3. State of the Art
Alzheimer's Disease (AD) is a degenerative brain disorder characterized clinically by progressive loss of memory, cognition, reasoning, judgment and emotional stability that gradually leads to profound mental deterioration and ultimately death. AD is a very common cause of progressive mental failure (dementia) in aged humans and is believed to represent the fourth most common medical cause of death in the United States. AD has been observed in races and ethnic groups worldwide and presents a major present and future public health problem. The disease is currently estimated to affect about two to three million individuals in the United States alone. AD is at present incurable. No treatment that effectively prevents AD or reverses its symptoms and course is currently known.
The brains of individuals with AD exhibit characteristic lesions termed senile (or amyloid) plaques, amyloid angiopathy (amyloid deposits in blood vessels) and neurofibrillary tangles. Large numbers of these lesions, particularly amyloid plaques and neurofibrillary tangles, are generally found in several areas of the human brain important for memory and cognitive function in patients with AD. Smaller numbers of these lesions in a more restrictive anatomical distribution are also found in the brains of most aged humans who do not have clinical AD. Amyloid plaques and amyloid angiopathy also characterize the brains of individuals with Trisomy 21 (Down's Syndrome) and Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch Type (HCHWA-D). At present, a definitive diagnosis of AD usually requires observing the aforementioned lesions in the brain tissue of patients who have died with the disease or, rarely, in small biopsied samples of brain tissue taken during an invasive neurosurgical procedure.
The principal chemical constituent of the amyloid plaques and vascular amyloid deposits (amyloid angiopathy) characteristic of AD and the other disorders mentioned above is an approximately 4.2 kilodalton (kD) protein of about 39-43 amino acids designated the .beta.-amyloid peptide (.beta.AP) or sometimes A.beta., A.beta.P or .beta./A4. .beta.-Amyloid peptide was first purified and a partial amino acid sequence was provided by Glenner, et al..sup.1 The isolation procedure and the sequence data for the first 28 amino acids are described in U.S. Pat. No. 4,666,829.sup.2.
Molecular biological and protein chemical analyses have shown that the .beta.-amyloid peptide is a small fragment of a much larger precursor protein (APP), that is normally produced by cells in many tissues of various animals, including humans. Knowledge of the structure of the gene encoding the APP has demonstrated that .beta.-amyloid peptide arises as a peptide fragment that is cleaved from APP by protease enzyme(s). The precise biochemical mechanism by which the .beta.-amyloid peptide fragment is cleaved from APP and subsequently deposited as amyloid plaques in the cerebral tissue and in the walls of the cerebral and meningeal blood vessels is currently unknown.
Several lines of evidence indicate that progressive cerebral deposition of .beta.-amyloid peptide plays a seminal role in the pathogenesis of AD and can precede cognitive symptoms by years or decades. See, for example, Selkoe.sup.3. The most important line of evidence is the discovery that missense DNA mutations at amino acid 717 of the 770-amino acid isoform of APP can be found in affected members but not unaffected members of several families with a genetically determined (familial) form of AD (Goate, et al..sup.4 ; Chartier-Harlan, et al..sup.5 ; and Murrell, et al..sup.6) and is referred to as the Swedish variant. A double mutation changing lysine.sup.595 -methionine.sup.596 to asparagine.sup.595 -leucine.sup.596 (with reference to the 695 isoform) found in a Swedish family was reported in 1992 (Mullan, et al..sup.7). Genetic linkage analyses have demonstrated that these mutations, as well as certain other mutations in the APP gene, are the specific molecular cause of AD in the affected members of such families. In addition, a mutation at amino acid 693 of the 770-amino acid isoform of APP has been identified as the cause of the .beta.-amyloid peptide deposition disease, HCHWA-D, and a change from alanine to glycine at amino acid 692 appears to cause a phenotype that resembles AD is some patients but HCHWA-D in others. The discovery of these and other mutations in APP in genetically based cases of AD prove that alteration of APP and subsequent deposition of its .beta.-amyloid peptide fragment can cause AD.
Despite the progress which has been made in understanding the underlying mechanisms of AD and other .beta.-amyloid peptide related diseases, there remains a need to develop methods and compositions for treatment of the disease(s). Ideally, the treatment methods would advantageously be based on drugs which are capable of inhibiting .beta.-amyloid peptide release and/or its synthesis in vivo.

Compounds for inhibiting .beta.-amyloid peptide release and/or its synthesis


A physical quantity sensor element is provided with a detecting portion, a driving portion, a beam portion which connects a detecting portion and the driving portion to each other, and in which the beam portion includes a branched portion. The beam portion includes two mass portion side beam portions which extend from two position of the driving portion, which are different from each other, and two supporting portion side beam portions which extend from two positions of the detecting portion, which are different from each other, and in which both end portions on the detecting portion side of two mass portion side beam portions are connected to each other, and both end portions on the driving portion side of two supporting portion side beam portions are connected to each other.

1. Technical Field
The present invention relates to a physical quantity sensor element, a physical quantity sensor, electronic equipment, and a movable body.
2. Related Art
Recently, as a physical quantity sensor element using a silicon micro electro mechanical system (MEMS) technology, for example, a capacitance type gyro sensor element (an angular velocity sensor) for detecting angular velocity has been known (for example, refer to JP-T-2007-509346).
For example, an angular velocity sensor according to JP-T-2007-509346 includes two mass portions which are indirectly connected to a frame thereof. The two mass portions are connected via a link device so as to necessarily move to an opposite direction along a Z direction. It is possible to sense the angular velocity of the sensor about a Y-axis by causing the two mass portions to vibrate through a reverse phase in the Z direction, and measuring the amplitude of angular vibration which is applied to the frame.
However, in the angular velocity sensor disclosed in JP-T-2007-509346, a hinge for connecting each of mass portions and a frame to each other is greatly deformed, and it is not possible to efficiently transfer Coriolis effect which acts on the mass portion to the frame, thereby resulting in deterioration of detection accuracy.

Physical quantity sensor element, physical quantity sensor, electronic equipment, and movable body


A pulsating metronome includes a case and a band for attaching the case to the wrist of a wearer. A vibration means is mounted to the case at a location such that, when the device is worn on the wrist of the wearer, the vibration means is imposed against the wearer""s wrist. A means is included for exciting the vibration means at predetermined intervals to impart vibrations against the wrist of the wearer so as to convey tempo information to the wearer.

The present invention relates generally to metronomes and relates more specifically to a metronome that employs a tactile pulse or vibration in place of an audible signal.
A metronome is an instrument, typically used by musicians, that is designed to mark exact time by a regularly repeated signal. Traditional mechanical metronomes are based upon the movement of a pendulum and make an audible xe2x80x9ctickxe2x80x9d sound at regularly spaced intervals. The musician can move a weight up or down on the pendulum to adjust the duration of the interval to correspond to the musical composition being performed.
More recently, electronic metronomes have been developed that keep time electronically and signal tempo by either an audible sound or a flashing light.
Whether mechanical or electronic, previously known metronomes suffer certain disadvantages. Because the musician must be able to adjust the tempo of the metronome and turn it on and off, the device must be placed within arm""s reach of the musician. In the case of metronomes that indicate tempo by a flashing light, the device must be positioned within the musician""s field of view. And whether the signal is emitted audibly or visually, conventional metronomes can be a distraction to others.
Other metronome-like devices are used for exercise and recreational purposes. Runners and walkers use watches that emit an audible xe2x80x9cbeepxe2x80x9d at regularly spaced intervals to help the exerciser maintain a steady pace. Because the watch is located on the lower arm, remote from the ear, and because the arm is constantly swinging back and forth, the sound emitted by the watch can sometimes be difficult to hear, unless the volume is turned up to a level that becomes a distraction to others.
Stated generally, the present invention comprises a metronome that keeps time by a tactile vibration, rather than an audible or visible signal. The metronome is incorporated into a watch and imparts the tactile vibration to the wearer""s wrist.
Stated more specifically, the present device includes a case and a band for attaching the case to the wrist of a wearer. A vibration means is mounted to that case at a location such that, when the device is worn on the wrist of the wearer, the vibration means is imposed against the wearer""s wrist. A means is included for exciting the vibration means at predetermined intervals to impart vibrations against the wrist of the wearer so as to convey tempo information to the wearer.
In a preferred embodiment the device includes a conventional watch, either analog or digital, mounted in the same case so that the metronome appears to be an ordinary watch. Also in the preferred embodiment, the vibration means is a plate attached to the back of the case.
Thus it is an object of the present invention to provide an improved metronome.


A solid-state high-voltage pulse generator based on a three-phase chopper capacitance charger is described. In a first phase, an intermediate capacitor is resonance-charged via a diode. In a second phase, the intermediate capacitor is discharged to the load through one or more solid-state switches. In a third phase, the energy remaining in the intermediate capacitor is returned to a power-supply filter capacitor. In one embodiment, the three-phase chopper includes an intermediate capacitor that is charged by first and fourth branches of a bridge and discharged by second and third branches of a bridge. In one embodiment, each branch of the bridge includes a diode in series with an inductor. In one embodiment, a composite solid-state switch connects the intermediate capacitor to a primary winding of an output transformer such that the intermediate capacitor discharges through the primary winding. In one embodiment, a secondary winding of the output transformer is provided to an output load. In one embodiment, the output load is a reactive load. In one embodiment, the output load is a capacitive load.

1. Field of the Invention
The invention relates to the field of solid-state high-voltage pulse power generators.
2. Description of the Related Art
High voltage pulse generators with fast rise time are typically used to drive gas discharge loads such as lasers, devices for pollution control applications and for plasma chemistry. In the past, such pulse generators used thyratrons to generate the desired pulses. However, thyratrons are relatively unreliable and they have high complexity resulting in a high price. Solid state devices such as thyristors, MOSFET transistors and Insulated Gate Bipolar Transistors (IGBTs), although much lighter and more reliable than thyratrons, handle less power than a thyratron. In order to replace one thyratron, one needs hundreds or thousands of solid state devices.
The power that each solid state transistor can produce is restricted by its saturation current (˜70 A) and by its breakdown voltage (˜600V), giving a maximum pulsed power Pav=Isat×Ubd/2=21 KW. For most plasma applications, the desired pulse length is about 100 nanoseconds. This means that the pulse energy the transistor can produce is typically not higher than 2.1 mJ. If the repetition rate is increased to 50-100 kHz, then the power will have a reasonable value (100 w-200 w). The main advantage of short pulses (<100 ns) in plasma devices is the high electrical strength of the gap that permits achievement of twice or triple the mean temperature of electrons. If the repetition rate is increased to more than 1000 Hz, the residual ionization will reduce the electrical strength of the plasma gap and eliminate the advantage of short pulses. This problem is typically solved by increasing the pulse length of the solid-state pulse generator and using one more output stages to compress the power. The second stage compressor, if desired, can be a spark gap, blumline, etc. To simplify the design of the compressor, the pulse length of the charger is typically held to a few microseconds or even as short as 1-2 microseconds.
Even when using an output compressor, in order to replace one thyratron one needs hundreds or thousands of solid state devices. The cost of all these devices is comparable to the cost of one thyratron, but the reliability of solid state devices is higher. Unfortunately, summing the output of a large number of transistors via a transformer is problematic because the transformer can cause dangerous overvoltage in the transistors.

Solid-state microsecond capacitance charger for high voltage and pulsed power


A fractionation system having a fractionation manifold with a plurality of connectors in fluid communication with one another and a plurality of valves disposed adjacent the connectors for selectively flowing fluid through the manifold. The connectors define a plurality of exterior ports for communication with wellstrings and fracturing fluid sources. A primary choke in communication with a tubing string and a secondary choke in communication with a casing string can be engaged with exterior ports, the secondary choke useable as a backup choke and for inducing sandouts. The present system can achieve a flow rate of up to 80 barrels per minute, or more, using only a single manifold and single power unit, and can be wirelessly operated. System components can incorporate self-aligning, self-positioning skids, or alternatively, the system can be transported using a single skid to facilitate portability and installation.

To increase production of a well, it is often necessary to fracture the well, which is performed by flowing fracturing fluid into the earth to mechanically create cracks in the ground. Fracturing fluid typically includes a liquid mixed with sand, small ceramic beads, or similar proppant material, which creates pressure within the well as the fluid accumulates, until the pressure causes cracks to form in the earth, or causes existing cracks in the earth to widen, thereby increasing the flow of hydrocarbons from the well.
Conventionally, when fracturing a well, numerous manifolds, i.e. a pumping manifold, a flowback manifold, a choke manifold, and other manifolds, must be installed at the wellhead surface, which can require six to eight hours, or longer, numerous personnel, and a large amount of space on a rig floor. Additionally, each manifold requires a series of hydraulic conduits or similar connections to enable actuation of the manifold, which further consumes limited space proximate to a wellhead and can create a safety hazard.
Fractionation manifolds typically include a series of valves and connectors used to flow fracturing fluid from a fluid vessel into the wellhead. Fluid is then retrieved from the wellhead and is flowed through different valves into a choke, which controls the back pressure on the well and ensures the flow of fluid directly through the choke. Sand, beads, and other particulates in the fluid are sent through a reverse line overboard, or to a pickle return tank, while the fluid, itself, can be reclaimed through a separate reverse line to the rig pits for treatment. Operation of the valves and chokes normally requires at least one operator, on-site, to manipulate appropriate hydraulic, electrical, and/or manual parts of the manifolds. Often, the one or more operators can be subject to inclement weather, and potential safety risks when manipulating the manifolds.
To reduce the possibility of choke failure, many fractionation manifolds incorporate use of an auxiliary choke. The primary and auxiliary chokes both communicate with the tubing string of the well, so that the auxiliary choke can be engaged if the primary choke fails.
A typical fractionation system, especially a system incorporating a second choke, is extremely large, cumbersome, and expensive, containing a large number of valves and connectors, and requiring a large number of hoses and conduits to ensure sufficient electrical and/or hydraulic connections. Additionally, most fractionation manifolds are difficult and time consuming to properly install, each valve and component requiring precise alignment using cranes and other devices adapted for manipulation of the heavy components. Further, most fractionation manifolds are limited regarding the orientation with which components can be installed and engaged, which can become a hindrance on offshore rigs and other drilling sites where space is limited. Also, most fractionation manifolds require on-site personnel to actuate valves, chokes, and other parts of the manifolds, increasing the time required for each operation, and the inherent risk to the operators.
Also, a typical fractionation system is limited to a flow rate of approximately 30 barrels of fluid per minute. When additional flow is necessary, multiple manifolds are used, increasing the time, expense, and space required, and necessitating additional cumbersome installation and operating procedures necessary to fracture and produce a well.
A need exists for a fractionation system that can be used to perform the functions of numerous manifolds using a single, readily transportable system that is efficient to install, remotely operable, and able to exceed the flow capacity of conventional manifolds while eliminating the need for numerous hydraulic and electrical lines, and the need for operators to be present on the rig floor during the fractionation process, thereby providing a significant safety benefit.
A need also exists for a fractionation system that can advantageously utilize limited space at a drilling site by enabling selective engagements of differing orientation between fractionation manifolds and chokes.
A further need exists for a fractionation system that can incorporate a second choke that is in communication with the casing of a drill string, rather than the tubing string, that is useable both as a backup choke during primary choke failure, and that is separately useable during sandouts to remove excess return fluid from a well.
An additional need exists for a fractionation system that is modular, able to be efficiently and easily aligned and installed through use of interlocking skids, or alternatively, a single unitary skid or similar transport member, that is able to accommodate flow rates in excess of conventional manifolds using only a single fractionation manifold and a single power unit.
Embodiments of the present invention meet these needs.

Fractionation system and methods of using same


An indoor GPS clock using GPS signals lower that xe2x88x92143 dBm for issuing disciplined frequency and time standard signals. The indoor GPS clock includes a correlation machine using long integration periods for enabling the indoor GPS clock to operate with low signal levels; a carrier-less tracking loop for tracking the low level signals without carrier offset feedback, a clock bias loop for providing clock bias feedback; and a reference oscillator using the clock bias feedback for providing disciplined frequency and time signals having greater accuracy than is available in conventional GPS positioning receivers. The indoor GPS clock also includes a holdover driver providing compensation for predicted drift in clock bias error for disciplining the reference oscillator for several hours when the GPS signal is no longer being received.

1. Field of the Invention
The invention relates generally to GPS clocks and more particularly to an indoor GPS clock using long integration periods for acquiring and tracking GPS signals lower than about xe2x88x92143 dBm and providing disciplined frequency and time standard signals.
2. Description of the Prior Art
Conventional GPS positioning receivers provide GPS-based time as a byproduct of the resolution of a three dimensional GPS-based location. Typically, this time is issued in the form of a data packet that identifies the GPS-based times of the pulses of a one pulse per second (1 PPS) output signal. However, the accuracy for such time is limited by the cycle period of the local reference oscillator in the GPS receiver and any uncalibrated electrical length that the signal travels before it is used. There are several GPS timing applications where these limitations are not acceptable. Therefore, GPS timing applications commonly require a higher frequency signal, for example 10 MHz, for use as an accurate time base for maintaining an internal time standard. In order to meet the needs of these applications, a special type of GPS receiver, termed a GPS clock, has been developed. GPS clocks use supplementary techniques, such as clock bias feedback, for providing an output signal having a frequency that closely tracks the frequency of the GPS signal.
In some cases accurate time and/or frequency are required at a user location that is inside of a building. It is well-known that GPS receivers do not function well within a building because the building attenuates the GPS signal to a level that is too low for acquisition and/or tracking. It is sometimes possible to avoid this problem by placing the GPS signal antenna outdoors or by a window with a clear sky view and then conducting an amplified antenna output signal or the frequency and time signal to where it is needed. However, there are certain circumstances where this is impractical.
A clear-view GPS signal available to a GPS antenna on earth from a GPS satellite is specified as xe2x88x92160 dBW (xe2x88x92130 dBm) by the GPS system specification ICD-GPS-200 Rev C published by Arinc Research Corporation of El Segundo, Calif. published Oct. 10, 1993 and last revised Oct. 11, 1999. Misra and Enge in xe2x80x9cGlobal Positioning Systemxe2x80x9d ISBN 0-9709544-0-9 page 288 also show xe2x88x92160 dBW (xe2x88x92130 dBm) as received power available to an isotropic antenna from a satellite at the zenith. Conventional GPS receivers acquire GPS signals as low as xe2x88x92130 dBm using a signal integration period matching the C/A PRN code epoch period of one millisecond. In addition, it is known by those skilled in the art that an integration period matching the GPS bit time of 20 milliseconds can be used for achieving a processing gain of 13 dB in order to acquire and/or track GPS signals as low as about xe2x88x92143 dBm.
The attenuation of the building will vary a great deal depending upon the type of building and the depth within the building. However, it is typically true that a building attenuates a GPS signal by more than 13 dB so that the GPS signal is lower than the signal acquisition that is achievable with a 20 millisecond integration. Recently, many workers have applied a great deal of energy to inventing techniques for receiving low level (that is more than 13 dB lower than open sky) signals. Unfortunately, to date these techniques have not been applied in an indoor GPS clock that is capable of providing the frequency and time accuracies that are required.
One of the problems that must be resolved for low GPS signal levels is the problem of GPS signal carrier tracking. Conventional GPS receivers employ closed loop carrier phase or carrier frequency feedback corrections for tracking a GPS signal. However, below 27 dB-Hz C/N0 (xe2x88x92143 dBm referred to the antenna) and 24 dB-Hz C/N0 (xe2x88x92146 dBm referred to the antenna) typical GPS carrier phase and frequency lock loops, respectively, are not able to lock reliably. Existing military type GPS receivers have used a technique of carrier aiding by Doppler calculations. However, techniques used in military receivers are not directly applicable to a high performance GPS clock because a military GPS receiver must operate in a high dynamic environment whereas a GPS clock is expected to operate in an environment that is stationary. Furthermore, the GPS clock must provide an accurate frequency standard signal as an output that tracks the carrier frequency of the GPS signal.
It is therefore an object of the present invention to provide an indoor GPS clock capable of using low level GPS signals for providing accurate GPS-based frequency and time.
Briefly, the indoor GPS clock of the present invention is a novel combination of features using a processing gain of greater than 13 dB for acquiring and tracking low level GPS signals for providing a highly accurate GPS-based frequency. In a base coherent embodiment, the indoor GPS clock uses GPS data bit length (20 millisecond) coherent integrations for acquisition and tracking of low level GPS signals. In an extended coherent embodiment, the indoor GPS clock uses coherent integration periods longer than the GPS bit data for acquisition of low level GPS signals. In a coherent-incoherent embodiment, the indoor GPS clock incoherently combines coherent integration periods for acquisition of low level GPS signals. The low level GPS signals are then tracked with carrier-less tracking using GPS data bit length coherent integration periods. A clock bias feedback loop provides feedback for disciplining frequency and time signals. A holdover driver compensates for drift in the disciplined frequency and time signals for at least several hours in the absence of the GPS signal.
An advantage of the present invention is that an accurate GPS-based frequency is provided within a building where GPS signal levels are lower than about xe2x88x92143 dBm.
These and other objects and features of the present invention will no doubt become obvious to those of ordinary skill in the art after having read the following detailed description of the preferred embodiments which are illustrated in the various figures.


An electrically conductive transmission line for transmitting RF signals, in particular for transmitting MR signals between a transmission and/or receiving coil and a transmitting and/or receiving unit, by which separate known matching networks can be avoided or reduced. A transmission line is proposed comprising a plurality of lead segments coupled by transformers having a transformer impedance ZL placed between two neighboring lead segments, wherein for power matching of the two transformers placed at opposite ends of a lead segment, the lead segment has a lead segment impedance Z0 or a dielectric constant ∈r and wherein the lead segment has a short length l. Thus, the lead segments themselves provide the matching of the transformers, and separate matching circuits are no longer needed.

The use of catheters containing conducting elements in a Magnetic Resonance Imaging (MRI) environment poses severe safety problems, mainly due to RF heating effects. This prevents the practical use of many transcatheter interventional instruments and thus hampers interventional procedures under MRI guidance despite clear advantages of this imaging method like strong soft tissue contrast and the absence of ionizing radiation.
For a reliably robust visualization of the catheter in the MR image it is necessary to connect a receiving antenna (e.g. a small coil or a loopless antenna) at its tip with the receiver of the MR scanner. One way to realize this connection without causing dangerous RF heating is to implement transformers in the transmission line as described, for instance, in WO 2006/003566. The transformers block induced common mode currents, while differential mode currents like the MR signal can pass.
A way of adjusting the transformers using additional lumped element matching networks, comprising at least one T-, L- and/or π-quadrupole, which each comprise at least two impedance elements in the form of a capacitor and/or an inductivity, is described in WO 2005/103748.
For optimal signal transmission it is necessary to match the output impedance of any transformer in the transmission line to its complex conjugated value (power matching). This can be accomplished by using the matching networks as described in WO 2005/103748. In particular a network is used to match the output of the transformer to a transmission line having typically Z0=50Ω impedance. Then this line is matched at its end using another network to the input of the next transformer. The matching networks contain lumped elements, normally capacitors.
On the one hand side it is not easy to solder these matching networks due to the small size, which is required to fit into a catheter. On the other hand side every additional soldering joint is a possible source of malfunction, especially in a flexible catheter, where stress and torque can occur.

Transmission line for RF signals without matching networks


A disk loading apparatus includes a disk selecting unit rotatable through a rotating angle which corresponds to a size of an inserted disk, a pair of guide arms that are spaced from the disk selecting unit and are rotated by the disk, a small diameter loading lever that is rotated by one of the guide arms, a large diameter loading lever that is moved by the guide arms, a slide cam unit that is moved by the small diameter loading lever or the large diameter loading lever, and a chuck unit which is disposed between the guide arms and the disk selecting unit and is operated by the slide cam unit to chuck the disk. The small diameter loading lever and the large diameter loading lever are disposed at a same height above the guide arms.

1. Field
Apparatuses consistent with exemplary embodiments relate to a disk apparatus capable of receiving and discharging a disk medium such as a compact disk (CD), a digital versatile disk (DVD), etc, and a disk loading apparatus that transports and chucks the disk medium.
2. Description of the Related Art
Generally, a slot-in type disk apparatus can directly receive and discharge a disk medium (hereinafter, referred to a disk) without using a tray. Inside the disk apparatus is disposed a disk loading apparatus which moves the disk to a chucking position and chucks the disk. The disk loading apparatus is configured to move and chuck various types disks having different diameters.
FIGS. 1 and 2 illustrate an example of a related art disk loading apparatus 100.
Referring to FIGS. 1 and 2, when loading a small diameter disk 101 having a diameter of 8 cm, an upper slider 130 is moved downwardly by a guide lever 120 and a push lever 110 to contact an outer circumferential surface of the small diameter disk 101. At this time, an end of the push lever 110 contacts the upper slider 130 at a P1 point. As the upper slider 130 moves downward in FIG. 1, a slider cam 140 assembled integrally with the upper slider 130 moves in the same direction and allows the disk 101 to be chucked.
Meanwhile, when loading a large diameter disk 101 having a diameter of 12 cm, the end of the push lever 110 is located at a P2 point of the upper slider 130 by a disk selecting unit 150. When the large diameter disk 101 enters in this status, the upper slider 130 is moved downward in FIG. 1 by the guide lever 120 and the push lever 110 pushed by an outer circumferential surface of the large diameter disk 101. As the upper slider 130 moves, the slider cam 140 moves in the same direction and allows the disk 101 to be chucked.
However, this related art disk loading apparatus 100 is configured such that the push lever 110, the guide lever 120 and a link 151 of the disk selecting unit 150 which are used to move the slider cam 140 and to chuck the disk 101 have a three-level structure as illustrated in FIG. 2. As a result, the related art disk loading apparatus 100 has a large height. Therefore, it is difficult to miniaturize the disk apparatus.
Also, due to a structural limitation of the related art disk loading apparatus 100, the push lever 110 is located at a place interfering with an area Z in which a pickup unit moves. Therefore, there is a space limitation for preventing the pickup unit and the push lever 110 from colliding with each other. If the pickup unit collides with the push lever 110 by an impact from the outside, the pickup unit may be damaged.

Disk loading apparatus with small and large diameter loading levers


In the present invention a new solar photovoltaic module is proposed comprising: a silicon based photovoltaic element; an intermediate layer deposited on said photovoltaic element to the incident light side; an interference filter deposited on the incident light side of said intermediate layer; a front element disposed on the incident light side of said interference filter. Said intermediate layer has a transparency of at least 90% for infrared light between 780 nm and 1200 nm and said interference filter is corrugated and composed of a multilayer comprising a plurality of dielectric layers designed to transmit at least 75% of the total incident solar infrared light between 780 nm and 1200 nm, and to reflect and diffuse incident visible solar light such that the perceived color of said reflected and diffused visible light by any observer positioned anywhere to the incident light side of said solar photovoltaic module and looking towards the front element of said solar photovoltaic module is defined by a Y10 tristimulus value not lower than 50 defined by an x value of 0.20 to 0.45 and a y value of 0.20 to 0.45 in a chromaticity diagram of a CIE 1964 Yxy color system using a white light source measured with a D65 light source with a 10-degree angular field.

Despite the wide diversity of available solar technologies, solar energy systems are still not considered as main stream technologies in building practice. So far most photovoltaic systems are optimized only for efficiency which implies absorbing a maximum number of photons, and hence leading to a dark blue and ideally black color appearance. Most of the photovoltaic cells on the market are crystalline cells with connecting ribbons which have an unaesthetic appearance.
One of the reasons of the lack of wide spread use of solar technologies for buildings is the lack of awareness and knowledge of integration possibilities among architects and the lack of solar products designed for building integration. In parallel there is a recent trend to transform buildings from energy users to energy producers. The old wide spread concept of adding solar panels on the roof of a building has evolved and a lot of effort is being done to merge the construction technology with the science and technology of photovoltaics in what is called the Building Integrated Photovoltaics. Architectural, structural and aesthetic solutions are being constantly seeken to integrate solar photovoltaic elements into buildings, allowing the incorporation of energy generation into everyday structures such as homes, schools, offices hospitals and all kind of buildings. Photovoltaic modules can have a wide variety of functions such as noise protection, safety, electromagnetic shielding, thermal isolation etc. Photovoltaic elements can also be used to combine these functions with an aesthetic function. With such an approach solar photovoltaic modules become more and more construction elements serving as building exteriors such as façades and inclined roofs. If well applied, solar photovoltaic cells can increase a building's character and its value.
The more technologies will be available to create aesthetic effects with photovoltaic cells the more the technology will be accepted and costs will decline. Not only new building construction will profit from this trend but also the improvement and modification of existing buildings. Architects who apply Photovoltaic cells in an intelligent manner can as such contribute largely to the acceptance of this technology.
One of the technology improvements would be to dispose of a solar photovoltaic module that has an appearance that is more aesthetic than the classical blue-black appearance. In other approaches front colored glass is integrated with the photovoltaic modules, such as explained in the following publication: "Efficiency of silicon thin-film photovoltaic modules with a front colored glass; S. Pélisset et al., Proceedings CISBAT 2011, pp. 37-42." In other approaches technology solutions have been initiated to render a specific color to a photovoltaic cell by the deposition of multilayer antireflection coatings on such photovoltaic elements, as for example described in the article: "Reduction of optical losses in colored solar cells with multilayer antireflection coatings; J. H. Selj et al., Solar Energy Materials & Solar Cells 95, pp. 2576-2582, 2011".
EP 2051124 discloses a design comprising, to the incident light side of the photoconversion element, a passive interference filter or an addressable optical resonance cavity, allowing to produce a specific color to an observer. The design in EP 2051124 requires a complex and expensive technology and is limited to produce specific colors, excluding white and grey and does not allow to produce a mate appearance of these colors.
In all approaches of prior art it is necessary to add additional light diffusing layers to a photovoltaic cell, such as a colored glass plate or an interference filter, which makes the realization process complex and expensive and it may also reduce the photoconversion efficiency. It is the objective of the present invention to bring a new approach in this field.

CSEM Centre Suisse d'Electronique et de Microtechnique SA—Recherche et Développement


The invention relates to a method for determining at least one property of hydrocarbon fluid, comprising: (a) providing a first chamber (1) filled with the hydrocarbon fluid and a second chamber (2) which is substantially empty, each of the first chamber (1) and second chamber (2) having a fixed volume; (b) transferring a sample of hydrocarbon fluid from the first chamber (1) to the second chamber (2); (c) measuring a pressure in at least one of the first chamber (1) and the second chamber (2); (d) repeating steps (b) and (c) a plurality of times. The invention also relates to an apparatus for implementing this method.

Hydrocarbon fluids contained in or recovered from subterranean formations are complex fluids containing many different chemical compounds.
In order to optimize hydrocarbon recovery in a process of extracting hydrocarbons from a subterranean formation, it is necessary to know the physical properties of the hydrocarbon fluid, in order to anticipate its volumetric and phase behavior as it travels from the subterranean formation up to surface capabilities, including separators and pipelines for instance, as well as the volumetric and phase behavior of the portion of the fluid remaining in the subterranean formation.
These physical properties, such as viscosity, density, compressibility, depend on pressure and temperature.
Conventionally, these properties are determined owing to a so-called pressure-volume-temperature (PVT) analysis. The PVT analysis is usually performed as follows:                a chamber having an adjustable volume, for instance owing to a piston, is provided;        a sample of hydrocarbon fluid is introduced into the chamber under relatively high pressure, and the chamber is sealed;        the volume of the chamber is increased, e.g. by moving the piston; and        the pressure in the chamber is measured.
From this measurement, various properties of the hydrocarbon fluid may be determined.
This conventional method raises a number of practical issues. In particular, due to the high pressure which is applied, it is necessary to use a large piston. This, in turn, implies that the chamber must have a large volume. The equipment used for the PVT analysis is thus very bulky and inconvenient to use on an extraction field. At the very least, it is impossible to introduce said equipment into an extraction well.
Ensuring tightness of the equipment is also a challenge.
Furthermore, due to the large volume of the chamber, the equipment has a large dead volume, which may result in poor accuracy.
There is thus a need for an improved method of measuring properties of a complex hydrocarbon fluid, which is easier to implement and relies on equipment having a smaller size.

Determination of properties of a hydrocarbon fluid


Video information may define video content. The video content may be characterized by capture information. A remote device may transmit at least a portion of the capture information to a computing device. The computing device may identify one or more portions of the video content based on the transmitted capture information. The remote device may receive the identification of the identified portion(s) of the video content from the computing device. The remote device may stream one or more portions of the video information defining at least some of the identified portion(s) of the video content to the computing device. The streamed video information may enable the computing devices to provide a presentation of at least some of the identified portion(s) of the video content using a buffer of the streamed video information, which may allow the computing device to present the video content without permanently storing the video information.

A user may use an image capture device to capture a video. Providing the entire video to another device may be resource intensive. For example, the user may have captured a lengthy video and transmitting information that defines the entire video to another device may require consumption of large amount of bandwidth, processing resources, battery power, and/or storage space.

Systems and methods for streaming video edits


The invention provides a quiescent stem cell having the capacity to differentiate into ectoderm, mesoderm and endoderm, and which does not express cell surface markers including MHC class I, MHC class II, CD44, CD45, CD13, CD34, CD49c, CD73, CD105 and CD90. The invention further provides a proliferative stem cell, which expresses genes including Oct-4, Nanog, Sox2, GDF3, P16INK4, BMI, Notch, HDAC4, TERT, Rex-1 and TWIST but does not express cell surface markers including MHC class I, MHC class II, CD44, CD45, CD13, CD34, CD49c, CD73, CD105 and CD90. The cells of the invention can be isolated from adult mammals, have embryonic cell characteristics, and can form embryoid bodies. Methods for obtaining the stem cells, as well as methods of treating diseases and the differentiated stem cells, are also provided.

A stem cell is commonly defined as a cell that (i) is capable of renewing itself; and (ii) can give rise to more than one type of cell through asymmetric cell division (Watt et al., Science, 284:1427-1430, 2000). Stem cells typically give rise to a type of multipotent cell called a progenitor cell; progenitor cells, in turn, proliferate and differentiate into lineage-committed cells that populate the body.
Pluripotent stem cells are thought to have the potential to differentiate into almost any cell type, while multipotent stem cells are believed to have the potential to differentiate into many cell types (Robertson, Meth. Cell Biol. 75:173, 1997; Pedersen, Reprod. Fertil. Dev. 6:543-552, 1994).
Stem cells exist in many tissues of embryos and adult mammals. Many different types of mammalian stem cells have been characterized and certain stem cells have not only been isolated and characterized, but have also been cultured under conditions to allow differentiation to a limited extent. Both adult and embryonic stem cells are able to differentiate into a variety of cell types and, accordingly, may be a source of replacement cells and tissues that are damaged in the course of disease or infection, or because of congenital abnormalities (Lovell-Badge, Nature 414:88-91, 2001; Donovan et al., Nature 414:92-97, 2001). Various types of putative stem cells exist which, when differentiated into mature cells, carry out the unique functions of particular tissues, such as heart, liver, or neuronal tissue. These cells are important for the treatment of a wide variety of disorders, including malignancies, inborn effors of metabolism, hemoglobinopathies, immunodeficiencies and the replacement of damaged and diseased tissues. Recent success at transplanting such stem cells have provided new clinical tools to reconstitute and/or supplement bone marrow after myeloablation due to disease, exposure to toxic chemical and/or radiation. Further evidence exists that demonstrates that stem cells can be employed to repopulate many, if not all, tissues and restore physiologic and anatomic functionality. The application of stem cells in tissue engineering, gene therapy delivery and cell therapeutics is also advancing rapidly.
Prior to the present invention, a basic problem existed, i.e., that obtaining sufficient quantities and populations of human stem cells which are capable of differentiating into most cell types was nearly impossible. Stem cells are in critically short supply.
Obtaining sufficient numbers of human stem cells has been problematic for several reasons. First, isolation of normally occurring populations of stem cells in adult tissues has been technically difficult and costly due, in part, to very limited quantity found in blood or tissue. The isolation of the cells is generally laborious, involving the harvesting of cells or tissues from a patient or donor, culturing and/or propagating the cells in vitro. Certain cell types, such as nerve cells and cardiac cells, differentiate during development, and adult organisms are not known to generally replace these cells. Even in cell types that are replaced in adult organisms (e.g., epithelial cells and hematopoietic cells), it has been a significant challenge to readily and inexpensively obtain stem cells in significant quantities. For example, mammalian hematopoietic cells (e.g., lymphoid, myeloid, and erythroid cells) are all believed to be generated by a single cell type called the hematopoietic "stem cell" (Civin et al., J. Immunol. 133:157-165, 1984). However, these hematopoietic stem cells are very rare in adults, accounting for approximately 0.01% of bone marrow cells. Isolation of these cells based on surface proteins such as CD34 results in very low yields. Schemes to fractionate human hematopoietic cells into lineage committed and non-committed progenitors are technically complicated and often do not permit the recovery of a sufficient number of cells to address multilineage differentiation (Berenson et al., 1991; Terstappen et al., 1991; Brandt et al., J. Clin. Invest. 82:1017-1027, 1988; Landsdorp et al., J. Exp. Med. 175:1501-1509, 1992; Baum et al., Proc. Natl. Acad. Sci. USA 89:2804-2808, 1992)
A second reason that obtaining sufficient number of human stem cells has been problematic is that procurement of these cells from embryos or fetal tissue has raised religious, ethical, and legal concerns. Alternative sources that do not require the use of cells procured from embryonic or fetal tissue are therefore highly desirable for clinical use of stem cells. Prior to the present invention, there have been few viable alternative sources of stem cells, particularly human stem cells.
It would therefore be of particularly great value in treating a wide variety of diseases to have an easily accessible quantity of embryonic like stem cells that are found in the adult body that can reliably differentiate into a desired phenotype.
In addition, it would also be advantageous to have stem cells that do not require feeder cells. Many adult stem cell propagation protocols require such cells, which creates risks including infection, cell fusion, and/or contamination. As such, adult stem cells are have often been very difficult to expand in culture (Reya et al., Nature 414:105-111, 2001; Tang et al. Science 291:868-871, 2001).
Thus, there remains a need in the art to develop methods for identifying, propagating, and altering the state (e.g., by differentiation or dedifferentiation) of stem cells and to provide a source of cells that are transplantable to in vivo tissues in order to replace damaged or diseased tissue.

This patent is subject to a terminal disclaimer.


Bioelectric implants are provided in three distinct embodiments, namely a bone/tissue anchor, a suture construction, and a plate. The bioelectric implants function in dual capacities as both fixation devices, and as galvanic cells for the production of electrical energy used for therapeutic purposes in tissue regeneration and healing. The bioelectric anchor may take the general form of a screw or pin having a hollow interior or cavity that extends through the body of the anchor. A coating can be applied to the cavity to form the anode portion of the galvanic cell. The outer surface of the anchor serves as a cathode. Bodily fluids and tissue act as an electrolyte to facilitate the chemical reactions necessary for the galvanic cell. For the suture construction, one or more strands of material are the cathode, and one or more strands of peripheral surrounding material act as the anode. Bodily fluids/tissue in contact with the suture act as an electrolyte. The bioelectric plate can be used in combination with the bioelectric anchor to supplement delivery of electrical energy. The plate has anode and cathode portions also making it a source of electrical energy.

It is well known to utilize a source of electrical power in order to speed the healing process in damaged bone and soft tissue. Through extensive research and development, it has been found that both electrical current and magnetic fields can play an important role in modifying tissue behavior. It is known that bone tissue generates its own electrical potentials during the healing process, and exposing the bone tissue to electrical energy at selected voltages and amperages can greatly enhance the speed of tissue regeneration.
Accordingly, a number of references disclose electrical implants that are used for various healing and regenerative purposes with respect to both bone and soft tissue. A typical electrical implant device includes probes or electrodes that are positioned adjacent the targeted tissue, and the electrodes are powered by an external power source, such as a subcutaneous battery. Discharged batteries must be replaced, and ultimately removed once the desired duration of electrical energy exposure has been achieved.
It is also known to utilize body fluids as an electrolyte in combination with anode and cathode elements implanted within the body to produce a galvanic cell capable of generating electrical potential for a specified treatment. Since the human body is mainly composed of water, even tissue and bone in contact with anode and cathode elements is sufficient for facilitating a galvanic reaction.
One early example of an electrical power source utilizing body fluids as an electrolyte is the U.S. Pat. No. 3,345,989. This reference discloses a pair of metal electrodes surgically implanted in body tissue in which one electrode acts as the anode and the other acts as the cathode. An implanted electronic device may close the circuit and therefore receive electrical power by use of insulated leads that extend from each electrode to the implanted device.
Another early example of an implanted device that acts as a bioelectric power supply is the invention found in the U.S. Pat. No. 3,421,512. This reference discloses an implanted pacemaker in which the electrical components are contained within a sealed housing formed by electrode plates that are sealed to one another. The electrode plates are made of selected materials to react with bodily fluids to form a galvanic power supply.
U.S. Pat. No. 3,353,539 discloses a biological power supply in which bodily fluid is used as the electrolyte to generate power from implanted electrodes. The electrodes are constructed of the similar metals resulting in production of electrical power.
U.S. Pat. No. 5,353,935 discloses a prosthetic implant for implantation into skeletal bone comprising an implantable base member having an internal housing surrounded partially by a porous wall, an anode secured in the internal housing in electrical contact with the porous wall, and a porous means placed in the internal housing for retaining a biocompatible electrolyte. When implanted into bone structure, the prosthetic implant generates sufficient current flow which results in in-vivo formation of calcium phosphate minerals between the implant and the surrounding bone, thereby, resulting in improved fixation and stability of the implant.
U.S. Pat. No. 5,725,377 discloses a dental implant that employs electrical bone growth stimulation by incorporating a galvanic cell in the implant. The implant is formed as a machine screw made of titanium. The machine screw contains an internal threaded portion for accommodating a cap screw to cover the top of the implant. The implant has a hollow portion with a small aluminum rivet pressed therein that makes intimate contact with the titanium implant. The rivet forms the anode of the cell which becomes the negative electrode of the battery. A slug of silver chloride is fastened to a cover screw. A saline solution is used as the electrolyte. Once activated, the reaction consists of the reduction of silver chloride to metallic silver. The slug of silver chloride forms the cathode of the cell and becomes the positive terminal of the battery.
U.S. Pat. No. 7,230,153 discloses a multi-layer conductive appliance having wound healing and analgesic properties. The appliance can be used as a wound dressing having at least one layer of a conductive material. When placed proximate to the portion of the body suffering from a pathologic condition, the dressing alters the electro-dynamic processes occurring in conjunction with the pathologic condition to promote healing and pain relief. The conductive material placed in contact with tissue surrounding the periphery of the wound and lowers the electrical potential and resistance of the wound thereby increasing wound current. Multi-laminate embodiments exhibit conductive material concentration gradients and a capacitive effect when sequential conductive layers are insulated by intervening non-conductive layers.
While it may be well known to provide a source of electrical power for enhancing tissue healing/regeneration, dedicated devices for generating electrical potential add to the overall cost and complexity of an orthopedic implant procedure. Furthermore, with respect to implanted batteries, the increased cost of using such batteries also results in a greater invasive procedure because the batteries must be separately implanted and monitored over time.
As orthopedic procedures continue to advance in the types and diversity of fixation devices used to repair damaged tissue, the cost of employing such fixation devices often becomes the limiting factor in whether the particular procedure can be conducted within cost limits allowed by the insurance carrier. The addition of a separate electrical generating device or a complex combination of an integral electrical generating device within a fixation device are not viable solutions in the present day medical care systems.
Therefore, there is a need to combine an orthopedic fixation device with an electrical energy source in a reliable, cost effective design. There is also a need to provide such a combination that has multiple potential uses for differing medical procedures without requiring complete re-design of the combination. There is also a need to provide such a combination that can deliver selected electrical energy parameters within a single implant. There is yet further a need to provide a fixation device that can be used also as an anchor for traditional sutures for repair of soft tissues, while the anchoring device can also perform its traditional function of anchoring the sutures.
These needs are satisfied with the present invention as described below with respect to preferred embodiments of the invention.


Embodiments of the present invention provide an augmented reality by defining a model representing a real-world system. After defining the model, a plurality of model simulations are performed using the defined model which produce predicted field data that is stored in memory. In turn, data from one or more sensors in the real-world system is received and the defined model is calibrated using the received field data relative to the stored predicted field data. Then, an augmented reality of the real-world system is provided using the calibrated model.

Embodiments of the invention generally relate to the field of computer programs and systems and specifically to the fields of product design and simulation and augmented and virtual reality. Embodiments may be employed in virtual reality, design, e.g. engineering system design, maintenance, augmented reality, systems operations, virtual presentations, and entertainment, e.g., video games and movies.
A number of existing product and simulation systems are offered on the market for the design and simulation of systems, parts, or assemblies of parts. Such product and simulation systems typically employ computer aided design (CAD) and/or computer aided engineering (CAE) programs. These systems allow a user to construct, manipulate, and simulate complex three-dimensional models of objects or assemblies of objects. These CAD and CAE systems thus, provide a representation of modeled objects using edges or lines, in certain cases with faces. Lines, edges, faces, or polygons may be represented in various manners, e.g. non-uniform rational basis-splines (NURBS).
These CAD systems manage parts or assemblies of parts of modeled objects, which are mainly specifications of geometry. In particular, CAD files contain specifications, from which geometry is generated. From geometry, a representation is generated. Specifications, geometries, and representations may be stored in a single CAD file or multiple CAD files. CAD systems include graphic tools for representing the modeled objects to designers; these tools are dedicated to the display of complex objects. For example, an assembly may contain thousands of parts. A CAD system can be used to manage models of objects, which are stored in electronic files.
The advent of CAD and CAE systems allows for a wide range of representation possibilities for objects. Examples include finite element models (FEM), finite volume models, and lattice Boltzmann models (finite particle models). These models may be derived from a CAD model, and thus, may represent one or more parts or an entire assembly. Further, said models may be programmed in such a way that the model has the properties of the underlying object or objects that it represents. When a FEM or other such object representation as is known in the art is programmed in such a way, it may be used to perform simulations of the object that it represents. For example, a FEM may be used to represent the interior cavity of a vehicle, the acoustic fluid surrounding a structure, and any number of real-world objects. Moreover, CAD and CAE systems along with FEMs, finite volume models, and lattice Boltzmann models can be utilized to simulate engineering systems. For example, CAE systems can be employed to simulate noise and vibration of vehicles.

Simulation augmented reality system for emergent behavior