The present invention relates to a class of compounds represented by the formula (I)

The present invention relates to novel compounds which bind to the integrin receptor xcex1vxcex23, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents.
Integrins are a group of cell surface glycoproteins which mediate cell adhesion and therefore are useful mediators of cell adhesion interactions which occur during various biological processes. Integrins are heterodimers composed of noncovalently linked xcex1 and xcex2 polypeptide subunits. Currently eleven different a subunits have been identified and six different xcex2 subunits have been identified. The various xcex1 subunits can combine with various xcex2 subunits to form distinct integrins.
The integrin identified as xcex1vxcex23 (also known as the vitronectin receptor) has been identified as an integrin which plays a role in various conditions or disease states including tumor metastasis, solid tumor growth (neoplasia), osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis and smooth muscle cell migration (e.g. restenosis artherosclerosis). Additionally, it has been found that such agents would be useful as antivirals, antifungals and antimicrobials. Thus, compounds which selectively inhibit or antagonize xcex1vxcex23 would be beneficial for treating such conditions.
It has been shown that the xcex1vxcex23 integrin and other xcex1v containing integrins bind to a number of Arg-Gly-Asp (RGD) containing matrix macromolecules. Compounds containing the RGD sequence mimic extracellular matrix ligands so as to bind to cell surface receptors. However, it is also known that RGD peptides in general are non-selective for RGD dependent integrins. For example, most RGD peptides which bind to xcex1vxcex23 also bind to xcex1vxcex25, xcex1vxcex21 and xcex1IIbxcex23. Antagonism of platelet xcex1IIbxcex23 (also known as the fibrinogen receptor) is known to block platelet aggregation in humans. In order to avoid bleeding side-effects when treating the conditions or disease states associated with the integrin xcex1vxcex23, it would be beneficial to develop compounds which are selective antagonists of xcex1vxcex23 as opposed to xcex1IIbxcex23.
The compounds of this invention are therefore selective xcex1vxcex23 integrin antagonist. The present invention includes compounds which inhibit the respective integrins and also includes pharmaceutical compositions comprising such compounds. The present invention further provides for methods for treating or preventing conditions mediated by the xcex1vxcex23 receptor in a mammal in need of such treatment comprising administering a therapeutically effective amount of the compounds of the present invention and pharmaceutical compositions of the present invention. Administration of such compounds and compositions of the present invention inhibits angiogenesis, tumor metastasis, tumor growth, osteoporosis, Paget""s disease, humoral hypercalcemia of malignancy, retinopathy, macular degeneration, arthritis, periodontal disease, smooth muscle cell migration, including restenosis and artherosclerosis, and viral diseases.
Tumor cell invasion occurs by a three step process: 1) tumor cell attachment to extracellular matrix; 2) proteolytic dissolution of the matrix; and 3) movement of the cells through the dissolved barrier. This process can occur repeatedly and can result in metastases at sites distant from the original tumor.
Seftor et al. (Proc. Natl. Acad. Sci. USA, Vol. 89 (1992) 1557-1561) have shown that the xcex1vxcex23 integrin has a biological function in melanoma cell invasion. Montgomery et al., (Proc. Natl. Acad. Sci. USA, Vol. 91 (1994) 8856-60) have demonstrated that the integrin xcex1vxcex23 expressed on human melanoma cells promotes a survival signal, protecting the cells from apoptosis. Mediation of the tumor cell metastatic pathway by interference with the xcex1vxcex23 integrin cell adhesion receptor to impede tumor metastasis would be beneficial.
Brooks et al. (Cell, Vol. 79 (1994) 1157-1164) have demonstrated that antagonists of xcex1vxcex23 provide a therapeutic approach for the treatment of neoplasia (inhibition of solid tumor growth) since systemic administration of xcex1vxcex23 antagonists causes dramatic regression of various histologically distinct human tumors.
The adhesion receptor integrin xcex1vxcex23 was identified as a marker of angiogenic blood vessels in chick and man and therefore such receptor plays a critical role in angiogenesis or neovascularization. Angiogenesis is characterized by the invasion, migration and proliferation of smooth muscle and endothelial cells. Antagonists of xcex1vxcex23 inhibit this process by selectively promoting apoptosis of cells in neovasculature. The growth of new blood vessels, or angiogenesis, also contributes to pathological conditions such as diabetic retinopathy including macular degeneration (Adamis et al., Amer. J. Ophthal., Vol. 118, (1994) 445-450) and rheumatoid arthritis (Peacock et al., J. Exp. Med., Vol. 175, (1992), 1135-1138). Therefore, xcex1vxcex23 antagonists would be useful therapeutic agents for treating such conditions associated with neovascularization (Brooks et al., Science, Vol. 264, (1994), 569-571).
It has been reported that the cell surface receptor xcex1vxcex23 is the major integrin on osteoclasts responsible for attachment to bone. Osteoclasts cause bone resorption and when such bone resorbing activity exceeds bone forming activity it results in osteoporosis (loss of bone), which leads to an increased number of bone fractures, incapacitation and increased mortality. Antagonists of xcex1vxcex23 have been shown to be potent inhibitors of osteoclastic activity both in vitro [Sato et al., J. Cell. Biol., Vol. 111 (1990) 1713-1723] and in vivo [Fisher et al., Endocrinology, Vol. 132 (1993) 1411-1413]. Antagonism of xcex1vxcex23 leads to decreased bone resorption and therefore restores a normal balance of bone forming and resorbing activity. Thus it would be beneficial to provide antagonists of osteoclast xcex1vxcex23 which are effective inhibitors of bone resorption and therefore are useful in the treatment or prevention of osteoporosis.
The role of the xcex1vxcex23 integrin in smooth muscle cell migration also makes it a therapeutic target for prevention or inhibition of neointimal hyperplasia which is a leading cause of restenosis after vascular procedures (Choi et al., J. Vasc. Surg. Vol. 19(1) (1994) 125-34). Prevention or inhibition of neointimal hyperplasia by pharmaceutical agents to prevent or inhibit restenosis would be beneficial.
White (Current Biology, Vol. 3(9)(1993) 596-599) has reported that adenovirus uses xcex1vxcex23 for entering host cells. The integrin appears to be required for endocytosis of the virus particle and may be required for penetration of the viral genome into the host cell cytoplasm. Thus compounds which inhibit xcex1vxcex23 would find usefulness as antiviral agents.
The present invention as a first object provides novel compounds of the following formula (I)
or a pharmaceutically acceptable salt, prodrug or ester thereof, wherein:
G is selected from the group consisting of
wherein Q is NH or O and Qxe2x80x2 is H, C1-C6 alkyl, phenyl, or phenyl-C1-C4-alkyl;
wherein Rxe2x80x2 and Rxe2x80x3 are independently H or C1-C4 alkyl;
B is (CH2)m(CHxe2x95x90CH)pY, wherein m=1,2,3, p=0,1, Y is CH2 or CO.
X is CH2 or Cxe2x95x90O;
R1 is selected from the group consisting of H, C1-C4 alkyl, C1-C4 alkoxy, OH, halogen, CF3;
A is CH2, NH, O, S(O), wherein n is zero, 1 or 2.
R2 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, aryl or C5-C7 monocyclic heteroaryl ring containing one to three heteroatoms selected from O, S, and N, unsubstituted or optionally substituted by one to three substituents independently selected from H, C1-C4 alkyl, C1-C4 alkoxy, OH, halogen, CF3;
R is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C4 alkynyl, aryl or aryl-C1-C4 alkyl.
The present invention includes within its scope all possible isomers, stereoisomers and optical isomers and their mixtures, the chemical and bioprecursors and metabolites of the compounds of formula (I).
It is another object of the invention to provide pharmaceutical compositions comprising compounds of the Formula I. Such compounds and compositions are useful in selectively inhibiting or antagonizing the xcex1vxcex23 integrin and therefore in another embodiment the present invention relates to a method of selectively inhibiting or antagonizing the xcex1vxcex23 integrin. The invention further involves treating or inhibiting pathological conditions associated therewith such as osteoporosis, humoral hypercalcemia of malignancy, Paget""s disease, tumor metastasis, solid tumor growth (neoplasia), angiogenesis, including tumor angiogenesis, retinopathy including macular degeneration and diabetic retinopathy, arthritis, including rheumatoid arthritis, periodontal disease, psoriasis, smooth muscle cell migration and restenosis in a mammal in need of such treatment. Additionally, such pharmaceutical agents are useful as antiviral agents, and antimicrobials.
The present invention relates to a class of compounds represented by the Formula I, described above.
A halogen atom is preferably chlorine or fluorine.
The alkyl, alkoxy, alkenyl and alkynyl groups and the alkylene and alkenylene chains may be branched or straight groups or chains, respectively.
An aryl group is, e.g., an aromatic C6-C20 mono- or poly-nuclear moiety, typically phenyl, naphthyl, unsubstituted or substituted by one to three substituents independently chosen from halogen, hydroxy, CF3, C1-C4 alkyl and C1-C4 alkoxy.
A C5-C7 monocyclic heteroaryl ring is preferably a C5-C6 heteromonocyclic ring, in particular selected from pyridine, pyrazine, pyridazine, pyrimidine, thiophene, pyrrole, pyrazole, imidazole, oxazole and isoxazole.
Accordingly an aralkyl group is e.g. benzyl or phenethyl, in which the phenyl ring is optionally substituted by one to three substituents independently selected from halogen, hydroxy, CF3, C1-C4 alkyl and C1-C4 alkoxy.
A C2-C6 alkenyl group is preferably an allyl group.
A C1-C6 alkyl group is preferably a C1-C4 alkyl group.
A C1-C4 alkyl group is preferably a methyl or ethyl group.
A C2-C4 alkynyl group is preferably an ethynyl group.
A C1-C4 alkoxy group is preferably methoxy, ethoxy, propoxy or butoxy.
Examples of pharmaceutically acceptable salts of the compounds of the invention are either those with inorganic bases, such as sodium, potassium, calcium and aluminum hydroxides, or with organic bases, such as lysine, arginine, N-methyl-glucamine, triethylamine, triethanolamine, dibenzylamine, methylbenzylamine, di-(2-ethyl-hexyl)-amine, piperidine, N-ethylpiperidine, N,N-diethylaminoethylamine, N-ethylmorpholine, xcex2-phenethylamine, N-benzyl-xcex2-phenethylamine, N-benzyl-N,N-dimethylamine and the other acceptable organic amines, as well as the salts with inorganic acids, e.g. hydrochloric, hydrobromic and sulphuric acids and with organic acids, e.g. citric, tartaric, maleic, malic, fumaric, trifluoroacetic, methanesulphonic and ethanesulphonic acids.
As stated above, the present invention also includes within its scope pharmaceutically acceptable bio-precursors (otherwise known as pro-drugs) of the compounds of formula (I), i.e. compounds which have a different formula to formula (I) above, but which nevertheless upon administration to a human being are converted directly or indirectly in vivo into a compound of formula (I).
Preferred compounds of the invention are those, in formula (I), wherein R, R1, X and A are as defined above;
B is (CH2)m(CHxe2x95x90CH)pY, wherein m=1,2,3, p=0 and Y is CH2;
R2 is a phenyl, naphthyl, pyridine, pyrazine, pyridazine, pyrimidine, thiophene, pyrrole, pyrazole, imidazole, oxazole and isoxazole unsubstituted or optionally substituted as defined above; and G is selected from the group consisting of
wherein Q is NH or O and Qxe2x80x2 is H, C1-C6 alkyl, phenyl, or phenyl- C1-C4-alkyl;
and the pharmaceutically acceptable salts, prodrugs and esters thereof.
Most preferred compounds of the invention are those wherein, in formula (I), B, X, R1, A and R are as defined above
R2 is a phenyl, thiophene, oxazole, isoxazole, or a pyridine ring unsubstituted or optionally substituted as defined above; and G is selected from the group consisting of
and the pharmaceutically acceptable salts, prodrugs and esters thereof.
Examples of specific preferred compounds according to the invention are the following:
3-phenyl-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
3-phenyl-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
3-phenyl-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{4-[2-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
3-(3-pyridinyl)-N-{4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
3-(3-pyridinyl)-N-{4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
3-(3-pyridinyl)-N-{4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-beta-alanine;
N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenyl-beta-alanine;
N-{3-oxo-4-[2-(2-pyridinylamino)ethyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{4-[2-(1H-imidazol-2-ylamino)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{4-[3-(1H-imidazol-2-ylamino)propyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
N-{4-[4-(1H-imidazol-2-ylamino)butyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)-beta-alanine;
3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoic acid;
3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoic acid;
3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-phenylpropanoic acid;
3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoic acid;
3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoic acid;
3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(3-pyridinyl)propanoic acid;
3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}oxy)-3-(pyridinyl)propanoic acid;
3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoic acid;
3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoic acid;
3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-phenylpropanoic acid;
3-({3-oxo-4-[3-(2-pyridinylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-ppyridinyl)propanoic acid;
3-({3-oxo-4-[4-(2-pyridinylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoic acid;
3-({3-oxo-4-[3-(1H-imidazol-2-ylamino)propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoic acid;
3-({3-oxo-4-[4-(1H-imidazol-2-ylamino)butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}sulfanyl)-3-(3-pyridinyl)propanoic acid;
4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoic acid;
4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoic acid;
4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-phenylbutanoic acid;
4-{3-oxo-4-[4-(pyridin-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoic acid;
4-{3-oxo-4-[3-(1H-imidazol-2-ylamino)-propyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoic acid;
4-{3-oxo-4-[4-(1H-imidazol-2-ylamino)-butyl]-3,4-dihydro-2H-1,4-benzoxazin-7-yl}-3-(3-pyridinyl)butanoic acid;
A further object of the present invention is to provide a compound of formula (I) as defined above or a pharmaceutically acceptable salt, prodrug or ester thereof, for use in a method of treatment of the human or animal body by therapy, in particular for treating conditions mediated by the xcex1vxcex23 integrin.
The object of the present invention is also to provide a pharmaceutical composition comprising a pharmaceutically acceptable carrier and/or diluent and as an active principle a compound of formula (I), as herein defined, or a pharmaceutically acceptable salt thereof.
The present invention also provides the use of a compound of formula (I), as defined above, in the preparation of a medicament having xcex1vxcex23 integrin inhibiting or antagonizing activity.
The present invention also provides a method for treating conditions mediated by the xcex1vxcex23 integrin in a mammal, including humans, in need of such treatment comprising administering to said mammal an effective xcex1vxcex23 inhibiting or antagonizing amount of a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof
More specifically, the present invention provides a method for inhibiting bone resorption, treating osteoporosis, inhibiting humoral hypercalcemia of malignancy, treating Paget""s disease, inhibiting tumor metastasis, inhibiting neoplasia (solid tumor growth), inhibiting angiogenesis including tumor angiogenesis, treating diabetic retinopathy, inhibiting arthritis, psoriasis and periodontal disease, and inhibiting smooth muscle cell migration including restenosis.
The compounds of the invention and the salts thereof can be prepared by or in analogy to the processes described hereafter. Accordingly, compounds of formula I and the salts thereof, can be for instance obtained by a process as described here below.
A compound of formula I wherein G is as defined above and Q is different from oxygen; X, B, A, R, R1 and R2 are as defined above can be obtained by reacting a compound of formula II
wherein B, X, A, R, R1 and R2 are as defined above, G1 is represented by G, as defined above under a) to g) wherein Q is different from oxygen and one or more nitrogens are protected with suitable protective groups, such as, for instance, carbobenzyloxy or t-butoxycarbonyl, removable with a suitable reducing agent, or with an acid, such as trifluoroacetic acid or hydrochloric or hydrobromic acid.
A compound of formula II can be obtained by:
1) reacting a compound of formula III
wherein G1, X, B, R, R1 and R2 are as defined above and A is NH, with a suitable reducing agent, such as an alkali metal borohydride or an alkali metal cyanoborohydride thus obtaining a compound of formula II wherein G1, X, B, R, R1 and R2 are as defined above and A is NH. A compound of formula III, wherein G1, B, X, R, R1 and R2 are as defined above and A is NH, can, in turn, be obtained by reacting a compound of formula IV
wherein G1, B, X, and R1 are as defined above and A is NH2, with a compound of formula V
wherein R and R2 are as defined above; or
2) Reacting a compound of formula IV wherein G1, B, X, and R1 are as defined above and A is SH, with a compound of formula VI
wherein R and R2 are as defined above, thus obtaining a compound of formula II wherein G, X, B, R, R1 and R2 are as defined above, and A is S; or
3) Reacting compound of formula IV where G1, B, X and R1 are as defined above and A is OH with a compound of formula VII
wherein R and R2 are as defined above, and W is Cl, Br, I, OH or OSO2C1-C4-alkyl or OSO2Aryl, thus obtaining a compound of formula II wherein G, X, B, R, R1 and R2 are as defined above, and A is O; or
4) Reacting a compound of formula II, wherein G1, X, B, R, R1 and R2 are as defined above, and A is S, with an oxydizing agent such as NalO4, oxone, H2O2 or a peracid, thus obtaining a compound of formula II wherein G1, X, B, R1, R2 and R are as defined above and A is S(O)n wherein n is 1 or 2, i.e. A is a sulfoxide or sulfone group; or
5) Reacting a compound of formula VIII
wherein X, R, R1, R2 are as defined above, and A is CH2, with a compound of formula IX
G1xe2x80x94Bxe2x80x94Wxe2x80x83xe2x80x83IX
wherein G1, B and W are as defined above, thus obtaining a compound of formula II wherein G1, X, B, R1, R2 and R are as defined above and A is CH2. A compound of formula VIII, as defined above, can, in turn, be obtained by reacting a compound of formula X
wherein X and R1 are as defined above, A is CH2, W is selected from Cl or Br and Z1 is a suitable amide protecting group, such as a p-methoxy-benxyl group, with magnesium followed by addition of the resulting compound to a compound of formula VI, wherein R and R2 are as described above, in the presence of suitable metal salts, like copper salts, followed by removal of Z1.
A compound of formula IV, as defined above wherein A is NH2, can be obtained by reduction of a compound of formula XI
wherein G1, X, B and R1 are as defined above.
A compound of formula IV, wherein G1, X, B and R1 are as defined above and A is SH or OH can be obtained by a compound of formula XII
wherein, X, B and R1 are as defined above, A is S or O and Z2 is a suitable protecting group for a xe2x80x94OH or a xe2x80x94SH moiety, such as methyl, p-methoxybenzyl, t-butyldimethylsilyl, p-nitrobenzyl, by removal of the Z2 protecting group.
A compound of formula XI can be obtained by reacting a compound of formula XIII
wherein X and R1 are as defined above, with a compound of formula IX, as defined above.
A compound of formula XII can be obtained by reacting a compound of formula XIV
wherein A, X, R1, and Z2 are as defined above, with a compound of formula IX, as defined above.
A compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is CH2, O or S, and G is as defined under a) wherein Q is oxygen, can be obtained by reacting a compound of formula XV
wherein B, X, R, R1, R2 are as defined above and A is CH2, O or S, with an inorganic cyanate, such as sodium or potassium or ammonium cyanate, or with an isocyanate of formula Qxe2x80x2NCO, wherein Qxe2x80x2 is as described above.
A compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is CH2, O or S, and G is as defined under a) wherein Q is different from oxygen, or under b) and c), and Qxe2x80x2 is hydrogen, can be obtained by reacting a compound of formula XV with a suitable guanylating agent, such as, for instance, N,Nxe2x80x2-di-t-butoxycarbonyl-Nxe2x80x3-triflylguanidine or 2-methylthio-2-imidazoline hydriodide or 2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodide, followed by removal of the protecting groups in the case where the guanilating agent is N,Nxe2x80x2-di-t-butoxycarbonyl-Nxe2x80x3-triflylguanidine.
A compound of formula XV, as defined above, can be obtained by reaction of a compound of formula VIII, wherein X, R, R1, R2 are as defined above, and A is CH2, O or S, with a compound of formula XVI
Z3xe2x80x94NHxe2x80x94Bxe2x80x94Wxe2x80x83xe2x80x83XVI
wherein B and W are as defined above and Z3 is a suitable amino protecting group such as, for instance, carbobenzyloxy or t-butoxycarbonyl, followed by removal of Z3.
A compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is NH, and G is as defined under a) wherein Q is oxygen, can be obtained by reacting a compound of formula XVII
wherein B and R1 are as defined above, G is as defined under a) wherein Q is oxygen, and A is NH2, with a compound of formula V, followed by reduction of the product with an alkali metal borohydride or an alkali metal cyanoboro-hydride. A compound of formula XVII, as defined above, can be obtained in analogy to the procedures described for the synthesis of compounds of formula IV, provided that G, as defined above, is substituted for G1.
A compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is NH, and G is as defined under a) wherein Q is different from oxygen, or under b) or c), and Qxe2x80x2 is hydrogen, can be obtained by reacting a compound of formula XV, wherein B, X, R, R1 and R2 are as defined above, and A is NH, with a suitable guanilating agent, such as, for instance, N,Nxe2x80x2-di-t-butoxy-carbonyl-Nxe2x80x3-triflylguanidine or 2-methylthio-2-imidazoline hydriodide or 2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodide, followed by removal of the protecting groups in the case where the guanilating agent is N,Nxe2x80x2-di-t-butoxy-carbonyl-Nxe2x80x3-triflylguanidine.
A compound of formula XV, wherein B, X, R, R1 and R2 are as defined above, and A is NH, in turn, can be obtained by reacting a compound of formula XIII, as defined above, with a compound of formula XVI, as defined above, followed by: a) reduction of the nitro group, b) reaction with a compound of formula V, as defined above, c) reduction of the resulting compound with an alkali metal borohydride or an alkali metal cianoborohydride, d) removal of the protectin group Z3.
A compound of formula X or XIII or XIV, as defined above, can be prepared according to general methods described in the literature.
Additionally, a compound of formula I can be obtained by a process which comprises:
a) converting a compound of formula (I) into another compound of formula (I), or separating a single isomer of a compound of formula (I) from a mixture thereof, or converting a compound of formula (I) into a salt thereof, or converting a salt of a compound of formula (I) into a free compound of formula (I);
b) reacting a compound of formula I wherein G, X, B, A R1 and R2 are as defined above and R is different from hydrogen with aqueous acids or aqueous bases thus obtaining a compound of formula I wherein R is hydrogen;
The compounds described above can be prepared as exemplified in the following procedures.
In a typical procedure, a compound of formula I, as defined above, can be obtained by treatment of a compound of formula II, as defined above, with hydrogen in the presence of a suitable catalyst, such as palladium on carbon, in a solvent like a lower alcohol or dioxane, or by treatment with trifluoroacetic acid or hydrobromic acid in acetic acid, followed by isolation of the product by chromatography.
In a typical procedure for the preparation of a compound of formula III, as defined above, a compound of formula IV, as defined above, a keto-ester of formula V and anhydrous calcium sulfate and catalytic acetic acid are mixed in an anhydrous alcohol, such as ethanol, and refluxed for 24 to 96 hours. The compound is isolated by column chromatography. The reduction of a compound of formula III with sodium cyanoborohydride in ethanol provides a compound of formula II, as defined above and wherein A is NH.
In a typical procedure for the preparation of a compound of formula II, as defined above and wherein A is S, a compound of formula IV, as defined above and wherein A is SH, is added to a solution of a compound of formula VI, as defined above, in a solvent like tetrahydrofuran or dichloromethane, in the presence of a small amount of an organic base such as diazabicycloundecene (DBU). The reaction is allowed to proceed from 12 to 48 hours, at a temperature from about 20 to about 40xc2x0 C., and the product isolated by column chromatography.
In a typical procedure for the preparation of a compound of formula II, as defined above and wherein A is O, to a dichloromethane or tetrahydrofuran solution containing a compound of formula IV, as defined above and wherein A is OH, triphenylphosphine and a compound of formula VII, as defined above and wherein W is OH, a solution of an alkyl azodicarboxylate in dichloromethane or tetrahydrofuran is added and the mixture stirred at a temperature from room temperature to about 40xc2x0 C. for 1 to 6 hours. The product is then isolated by column chromatography. The procedure described above is similar to procedures disclosed in the literature (see, for instance, KRCHNAK, V., FLEGELOVA, Z., WEICHSEL, A. S., LEBL, M. Tetrahedron Letters 1995, 36, 6193-6196; or BROWN, R. F. C., JACKSON, W. R., McCARTHY, T. D. Tetrahedron 1994, 18, 5469-5488).
In a typical procedure for the preparation of a compound of formula II, as defined above and wherein A is SO2, a compound of formula II, as defined above and wherein A is S, is treated with 30% aqueous H2O2 in an alcohol as a solvent, or with NalO4 in water and methanol, or acetone and water, (as described, for instance, in BEIER, C., SCHAUMANN, E. Synthesis 1997, 11, 1296-1300).
In a typical procedure for the preparation of a compound of formula II, as defined above and wherein A is SO, a compound of formula II, as defined above and wherein A is S, is treated with oxone in a mixture methanol/water as a solvent (as described, for instance, in HINTERBERGER, S., HOFER, O., GREGER, H. Tetrahedron 1998, 54, 487-496).
In a typical procedure for the preparation of a compound of formula II, as defined above and wherein A is CH2, a Grignard reagent obtained from a compound of formula X, as defined above and wherein W is Cl or Br and P1 is p-methoxybenzyl, is added to a mixture of cuprous iodide (Cul) and dry tetramethylene diamine (TMEDA) in dry tetrahydrofuran at a temperature of about xe2x88x9278xc2x0 C. The mixture is then stirred at about xe2x88x9278xc2x0 C. for between 15 minutes to 1 hours, then a tetrahydrofuran solution of chlorotrimethyl silane and a compound of formula IV, as defined above, is added and the temperature allowed to rise to about xe2x88x9230xc2x0 C. After a period of 12 to 36 hours, the reaction is treated with a saturated aqueous solution of ammonium chloride and ammonium hydroxide and extracted with a suitable solvent, such as dichloromethane, chloroform, diethylether, ethyl acetate and the product isolated by column chromatography (see, for instance, VAN HEERDEN, P. S., BEZUIDENHOUDT, B. C. B., FERREIRA, D. Tetrahedron 1996, 52, 12313-12322; or VAN HEERDEN, P. S., BEZUIDENHOUDT, B. C. B., FERREIRA, D. J. Chem. Soc. Perk. Trans. 1, 1997, 1141-1146). Then, the p-methoxybenzyl group is removed by catalytic hydrogenolysis, using a supported metal catalyst, such as palladium on carbon in a solvent like methanol or ethanol, to give a compound of formula VIII, as defined above and wherein A is CH2. A compound of formula VIII, as defined above, is then reacted with a compound of formula IX, as defined above and wherein W is typically OSO2CH3, in the presence of an organic base, such as potassium hexamethyldisilazide in a solvent like tetrahydrofuran or dimethylformamide or mixtures thereof, at a temperature from room temperature to about 100xc2x0 C. for 1 to 6 hours, the product isolated by column chromatography thus giving a compound of formula II, as defined above and wherein A is CH2.
In typical procedure for the preparation of a compound of formula IV, as defined above and wherein A is NH2, a compound of formula XI, as defined above, is reduced by treatment with a mixture of titanium tetrachloride and tin dichloride in a solvent like tetrahydrofuran or diisopropyl ether or diethyl ether, at a temperature from about 20 to about 40xc2x0 C. and under an atmosphere of an inert gas. A compound of formula XI, as defined above, can be obtained by treatment of a compound of formula XIII, as defined above, with a compound of formula IX, as defined above and wherein W is typically OSO2CH3, in the presence of an organic base, such as potassium hexamethyldisilazide in a solvent like tetrahydrofuran or dimethylformamide or mixtures thereof, at a temperature from room temperature to about 100xc2x0 C. for 1 to 6 hours, and the product isolated by column chromatography.
In typical procedure for the preparation of a compound of formula XII, as defined above and wherein A is O or S and Z2 is a protecting group such as methyl, ethoxymethyl, p-methoxybenzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, p-nitrobenzyl or other suitable protecting group (see: GREENE, T. W., WUTS, P. G. M. Protective group in organic synthesis, Wiley, 1999), a compound of formula XIV, as defined above, is reacted with a compound of formula IX, as defined above and wherein W is typically OSO2CH3, in the presence of an organic base, such as potassium hexamethyldisilazide in a solvent like tetrahydrofuran or dimethylformamide or mixtures thereof, at a temperature from room temperature to about 100xc2x0 C. for 1 to 6 hours.
In typical procedure for the preparation of a compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is CH2, O or S, and G is as defined under a) wherein Q is oxygen and Qxe2x80x2 is hydrogen, a compound of formula XV, as defined above, is reacted with a cyanate salt, as e.g. an ammonium or sodium or potassium salt, in solvent such as acetic acid or water, at a temperature from about 50 to about 100xc2x0 C., for 2 to 12 hours (see, as an example, Organic Synthesis vol. IV, p. 49, 1963).
In typical procedure for the preparation of a compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is CH2, O or S, and G is as defined under a) wherein Q is oxygen and Qxe2x80x2 is different from hydrogen, a compound of formula XV, as defined above, is reacted with an isocyanate of formula Qxe2x80x2NCO, wherein Qxe2x80x2 is as defined above, in a solvent like dichloromethane, acetonitrile, tetrahydrofuran, dioxane or toluene, in the presence of triethylamine, at a temperature from room temperature to about 100xc2x0 C. and for 4 to 24 hours. The resulting compound is isolated by column chromatography.
In a typical procedure for the preparation of a compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is CH2, O or S, and G is as defined under a) wherein Q is different from oxygen, or under b) and c), and Qxe2x80x2 is hydrogen, a compound of formula XV is treated with a suitable guanylating agent, like N,Nxe2x80x2-di-t-butoxycarbonyl-Nxe2x80x3-triflylguanidine or 2-methylthio-2-imidazoline hydriodide or 2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodid in a solvent like dichloromethane, tetrahydrofuran, dioxane or a lower alcohol, at a temperature from room temperature to reflux, for 24 to 72 hours, followed by evaporation of the solvent and isolation of the product by chromatography. In typical procedure for the preparation of a compound of formula XV, as defined above, a compound of formula VIII, wherein X, R1, R2 are as defined above, R is different from hydrogen and A is CH2, O or S, with a compound of formula XVI, as defined above and wherein W is Br or OSO2CH3, in the presence of an organic base, such as potassium hexamethyldisilazide in a solvent like tetrahydrofuran or dimethylformamide or mixtures thereof, at a temperature from room temperature to 100xc2x0 C. for 1 to 6 hours. The resulting compound is isolated by column chromatography, and the protecting group Z3 is then removed following the standard procedures described in the literature (see: GREENE, T. W., WUTS, P. G. M. Protective group in organic synthesis, Wiley, 1999).
In typical procedure for the preparation of a compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is NH, G is as defined under a) wherein Q is oxygen and Qxe2x80x2 is as defined above, a compound of formula XVII, as defined above, is mixed with a keto-ester of formula V in the presence of anhydrous calcium sulfate and catalytic acetic acid, in a solvent like an anhydrous alcohol, such as ethanol, and refluxed for 24 to 96 hours. The compound is isolated by column chromatography, then is treated with sodium cyanoborohydride in ethanol thus giving a compound of formula I, as defined above. A compound of formula XVII, as defined above, can be obtained using the same procedure described above for the synthesis of compounds of formula IV, provided that G, as defined under a), is substituted for G1, and wherein A is NH2.
In typical procedure for the preparation of a compound of formula I, wherein B, X, R, R1, R2 are as defined above, A is NH, G is as defined under a) wherein Q is different from oxygen, or under b) or c), and Qxe2x80x2 is hydrogen, a compound of formula XV, wherein B, X, R, R1 and R2 are as defined above, and A is NH is reacted with a suitable guanylating agent, like N,Nxe2x80x2-di-t-butoxycarbonyl-Nxe2x80x3-triflylguanidine or 2-methylthio-2-imidazoline hydriodide or 2-methylthio-1,4,5,6-tetrahydropyrimidine hydriodid in a solvent like dichloromethane, tetrahydrofuran, dioxane or a lower alcohol, at a temperature from room temperature to reflux, for 24 to 72 hours, followed by evaporation of the solvent and isolation of the product by chromatography. In the case where the guanilating agent is N,Nxe2x80x2-di-t-butoxycarbonyl-Nxe2x80x3-triflylguanidine, the product is then treated with trifluoroacetic acid, to remove the nitrogen protecting groups, the trifluoroacetic acid is evaporated to afford the desired compound. A compound of formula XV, as defined above, can be obtained using the synthetic sequence described before and applying some of the experimental procedures described before.
In a typical procedure, a compound of formula I, as defined above and wherein R is hydrogen, is obtained by treatment of a compound of formula I, as defined above and wherein R is different form hydrogen, with a mixture of an aqueous acid, like hydrochloric acid, and a lower alcohol or dioxane, at a temperature from room temperature to about 40xc2x0 C., for 1 to 24 hours.
Alternatively, a compound of formula I, as defined above and wherein R is different form hydrogen, is treated with an aqueous base, like sodium or lithium or potassium hydroxide, in a solvent like methanol or ethanol or dioxane, at a temperature from room temperature to about 40xc2x0 C., for 1 to 24 hours. The solution is then treated with an acid and the compound filtered.
A compound of formula X or XIII or XIV, as defined above, can be obtained according to general synthetic methods for 1,4-benzoxazines as described, for instance, in METHODS OF ORGANIC CHEMISTRY (HOUBEN-WEIL), volume E 9a, pp. 141-177, George Thieme Verlag, Stuttgart 1997, or by suitable modifications of such methods as known to those skilled in the art. Also the optional salification of a compound of formula (I) as well as the conversion of a salt into the free compound and the separation of a mixture of isomers into the single isomers may be carried our by conventional methods. For example, the separation of optical isomers may be carried out by salification with an optically active base or acid and by subsequent fractional crystallisation of the diastereoisomeric salts, followed by recovering of the optically active isomeric acids or bases, respectively.
When in the compound of formula (I), and in the intermediate products thereof, groups are present which need to be protected before submitting them to the here-above illustrated reactions, they may be protected before the reactions take place and then deprotected, according to methods well known to those skilled in the art.
The compounds of formula (I) and the pharmaceutically acceptable salts thereof are herein defined as the xe2x80x9ccompounds of the present inventionxe2x80x9d, the xe2x80x9ccompounds of the inventionxe2x80x9d and/or the xe2x80x9cactive principles of the pharmaceutical compositions of the inventionxe2x80x9d.
The following examples describe the invention without limiting it.

Substituted benzoxazines as integrin antagonists

Abstract: or a pharmaceutical acceptable salt, prodrug or ester thereof, pharmaceutical compositions comprising compounds of the formula (I), and methods of selectively inhibiting or antagonizing xcex1vxcex23 integrin.


A memory device protective carrier is disclosed for protecting small memory devices. The container includes a non-deformable, rigid exterior case having first and second shells and a securing mechanism to adjustably secure the shells in an open or closed position so that a containment chamber is defined between the shells in the closed position. A deformable, resilient receiving insert and a resilient securing insert are secured respectively within the first and second shells. Sealing lips of the inserts are compressed in the closed position to form a fluid seal so that a memory device secured within the containment chamber is protected by the rigid case and resilient inserts against damage from impact injury or fluid contaminants.

The present invention relates to containers for memory devices, and in particular relates to a device that both contains and protects memory devices.
It is well known that memory devices for storage of data for modern electronic components, such as computers, cameras, entertainment systems, etc., are becoming increasingly smaller. For example, solid memory technology currently and commonly referred to in the art as xe2x80x9cminiature hard drivesxe2x80x9d, xe2x80x9cflash memoriesxe2x80x9d, xe2x80x9cSONYxe2x80x9d brand name xe2x80x9cmemory sticksxe2x80x9d may be readily secured in containers as small as two inches in length and width and one-half inch in depth. Such small memory devices provide substantial conveniences in storing, backing-up and transferring data such as computer programs, visual images, audio data, etc. Because such memory devices are so small, however, they also give rise to significant risks related to transport of the devices. For example, dropping of the devices could damage them, exposure to moisture could likewise injure them, or contact of data transfer ports of the devices with foreign objects could also harm them.
It is known that some modern protective carriers exist for solid memory devices, such as a memory card protective carrier disclosed in U.S. Pat. No. 6,230,885 that issued on May 15, 2001 to the owners of all rights in the invention described herein, which patent in hereby incorporated herein by reference. The memory card protective carrier disclosed therein provides for a protective band to overlie data transfer ports of the memory card whenever the card is secured within the carrier. However, neither that carrier nor any known memory device protective carrier provides for adequate protection of a memory device against impact damage resulting from dropping the carrier, or from moisture contamination from liquid or vapor fluid contaminants. Additionally, known carriers for small memory devices are typically made of a hard plastic that is very slippery, such as well known audio cassette and xe2x80x9cVHSxe2x80x9d format video tape plastic containers. It is well known that such containers are slippery to physically handle and that they frequently slide off of counter tops and tables in minor accidents, and are thereby frequently damaged upon impact with a floor.
Accordingly, there is a need for a memory device protective container that provides protection for memory devices against damage from an unintended impact and from fluid contaminants.
The invention is a memory device protective container for containing and protecting a memory device. The container includes a rigid exterior case having a first shell that defines a first peripheral edge, having a second shell that defines a second peripheral edge, and having a securing mechanism for adjustably securing the first and second peripheral edges from an open position to a closed position wherein the edges are adjacent each other to define a containment chamber between the first and second shells. A resilient receiving insert is dimensioned to nest within the first shell, and the resilient receiving insert defines a first sealing peripheral lip that is positioned adjacent to the first peripheral edge of the first shell whenever the resilient receiving insert nests within the first shell. The resilient receiving insert also defines a first base extending between the first sealing peripheral lip. The first base has at least one first flared tongue extending away from a shell contact surface of the first base and the flared tongue is dimensioned to pass through and be secured by a first tongue slot defined within the first shell. The resilient receiving insert also defines one or more receiving posts extending from a side of the first base opposed to the shell contact surface into the containment chamber. The flexible receiving posts are positioned to receive and secure the memory device between the posts.
A resilient securing insert is dimensioned to nest within the second shell, and the resilient securing insert defines a second sealing peripheral lip that is positioned adjacent to the second peripheral edge of the second shell whenever the resilient securing insert nests within the second shell. The resilient securing insert also defines a second base extending between the second sealing peripheral lip and the second base has at least one second flared tongue extending from a shell contact surface of the second base that is dimensioned to pass through and be secured by a second tongue slot defined within the second shell. The resilient securing insert also defines at least one securing rib extending from a side of the second base opposed to the shell contact surface into the containment chamber between the inserts. The securing rib is positioned and dimensioned to pass between the flexible posts of the resilient receiving insert to secure the memory device against movement within the containment chamber whenever the first and second peripheral edges of the first and second shells are positioned adjacent each other.
The rigid exterior case provides durability to the container and also provides a firm structure to support the soft, resilient inserts so that the memory device is protected against any damage resulting from an impact upon the rigid exterior case. In a preferred embodiment, the flared tongues of the inserts extend through the tongue slots defined within the first and second shells a distance beyond an exterior surface of the shells so that the soft, resilient flared tongues provide enhanced friction to the exterior case thereby further reducing a risk of accidental impact damage to the memory device secured within the containment chamber. In an additional preferred embodiment, the first sealing peripheral lip and second sealing peripheral lip are cooperatively dimensioned to contact and compress against each other to form a fluid seal restricting fluid movement into or out of the containment chamber whenever the securing mechanism secures the first and second peripheral edges of the first and second shells adjacent each other.
In a further embodiment, the resilient receiving insert may also include at least one support ridge extending from the first base between the flexible receiving posts into the containment chamber to restrict smooth surface contact between the memory device and the first base of the resilient receiving insert. By restricting smooth surface contact between the first base and the memory device, any possible contamination by moisture or a foreign object is minimized. Additionally, because the support ridge raises the memory device away from contact with the first base, extraction of the memory device by the fingers of a user is facilitated.
Accordingly, it is a general object of the present invention to provide a memory device protective container that overcomes the deficiencies of prior art containers.
It is a more specific object to provide a memory device protective container that facilitates containment, ease of access, and protection of memory devices within the container.
It is yet another object to provide a memory device protective container that protects memory devices within the container against contamination from fluids.
It is a further object to provide a memory device protective container that enhances friction of an exterior case of the container.
These and other objects and advantages of the present memory device protective container invention will become more readily apparent when the following description is read in conjunction with the accompanying drawings.


A zipper pull attachment adapted to be clipped to a zipper pull tab and left in place to aid in opening and closing the zipper. The zipper pull attachment includes a vertical clip member, a ring member movably attached to the lower end of the clip member, and a fixed horizontal handle member secured horizontally through the ring member in the plane of the ring, with handle ends extending from the sides of the ring in balanced fashion.

Zipper pull attachments use a grip-enhancing device more or less permanently secured to a zipper pull tab for regular use in operating the zipper. Patent examples include those shown in U.S. Pat. No. 4,918,794 to Harvey et al. (flexible elongated attachment for a zipper pull tab with the appearance of a miniature necktie); U.S. Pat. No. 5,930,874 to Yamazaki et al. (zipper pull with buckle type connector structure for attaching a fabric pull strap); and U.S. Pat. No. 7,111,714 to Bell, III (slide faster with a chord-type pull handle for hanging towels, shoes, etc., with one end of the handle connected to a zipper pull tab and the other end connected to the zippered article). Non-patent examples include pieces of cord or ribbon knotted through the zipper pull tab's opening; metal rings attached to the zipper pull tab with a spring hook or clip; and ornaments such as cross charms attached to the zipper pull tab with clips, chains, or swivel hooks.
Zipper pulling aids are also known, in which a separate handle with a hook at one end allows the user to reach and pull an otherwise difficult zipper by briefly hooking the opening in the pull tab. Patent examples include U.S. Pat. No. 4,997,222 to Reed (elongated zipper pulling device with a handle end, and a helical or spiral end adapted to be threaded through a zipper pull tab); U.S. Pat. No. 5,100,191 to Detrick et al. (zipper operating device shaped like a key so that it can be kept on a keychain when not in use); and U.S. Pat. No. 6,494,512 to Cada et al. (zipper pulling device with a jackknife type handle and a hook member that pivots or folds into the handle). Non-patent examples include the "Zip It" zipper pull aid, with a t-shaped handle having a hook in one end adapted to reach and fit through a zipper pull tab opening, and an optional ring attachment that can be clipped to the zipper pull tab to make it easier to hook.
Prior attachment-type pulls are relatively small or weak and provide only moderate assistance with difficult zippers, and are often prone to twisting into odd positions that can make them more difficult to operate. The hook-equipped reach-and-pull devices are too cumbersome to carry, and are relatively awkward to use except when the user has time and privacy.


A method for contact-free drying of a paper or board web or of any other corresponding continuous web. During drying, both infrared radiation and drying air jets are used. The web is carried by the air jets through the dryer free of contact. The moving web is first passed into an infrared drying gap, in which a drying energy pulse of relatively short duration is directed at the web, the power of the energy pulse being substantially higher than the average drying power of the dryer per unit of area. After the infrared drying gap, the web is immediately passed into an airborne web drying gap wherein the web is supported and dried by means of air jets. Air is brought into the infrared unit, which air having been heated in the infrared unit is passed as replacement air and/or drying air for the airborne web drying unit or units placed after the infrared unit. The air flows to be passed into the infrared unit are passed in connection with the inlet gap of the web to both sides of the web so as to form both accompanying and sealing air jet flows.

The invention concerns a method for contact-free drying of a paper or board web, or of any other corresponding continuous web, in which method both infrared radiation and drying air jets are used for drying, the air jets also supporting the web as it runs through the dryer, so that the web is carried free of contact, preferably from two sides, and in which method, after the infrared drying gap, the web is substantially immediately passed into an airborne web-drying gap, wherein the web is supported and dried by means of air jets.
Also included herein is a description of a device intended for carrying out the method of the invention, which device comprises an infrared drying unit and an airborne web-drying unit or airborne web-drying units, which infrared drying unit comprises a series of infrared radiators and an infrared treatment gap fitted in its connection, through which gap the web to be dried can be passed. The airborne web-drying unit or units comprise a box portion, inside of which a nozzle box or boxes are fitted, in connection with which there are nozzle parts, through which drying and supporting air jets are applied to the web to be dried. The infrared drying unit and airborne web-drying unit are integrated with each other both structurally and functionally, and the infrared unit is placed, in the direction of running of the web to be dried, immediately before the airborne web-drying unit.
The present invention relates to the drying of a paper web, board web, or of any other corresponding moving web. A typical object of the invention is the drying of a paper web in connection with its coating or surface-sizing.
As is known in the prior art, paper webs are coated either by means of separate coating devices or by means of on-machine devices or surface-sizing devices integrated in paper machines and operating in the drying section of a paper machine. At the final end of a multi-cylinder dryer, the web to be coated is passed to a coating device, which is followed by an intermediate dryer and finally, e.g., by one group of drying cylinders as an after-dryer. A typical application of the present invention is the intermediate dryer after the coating device, the invention being, however, not confined to the intermediate dryer alone.
In the prior art, so-called airborne web dryers are known, wherein a paper web, board web, or equivalent is dried free of contact. Airborne web dryers are used, e.g., in paper coating devices after a roll coater or a spread coater to support and to dry the web, which is wet with the coating agent, free of contact. In airborne web dryers various blow nozzles and nozzle settings for drying and supporting air are applied. The blow nozzles can be divided into two groups, i.e. pressure or float nozzles, and negative-pressure or foil nozzles, both of which can be applied in the dryer and the method in accordance with the invention.
The prior art airborne web dryers that are used most commonly are based exclusively on air flows. It is partly for this reason that the airborne web dryer becomes quite spacious, since the distance of effect of the airborne web dryer must be relatively long in order that a sufficient high drying capacity could be obtained. Another reason for these drawbacks is that in air drying the depth of penetration of the drying remains relatively low.
In the prior art, different dryers are known which are based on the effect of radiation, in particular of infrared radiation. The use of infrared radiation provides the advantage that the radiation has a relatively high depth of penetration, which depth of penetration is increased when the wavelength becomes shorter. The use of infrared dryers in the drying of paper webs has been hampered, e.g., by the risk of fire, because the temperatures in infrared radiators become quite high, e.g. 2000.degree. C., in order that a drying radiation with a sufficiently short wavelength could be achieved.
With respect to the prior art, reference is made to the German published Patent Application (DE OS) No. 2,351,280, which describes a sort of a combination of an airborne web dryer and an infrared dryer operating by means of pressure nozzles. In the patent application mentioned above, a one-sided airborne web dryer is described, which comprises nozzle boxes placed one after the other at distances from each other. The edge portions of these boxes are provided with nozzle slots, through which air jets are directed at the web placed above expressly perpendicularly. The air jets are deflected outward from the nozzle box when they meet the web. Between the nozzles, infrared radiators are fitted, which fill the gap between the nozzles. This type of dryer has not become widely used, probably due to the fact that the nozzle construction has not been successful in providing a constructionally or energy-economically favorable combination of air drying and radiation drying. Moreover, the construction is one-sided, and it requires a relatively abundant space in the direction of running of the web if sufficiently high drying capacities are to be reached, e.g., in paper finishing plants.
Particular problems in infrared drying have been the strong formation of dust and high humidity of air.
Electric infrared dryers, used separately or exclusively, are also energy-economically unfavorable owing to the relatively high cost of electric energy, as compared, e.g., with natural gas.
In paper coating stations, including on-machine coating stations, separate infrared dryers have been used whose drying is based exclusively on the radiation effect. However, use of these infrared dryers has not yielded a sufficiently good adjustability of paper quality and evaportion. Moreover, the drying process becomes highly dependent on the operating quality of the infrared dryer.
It is an object of the present invention to solve the problem described above.
It is a particular object of the present invention to develop a novel application of an infrared dryer, in which the air technique particularly has been solved in a better way than in the prior art.
A further object of the invention is to provide a method and to describe a device by means of which the overall control of the coating-drying of a paper web can be improved.
Another objective of the invention is to provide a novel application of an infrared dryer so that it is possible to attain a dryer with more favorable investment costs and operating costs, as compared with the prior art. In view of achieving this objective by means of the invention, attempts are made to obtain a higher drying capacity, a lower size of equipment, and a lower heat and humidity load in the machine hall.
It is a particular object of the invention to provide an infrared dryer that can be used for adjusting the ultimate moisture profile of the web produced by the paper machine.
In view of achieving the objectives given above, as well as others, the method of the invention is mainly characterized as follows:
the moving web is first passed into an infrared drying gap in which a drying energy pulse of relatively short duration is directed at the web, the power of the energy pulse being substantially higher than the average drying power of the dryer per unit of area, and PA1 air is brought into the infrared unit, which air, having been heated in the infrared unit, is passed as replacement air and/or drying air for the airborne web-drying unit or units placed after the infrared unit.
On the other hand, the drying device in accordance with the invention is mainly characterized in that the infrared unit comprises air and nozzle devices, through which air flows can be passed into the treatment gap of the infrared unit and/or in connection with the heated parts of the infrared unit, which air flows are passed for replacement and/or drying air for the subsequent airborne web-drying unit or units.
By means of the invention, it is possible to accomplish drying with improved overall profitability, wherein both the investment costs and the operating costs are taken into account.
Owing to the invention, an increased evaporation capacity, a reduced heat and humidity load in the machine hall, as well as economies in the lifting and auxiliary equipment for the infrared dryer are obtained. On the basis of measurements, drying test runs, and theoretical examinations carried out by the inventor, it has been ascertained that the solution of the invention, from an evaporation standpoint, and also in view of the quality of the paper web, results in a considerable improvement over the prior art dryer arrangements in which the infrared dryer and the airborne web dryer are provided as separate, independently operating units.
The method and device in accordance with the invention are particularly well suited for an on-machine dryer after a coating or surface-sizing apparatus and moreover, if necessary, also for adjustment of the ultimate moisture profile of the paper web.
In the present invention, an open hood does not have to be constructed above the dryer, which is the case in the prior art devices, for in the infra-airborne combination of the invention mere spot exhaustion is enough, because the system of exhaust ducts in the airborne web dryer provides adequate ventilation.
When natural gas or a corresponding fuel is used for the heating of the drying air for the airborne web dryer unit or the heating of the drying air for the airborne web dryer unit or units, the operating cost of the method and the device making use of the invention per unit of quantity of evaporated water becomes considerably more favorable as compared with a dryer in which electric infrared drying along would be used. This advantage is due to the fact that in the invention the energy transferred into the paper web in the electric infrared unit is utilized efficiently in the airborne web drying unit or units following after the infrared unit.

Method for on-machine coating-drying of a paper web or the like


In a main-scanning direction, light incident on a resonance mirror is convergent light and a first lens of a second optical system has a negative refractive power. Consequently, even with a small angle of deflection, the distance from the resonance mirror to a photoconductor required for obtaining a desired scanning width in the main-scanning direction can be reduced. Moreover, in a sub-scanning direction, light incident on the resonance mirror is parallel light, and the first lens of the second optical system has a negative refractive power and a second lens thereof has a positive refractive power. In addition, the first lens has both surfaces formed with a free curved surface and the second lens thereof also has a free curved surface. This permits keeping the sub-scanning magnification uniform, thus avoiding, even in high-speed drawing with a plurality of beams, image quality deterioration due a change in an interval in the sub-scanning direction between the plurality of beams.

1. Field of the Invention
The present invention relates to a laser scanner.
2. Description of Related Art
Suggested in a conventional field of a laser scanner, for example, as shown in JP-A-2006-227044, is technology of deflecting, with a deflector (for example, resonance mirror), laser light transformed into convergent light in a main scanning direction and then condensing it onto a surface to be scanned with a scanning lens that has a negative refractive power (optical power) in the main-scanning direction and having arcsine property to thereby scan the surface to be scanned at a constant speed. As in JP-A-2006-227044, with configuration such that convergent light is made incident on the deflector in the main-scanning direction and the scanning lens has a negative refractive power in the main-scanning direction, even with a small angle of deflection by the deflector, the distance from the deflector to the surface to be scanned required for obtaining a desired scanning width in the main-scanning direction can be reduced, thus permitting downsizing of the device.
However, in a conventional laser scanner, in a case where the number of scanning lenses used is one, the sub-scanning magnification is not uniform in the main-scanning direction, thus causing, for example, upon high-speed drawing with a plurality of beams, a problem of deteriorated image quality due to a change in the interval in a sub-scanning direction between the plurality of beams (irradiation spots) depending on the position thereof on the surface to be scanned.

Konica Minolta Business Technologies, Inc.


The present invention relates to a process of stabilizing micellular particles such as vesicles and increasing the shelf life by suspending the particles in a polymeric gel matrix. The invention also relates to such particles suspended in the gel matrix with a protective gel surface thereabout which is capable of becoming fluid and converting the protective surface of an aqueous suspension.

1. Field of the Invention
The present invention relates to vesicle stabilization, and more particularly to such stabilization by suspending micellular particles such as vesicles in a polymeric gel matrix.
2. Description of Prior Art
The use of micellular particles such as phospholipid vesicles (or liposomes as they are commonly referred to) as carriers for pharmaceutical and diagnostic agents has been the subject of extensive investigation, Ryman B.E., et al., Ann. N.Y. Acad. Sci., 308, 281 (1978); Gregoriadis, G., Ed., "Liposome Technology", CRC Press, Inc., Boca Raton, Fla., Vol. II (1984); Fendler J.H., Acc. Chem. Res., 13, 7 (1980); and Weinstein J.N., et al., Science, 204, 188 (1979). Examples of the potential application of phospholipid vesicles include consideration as carriers of enzymes, drugs (particularly anti-tumor drugs), chelating agents, hormones, radionuclides, cell-modifying substances, antigens, antibodies, interferon inducers, and virus subunit particles. However, liposomes (especially small sonicated vesicles) are thermodynamically unstable at temperatures below the phase transition temperature, and tend to aggregate or fuse, to form larger unilamellar vesicles on long-term storage, Sheetz M.P., et al., Biochemistry, 11, 4573 (1972); Lawaczeck R.L., et al., Biochem, Biophys. Acta, 443, 313 (1976); Larrabee H.L., Biochemistry, 18, 3321 (1978); and Shullery S.E., et al., Biochemistry, 19, 3919 (1980).
Aggregation or fusion of the small particles into larger particles alters the properties of the vesicles, which can in turn modify the permeability of the vesicles and in vivo biodistribution, Kao Y.J., et al., Biochem. Biophys. Acta., 677, 453 (1981); and Abra R.M., et al., Biochem. Biophys. Acta., 666, 493 (1981). It is accordingly highly important to be able to store micellular particles without having the particles aggregate or fuse together with the resultant potential change in important properties.


The present invention provides a method for forming a three-dimensional wafer stack having a single metallized stack via with a variable cross-sectional shape. The method uses at least first and silicon wafers. Each wafer has one or more integrated circuits formed thereon. One or more through-vias are formed in each silicon wafer followed by oxide formation on at least an upper and lower surface of the silicon wafer. The wafers are aligned such that each wafer through via is aligned with a corresponding through via in adjacent stacked wafers. Wafers are bonded to form a three-dimensional wafer stack having one or more stack vias formed from the alignment of individual wafer vias. Via metallization is performed by depositing a seed layer in each of the stack vias followed by copper electroplating to form a continuous and homogeneous metallization path through the three-dimensional wafer stack.

As integrated circuit dimensions have moved progressively smaller, they are approaching a physical limit below which devices cannot be fabricated. Therefore, the traditional two-dimensional model of integrated circuits is undergoing a change towards three-dimensional integration. There are many challenges to overcome to make the progression to a three-dimensional paradigm. First, most integrated circuit fabrication techniques rely on modifying a wafer surface in some manner to form components and metallization paths. Therefore three-dimensional integration will likely rely on multiple stacked wafers with devices formed in each individual wafer.
Stacking multiple wafers presents many challenges. To adhere multiple wafers to one another, the wafers must be extremely flat to ensure wafer-to-wafer contact. Another challenge is interconnection among the devices positioned on various wafers. This requires vertical metallization to integrate devices positioned on different wafer.
U.S. Pat. No. 7,385,283 describes a method for making a three-dimensional integrated circuit. In this method, metal interconnects are aligned and a metal to metal bond formed during wafer stacking. At the same time, a non-metal to non-metal bond is formed between adjacent wafers. While this technique is one approach to vertical integration, the metallization of vias prior to wafer bonding can create problems during the wafer bonding process. If heat is used to bond the wafers, metal ions may diffuse into the wafer-to-wafer bonding region; for copper via metallization, diffused copper can "poison" nearby devices. For silicon wafers, copper doping forms deep level traps, seriously affecting the electrical properties of the overall 3-D stack. If chemical mechanical polishing is performed prior to the bonding, the metallization in the vias may not be even with the surface, resulting in difficulty forming a metal-to-metal bond between adjacent wafer vias and possible "shorts" between device levels. Further, the need to perform via metallization on each individual wafer followed by inter-wafer via bonding adds expensive and time-consuming processing steps to the overall process.
Thus there is a need in the art for improved techniques for vertical integration of wafers to form multi-layer integrated circuits.

Forming through-silicon-vias for multi-wafer integrated circuits

Hong Kong Science Park, Shatin, New Territories, Hong Kong

Hong Kong Applied Science and Technology Research Institute Company Limited


Provided is a data generation device for generating input data to be inputted to a parallel processing device. The data generation device includes: a controller configured to output padding data; and a data processing device configured to receive original data and to generate the input data in which at least a portion of the original data is padded with the padding data. The data processing device includes: a first multiplexer configured to receive the padding data and the original data; a register configured to store data outputted from the first multiplexer; and a second multiplexer configured to receive data outputted from the first multiplexer and data stored in the register.

The present disclosure herein relates to an electronic device, and more particularly, to a data generation device for generating input data to be inputted to a parallel processing device.
The parallel processing device is a device for high-speed processing of high-volume data such as video, voice and text. The parallel processing device may be used in fields where high-speed data processing such as compression and restoration of data, recognition through machine learning, and artificial intelligence based on neural network is required. The parallel processing device may process an algorithm by configuring a plurality of memories, a processing element (PE), and so on for parallel processing. Data for parallel processing may be sequentially inputted to a parallel processing device or inputted in parallel through a plurality of memories.
Data processed with data compression and decompression and artificial intelligence algorithms generally have a dependency between data, and because of this, in the parallel processing operation, it may be necessary to reprocess the previously processed data or to process the values outside the boundaries of the original data by padding them with a special value.
Therefore, the parallel processing device must perform a complicated operation such as a memory access or an operation unit control for data processing.

Data generation device for parallel processing

ELECTRONICS AND TELECOMMUNICATIONS RESEARCH INSTITUTE


An oscillationless semisubmerged high-speed vessel comprises at least one lower hull submerged below the water surface in the cruising state of the vessel, an upper hull above the water surface and struts connecting the lower hull and an upper hull. The lower hull possesses horizontal fins controlling longitudinal and transverse oscillations of the vessel, steering devices, water ballast tanks for adjusting water line of the vessel and propelling means. The struts are so designed that the water plane area is small so as to minimize the oscillation force, i.e. the vessel does not have a self-stabilizing ability both longitudinally and transversely with only reverse buoyancy kept by the struts when the vessel heels. The struts are constructed to have a sufficient strength for connection of the lower hull and an upper hill. The bulged structures are constructed to contain the propelling means. The struts and the bulged structures are disposed in a midship part of the lower hull to minimize longitudinal oscillations of the vessel due to the wave heaving forces which are vertical components of wave exciting forces generated at both fore and aft parts of the vessel. Steering devices are disposed at a fore part of the lower hull to prevent the vessel from transverse oscillations at an initial stage of healing. Therefore the vessel of this invention can eliminate the oscillations longitudinally and transversely. Thus the vessel of this invention can be an oscillationless high speed vessel which navigates for a long time without causing large accelerative oscillations due to waves on the sea surface.

This invention relates to semisubmerged high-speed vessels, and more particularly to vessel hull structures and hull equipment designed to make the vessel oscillationless. The vessel is an oscillationless vessel of the type in which a mono-lower hull or twin-lower hulls under water and an upper hull above water are connected by way of struts.
It is a universal requirement of transportation media to carry objects faster, cheaper and in greater quantities. In the marine transportation business, the fulfilment of these requirements has been an ever continuing goal from ancient times. The same goal has been sought also in the shipbuilding industry. In particular, to increase the speeds of vessels is the biggest requirement of naval architectural technology. Recent remarkable progress in aeronautical engineering makes the requirement of vessel speed urgent.
High speeds of a vessel such as 30 Knots to 40 Knots have already been realized by warships. However, it has not yet been achieved by merchant vessels in navigating for a long time across the ocean.
Vessels are subjected to large oscillations due to waves during navigation in oceans. When the oscillation generates an acceleration of more than (1/2)G, the human body cannot endure this motion for a long time, and further, the hull, machinery and equipment are also likely to be damaged.
The duration of high speed navigation of warships is limited. Therefore, the oscillation problem of a warship has been solved by using hull, machinery and equipment which can endure the problem during this limited time and also by training the crews.
For a merchant vessel, however, whose business is to transport, the problem cannot be solved in the same way as that for warships. A vessel which can carry objects for a long time at high speed without oscillation in waves is desired. As a method to control oscillation in the conventional displacement mono-hull vessel, the use of bilge keels or movable foil stabilizers has been tried but sufficient stabilization has not yet been obtained. In particular, it has been impossible to control the pitching oscillation. As long as the vessel has self-stabilizing ability, the vessel is inevitably subjected to large heeling forces and heel recovery forces which oscillate the vessel.
It has been considered to use a submarine as a merchant cargo vessel. A submarine does not oscillate and has a high propulsion efficiency at high speed, but it has a risk of safety in the deep sea water and needs a lot of ballast to sink in water when it carries cargoes lighter than water. Further, the cargo space is limited under water and thus it is extremely not uncommon as a merchant vessel.
As one development of modern shipbuilding technology, hydrofoil vessels have appeared. .Since these vessels have no self-stabilizing ability in a state of cruising, no oscillation takes place when a vessel is subjected to waves, but it cannot be a large vessel because the area of the foil is limited to support the vessel weight. Recent air cushion vehicles called ACV including hover craft and surface effect ships have a high propulsion efficiency such as to achieve a high speed of almost 100 Knots. The ACV, however, has a weak point in maneuverability and thus it is not suitable for navigation in waves as a merchant vessel.
Catamaran type vessels have been considered. Originally, the twin hull vessel was just a combination of two conventional displacement mono-hull type vessels. In order to improve the propulsion efficiency, the vessel movability and carriability of cargo, a vessel called SWATH which means Small Waterplane Area Twin Hulls is becoming popular.
SWATH consists of two lower hulls under water, an upper hull above water and struts connecting these. SWATH navigates in a semisubmerged state and this vessel receives the buoyancy force derived from the displacement of the submerged hulls. Thus the scale up to a large vessel can be easily done and the cargo can be carried on the upper hull without limitation. However, as long as self-stabilizing ability is needed for the SWATH, SWATH cannot avoid oscillation. And also it causes big trouble that SWATH has the submerged hulls in the shallow draft state.
An Extended Performance Hydrofoil vessel called EPH which navigates in a semisubmerged state has also been considered. EPH is equipped with mono buoyancy tank and hydrofoils. EPH has no self-stabilizing ability in a state of cruising, and therefore EPH is an oscillationless vessel. But it causes big trouble that EPH has a submerged hull in the shallow draft state.
The submerged hull generates large wave exciting forces at hull shape changes during navigation in the shallow draft state. The vertical component of the wave exciting force is the wave heaving force. The wave heaving force is a source of oscillation of the vessel. End structures including struts at the fore and aft of the vessel form hull shape changes parts and can be a source of wave heaving force which may cause the oscillation of the vessel particularly in the longitudinal direction. Further a high-power propelling means of the multi-axial type concentrated at the aft part forms a hull shape change and can be a source of a large wave heaving force causing a longitudinal oscillation of the vessel.
The foregoing is the background of the pursuit of the oscillationless ocean going vessel of the type according to this invention.

Oscillationless semisubmerged high-speed vessel


A workflow engine tool is disclosed that enables scientists and engineers to programmatically author workflows (e.g., a directed acyclic graph, “DAG”) with nearly no overhead, using a simpler script that needs almost no modifications for portability among multiple different workflow engines. This permits users to focus on the business logic of the project, avoiding the distracting tedious overhead related to workflow management (such as uploading modules, drawing edges, setting parameters, and other tasks). The workflow engine tool provides an abstraction layer on top of workflow engines, introducing a binding function that converts a programming language function (e.g., a normal python function) into a workflow module definition. The workflow engine tool infers module instances and induces edge dependencies automatically by inferring from a programming language script to build a DAG.

In the era of big data and artificial intelligence (AI), intelligent use of data has become an important factor in the success of many businesses. Data often forms a foundation for advanced analytics, AI, and business operation efficiency. As more businesses become data-driven and data volume grows rapidly, there is an increasing need to manage and execute complicated data processing pipelines that extract data from various sources, transform it for consumption (e.g., extracting features and training AI models), and storing it for subsequent uses. Workflow engines are often used to manage data workflow pipelines at scale.
Despite the benefits of workflow engines, full utilization of workflow engines remains burdensome, due to steep learning curves and the effort needed to author complicated workflow pipelines. A directed acyclic graph (DAG) defines a workflow pipeline for exploiting data to produce some desired results. Typically, users (e.g., engineers and scientists) interact with a graphical user interface (GUI) to manually compose DAGs, or must learn a special syntax to generate DAGs programmatically. Neither of these approaches is natural or intuitive, and both are prone to error. Generating, adapting, and reviewing the generation of DAGs can introduce significant overhead effort when DAGs become large and complex.


A method of welding a gas turbine engine substrate composed of a gamma prime precipitation strengthened nickel based superalloy, including the steps of: applying weld beads on the substrate to form a continuous layer the thickness of the weld beads; using a filler material made of a first material exhibiting comparable strength and ductility as the substrate, and a second material exhibiting greater ductility than the substrate; and creating crack propagation mitigating regions within the continuous layer by increasing the percentage of the second material in the crack propagation mitigating regions over the percentage of the second material in the remainder of the continuous layer.

High strength gamma-prime-strengthened nickel based superalloys used in gas turbine hot sections are generally described as those which have high strength even at temperatures of 1600 degrees Fahrenheit or higher. Generally, in order to restore both dimension and geometry of damaged hot section components such as turbine blades and nozzle guide vanes and maintain elevated temperature properties (both environmental resistant and creep resistant properties etc), advanced superalloy filler materials are laser deposited onto worn or damaged areas of components. Thus, damaged advanced turbine superalloy (including directionally solidified and single crystal cast) components are completely repaired and restored to their original geometry and dimension with excellent elevated temperature properties.
Advanced nickel-based superalloys with high volume fraction of gamma prime precipitates, (i.e. gamma-prime-strengthened nickel based superalloys) such as INCONEL® 738 manufactured by Special Metals Company, René® 80, manufactured by Reade Advanced Materials, and CM-247 manufactured by The C-M Group, as well as single crystal or directionally solidified (DS) superalloys, are susceptible to cracking in both the heat affected zone and in weld beads resulting from welding using filler alloy having the same or similar composition (i.e. "even-matched") as the base metal (i.e. the substrate). Therefore, many weld repair processes are carried out using conventional solid solution strengthened welding alloys such as INCONEL® 625 manufactured by Special Metals Company, or oxidation resistant high strength Co based weld fillers, which are softer (i.e. "under-matched") than most gamma-prime-strengthened nickel based superalloys, due to the low Al and Ti content. However, the use of under-matched filler is not desirable for component repairs that require considerable strength. Further, the large thermal expansion mismatch between the high strength Co base fillers and the nickel superalloy substrate could produce high thermo-mechanically induced damage and low thermal mechanical fatigue life during service. To extend the repaired component life and to repair the high-stressed region, ideally the weld metal used should have either the same or close composition as the base metal so that the thermal expansion and creep properties of the weld will closely match the base metal. This is particularly attractive for advanced nickel based superalloy components. However, it is very difficult to produce a crack-free weld with nickel based alloy filler with high Al and Ti contents due to segregation as well as solidification shrinkage or thermal contraction or shrinkage strains from gamma prime precipitation.
Several approaches have been taken toward eliminating the cracks in nickel based superalloy weld buildup for component repairs that require considerable strength. U.S. Pat. No. 4,336,312 describes a combination of a controlled chemical modification of a cast nickel-based superalloy material along with a pre-weld thermal conditioning cycle. U.S. Pat. No. 6,364,971 describes a laser welding technique used following a pre-conditioning hot isostatic process. U.S. Pat. No. 633,484 describes a welding technique wherein the entire weld area is preheated to a maximum ductility temperature range, and this elevated temperature is maintained during the weld and solidification of the weld. These patents are incorporated herein by reference.
Other approaches include 1) laser powder weld build-up while heating the component substrate (see U.S. Pat. Nos. 5,106,010, 6,037,563, 6,024,792, and EP patent 0861927); and using low energy laser beams to re-heat each deposited layer (see U.S. Pat. Nos. 5,900,170, 5,914,059, and 6,103,402). There patents are incorporated herein by reference. While heating the components during laser powder welding is effective, it is an expensive process, can cause distortion of the component, and has the potential of affecting the microstructure of the superalloy due to incipient melting at the grain boundaries. For example, turbine blades are often repaired using a technique known as hot-box welding. Hot-box weld repairs may take eight hours or more to complete, and the requirement for working inside of the hot box to maintain the elevated temperature makes it difficult to perform such welds robotically.
Techniques have therefore been developed that permit weld build-up at room temperature for component repairs that require considerable strength. US patent application 20080210347, incorporated herein by reference, discloses a method for welding superalloy components at ambient temperature conditions while reducing the propensity of the superalloy material to crack as a result of the weld. A root pass region of the weld is formed using a filler material that exhibits ductility that is higher than that of the base superalloy material. The ductile material mitigates stress in the root region, thereby preventing the formation of cracks. A remaining portion of the weld is formed using a filler material that essentially matches the base superalloy material. However, the amount of "even-matched" filler material build-up is limited to a certain height in order to avoid cracking.
For laser weld repair by deposition there are many different superalloy compositions designed for different applications, and alloy powders and/or alloy wires can be used as the filler materials for component repairs that require considerable strength. However, commercially available superalloy powders or wires are limited in terms of composition and availability. This situation thus largely limits the application of laser welding repair. For example, as noted above, laser depositions at room temperature using INCONEL® 738 powder or wire for repairing INCONEL® 738 blade (i.e. even-matched), or using Mar-M-247®, manufactured by MetalTek, powder or wire for repairing CM-247 blade (even-matched), will in most cases produce significant cracking due to the high contents of Al and/or Ti in the fillers. Therefore, a superalloy composition with reduced Al and Ti contents should be used for repair of INCONEL® 738 and CM-247, preferable at room temperature, for component repairs that require considerable strength. It has been reported that INCONEL® 939, manufactured by Special Metals Company, which contains a much smaller amount of Al compared to INCONEL® 738, could be successfully used in laser welding repair of INCONEL® 738. However, because of the much lower Al content, the resulting weld has a reduced oxidation and corrosion resistance. Further, INCONEL® 939 powder is much more expensive than INCONEL® 738 powder, and is not a commercially available superalloy powder.
U.S. Pat. No. 6,872,912, incorporated herein by reference, discloses an ambient temperature process for almost crack-free welding of a nickel-based single crystal superalloy component containing at least 5 weight percent total of Ti and Al, using a filler alloy which is a composition of nickel based single crystal superalloy, except that the total of Al and Ti is reduced below 5 weight percent. Welds created with this uniformly composed filler material reduce the susceptibility of the weld build-up to cracks even for components that require considerable strength. Those filler alloys, however, are not usually commercially available, and hence are costly and the process is not easy to implement.

Superalloy repair welding using multiple alloy powders


Disclosed are various embodiments for creating and providing narratives associated with a type of subject entity (e.g., person, movie, place, etc.). A narrative for the subject entity can be generated according to a narrative template. The narrative template can be selected based on a variety of factors. Following the selection of a narrative template, fields in the selected template are filled with stored data associated with the subject entity. The new or updated narrative may be stored in a memory. In response to a request for information related to the subject entity, the narrative can be transmitted to a client device.

In today's technological society, many people resort to online resources to obtain information pertaining to a variety of subjects. However, following a change regarding a particular subject entity, a system may need to update its information to remain accurate. If information is vast, the task of keeping things up-to-date may be problematic.

This patent is subject to a terminal disclaimer.

Dynamic creation and storage of narratives in multiple languages


This application discloses an automated apparatus for cleaning the interior surface of a pipe. The device includes a vehicle which propels itself down the inside of the pipe. A cleaning system is fixed to the vehicle and uses arms to reach the walls of the pipe. At the end of each arm sits a spray nozzle assembly equipped with spray nozzles. The spray nozzle assembly rotates or oscillates to spray clean the pipe surface. The arms and spray nozzle assembly interchange with other such cleaning systems depending on the shape or type of pipe and the desired cleaning technique. The apparatus is tethered to a source of fluid under pressure and a power source both of which are located off-board the apparatus at a remote location. An operator supervises the device's operation, controlling the speed and direction of travel of the vehicle, the speed and direction of oscillation and rotation of the cleaning system, and the fluid pressure delivered by the spray nozzles.

Pipes used to carry liquids and gases commonly transport all types of materials including water, natural gas, solid and liquid sewage, as well as various other accumulations from the pipe. Over time, these pipes require servicing and cleaning. Taylor et al. disclose automated systems for cleaning the outside of a pipeline in U.S. Pat. No. 5,520,734. Taylor et al. excavate under subterranean pipe and restore it by first cleaning the pipe and then applying a protective coating to the outer surface. As yet, however, nobody has automated a process for cleaning or restoring the inside of a pipe.
The interior surface of a pipeline carrying solids, liquids and gases generally degrades over time as the pipe walls interact chemically and physically with the substances flowing through them. In particular, a sewer system's interior walls corrode and deteriorate because corrosive materials contaminate the surface degrading the metal and concrete used to build the sewer. The corrosive material arises from both the sewage and waste water itself, and also from the digestive by-products of bacteria found in the sewage which proliferate in the anaerobic environment. The corrosion causes the walls of the sewer pipe to physically decay, eventually reducing their overall thickness.
The principal source of corrosion is sulfuric acid, which arises as a product of the materials transported in a sewer pipe and the sewer environment itself. Various metal sulfates found in the sewage quickly convert into hydrogen sulfide by: reducing to sulfide ions in the waste water, combining with hydrogen in the water and outgassing above the liquid as hydrogen sulfide gas. Additional hydrogen sulfide originates from bacteria containing contaminants which accumulate on the relatively rough concrete below the maximum liquid level. Bacteria found in these accumulations thrive in the anaerobic sewer environment producing hydrogen sulfide gas as a respiratory bi-product. Oxygen from the liquid below and oxygen condensing from the water in the air react with the hydrogen sulfide on the pipeline walls creating the highly corrosive sulfuric acid. The sulfuric acid attacks the calcium hydroxide in the concrete sewer walls leaving calcium sulfates which ultimately crumble and fall off of the interior of the wall substantially reducing its thickness.
The waste water level varies over the course of a 24 hour period. The flow is at its lowest level between 1:00 AM and 6:00 AM in the morning but it rises distinctly in the daytime and the pipe may operate near capacity. Because of the gaseous nature of the hydrogen sulfide, the pipe walls are predominately corroded in the portions of the wall above the minimum liquid level. Portions of the walls which are always below the water level are not subjected to such high concentrations of hydrogen sulfide gas or sulfuric acid and consequently do not experience the same levels of decay.
Eventually the sewer walls must be restored or they can suffer permanent damage leading to great expense. The restoration process is a two step operation that consists of first cleaning all of the contaminants (including any possibly existing outer layers of corrupted concrete) from the surface of the pipe, i.e. a process herein defined as scarifying, and then applying a protective coating over the newly cleaned (scarified pipe surface. Attempting to apply a protective coating without as aforesaid first cleaning the pipe surface is futile because it does not stop the decay that has already began underneath the coating. Furthermore, the protective coating itself does not adhere well to the contaminated surface. Thus, cleaning is an essential element of the restoration process.
As previously mentioned, a sewer system typically operates at high capacity during the day with decreasing flow overnight. In order to restore the sewer pipes without diverting the flow (a costly and sometimes impossible alternative), a bulk of the work must be done at night during the brief period when the flow is at a minimum. As previously outlined, the restoration process involves both cleaning the pipe surface and applying a protective coat. In practice, the rate of restoration is impaired because manual cleaning takes a proportionally greater amount of time than does the application of the protective coat. Consequently, a need exists for an automated cleaning process. Such a process will improve the rate of cleaning of the pipeline's interior walls making restoration without diversion a cost-effective possibility. Further, automation of the process can help to ensure that the same intensity of cleaning is applied to the entire surface without the quality variation that is inherent in manual execution.
Several patents such as Taylor et al. (U.S. Pat. No. 5,520,734), describe automated processes for cleaning the outside surface of pipelines using spray nozzle jets; however, none have attempted to automate the cleaning of the interior surface of a pipeline.

Spray cleaner for interior surface of pipeline