The present invention has the objective of offering drug for treating abnormalities in bone marrow which corrects the biological balance in the bone marrow, in particular which has the effect of suppressing inflammatory cell infiltration and suppressing cell growth-differentiation factor increase.

This invention relates to a drug for treating abnormalities in bone marrow which cures abnormalities in the bone marrow.
The bone marrow is an organ responsible for part of haematopoiesis, and since it is in contact with the medullary cavity and cancellus bone it is possible that, as a result of bone marrow abnormalities, there will occur abnormalities in the bone and other surrounding tissues, and serious illness will be exhibited. The bone marrow abnormalities referred to here are defined as those where general abnormality of the biological balance in the bone marrow is indicated, such as viral and bacterial infections in the bone marrow, cellular infiltration of the bone marrow, abnormalities of the bone marrow haematopoiesis, proliferation of malignant neoplasms in the bone marrow and concentration changes in cell growth-differentiation factors.
For example, the inflammation of the bone and bone marrow which is brought about by many pathogenic factors such as pyogenic bacteria, tuberculosis, syphilis, fungi and specified viruses or exogenous matter is termed osteomyelitis and, when there is osteomyelitis, as a result of the impeded blood circulation and infiltration of neutrophils into the bone marrow region, there occur surrounding bone decalcification and tissue breakdown, with resulting pain. While the occurrence of acute osteomyelitis is declining due to the widespread use of antibiotics, as a result of for example the appearance of resistant microorganisms, osteomyelitis which from the outset follows a subacute or chronic course remains a problem [Green, N. E. et al., J. Bone Joint Serg., 63-A, p107-114 (1981)].
In rheumatoid arthritis, it has been reported that there is an increase in the concentration of components which induce a proliferation of synoviocytes in the bone marrow and, moreover, that abnormal myelocytes are found within the bone marrow and changes in cell ratios such as an increase in the T cell ratio are shown [Ochi, T., Igaku no Ayumi, 161, p609-613 (1992)]. Since myelocytes differentiate into neutrophils, it can be expected that the number of neutrophils showing abnormal activity will increase in the bone marrow and contribute to an aggravation of the condition. Moreover, since the progress of a condition where marked changes in the bone marrow are exhibited is rapid and the outlook for the patient is severe [Ochi, T. et al., Arthritis Rheum., 31, p37 (1988)], there is the possibility that early stage improvement in the pathological changes in the bone marrow could be linked to the cure of the disease. In addition, in the treatment of rheumatoid arthritis there is also the problem that there is a considerable likelihood of multiple agents which show serious side effects being used concomitantly, such as steroids which display a variety of adverse-side effects and gold preparations compounds which exhibit hematopoiesis decrease.
In leukaemia, irrespective of cell type and whether it is acute or chronic, or whether it is myelogenicor lymphocytic leukaemia, the bone marrow is the location of a markedly increased production of leukaemia cells, and normal blood components decline. Again, in multiple myeloma, a principal feature is the proliferation of tumours of plasma cells, which are cells at the end of the B cell lineage, and a multiplicity of these is produced in the bone marrow at sites of active haematopoiesis. In leukaemia, multiple myeloma and the like, an increase in cell growth-differentiation factor activity in the bone marrow and an abnormal proliferation of cells are found, and the abnormalities in the biological balance in the bone marrow are believed to be closely connected with the presentation and continuance of the diseased state. Furthermore, hematopolesis decrease is widely known to be a adverse-side effect of the chemotherapeutic agents used in treatment, and even with therapy by homologous bone marrow transplantation the transplantation results are imperfect and carry the risk of subsequent recurrence.
Thus, inflammatory cell infiltration into the bone marrow, abnormal cell proliferation or an abnormal increase in cell growth-differentiation factor activity in the bone marrow are closely related with many bone marrow abnormalities, and the development of drugs based on a hitherto unavailable novel mechanism of action is desired so as to correct the biological balance in the bone marrow and treat bone marrow abnormalities. Now, the aforementioned disorders in which bone marrow abnormalities are shown have just been given as examples, and there are no restrictions thereto.
Bisphosphonic acid compounds suppress excessive bone resorption in tumour-induced osteolysis, Paget disease and osteoporosis, and some have already been used for medical treatment. These compounds are disclosed in, for example, EP177443, EP337706, AU8551534, EP317505, EP27982 and EP94714.
Furthermore, in EP100718, U.S. Pat. No. 4,234,645, EP84822, WO9203451 and WO935052, bisphosphonic acid compounds with an anti-inflammatory action are disclosed. However, the anti-inflammatory effects described therein form a basis for the treatment of skeletal system disorders such as arthritis, osteoarthritis and ankylosing spondylitis.
In relation to the anti-inflammatory action of bisphosphonic acid compounds, the effects on for example arthritic model rats have been pathologically analysed [Flora, L. et al., Arthritis and Rheumatism, 22, p340-346 (1979)] but no investigations relating to bone marrow changes have been carried out.
Again, in WO97/49711 and WO97/04785 for example, bisphosphonic acid compounds have been disclosed which exhibit an antitumour action and, moreover, it has also been reported that bisphosphonic acid compounds exhibit antitumour actions by inhibiting cell growth [Claire, M. et al., Br. J. Haematol., 98, p665 (1997)], [Knamori, M. et al., J. Exp. Cancer Res., 16, p39 (1997)]. However, depending on the particular compound, there are also examples which cause an increase in tumour growth [Kostenik, P. J. et al., Cancer Res., p5452 (1993)], so an antitumour action is not a characteristic common to the bisphosphonic acid structure.
In U.S. Pat. No. 4,067,971, there is disclosed a bisphosphonic acid compound used for the treatment of hypoxia and ischemic tissue disease but this compound depends on an oxygen-releasing action from red blood cells and it does not correct abnormalities of red blood cell formation. in the bone marrow.
Thus, it is already known that many bisphosphonic acid compounds have a bone resorption suppression effect, an anti-inflammatory effect and an anti-rheumatic effect, and that some bisphosphonic acid compounds exhibit an antitumour effect and show efficacy in the treatment of hypoxia. However, no findings have hitherto been obtained to indicate that bisphosphonic acid compounds are effective in the treatment of bone marrow abnormalities.
The present invention aims to offer a drug which, by correcting bone marrow abnormalities as exemplified above, is effective in the treatment of bone marrow diseases.
As a result of painstaking research conducted with this objective, the present inventors have discovered that the methanebisphosphonic acid derivatives represented by general formula (I) below, and salts thereof, have the effect of correcting the biological balance in the bone marrow, in particular suppressing inflammatory cell infiltration and suppressing cell growth-differentiation factor increase, and have efficacy in the treatment of bone marrow abnormalities. The present invention has been perfected based on this discovery.
In order to realise the aforesaid objective, the present invention has the following constitution. Specifically, the present invention relates to a bone marrow abnormality treatment agent in which the effective component is a methanebisphosphonic acid derivative represented by general formula (I):
[where, in the formula,
(a) R1 is hydrogen, and R2 is Arxe2x80x94Xxe2x80x94, Hetxe2x80x94Xxe2x80x94, Arxe2x80x94Xxe2x80x94Axe2x80x94, Het-Xxe2x80x94Axe2x80x94, Arxe2x80x94Xxe2x80x94Axe2x80x94N(R3)xe2x80x94, Hetxe2x80x94Xxe2x80x94Axe2x80x94N(R3)xe2x80x94 (here Ar is an unsubstituted or substituted aryl, Het is an unsubstituted or substituted monocyclic 5- or 6-membered monoaza, diaza or thiaza aryl which is bonded via a ring carbon atom, X is S, O or NH, A is alkylene and R3 is hydrogen or a lower alkyl) or N-phenylthiocarbamoyl, or
(b) R1 is hydrogen or hydroxy, and R2 is R4xe2x80x94Axe2x80x94 (here A is alkylene, R4 is hydrogen, Ar (Ar has the same meaning as above), an unsubstituted or substituted monoaza, diaza or thiaza aryl which is bonded via a ring carbon atom or ring nitrogen atom, a mono- or di-substituted amino (the substituent groups being alkyl, Ar-alkyl, Arxe2x80x94X-alkyl (X represents S or O) or Het-alkyl, and may be the same or different, but excluding the case of dialkyl; Ar and Het have the same meanings as above), or Ar-substituted alkyleneamino (Ar has the same meaning as above))],
or ester thereof, medicinally acceptable salt thereof, or a hydrate of these.
Optimum Mode for Practising the Invention
The present invention relates to the use, for the treatment of bone marrow abnormalities, of the methanebisphosphonic acid derivatives of formula (I)
[where, in the formula,
(a) R1 is hydrogen, and R2is Arxe2x80x94Xxe2x80x94, Hetxe2x80x94Xxe2x80x94, Arxe2x80x94Xxe2x80x94Axe2x80x94, Hetxe2x80x94Xxe2x80x94Axe2x80x94, Arxe2x80x94Xxe2x80x94Axe2x80x94N(R3)xe2x80x94, Hetxe2x80x94Xxe2x80x94Axe2x80x94N(R3)xe2x80x94 (here Ar is an unsubstituted or substituted aryl, Het is an unsubstituted or substituted monocyclic 5- or 6-membered monoaza, diaza or thiaza aryl which is bonded via a ring carbon atom, X is S, O or NH, A is alkylene and R3 is hydrogen or a lower alkyl) or N-phenylthiocarbamoyl, or
(b) R1 is hydrogen or hydroxy, and R2 is R4xe2x80x94Axe2x80x94 (here A is alkylene, R4 is hydrogen, Ar (Ar has the same meaning as above), an unsubstituted or substituted monoaza, diaza or thiaza aryl which is bonded via a ring carbon atom or ring nitrogen atom, a mono- or di-substituted amino (the substituent groups being alkyl, Ar-alkyl, Arxe2x80x94X-alkyl (X represents S or O) or Het-alkyl, and may be the same or different, but excluding the case of dialkyl; Ar and Het have the same meanings as above), or Ar-substituted alkyleneamino (Ar has the same meaning as above))],
or esters thereof, medicinally acceptable salts thereof, or hydrates of these.
The unsubstituted aryl represented by Ar is phenyl, while the substituted aryl is phenyl which is mono- or poly-substituted, for example di- or tri-substituted, with for example a lower alkyl (optionally substituted with an amino, lower alkylamino, di-lower alkylamino or tri-lower alkylsiloxy), lower alkenyl (optionally substituted with an amino, lower alkylamino, di-lower alkylamino or tri-lower alkylsiloxy), C3-8 cycloalkyl (optionally substituted with an amino, lower alkylamino, di-lower alkylamino or tri-lower alkylsiloxy), lower alkoxy (optionally substituted with an amino, lower alkylamino, di-lower alkylamino or tri-lower alkylsiloxy), lower alkylthio (optionally substituted with an amino, lower alkylamino, di-lower alkylamino or tri-lower alkylsiloxy), trifluoromethyl, halogen and/or phenyl (optionally substituted with a lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or halogen).
The monocyclic 5- or 6-membered monoaza aryl, diaza aryl or thiaza aryl is for example pyrrolyl, imidazolyl, including 1-, 2-, 4-or 5-imidazolyl, pyrazolyl, including 1- or 3-pyrazolyl, thiazolyl, including 2- or 4-thiazolyl, or pyridyl, including 2-, 3- or 4-pyridyl. Said groups can be substituted with one or more than one alkyl group. Preferred examples of substituted such groups include lower alkyl-substituted-1-imidazole and -5-imidazole, 5-lower alkyl-2-thiazolyl, for example 5-methyl-2-thiazolyl or 5-ethyl-2-thiazolyl, and lower alkyl-substituted 2- and 3-pyridyl.
The unsubstituted or substituted monocyclic 5- or 6-membered monoaza aryl, diaza aryl or thiaza aryl which is bonded via a ring carbon atom, and which is denoted by Het, is preferably a radical selected from the group comprising 2-, 4- and 5-imidazolyl, 3-pyrazolyl, 4-thiazolyl and 2-, 3- and 4-pyridyl, and it may be unsubstituted or lower alkyl-substituted.
The unsubstituted or substituted monocyclic 5- or 6-membered monoaza aryl, diaza aryl or thiaza aryl, which is bonded via a ring carbon atom or ring nitrogen atom, is preferably a radical selected from the group comprising pyrrolyl, imidazolyl, pyrazolyl, thiazolyl and pyridyl, and it may be unsubstituted or lower alkyl-substituted.
The unsubstituted or substituted bicyclic monoaza aryl, diaza aryl or thiaza aryl, which is bonded via a ring carbon atom or ring nitrogen atom, is for example an imidazo[1,2-a]pyridyl, preferably imidazo[1,2-a]pyridin-3-yl.
Alkyl is preferably a lower alkyl; the alkylene is preferably a lower alkylene; Ar-alkyl is for example a phenyl-lower alkyl, and substitution within the phenyl ring thereof is possible, as described above.
The amino which is mono- or di-substituted by means of alkyl, Ar-alkyl, Ar-O-alkyl, Ar-S-alkyl or Het-alkyl is preferably phenyl lower alkylamino, N,N-diphenyl lower alkylamino, N-phenoxy lower alkylamino, N-phenoxy lower alkyl-N-lower alkylamino, N-phenoxy lower alkyl-N-phenyl lower alkylamino, N,N-diphenoxy lower alkylamino, N-phenylthio lower alkylamino, N-phenylthio lower alkyl-N-lower alkylamino, N-phenylthio lower alkyl-N-phenyl lower alkylamino, N,N-diphenylthio lower alkylamino, N-pyridyl lower alkyl-N-lower alkylamino, N-pyridyl lower alkyl-N-phenyl lower alkylamino, N-phenoxy lower alkyl-N-pyridyl lower alkylamino, N-phenylthio lower alkyl-N-pyridyl lower alkylamino or N,N-dipyridyl lower alkylamino, and the phenyl or pyridyl moiety thereof may also be substituted as described above.
Ar-substituted alkyleneamino is preferably a substituted C4-6 cyclic amino, for example 1,4-butyleneamino (that is to say pyrrolidin-1-yl) or 1,5-pentyleneamino (that is to say piperidin-1-yl), or a lower alkyleneamino, which is substituted by means of a phenyl group (the phenyl group may also itself be substituted), for example 2-(4-chlorophenyl)-1,4-butyleneamino or 3-phenyl-1,5-pentyleneamino.
Halogen indicates, for example, fluoro, chloro or bromo, and preferably chloro, but it may also be iodo.
Where a group or compound is modified by means of the term  ower"", this indicates that it may contain up to seven carbon atoms.
Lower alkyl includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- and tert-butyl, and also the corresponding pentyl and hexyl groups. A C1 to C4 alkyl is preferred.
Lower alkenyl is, for example, vinyl, 1-propenyl, allyl, 1-butenyl, 2-butenyl, 3-butenyl or the like. A C2 to C4 alkenyl is preferred.
C3 to C8 cycloalkyls are, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, with cyclopentyl or cyclohexyl being preferred.
Lower alkoxy includes, for example, methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy, and also the corresponding pentoxy and hexoxy groups. A C1 to C4 alkoxy is preferred.
Lower alkylthio refers to, for example, methylthio, ethylthio, n-propylthio, isopropylthio and n-butylthio, with a C1 to C4 alkylthio being preferred.
Lower alkylene is a straight chain or branched C1 to C7 alkylene, such as for example methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, 2-methyl-1,3-propylene, 2,4-or 1,5-dimethyl-1,5-pentylene. The lower alkylene which is a substituent group in the case where R3 is a di-substituted amino will have at least two carbon atoms and preferably contain from 4 to 6 carbon atoms.
For the treatment of bone marrow abnormalities, the present invention relates in particular to the use of methanebisphosphonic acid derivatives where, in formula (I),
(a) R1 is hydrogen and R2is Arxe2x80x94Sxe2x80x94, Arxe2x80x94Oxe2x80x94, Arxe2x80x94NHxe2x80x94, Hetxe2x80x94NHxe2x80x94, Hetxe2x80x94Sxe2x80x94, Arxe2x80x94Sxe2x80x94Axe2x80x94, Arxe2x80x94Sxe2x80x94Axe2x80x94NHxe2x80x94 or Hetxe2x80x94Sxe2x80x94Axe2x80x94NHxe2x80x94 (here Ar is phenyl (which may also be substituted with a lower alkyl, lower alkylthio, trifluoromethyl or halogen), Het is thiazolyl (which may also be substituted with a lower alkyl) or pyridyl (which may also be substituted with a lower alkyl), and A is a lower alkylene) or N-phenylthiocarbamoyl, or
(b) R1 is hydrogen or hydroxy, and R2 is R4xe2x80x94Axe2x80x94 (here A is lower alkylene and R4 is hydrogen, unsubstituted or lower alkyl-substituted imidazolyl, pyridyl or imidazo[1,2-a]pyridyl bonded via a ring carbon atom or ring nitrogen atom, mono- or di-substituted amino (the substituent groups being lower alkyl, Ar-lower alkyl, Ar-O-lower alkyl, Ar-S-lower alkyl or pyridyl-lower alkyl, and may be the same or different, although the dialkyl case is excluded; Ar represents phenyl (which may be substituted with a lower alkyl, lower alkylthio, trifluoromethyl or halogen), or an Ar-substituted C4-6 alkyleneamino (Ar represents phenyl (which may be substituted with a lower alkyl, lower alkylthio, trifluoromethyl or halogen)),
and the esters thereof, medicinally acceptable salts thereof, and the hydrates of these.
For the treatment of bone marrow abnormalities, the present invention also relates in particular to the use of methanebisphosphonic acid derivatives where, in formula (I),
(a) R1 is hydrogen and R2 is unsubstituted or halogen-substituted phenylthio, lower alkyl-substituted phenylthio, lower alkylthio-substituted phenylthio, unsubstituted or halogen-substituted phenoxy, lower alkyl-substituted phenoxy, lower alkoxy-substituted phenoxy, lower alkylthio-substituted phenoxy, unsubstituted or halogen-substituted phenylamino, lower alkyl-substituted phenylamino, lower alkoxy-substituted phenylamino, lower alkylthio-substituted phenylamino, unsubstituted or lower alkyl substituted thiazolylamino, pyridylthio or N-phenylthiocarbamoyl, or
(b) R1 is hydrogen or hydroxy, and R2 is R4xe2x80x94Axe2x80x94 (here A is a C1-7 alkylene and R4 is an unsubstituted or lower alkyl-substituted imidazolyl, pyridyl or imidazo[1,2-a]pyridyl bonded via a ring carbon atom or ring nitrogen atom), or
(c) R1 is hydroxy, and R2 is R5xe2x80x94Axe2x80x94 (here A is a C1-7 alkylene and R5 is hydrogen, N-phenyl(C1-4 alkyl)xe2x80x94Nxe2x80x94(C1-4 alkyl)amino, N-phenoxy(C1-4 alkyl)xe2x80x94Nxe2x80x94(C1-4 alkyl)amino, N-phenylthio(C1-4 alkyl)xe2x80x94Nxe2x80x94(C1-4 alkyl)amino, N-pyridyl-(C1-4 alkyl)-Nxe2x80x94(C1-4 alkyl)amino or phenyl-substituted C4-6 cyclic amino (the phenyl group may also itself be substituted),
and the esters thereof, medicinally acceptable salts thereof, and the hydrates of these.
For the treatment of bone marrow abnormalities, the present invention preferably relates in particular to the use of methanebisphosphonic acid derivatives where, in formula (I),
(a) R1 is hydrogen, and R2 is an unsubstituted or chloro-substituted phenylthio, C1-4 alkyl-substituted phenylthio, C1-4 alkylthio-substituted phenylthio, unsubstituted or chloro-substituted phenoxy, C1-4 alkyl-substituted phenoxy, C1-4 alkoxy-substitutedphenoxy, C1-4 alkylthio-substituted phenoxy, unsubstituted or chloro-substituted phenylamino, C1-4 alkyl-substituted phenylamino, C1-4 alkoxy-substituted phenylamino, C1-4 alkylthio-substituted phenylamino, unsubstituted or C1-4 alkyl-substituted thiazolylamino, phenylthio or 2-pyridylthio-substituted C1-4 alkylamino, 2-, 3- or 4-pyridylthio, or N-phenylthiocarbamoyl, or
(b) R1 is hydrogen or hydroxy, and R2 is R4xe2x80x94Axe2x80x94 (here A is methylene, ethylene, propylene or pentylene, R4 is imidazol-1-yl, imidazol-4-yl, imidazol-5-yl, 1-methylimidazol-2-yl, 5-methylimidazol-2-yl, 4-methylimidazol-5-yl, 2- or 3-pyridyl, or imidazo[1,2-a]pyridyl-3-yl), or
(c) R1 is hydroxy, and R2 is R5xe2x80x94Axe2x80x94 (here A is methylene, ethylene, propylene or pentylene, R5 is hydrogen, N-methyl-N-(2-phenylethyl)amino, N-methyl-N-(3-phenylpropyl)amino, N-methyl-N-(5-phenylpentyl)amino, N-methyl-N-(2-phenoxyethyl)amino, N-methyl-N-(3-phenoxypropyl)amino, N-methyl-N-(2-phenylthioethyl)amino, N-methyl-N-(3-phenylthiopropyl)amino, N-methyl-N-[2-(3-pyridyl)ethyl)amino, N-methyl-N-[3-(2-pyridyl)propyl)amino, 4-phenylpiperidin-1-yl, 4-phenylpiperidin-2-yl, 3-(4-chlorophenyl)pyrrolidin-1-yl or 3-(4-chlorophenyl)pyrrolidin-2-yl),
and the esters thereof, medicinally acceptable salts thereof, and the hydrates of these.
Amongst the compounds of the present invention, particularly desirable for the treatment of bone marrow abnormalities are the methanebisphosphonic acid derivatives represented by general formula (Ia):
[where, in the formula, B represents xe2x80x94Xxe2x80x94(CH2)nxe2x80x94 (n is an integer in the range 0 to 6); X represents S, O or NH; Y represents a straight chain or branched chain lower alkyl comprising from 1 to 6 carbon atoms (which may also be substituted with an amino group, lower alkylamino group, di-lower alkylamino group or tri-lower alkylsiloxy group) or phenyl (which may also be substituted with a lower alkyl, lower alkoxy, lower alkylthio, trifluoromethyl or halogen), Z denotes a lower alkyl group, trifluoromethyl group, lower alkenyl group, lower alkoxy group, lower alkylthio group or C3-8 cycloalkyl group, and m represents an integer in the range 0 to 2], and preferred are methanebisphosphonic acid derivatives selected from 1-hydroxyethane-1,1-bisphosphonic acid, 3-[N-(3-phenylpropyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-[N-(5-phenylpentyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-[N-3-(2-pyridyl)propylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-[N-(3-phenoxypropyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-[N-(2-phenoxyethyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 4-(4-phenylpiperidin-1-yl)-1-hydroxybutane-1,1-bisphosphonic acid, 3-[3-(4-chlorophenyl)pyrrolidin-1-yl]-1-hydroxypropane-1,1-bisphosphonic acid, 2-(imidazol-1-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(imidazol-2-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(imidazol-4-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(imidazol-5-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 3-(imidazol-4-yl)-1-hydroxypropane-1,1-bisphosphonic acid, 2-(1-methylimidazol-2-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(4-methylimidazol-5-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(2-pyridyl)ethane-1,1-bisphosphonic acid, [(5-n-butyl-2-thiazolyl)amino]methane-1,1-bisphosphonic acid, [(5-methyl-2-thiazolyl)amino]methane-1,1-bisphosphonic acid, [(2-thiazolyl)amino]methane-1,1-bisphosphonic acid, (2-pyridylthio)methane-1,1-bisphosphonic acid, 3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-[N-(3-phenylthiopropyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-(pyrrolidin-1-yl)-1-hydroxypropane-1,1-bisphosphonic acid, 2-(piperidin-1-yl)-1-hydroxyethane-1,1-bisphosphonic acid, [N-(4-phenylthiobutyl)-amino]methane-1,1-bisphosphonic acid, [N-[4-(2-pyridylthio)butyl]amino]methane-1,1-bisphosphonic acid, (N-phenylaminothiocarbonyl)methane-1,1-bisphosphonic acid, 2-(imidazo[1,2-a]pyridin-3-yl)-1-hydroxyethane-1,1-bisphosphonic acid, phenoxymethane-1,1-bisphosphonic acid, thiomorpholinomethane-1,1-bisphosphonic acid, (4-chlorophenylthio)methane-1,1-bisphosphonic acid and (4-methylthiophenylthio)methane-1,1-bisphosphonic acid.
An especially preferred embodiment of the present invention is a compound selected from 1-hydroxyethane-1,1-bisphosphonic acid, 2-(imidazol-1-yl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(3-pyridyl)-1-hydroxyethane-1,1-bisphosphonic acid, 2-(2-pyridyl)ethane-1,1-bisphosphonic acid, (4-chlorophenylthio)methane-1,1-bisphosphonic acid, (4-methylthiophenylthio)methane-1,1-bisphosphonic acid, 3-[N-(2-phenylthioethyl)-N-methylamino]-1-hydroxypropane-1,1-bisphosphonic acid, 3-(pyrrolidin-1-yl)-1-hydroxypropane-1,1-bisphosphonic acid, (N-phenylaminothiocarbonyl)methane-1,1-bisphosphonic acid and 2-(imidazo[1,2-a]pyridin-3-yl)-1-hydroxyethane-1,1-bisphosphonic acid, the medicinally acceptable salts thereof and hydrates of these.
The medicinally acceptable salts of the compounds of formula (I) are the salts with bases, preferably the alkali metal salts such as the potassium and sodium salts, the alkaline earth metal salts such as the calcium and magnesium salts, or the ammonium salts with ammonia or with organic amines.
The aforesaid methanebisphosphonic acid derivatives are already known or can be manufactured by methods which are themselves known. Thus, for example, the compounds of formula (I) where R1 is hydrogen and R2 is Arxe2x80x94Sxe2x80x94 can be obtained by reacting a tetra lower alkyl methanebisphosphonate with a disulphide of formula Arxe2x80x94Sxe2x80x94Sxe2x80x94Ar in the presence of a strong base, for example NaH, and then subjecting the tetra lower alkyl ester obtained to hydrolysis.
The compounds corresponding to formula (I) in which R1 is hydrogen and R2 is Hetxe2x80x94NHxe2x80x94 can be obtained, for example, by reacting a mixture of H3PO3 and PHal3 (here Hal is a halogen, preferably chloro) with a formyl amide of formula Hetxe2x80x94NHxe2x80x94CHO, or by heating the amine Hetxe2x80x94NH2 along with a lower alkyl orthoformate and di-lower alkyl phosphite, and then subjecting the reaction product to, for example, acid hydrolysis.
The compounds of formula (I) in which R1 is a hydroxyl group and R2 is amino-Axe2x80x94 are disclosed in DE-OS-2405254. The production of compounds of formula (I) where R1 is hydrogen and R2 is Arxe2x80x94Sxe2x80x94Axe2x80x94N(R3)xe2x80x94 or Hetxe2x80x94Sxe2x80x94Axe2x80x94N(R3)xe2x80x94 is disclosed in, for example, EP-A-464509.
Where the methanebisphosphonic acid derivatives relating to the present invention are to be used in the treatment of bone marrow abnormalities, they may be offered for use as they are or in the form of medicinal compositions mixed with known pharmaceutically acceptable carriers, excipients and the like.
Administration may be by oral administration in the form of tablets, capsules, powders, granules, pills or the like, or by parenteral administration in the form of an injection, syrup, ointment, suppository or the like. The dose will differ according to the patient, administration route and symptoms, etc, but will lie in the range about 0.1 mg to 5 g and preferably about 1 mg to 2 g, with this amount being administered orally or perenterally once per day or divided-up for administration a number of times per day.

Abstract: The present invention relates to drug for treating abnormalities in bone marrow which has, as an effective component, a methanebisphosphonic acid derivative, ester thereof, medicinally acceptable salt thereof, or a hydrate of these.

Abstract: The methanebisphosphonic acid derivatives of the present invention show an outstanding bone marrow abnormality therapeutic effect, so efficacy can be expected in the prevention and treatment of rheumatoid arthritis, multiple myeloma, osteomyelitis and other bone marrow abnormalities. Furthermore, application can also be expected in the prevention and treatment of hypoplastic anaemia, myelocytic leukaemia and other such haematopoietic disorders.


A mechanism for supplying power assistance to the steering column of a vehicle is arranged to operate in response to signals indicating that power assistance is required, and therefore has periods in which it is inoperative and periods in which it is operative, all while the vehicle is in motion. The mechanism comprises a motor driving a speed reducing mechanism which is coupled to the steering column. The mechanism includes an epicyclic gear train, the planet wheel carrier of which is fitted around the steering column, the epicyclic gear train being driven by the power assistance motor. The outer crown of the epicyclic gear train is mounted so as to be free to rotate about the steering column, but when power assistance is required the outer crown is prevented from rotating by means of a releasable blocking or braking means actuated by an electro-magnet, thus causing the planet wheel carrier to rotate the steering column.

In the prior art, it has in the past been proposed to provide various kinds of power assistance means for assisting the rotation of the steering column in a steerable vehicle. In general, such a mechanism includes a motorised speed reducing means comprising essentially an electric motor and a speed reducing means or gearbox. The output shaft of the motor is coupled through an output pinion, or any other suitable means of transmission, in such a way that it is coupled mechanically with the steering column or with a pinion or gear wheel mounted on the latter. Because of this, detection of the forces exerted by the driver on the steering wheel, for example by means of a sensor for detecting angle of rotation or a sensor which detects the torque exerted on the steering wheel, enables a command to be produced for appropriate proportional action of the motorised speed reducing means, so as to apply the required additional power to assist operation of the steering column.
Pneumatic or hydraulic power assistance systems for steering have also been proposed, although the preferred embodiment of the present invention uses an electric motor as the source of mechanical energy to be used for assisting the steering. In a first type of power assisted steering system, the motorised speed reducing means or source of mechanical assistance energy is compelled to follow complex instructions such that it can provide power assistance under widely differing driving conditions. Such systems are expensive and complicated, and their reliability is affected accordingly.
Therefore, it has also been proposed to arrange the power assisted steering system such that it is only activated temporarily, i.e. during those periods when assistance is actually required, for example when it is called for by particular driving conditions or when the driver is exerting too much effort on the steering wheel. Such a system can therefore be said to be acting intermittently. Power assistance is especially valuable during parking, while the vehicle is moving slowly and the driver has a frequent need to exert relatively high forces on the steering wheel. However the same is also true for steering at low speed in general.
In this type of power assisted steering system, when the speed of the vehicle exceeds a certain limited value the power assistance is no longer operative, and the driver feels a resistive torque on the steering column. This resistive torque is caused partly by the forces exerted by the road on the road wheels, and partly by the inertia of the motorised speed reducing means, that is to say mainly the inertia of the rotatable parts of the latter. This feature of systems in the prior art is of special disadvantage in that the multiplication ratio of the speed reducer causes the inertia of the rotor of the electric motor to play a dominant part in the generation of the resistive forces. This somewhat negates the additional convenience afforded by this kind of temporary power assistance mechanism, even though it does have the advantage of being cheaper than a conventional "all speeds" power assistance system.

Discontinuous power assistance mechanism for a steering column of a vehicle having steerable wheels


In a cutting tool for chip removing machining a holder for a cutter has a body received therein and movable with surfaces to bear against the cutter for defining the position of the cutter in the direction of an intended axis of rotation of the holder as well as a screw which may be screwed in a threaded bore in the holder. Spring members are arranged to act between the holder and the body for biasing the body against said screw portions.

The present invention relates to a cutting tool for chip removing machining, preferable milling, comprising at least one cutter, a holder holding the cutter, means for securing the cutter to the holder with a cutting edge of the cutter in a selectable cutting functional position in the direction of an intended axis of rotation of the holder as well as an arrangement for determining the position of the cutter with respect to the holder in the direction of said axis of rotation for enabling securing of the cutter through said means with the cutting edge in said selectable position, said arrangement comprising a body movably received in the holder and movable with surfaces to bear against the cutter for defining the position of the cutter in the direction of said axis of rotation as well as a screw which may be screwed in a threaded bore in the holder transversally to said axis of rotation and which has portions adapted to act upon said body in the direction of said axis of rotation upon screwing in said threaded bore, as well as an arrangement for determining the position of a cutter with respect to a holder in a cutting tool according to the preamble of the appended independent arrangement claim and a method for securing a cutter to a holder in a cutting tool according to the preamble of the appended method claim.
The invention relates to cutting tools for chip removing machining in general, such as for example turning or milling, but it is particularly interesting for machining in the form of milling, especially face milling, which is the reason for describing exactly this application hereinafter for illuminating, but accordingly not restricting the invention. In a cutting tool of the type defined in the introduction in the form of a face milling cutter one or more cutters may be arranged adjacent to a said arrangement for adjusting the position of a cutting edge on exactly these cutters. It is usually a question of cutters which have to project with the cutting edge thereof in the direction of said axis of rotation, i.e. in the cutting depth direction of the face milling cutter, longer than the corresponding cutting edge of the rest of the cutters of the cutting tool. It is important to be able to set or adjust the selectable cutting functional position of said cutting edge with a high accuracy so as to obtain an even surface in the face milling operation.
U.S. Pat. No. 5,391,023 describes a cutting tool of the type defined in the introduction. Said screw is in this cutting tool screwed into the holder thereof and displaces than a body, which in its turn displaces a cutter so that a cutting edge of the cutter arrives to a desired position. When the screw has been screwed in so far that the desired position of the cutting edge has been reached the screw has to be locked through a locking unit. When the locking of the screw and by that the body is carried out by means of the locking unit the setting of the cutter is influenced, so that there is a risk that it will differ from the desired position. Another drawback of this cutting tool and the arrangement thereof for determining the position of the cutter consists in that there is a play between said body and a bore in the holder receiving the body, which means that this play will during later machining be absorbed and change the position of the cutting edge.
It is desirable to provide a cutting tool of the type defined in the introduction for which said selectable position of the cutting edge of said cutter may be obtained with a higher accuracy than for such cutting tools already known.
According to an aspect of the present invention, a cutting tool is arranged with spring members adapted to act between the holder and said body for biasing the body against said portions of the screw.
This means that no locking unit is required, since the body of said arrangement will always be kept biased, i.e. under pretension, against said portions of the screw. Thus, the position of said body and by that the cutter will not be influenced by carrying out any locking of the body as for cutting tools of this type already known.
According to an embodiment of the invention said spring members are adapted to press said body oppositely to the screwing home direction of said screw in said threaded bore against said portions of the screw. This constitutes an advantageous and simple way of obtaining biasing of the body against screw portions for defining an exact position of the body and by that the cutter before this is secured with respect to the holder by said means.
According to another embodiment of the invention the cutter is so arranged in the holder with respect to said screw that the screw is adapted to influence the body to be displaced with said surfaces in the direction against said cutting edge upon screwing the screw in the unscrewing direction in said threaded bore so as to reach a position defining said selectable position of the cutting edge. It is totally contrary to cutting tools of this type already known to unscrew a screw in an arrangement of this type until the correct position has been reached of said body and by that the cutter influenced thereby, wherein in the cutting tools already known a screw is screwed in the screwing home direction for displacing a said body and by that the cutter to the desired position. This in combination with said biasing makes it very comfortable to carry out the adjustment of the cutter before it is secured to the holder.
According to another embodiment of the invention the holder is designed to hold the cutter with a surface directed towards said body and inclined with respect to a centre axis of said threaded bore for translating an axial movement of the screw when screwing into a movement of the body so that this comes closer to the cutter or displaces this in said intended rotation axis direction.
According to another embodiment of the invention said portion of the screw comprises a part of the lower side of a head of the screw, and the head of the screw may according to another embodiment of the invention be substantially conical, and said body has then a substantially conical part designed to provide said surface for bearing against said screw portions. A well defined very exact position of the body at a determined screwing depth of the screw is obtained by this conical shape in combination with said biasing.
According to another embodiment of the invention said body is sleeve-like with a through hole designed to receive the screw, and said screw portion is adapted to bear against said surfaces in the form of inner surfaces of the sleeve-like body. The holder has then advantageously a cavity, in the bottom of which said threaded bore is arranged, and this sleeve-like body is received in the cavity while being displaceable in the direction of said threaded bore.
According to another embodiment of the invention said spring members are formed by a compression spring, for example in the form of one or more cup springs, arranged to act between the bottom of said cavity and surfaces of the lower side of the sleeve-like body directed towards the cavity. Said biasing may by this be obtained through very simple means and with a higher accuracy.
According to another embodiment of the invention the location of the threaded bore in the cavity and the design of the sleeve-like body are so adapted to each other that the sleeve-like body is pressed tightly against a lateral wall of said cavity upon biasing action of said screw portions upon the body. Any play between said body and the bore in the holder and by that the holder is by this eliminated, so that at the same time the drawbacks mentioned above of such a play are eliminated and said selectable position of the cutting edge may be obtained with a very high accuracy.
More exactly, this may according to another embodiment of the invention be realized by the fact that the centre axis of said threaded bore is laterally displaced with respect to the centre axis of said cavity for pressing the sleeve-like body tightly against a lateral wall of said cavity on biasing action of said screw portions upon the body. Thus, a certain eccentricity is present between the cavity and the threaded bore for reliably eliminating said play.
According to another embodiment of the invention the cutting tool comprises a plurality of cutters distributed on the holder around said intended axis of rotation, and only some of said cutters of the cutting tool are arranged adjacent to a said arrangement for position determination. It is then preferred that the cutting tool is a face milling cutter. It is also within the scope of the invention to have a said arrangement adjacent to all cutters.
The invention also relates to an arrangement according to an aspect of the invention provided with spring members adapted to act between the holder and said body for biasing the body against said portions of the screw. The advantages of such an arrangement as well as an arrangement according to different embodiments of the invention as clearly as desired from the description above of the cutting tool according to the invention.
The invention also relates to a method for securing a cutter to a holder of a cutting tool of the type defined in the introduction, for a cutting tool which further has spring members adapted to act between the holder and said body for biasing the body against said portions of the screw, the screw is firstly screwed in the screwing home direction in the threaded bore, the screw is then screwed in the unscrewing direction in the threaded bore until the body influences said cutter in the direction of said intended axis of rotation to reach said selectable position, and then the cutter is then secured in this position. This constitutes a simple and comfortable way to obtain a precise securing of the cutter in a selectable position with respect to the holder of the cutting tool.
Further advantages as well as advantageous features of the invention appear from the description following.

Cutting tool, an arrangement and a method for chip removing machining with spring members for biasing a clamping body


An apparatus including a ring oscillator and related methods are disclosed. The ring oscillator includes at least two ring loops. A first ring loop includes a plurality of series coupled delay cells. At least one additional ring loop includes a plurality of series coupled delay cells. The at least one additional ring loop is coupled to the first ring loop by one or more common delay cells shared between the first ring loop and the at least one additional ring loops.

Voltage controlled oscillators (VCOs) are used in phase locked loops (PLLs) to generate digital or analog clock signals for microprocessors, wireless communications systems, etc.
One type of VCO commonly used is an LC-tank based VCO. LC-tank VCOs generate clock signals with a high quality factor (Q-factor, or simply 'Q'), but have several undesirable design constraints and are relatively expensive to implement in integrated circuits (ICs). Furthermore, LC-tank VCOs have a relatively narrow frequency tuning-range, which leads to a low process variation tolerance during manufacturing and negatively impacts product yield.
Another type of VCO commonly used is a ring based oscillator. A ring oscillator is a device composed of an odd number of inverting delay cells (e.g., inverters, NAND gates, etc.) whose output signal oscillates between two voltage levels. The delay cells are coupled to each other in series where the output of the last delay cell is fed back into the input of the first delay cell to form a chain.
FIG. 1 illustrates an example of a conventional ring oscillator. As shown, a conventional ring oscillator 100 can be formed of a plurality of inverters coupled together in series. Because a single inverter computes the logical NOT of its input, the last output of an odd numbered chain of inverters is the logical NOT of the first input. This final output is asserted a finite amount of time after the first input is asserted, and thus, the feedback of this last output to the first input causes oscillation.
Ring oscillators are capable of generating a wider frequency tuning-range than are LC-tank VCOs, which can help overcome process variations experienced during manufacturing, and therefore improve product yield. However, conventional ring oscillators suffer from relatively poor signal quality (as measured by, e.g., phase noise or jitter) due to a lower Q-factor as compared to LC-tank VCOs. This can be a significant drawback of ring oscillators for certain applications.

Ring oscillator using analog parallelism


Industrial waste-water, particularly cooling water containing water conditioning chemical additives, which heretofore has been discharged to the environment as blowdown because of high silica content, may now be treated for selective silica removal to condition it for reuse in industrial systems. It has been discovered that silica may be effectively and selectively removed from such waste-water streams without the consequential removal of its beneficial chemical conditioning additives by passing such water over activated alumina and thereafter returning it to the system from which it was withdrawn thereby maintaining the silica concentration in the system below its scale formation level.

The largest source of industrial waste-water which is discharged to the environment is blowdown from cooling systems. Over 30 billion gallons per day are discharged in the United States from industrial facilities, and this figure does not include utilities which are the largest users of cooling water. Blowdown can contain heat, toxic chemicals--in the form of water conditioning agents, such as, corrosion and scale inhibitors, and disperants--and also have a high degree of dissolved solids. Thus, blowdown which is discharged to the environment constitutes a major source of pollution.
By reason of the high concentration of dissolved solids in raw cooling water, including hardness such as calcium and magnesium compounds, which makes it scaling and corrosive to metallic parts of cooling systems such as heat exchangers, it is customary to add corrosion inhibitors such as soluble alkali metal chromates to the cooling water as well as softening agents and scale inhibitors such as phosphonates, polymaleic anhydrides or polyacrylates. Dissolved silica is a major scale forming material found in cooling water. It is the most ubiquitous material in cooling water and no known inhibitor, chelant or dispersant exists which will significantly control its tendency to form scale when its concentration in a cooling water system exceeds its solubility limit of roughly about 150 to about 200 milligrams per liter. Above such limits it polymerizes to form scale on heat exchange surfaces. It may also react with multivalent cations, such as magnesium and calcium, to form scale.
Heretofore, the only practical method employed to control the silica concentration in cooling water systems has been to discharge a blowdown stream from such systems to the environment when, due to water evaporation from the system, the silica concentration begins to approach its limits of solubility. Thereafter, fresh water makeup of low silica concentration is added to the system to compensate for the water deficiency created by the blowdown and evaporation from the system, and the total silica concentration of the system is reduced to a safe level.
The blowdown method of silica control is undesirable in at least two important respects. First, the fresh water makeup to replace the blowdown water losses must be treated with chemical additives for water softening, and corrosion and scale inhibition to condition it for use in a cooling water system--at a cost which, on an industry wide level, has been estimated at about five billion dollars a year. The value of such treating chemicals which are lost from the system in blowdown have been estimated at a billion dollars per year. This represents an expense which could be avoided if blowdown could be conditioned for reuse without removal of such chemical additives. Secondly, and more importantly, the blowdown must eventually be released to the environment and by reason of the chemical conditioning agents it contains thus constitutes it as major source of pollution. In many instances where local regulations exist on chromate discharges to natural streams and sewer systems and the like, it is necessary to treat the chromate containing blowdown by costly ion exchange or chromate distruction processes to reduce its chromate content to acceptable levels prior to discharge. Even then, the non-chromate chemical additives and highly dissolved solids such as alkali metal chlorides, carbonates and sulfates are discharged to the environment as pollutants. Aside from the natural desire which has always existed to eliminate pollution sources such as blowdown there is also an increasing concern evidenced by recent environmental legislation to strictly regulate discharges from cooling water systems with the ultimate goal to totally eliminate the discharge of pollutants contained therein.
Previous efforts to remove silica from the blowdown streams of cooling water systems such as by softening, reverse osmosis, demineralization and/or evaporation processes are non-selective in that not only silica but the other beneficial water conditioning chemicals are eliminated from the treated water as well. Ion exchange methods have also been attempted for silica removal, but have proved generally unacceptable because the high sulfate content of cooling water excludes absorption of silica by conventional ion-exchange resins. Ion exchange resins can only be employed for silica removal from cooling water if such water is first demineralized to remove the interfering sulfates. The above mentioned methods have not proved entirely satisfactory and hence have been used only to a limited extent.
Most attention to silica removal from water to prevent scaling has been directed to the treatment of raw water--to prepare it as boiler feed water for steam power production--wherein such raw water has not been previously conditioned by the addition of chemical additives such as chromates, phosphonates and/or sulfates. In such case wherein the removal of silica is the only concern the prior art evidences that a number of researchers in the late 30's and 40's tested a variety of compounds for removal of soluble silica. The compounds tested include ferric sulfate, magnesium sulfate, magnesium oxide, aluminum hydroxide, sodium aluminate and activated alumina.
Thus, although a number of methods exist for silica removal generally such methods are not suitable for application to the treatment of chemically conditioned water such as is normally found in typical cooling water systems.
Activated alumina is known to have silica removing properties. Behrman and Gustafson "Removal of Silica from Water", Industrial Engineering Chemistry, 1940, pp. 468-72, describe a series of experiments on silica removal from raw water utilizing granular activated alumina and found reduction of silica in water from 50 milligrams per liter to 5 milligrams per liter. Additionally, they found that activated alumina could be regenerated for reuse by washing it with a solution of strong acid followed by a solution of strong alkali.
Although activated alumina has long been known as an absorbent for silica in the treatment of raw water such as boiler feed water and the like, to my knowledge heretofore there has been no attempt to apply it to the removal of silica from a water stream containing sulfates and the various dispersants, corrosion and scale inhibitors, and water softeners normally found in typical cooling water systems--particularly chromates and phosphonates.
Activated alumina is known as an absorbent for organic and inorganic compounds in their nonionic, cationic and anionic forms. Activated alumina has sites available for both cation and anion absorption and both cation and anion exchange can occur simultaneously on the alumina surface, although one or the other usually predominates. Activated alumina's characteristic as being an ion absorbent would make it appear to be unsuitable for use in the treatment of cooling water blowdown for silica removal since one would expect the alumina to remove beneficial water treatment additives contained therein and/or that such additives would so saturate the active absorption sites on the alumina surface so as to render it incapable of removing silica.

Industrial waste-water reuse by selective silica removal over activated alumina


A novel parafocusing X-ray diffractometer operates by irradiating a thin ring of fine crystals with a point source of monochromatic X-rays and passing the cone of diffracted X-rays at each focal point through a pinhole to an X-ray sensor, thereby obtaining optimum values for both line intensity and resolution of lines.

This invention relates to a novel instrument and to a new and advantageous method afforded by that instrument for obtaining the X-ray diffraction data of a polycrystalline powder.
Conventional powder diffractometers or powder cameras register diffraction lines that represent a portion of the cone of diffracted rays emanating from a powder sample irradiated with a beam of monochromated X-rays. In the Debye-Scherrer-Hull technique, a pencil beam of monochromatic X-rays impinges upon a thin cylindrical specimen consisting of a very large number of tiny crystals of 0.001 cm or less diameter. The monochromatic radiation is usually the K.alpha..sub.1 .alpha..sub.2 doublet obtained by the use of an appropriate filter or a crystal monochromator. The geometrical factors determining the resolution of the lines in a Debye-Scherrer-Hull diffraction pattern are: R, the radius of the camera; r, the radius of the cylindrical sample; h, the length of the sample; .delta., the divergence of the impinging X-ray beam; and .sigma., the difference between the wavelengths of K.alpha..sub.1 and K.alpha..sub.2. For a fixed camera radius, the optimum resolution corresponds to the limit as r, h, .delta., and .sigma. all approach zero. However, under these conditions the exposure times become inordinately long.
For this reason, parafocusing cameras or diffractometers have gained preference. In the Bragg-Brentano configuration, a rectangular flat-faced briquet of powdered sample is irradiated by a divergent beam of monochromatic X-rays and a small portion of the total diffracted radiation is selected by an appropriately placed narrow receiving slit which lets the focused radiation enter a suitable X-ray detector such as a Geiger-Muller counter. During the exposure, the X-ray detector assembly is turned at twice the angular velocity of the turning sample holder in order to maintain parafocusing conditions. For precision measurements of interplanar spacings, the rectangular sample surface must be exactly tangent to the focusing circle at the center of the goniometer circle and must also be sufficiently short to be a good approximation to the parafocusing circle. Moreover, the sample should be very thin, approximately 0.05 mm thick for a sample having a linear absorption coefficient less than 50 cm.sup.-1. A highly objectionable feature of this flat surface specimen technique is the great tendency to preferred orientation of the crystallites and the resulting distorted relative intensities of the powder reflections.
Three principal disadvantages of conventional X-ray cameras or diffractometers are: (1) only a small fraction of the total diffraction cone for a particular set of interplanar spacings is measured; (2) the accuracy of the interplanar spacing measurements is markedly dependent on the Bragg angle of direction, i.e., .sup..DELTA.d /d=-cot.theta..DELTA..theta. where d is the interplanar spacing in Angstrom units and .theta. is the Bragg angle, and (3) the difficulty of achieving random orientation of the powder particles. Additionally, maximum line intensity and optimum resolution of lines in the diffraction pattern cannot both be achieved by known diffractometers. A major object of this invention is to provide a parafocusing powder diffractometer that avoids these disadvantages. Other objects and advantages of the present invention will be apparent from its description which follows.


Semiconductor devices are provided. A semiconductor device includes a peripheral circuit region and a first memory region that are side by side on a substrate. Moreover, the semiconductor device includes a second memory region that is on the peripheral circuit region and the first memory region. Related methods of programming semiconductor devices are also provided.

The present disclosure relates to semiconductor devices and methods of programming the same. A three-dimensional integrated circuit (3D-IC) memory technique has been developed to increase a memory capacity of a semiconductor memory device. The 3D-IC memory technique includes a variety of methods for arranging memory cells three-dimensionally. In addition to the 3D-IC memory technique, a patterning technique for fine patterns and a multi-level cell (MLC) technique may be used to increase the memory capacity of the semiconductor memory device. However, the patterning technique for the fine patterns may be relatively expensive, and the MLC technique may not be suitable to increase the number of bits per a unit cell. Thus, the 3D-IC memory technique may help to increase the memory capacity. In addition, if the patterning technique for the fine patterns and the MLC technique are combined with the 3D-IC memory technique, then the memory capacity may be further increased. Also, the patterning technique for the fine patterns and the MLC technique may be developed independently of the 3D-IC memory technique.

Semiconductor devices including a peripheral circuit region and first and second memory regions, and related programming methods


A pharmaceutical composition for treating an inflammatory condition contains a non-steroidal anti-inflammatory drug (NSAID) and a physiologically acceptable aromatic hydroxysulphonic acid. The two components may be for simultaneous, separate or sequential use. Administration of the two components, for example of aspirin with ethamsylate, reduces the damage which the NSAID does to the gastrointestinal tract while having no deleterious effect on the anti-inflammatory activity.

The present invention relates to pharmaceutical compositions containing aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).
The non-steroidal anti-inflammatory drugs are a group of compounds which inhibit the biosynthesis of prostaglandins. The group embraces a wide range of chemical structures, but can be subdivided into several general structural types. These types are described in Chapter 5 of "The Clinical Pharmacology of Anti Inflammatory Compounds" by Brooks et al. One general type is based on a carboxylic acid structure while a second is based on enolic acid. Within the first general type are the aspirin-like NSAIDs, which have a structure based on salicylic acid and which include aspirin as well as diflunisal. Also within this general type are those compounds which are structurally related to propionic acid, such as naproxen and ibuprofen, and those related to acetic acid such as diclofenac and indomethacin. The second general type includes pyrazolones such as oxyphenbutazone and oxicams such as piroxicam.
NSAIDs have been extensively used in recent years for the treatment of chronic rheumatic or arthritic conditions and for the management of pain. The compounds are believed to bring relief by inhibiting prostaglandin synthetase at affected joints or in other body tissues. However, the compounds have recently been linked to increased occurrence of gastrointestinal blood loss resulting in anaemia and leading to peptic and duodenal ulcers in patients who use the drugs particularly over long time periods. These adverse reactions have been widely described, both in the press and in the scientific literature. For example, A. and E. Keat in an article in the June 1985 issue of "Update" described the adverse gastrointestinal tract reactions to antirheumatic drugs and in particular they mention that aspirin is known to be responsible for mucosal erosions, blood losses of around 5 ml per day, and for duodenal ulcers. B. J. R. Whittle and J. R. Vane in a paper, Arch. Toxicol, Suppl., 7, 315-322 (1984) considered the biochemical basis for the gastrointestinal toxicity of non-steroid antirheumatoid drugs and the effects of NSAIDs in inducing gastric damage.
In the shorter term, bleeding from the gastrointestinal tract is produced and gradual erosion of the gastric mucosa can lead to subsequent ulceration. These adverse effects on the gastrointestinal tract are believed to have two principal causes. Firstly many of the NSAIDs are chemical irritants which may annoy the gastric mucosa. Secondly, the NSAIDs inhibit prostaglandin synthesis not only in the joints but also, non-specifically, in the gut. Since some prostaglandins have a protective role in the gut, their absence makes the mucosa even more susceptible to damage by irritation.
In an attempt to overcome these drawbacks recent work has aimed at producing NSAIDs which have prostaglandin-like properties. These however have their own associated disadvantages in having secondary effects on smooth muscle activity.
The present inventors have discovered that by treatment with aspirin and an aromatic hydroxysulphonic acid in combination. gastrointestinal bleeding due to the aspirin can be significantly reduced, apparently without the introduction of further side effects.
Such aromatic hydroxysulphonic acids include ethamsylate (also known as cyclonamine). I, dobesilate calcium, II, and 263-E, III, which is the diethylamine salt of persilic acid. The formulae of these three compounds are shown below. ##STR1##
Ethamsylate is a known treatment for a variety of conditions where bleeding occurs from small blood vessels. For example, it has been used to control menorrhagia and bleeding during gynaecological surgery, to control haemorrhage during or after general surgery, to stop nose bleeds and control surgical haemorrhage in ear, nose and throat surgery and to limit or prevent periventricular haemorrhage in low birth weight babies. There have also been suggestions, based on qualitative observations, that ethamsylate may be a useful treatment for bleeding gastric ulcers. No use of ethamsylate in connection with iatrogenically induced bleeding has been mentioned.
The mode of action of ethamsylate is not well understood. Ethamsylate has been suggested to inhibit the operation of some prostaglandins. Work by the present inventors and others suggests that ethamsylate possibly has a selective inhibitory effect on prostaglandins PGF.sub.2 alpha and PGI.sub.2 (R. A. Hutton et al., Thrombosis and Haematosis 56, 6-8 (1986). The related compound 236-E is thought to be a prostaglandin synthetase promoter. Prostaglandins vary in their effects in the body, and a chemical which affects some prostaglandins in a particular manner may have a different or opposite effect on other prostaglandins.
The related compound, dobesilate calcium, is known to affect platelet aggregation and has been shown to inhibit artificially induced thrombus formation in hamster cheek pouches when administered by intraperitoneal injection (M. Michal et al, Thrombosis Research 40, 215-226 (1985). When the dobe-silate calcium was administered by injection in combination with aspirin a synergistic inhibition of thrombus formation was observed.

Pharmaceutical compositions containing non-steroidal anti-inflammatory drugs


Maintenance carriers can include one or more tools to perform a maintenance operation. These carriers may include removable cartridges that include the tool or consumables, such as a cleaning fluid, compressed gas, or disposable items. Maintenance carriers can also be configured to move along with other carrier traffic in the automation system and may be selectively deployed.

In-vitro diagnostics (IVD) allows labs to assist in the diagnosis of disease based on assays performed on patient fluid samples. IVD includes various types of analytical tests and assays related to patient diagnosis and therapy that can be performed by analysis of a liquid sample taken from a patient's bodily fluids, or abscesses. These assays are typically conducted with automated clinical chemistry analyzers (analyzers) onto which fluid containers, such as tubes or vials containing patient samples have been loaded. The analyzer extracts a liquid sample from the vial and combines the sample with various reagents in special reaction cuvettes or tubes (referred to generally as reaction vessels). In some conventional systems, a modular approach is used for analyzers. A lab automation system can shuttle samples between one sample processing (module) and another module. Modules may include one or more stations, including sample handling stations and testing stations (e.g., a unit that can specialize in certain types of assays or can otherwise provide testing services to the larger analyzer), which may include immunoassay (IA) and clinical chemistry stations. Some traditional IVD automation track systems comprise systems that are designed to transport samples from one fully independent module to another standalone module. This allows different types of tests to be specialized in two different stations or allows two redundant stations to be linked to increase the volume of sample throughput available. These lab automation systems, however, are often bottlenecks in multi-station analyzers. Relatively speaking, traditional lab automation systems lack large degrees of intelligence or autonomy to allow samples to independently move between stations.
In an exemplary prior art system, a friction track, much like a conveyor belt, shuttles individual carrier mechanisms, sometimes called pucks, or racks of containers between different stations. Samples may be stored in sample containers, such as test tubes that are placed into a puck by an operator or robot arm for transport between stations in an analyzer along the track. Automation systems are inherently complex mechanical systems, often having moving parts and surfaces that interact with carriers. The automation system may also include instruments, such as pipettes or robot arms that interact with samples or sample carriers. Due to the complex nature of these systems, failures of systems can occur that affect the reliability of the automation system. Failures may result in down time of the analyzer or analyzer stations that prevent further sample analysis until a repair technician can fix the problem. Many failures are preventable with proper maintenance. However, prior art systems either forego most maintenance operations or make maintenance a difficult manual task. Accordingly, many prior are systems suffer downtime from preventable failures that may have been mitigated had maintenance been a more viable option for operators.


A method is disclosed with provides stable growth of SiC single crystals, particularly 4H—SiC single crystals, with an effective crystal growth rate for a prolonged time even at a low temperature range of 2000° C. or lower. A raw material containing Si, Ti and Ni is charged into a crucible made of graphite and heat-melted to obtain a solvent. At the same time, C is dissolved out from the crucible into the solvent to obtain a melt. A SiC seed crystal substrate is then brought into contact with the melt such that SiC is supersaturated in the melt in the vicinity of the surface of the SiC seed crystal substrate, thereby allowing growth and production of an SiC single crystal on the SiC seed crystal substrate.

A. Field of the Invention
The present invention relates to SiC single crystals and production method thereof and more specifically, relates to SiC single crystals for preparing power device substrates by solution growth and to production method thereof.
B. Description of the Related Art
SiC has attracted attention as a material for power devices which have performance limits beyond that of Si power devices because SiC has a bandgap that is about three times higher than Si, a dielectric breakdown voltage that is about seven times higher than Si, and thermal conductivity that is about three times higher than Si. SiC is an ionic covalent crystal and crystallographically includes polytypes with single composition and various stacked structures relative to the c-axis direction. There are polytypes such as 4H (hexagonal crystal system having four molecules in one cycle), 6H (hexagonal crystal system having six molecules in one cycle), 3C (cubic system having three molecules in one cycle), and 15R (rhombohedron system having 15 molecules on in one cycle).
Different polytypes of SiC have different appearance ratio and different thermal physical properties such as thermal stability, bandgap, mobility and impurity level. Uniform single crystal substrates in which only one polytype exists are required in order to apply SiC for optical and electronic devices. In particular, 4H—SiC having a large bandgap is required for power devices.
Growth methods of SiC single crystals have been known such as sublimation, CVD and solution growth methods. The most frequently used method for production of SiC single crystals is sublimation because the liquid phase does not exist at ordinary pressure. In sublimation, highly pure SiC powder is heated at 2200° C. to 2500° C. and the sublimed raw material is fed to the surface of a seed crystal which has been brought to a temperature lower than the powder, thereby allowing re-crystallization. Because various chemical species composed of Si and C are mixed in the sublimed gas and complex reactions occur, polymorphic transition easily occurs and lattice defects such as dislocation are produced. As dislocation causes leaks when PN diodes are produced, it is desired to reduce dislocation density (EPD).
In the CVD method, a single crystal seed crystal substrate is simultaneously fed with diluted carbohydrate gas and silane gas and SiC single crystals are grown epitaxially at the substrate surface by chemical reaction. In CVD method, balanced etching and deposition promote growth. Therefore, the growth rate is slow and it is not suitable for the production of bulk single crystals, and this method is mainly used as an epitaxial growth method of drift layers.
In solution growth, a melt containing Si and C is brought into contact with seed crystals having a lower temperature than that of the melt so as to allow supersaturation of SiC in the melt, thereby allowing growth of SiC single crystals on the surface of seed crystals. In the solution growth method, single crystals having high quality can be obtained because they have less lattice defects and less crystal polymorphism compared to other growth methods. However, at a practical temperature of 2000° C. or lower, solubility of C in a Si melt is extremely low, causing a lower growth rate.
Japanese Patent Application Laid-open No. 2004-002173 discloses a solution growth method in which a single crystal is grown on a seed crystal substrate from a melt of an alloy comprising Si, C and M (wherein M is either Mn or Ti), wherein an atomic ratio between Si and M is Si1-xMx wherein 0.1≦x≦0.7 when M is Mn and 0.1≦x≦0.25 when M is Ti.
Japanese Patent Application Laid-open No. 2007-261843 discloses a method of SiC single crystal growth on a SiC seed crystal substrate by contacting the seed crystal substrate with a melt comprising Si, C, V and Ti wherein an atomic ratio between Si and V represented by [V]/([Si]+[V]) satisfies the relation 0.1≦[V]/([Si]+[V])≦0.45 and an atomic ratio between Si and Ti represented by [Ti]/[Si]+[Ti]) satisfies the relation 0.1≦[Ti]/[Si]+[Ti])≦0.25, and supercooling the melt in the vicinity of the seed crystal substrate to allow supersaturation of SiC in the melt.
Japanese Patent Application Laid-open No. 2007-076986 discloses a method of SiC single crystal growth on a seed crystal substrate for SiC growth by contacting the seed crystal substrate with a melt comprising Si, Ti, M (M: any one of Co, Mn and Al) and C, wherein an atomic ratio between Si, Ti and M is SixTiyMz wherein 0.17≦y/x≦0.33 and 0.90≦(y+z)/x≦1.80 when M is Co or Mn and 0.17≦y/x≦0.33 and 0.33≦(y+z)/x≦0.60 when M is Al, and supercooling the melt in the vicinity of the seed crystal substrate to allow supersaturation of SiC in the melt.
According to the method disclosed in Japanese Patent Application Laid-open No. 2004-002173 in which Mn or Ti is added, the C concentration in the melt at 2000° C. or lower can be increased compared to Si—C dual systems so that the crystal growth rate can be increased. Especially, addition of Ti allows the production of SiC single crystals having high quality with a few times higher growth rate than the conventional liquid phase growth from Si—C dual system melts. However, although addition of Ti allows stable growth with respect to the growth of 6H—SiC single crystals, 6H—SiC polytype is mixed during the growth of 4H—SiC single crystals which are promising for power device applications, so that stable growth cannot be obtained. In addition, the C concentration in the melt is significantly increased by addition of Mn; however, stable growth cannot be obtained for a prolonged time because the vapor pressure of Mn is low.
According to the methods disclosed in Japanese Patent Application Laid-open No. 2007-261843 and Japanese Patent Application Laid-open No. 2007-076986, the Si—Ti—C triple system is further added with V, Co, Mn or Al to increase the C concentration of the melt and liquid phase growth is carried out by using the melt having a higher C concentration. However, neither method provides the crystal growth rate comparable to that of sublimation regarding the growth of 4H—SiC single crystals.
The present invention is directed to overcoming or at least reducing the effects of one or more of the problems set forth above.

SiC single crystal and production method thereof


A display apparatus and a control method thereof are provided. For example, a display apparatus which may control a hidden external apparatus that cannot be directly controlled by a remote control device and a control method thereof. Some of the disclosed example embodiments may provide a display apparatus which may analyze received first control information for the hidden external apparatus and output second control information for controlling the hidden external apparatus, and a control method thereof.

1. Field
The present disclosure relates generally to a display apparatus and a control method thereof, for example, to a display apparatus which controls a hidden device that cannot be controlled by a remote control device and a control method thereof.
2. Description of Related Art
A remote control device is often used as an interface between a display apparatus that can output not only a broadcast but also a content, and a user. Also, a user voice or a user motion can be used as an interface between a display apparatus and a user.
With the development of technology, the functions of a display apparatus have been diversified (for example, executing various applications, games, etc.), and a display apparatus can be connected with various external apparatuses (e.g., a set-top box, a DVD player, etc.) to operate.
In the case where an external apparatus connected with a display apparatus is stored inside furniture considering an interior design, a nearby display apparatus may unnecessarily receive an optical signal output from a remote control device used for an external apparatus.

Display apparatus and method for controlling of display apparatus


A method of and apparatus for accelerating the cooling of a beverage can and/or ice tray utilizing at least one body that presents a density and thermal conductivity, defines a standard beverage can and/or ice tray receiving receptacle configured to form a minimum contact surface area of engagement with at least one can and/or tray, and preferably further defines a series of thru-holes, so as to promote accelerated cooling through conduction, convection within a compartment.

Field of the Invention
The present invention relates generally to methods of and apparatuses for cooling a liquid in a compartment, such as a commercial or residential freezer; and more particularly, to a method of and apparatus for accelerating cooling that utilizes conduction, convection, and/or radiant heat transfer.
Discussion of Prior Art
Methods of cooling a stand-alone liquid, such as a beverage or water, in a residential or commercial grade freezer has long consisted of simply placing the liquid in a container, and placing the container on a flat surface or rack within the freezer. For example, ice trays have been used to cool water, so as to form ice cubs. Due to minimal contact surface area of engagement between the internal surfaces of the freezer and the container, thermal or radiant heat transfer between the outside surface of the container and its surroundings is the predominate method of conventional heat transfer in such systems. Standard beverage cans such as 1-4 shown in FIG. 1 have long been placed in a refrigerator or freezer in effort to cool the liquid placed therein.


A molded plastic electrical wiring box having knock-out regions comprising a two-flap structure with the flaps having essentially planar offset surfaces providing a frangible bridge or web to separate the flaps.

This invention relates to electrical wiring boxes. More particularly, it is concerned with molded plastic electrical wiring boxes having a knock-out structure for accomodating non-metallic sheathed cables.
Typically, electrical wiring boxes include knock-out arrangements for permitting the passage of electrical wiring between the interior and the exterior of the box. Molded plastic boxes generally have knock-outs which are formed as an integral part of the box and which are held in place in the walls of the box by frangible connections so that they may be readily removed to provide apertures through the walls for the passage of electrical wiring to the interior of the box.
Various knock-out structures have been employed in molded plastic wiring boxes in order to provide solutions to various problems. One significant concern is the size of the opening remaining in the knock-out aperture after a cable has been inserted. Obviously, the tighter the cable fits within the aperture, the less opportunity there is for dirt and other undesirable materials to enter the box. Also, when the box is mounted in the wall space, there is a desire to minimize the flow of air through openings in the box into the room so as to minimize heat loss caused by drafts through the box. Certain known knock-out structures permit some additional closure of the remaining opening after a cable has been inserted in the knock-out aperture. However, most known types of knock-out structures do not adapt to a variety of cable sizes so as to minimize the remaining opening regardless of the cable size.
Application Ser. No. 909,424 filed May 25, 1978, in the names of William O. Arnold et al. and assigned to the assignee of the present application, discloses a molded plastic electrical outlet box having a two-flap integrally molded knock-out structure. The two-flap knock-out structure shown therein accomodates a variety of cable sizes while closing to minimize the opening which remains after insertion of the cable into the box. However, because of the detailed configuration of the knock-out structure, in some instances difficulties are encountered in achieving facile release of the molded box from the mold.


A bearing pin for simple, reliable attachment to a support. A bearing sleeve is pressed over a knurled surface of a pin which is fastened to the support. To prevent movement of the pin with respect to the support, the pin has a support engaging surface forming an edge with the knurled surface. The knurling is continued up to that edge, so that pin material is upset axially beyond the support engaging surface. Upon fastening of the pin to the support, the axially upset material bites into the surface of the support to prevent rotation of the pin. This same knurling, or alternative upset pattern, prevents relative movement between the bearing sleeve and the pin.

1. Field of the Invention
Many mechanisms require that a link be journaled for sliding and/or pivoting movement with respect to a support. One well-known device for this function is a bearing pin which extends perpendicularly from a support to permit movement in a plane perpendicular to the pin axis. Because of the importance of low production and assembly costs, bearing pins are often as simple as possible, usually have relatively loose tolerances, and are held in place by inexpensive techniques, such as staking. To minimize friction in the operating mechanism, it is common to provide a low friction surface layer or sleeve, such as a bronze bushing or a plastic sleeve or coating.
2. Description of the Prior Art
The assembly of known bearing pins having sleeves or bushings is usually a source of undesirable compromise, with either cost or performance suffering. This is particularly true if it is desired that the bearing pin incorporate retainer or axial thrust surfaces to keep the link from sliding axially off the bearing pin. Probably the oldest solution to this problem, for a pin having a thrust surface at the free end, is to provide some kind of head to retain the link directly, or to retain a thrust washer. If the pin is made of steel or similar low cost, high strength material, either a lot of material below the head is removed, as by a turning operation in a lathe; or a head is formed by upsetting, with risk of deformation of the pin surfaces underlying the bearing surface; or a still more expensive technique is required.
A frequent requirement is that the bearing sleeve or bushing not move with respect to the pin. This is especially the case where movement between the bushing and pin will cause looseness, or generate wear particles which damage or contaminate the apparatus in which the mechanism is used. When the bushing is made of a soft bearing metal, such as brass or a porous bronze, the bushing may simply be a press fit over the pin, in which the interference between the bushing and the pin itself provides a sufficient grip. Alternatively, and especially where the bushing includes a thrust surface at the end of the bearing pin adjoining the support to which it is fastened, the pin could be relieved slightly with respect to the end face of the bearing bushing, so that the bushing itself is held tightly against the support. However, if the bearing bushing is made of a low friction plastic (synthetic resin) material, a sufficient interference fit to guarantee that there be no relative movement may distort the somewhat elastic material of the bushing sufficiently that the bearing surfaces are no longer sufficiently true cylindrical or planar surfaces.


The present invention allows gaming devices to set or modify game parameters through the use of random events such as spinning slot machine reels or random number generators. In some embodiments, game parameters may be established with various initial values, and then, by spinning the gaming devices' reels, for example, random reel values lining up on the payline may be used as new game parameter values. Parameter values may be used to control or initialize almost any aspect of the gaming device play experience, ranging from the types of symbols seen on the reels, to the appearance or behavior of game characters, to the rate at which “complementary” points are awarded.

Gaming devices (e.g., reeled slot machines, video poker machines, etc.) generate more than $15 billion per year in revenue for casinos in the United States alone. This revenue accounts for more than half of the total gaming revenue for a typical United States casino. The situation is similar in other countries and regions in which gaming devices are popular, such as Europe and Australia. Accordingly, casino operators are interested in increasing the enjoyment of playing a slot machine in order to maintain or increase this level of revenue.
Since casino profits are directly proportional to the amount wagered by patrons, casinos are highly motivated to expand and retain share within their given market. Play duration, average wager amount, and rate of play are significant factors contributing to the profitability of the slot floor of a casino.
One way in which casinos have sought to boost profitability associated with these factors is to make the machines as entertaining as possible. Many techniques are currently used to entertain players at a slot machine, such as the use of attractive colors and graphics, sound effects associated with winning payouts, and jackpots or bonus rounds that offer players the chance to win a large amount of money for only a small wager. While such efforts have made modern slot machines more entertaining than the previous generation of machines, competing entertainment options open to consumers have expanded. Casinos now compete not only with the casino across the street, but with alternative player entertainment options such as home theater systems, handheld video game devices, greatly expanded television and movie offerings, and the like. Accordingly, a need exists for enhancing the entertainment value of gaming devices.

Method and apparatus for setting game parameters


A method for identifying log likelihood ratio (LLR) values includes programming codewords into nonvolatile memory devices in response to receiving host-requested write instructions and performing background reads of the programmed codewords in a block at a default threshold voltage, at one or more threshold voltage offset that is less than the default threshold voltage and at one or more threshold voltage offset that is greater than the default threshold voltage. One of the background reads is decoded to identify the stored codeword(s) and a set of LLR values is identified using the stored read results and the identified codeword(s). The process of performing background reads, storing, decoding and identifying is repeated to identify a set of LLR values for each block and further to identify updated sets of LLR values. Host-requested reads are performed and are decoded using LLR values from the updated set of LLR values corresponding to the block that was read.

Error correction methods that use soft information have been widely adopted to obtain the low levels of Uncorrectable Bit Error Rate (UBER) required for client and enterprise Solid State Drives (SSD's). Error correction methods that use soft information typically require testing sample flash memory devices in a lab to identify Log Likelihood Ratio (LLR) values that indicate the Bit Error Rate (BER) of the tested devices. The LLR's are then stored in tables in each SSD that are used by the memory controller for decoding reads of NAND flash memory chips.
The process of characterizing NAND flash memory chips is expensive and time consuming. In addition, the characteristics of NAND flash memory chips change during the lifetime of the NAND flash memory device, making accurate characterization difficult and requiring the storage of numerous LLR tables. Also, the storage space required for storing the LLR tables adds expense to the SSD.
Accordingly, there is a need for a method and apparatus that will allow for error correction using soft information that does not require lab testing of exemplary NAND flash memory chips and that will provide LLR values that accurately indicate the BER of the NAND flash memory chips.


An input device and an air conditioner including the same, wherein the input device receives operation input of an air conditioner including an outdoor unit and an indoor unit, and the input device includes a display unit, a communication unit to communicate with the indoor unit, an interface unit to provide an interface for exchanging data with an external device, and a controller to perform control such that a home screen including a plurality of icon items is displayed on the display unit and to perform control such that temperature information set through a temperature setting item in the home screen is transmitted to the external device through the interface unit.

1. Field of the Invention
An input device and an air conditioner including the same, and more particularly, to an input device that is capable of remotely controlling an external device and an air conditioner including the same.
2. Description of the Related Art
An air conditioner is an apparatus that discharges cool or hot air into a room in order to adjust room temperature, thereby providing a comfortable room environment to users. Generally, the air conditioner includes an indoor unit installed in the room, the indoor unit including a heat exchanger, and an outdoor unit for supplying refrigerant to the indoor unit, the outdoor unit including a compressor and a heat exchanger.

Input device and air conditioner including the same


A heat pump arrangement includes an evaporator, a first condenser and a compressor connected in a circuit containing a heat-carrying medium. The compressor is arranged downstream of the evaporator and the first condenser is arranged downstream of the compressor as viewed in the direction of the flow of the medium, whereby the compressor receives medium in the vapor phase from the evaporator and delivers medium in the liquid phase to the evaporator through the first condenser. The heat pump arrangement further has an expander, a second condenser connected downstream of the expander and a pump arranged between the output of the second condenser and the evaporator. The temperature in the first condenser which is designed for extracting useful heat is higher and the temperature in the second condenser is lower than the temperature in the evaporator and further, the expander which is driven by means of a first partial flow of the medium flowing from the evaporator is coupled in a force-transmitting manner with the pump as well as with the compressor for the remaining second partial flow of the medium flowing from the evaporator.

This invention relates to a heat pump arrangement which includes a circuit containing a heat-carrying medium, as well as an evaporator, a first condenser and a compressor connected in the circuit. The compressor is arranged in the circuit downstream of the evaporator as viewed in the direction of the flow of the medium and recirculates the medium through the first condenser to the evaporator.
In the broad sense, heat pump arrangements of the above-outlined type serve for generating a useful temperature from a lower temperature difference.
It is a desideratum, particularly when the above-noted temperature difference is small, to drive the heat pump arrangement with as little external energy input as possible. In known heat pump arrangements, the compressor is driven by external energy, for example, by an internal combustion engine or an electromotor.


An apparatus for centrifugal casting of hollow articles in particular pipes. The apparatus has an elongate generally cylindrical hollow mould with a center conductor extending along the longitudinal axis so that the combination acts as a coaxial waveguide. A microwave source and waveguide system are provided to direct substantially TEM mode radiation into one end of the mould. The mould and center conductor are terminated at the other end by a short circuit to microwave radiation so that standing waves are established in the mould. The invention also provides a method for centrifugal casting of such articles in which a casting composition is placed in a hollow rotating mould and microwave radiation is directed into the mould to heat the casting composition.

1. Field of the Invention
This invention relates to centrifugal casting of pipes. Although the method and apparatus of this invention will hereinafter be described primarily with reference to the manufacture of centrifugally cast glass filament reinforced pipes the invention is also applicable to other types of centrifugally cast pipes and other centrifugally cast articles.
2. Description of the Prior Art
In the known centrifugal casting process for glass reinforced plastic pipes, liquid resin and hardening agent are placed inside a rotating cylindrical mould along wit the required reinforcements and fillers in the appropriate order and amounts. The centrifugal force created by the rotation causes the solid materials to migrate through the liquid resin to the outer wall and compact in the normal way. The glass filaments usually take several minutes to compact fully due to the high viscosity of the liquid resin and the large specific surface area of the glass filaments. After an appropriate delay, heat is applied to the pipe either by blowing heated air along the bore of the uncured pipe or by applying heat to the outside of the mould through an appropriate medium such as heated air, oil or water. The heating accelerates the triggering of the curing of the resin and hardener. In either case, the heat is conducted through the surface of the pipe and must spread through the rest of the pipe wall by conduction. This is a slow process as most plastics are poor thermal conductors. These processes also often result in uneven heating of the pipe resulting in some parts of the pipe curing more slowly than other.


Systems and methods for the manipulation of captured light fields and captured light field image data in accordance with embodiments of the invention are disclosed. In one embodiment of the invention, a system for manipulating captured light field image data includes a processor, a display, a user input device, and a memory, wherein a depth map includes depth information for one or more pixels in the image data, and wherein an image manipulation application configures the processor to display a first synthesized image, receive user input data identifying a region within the first synthesized image, determine boundary data for the identified region using the depth map, receive user input data identifying at least one action, and perform the received action using the boundary data and the captured light field image data.

Imaging devices, such as cameras, can be used to capture images of portions of the electromagnetic spectrum, such as the visible light spectrum, incident upon an image sensor. For ease of discussion, the term light is generically used to cover radiation across the entire electromagnetic spectrum. In a typical imaging device, light enters through an opening (aperture) at one end of the imaging device and is directed to an image sensor by one or more optical elements such as lenses. The image sensor includes pixels or sensor elements that generate signals upon receiving light via the optical element. Commonly used image sensors include charge-coupled device (CCDs) sensors and complementary metal-oxide semiconductor (CMOS) sensors.
Image sensors are devices capable of converting an optical image into a digital signal. Image sensors utilized in digital cameras are typically made up of an array of pixels; the number of pixels determines the megapixel rating of the image sensor. For example, an image sensor having a width×height of 2272×1704 pixels would have an actual pixel count of 3,871,488 pixels and would be considered a 4 megapixel image sensor. Each pixel in an image sensor is capable of capturing light and converting the captured light into electrical signals. In order to separate the colors of light and capture a color image, a Bayer filter is often placed over the image sensor, filtering the incoming light into its red, blue, and green (RGB) components that are then captured by the image sensor. The RGB signal captured by the image sensor using a Bayer filter can then be processed and a color image can be created.
In photography, depth of field is the distance between the nearest and farthest objects in a picture that appears acceptably sharp. Depending on the desire of the photographer, it can be desirable to have the entire image be sharp, in which case a large depth of field is desired. Conversely, a small depth of field will emphasize certain aspects of a picture (that will appear sharp) while de-emphasizing the other aspects of the picture (that will appear out of focus). When taking pictures, the size of the image sensor corresponds to the depth of field of the image captured by the image sensor, with smaller sensors having a larger depth of field. Alternately, a variable aperture in front of the lens adjusts to vary the depth of field captured—a smaller aperture enabling a larger depth of field and vice versa. Cellular telephones are often equipped with a small digital camera, often employing an image sensor around 4 mm. This gives cellular telephone cameras a large depth of field. For comparison, an image sensor in a DSLR camera typically measures between 18 mm and 36 mm, giving a DSLR a smaller depth of field than a cellular telephone camera. This is assuming that both the DSLR and the cellular telephone camera have maximal aperture settings for the captured photographs.

Systems and method for performing depth based image editing