The present invention relates to novel synthetic methods for the preparation of indolylquinones. The methods of the present invention are directed to synthetic reactions involving indoles and halo-quinones in solvent and in the presence of a metal carbonate. The invention also relates to bis- and mono-indolylquinones of high purity and pharmaceutical compositions containing the same.

The present invention relates to novel synthetic methods for the preparation of both known and novel indolylquinones. Many indolylquinones, in particular the class of indolylquinones known as the asterriquinones, have utility, in the treatment of cell proliferative disorders such as cancer. In addition, many indolylquinones are known to be useful as dyes. Finally, indolylquinones are also known to exhibit antifungal and antibacterial properties. However, in general, indolylquinones are isolated from natural sources and are not prepared synthetically. The present invention is directed to a synthetic method for the preparation of indolylquinones, and to novel compounds prepared using said method. In particular, the methods of the present invention are directed to synthetic reactions involving indoles and halo-quinones in solvent and in the presence of a metal carbonate. These methods provide a direct and simple means of preparing the compounds of interest, indolylquinones.
2.1 Isolation from Natural Sources and Therapeutic Utility of Indolylquinones
Research interest concerning indolylquinones grew out of early observations that extracts of Chaetomium exhibited antibiotic properties. These observations led researchers to attempt the isolation of active species from cultures of these microorganisms. For example, Brewer et al. disclose the isolation of a purple pigment, which was termed cochliodinol, from isolates of Chaetomium cochliodes and Chaetoinium globosum (1968, xe2x80x9cThe Production of Cochliodinol and a Related Metabolite by Chaetomium Species,xe2x80x9d Can. J. Microbiol. 14:861-866). Brewer et al. also disclose the synthetic conversion of cochliodinol to a diacetate compound. Id. Further, the antifungal properties of cochliodinol have also been documented (Meiler et al., 1971, xe2x80x9cThe Effect of Cochliodinol, a Metabolite of Chaetomium cochliodes on the Respiration of Microspores of Fusarium oxysporum,xe2x80x9d Can. J. Microbiol. 17: 83-86).
The structure of cochliodinol was elucidated by Jerram et al. in 1975. (1975, xe2x80x9cThe Chemistry of Cochliodinol, a Metabolite of Chaetomium spp.,xe2x80x9d Can. J. Chem. 53:727-737). Jerram et al. reported the structure of cochliodinol as: 2,5-dihydroxy-3,6-di(5xe2x80x2-(2xe2x80x3-methylbut-xcex942xe2x80x3-ene)-indolyl-3xe2x80x2)-cyclohexadiene-1,4-dione. The conversion of cochliodinol to various other derivatives, including its dimethyl and diacetyl analogues, was also disclosed. Id. Some of these derivatives were highly colored and suitable for use as dyes, while others were colorless. Id. Sekita discloses the isolation of other bis(3-indolyl)-dihydroxybenzoquinones, including isocochliodinol and neocochliodinol from Chaetoinium muroum and C. amygdalisporum (1983, xe2x80x9cIsocochliodinol and Neocochliodinol, Bis(indolyl)-benzoquinones from Chaetomium spp.,xe2x80x9d Chem. Pharm. Bull. 31(9): 2998-3001).
Despite the therapeutic potential of cochliodinol and its derivatives, efficient methods suitable for large scale production of these compounds have remained elusive. U.S. Pat. No. 3,917,820 to Brewer et al. discloses the purple pigment cochliodinol and a process for its production by culturing various types of Chaetomium under aerobic conditions. However, the methods of Brewer require long incubation periods for cochliodinol production (2-8 days), the use of benzene, a known carcinogen, to effect chromatographic separation of cochliodinol from the culture and are limited to the few naturally occurring compounds. Moreover, Brewer discloses the isolation of only small quantities (0.75 grams) of cochliodinol from Chaetomium.
Another class of indolylquinones known as the asterriquinones in which the nitrogen of the indole ring is substituted, has been shown to exhibit antitumor activity. Arai et al. proposed the general name xe2x80x9casterriquinonesxe2x80x9d for the class of indolylquinones based upon asterriquinone (1981, xe2x80x9cMetabolic Products of Aspergillus terreus IV. Metabolites of the Strain IFO 8835. (2) The Isolation and Chemical Structure of Indolyl Benzoquinone Pigments,xe2x80x9d Chem. Pharm. Bull. 29(4): 961-969). It should be noted that as used herein, the term xe2x80x9casterriquinonexe2x80x9d has a more general meaning, and is used interchangeably with the term xe2x80x9cindolylquinone.xe2x80x9d Yamamoto et al. disclose the antitumor activity of asterriquinone, i.e., 2,5-bis[N-(1xe2x80x3,1xe2x80x3-dimethyl-2xe2x80x3-propenyl)indol-3xe2x80x3-yl]-3,6-dihydroxy-1,4-benzoquinone, and its isolation from the fungus Aspergillus terreus (1976, xe2x80x9cAntitumor Activity of Asterriquinone, a Metabolic Product from Aspergillus terreus,xe2x80x9d Gann 67:623-624).
Arai et al. disclose the isolation and characterization of 11 different kinds of bisindolyl-dimethoxyl-p-benzoquinones from Aspergillus terreus. Id. The isolation and structural determination of a number of other asterriquinones have also been reported. (Arai et al. 1981, xe2x80x9cMetabolic Products of Aspergillus terreus VI. Metabolites of the Strain IFO 8835. (3) the Isolation and Chemical Structures of Colorless Metabolites,xe2x80x9d Chem. Pharm. Bull. 29(4): 1005-1012; Kaji et al., 1994, xe2x80x9cFour New Metabolites of Aspergillus Terreusxe2x80x9d, Chem. Pharm. Bull. 42(8): 1682-1684).
However, the separation of asterriquinones is troublesome because there are so many kinds of homologous pigments in the Aspergillus extracts. Moreover, the chromatographic purification of asterriquinones is typically carried out using benzene, a known carcinogen, as a solvent. Finally, only milligram quantities of asterriquinones have actually been isolated from these natural sources.
In view of their potential as anticancer agents, research has been directed to determination of the relationship between structure and antitumor activity of asterriquinones. For example, Arai et al. reported a study in which hydroxyl benzoquinone derivatives obtained by demethylation of bisindolyl-dimethoxyl-p-benzoquinones were found to have greater antitumor activity than the methoxyl derivatives (1981, xe2x80x9cMetabolic Products of Aspergillus terreus V. Demethylation of Asterriquinones,xe2x80x9d Chem. Pharm. Bull. 29(4): 991-999). Shimizu et al. noted that the presence of free hydroxyl groups in the benzoquinone moiety, as well the number and position of tert-, isopentenyl, or both pentyl groups, seems to have an effect on the antitumor activity of the compound (1982, xe2x80x9cAntitumor Effect and Structure-Activity Relationship of Asterriquinone Analogs,xe2x80x9d Gann 73: 642-648). In an attempt to obtain information towards the development of more potent asterriquinone derivatives, Shimizu et al. conducted an investigation into the structure-activity relationship of asterriquinones in which the action mechanism of asterriquinone in its antitumor activity with reference to its interaction with DNA molecules and the plasma membrane of tumor cells was studied (1990, xe2x80x9cInteraction of Asterriquinone with Deoxyribonucleic Acid in Vitro,xe2x80x9d Chem. Pharm. Bull. 38(9): 2617-2619). It was reported that a correlation exists between the pKa value of the asterriquinone derivative and its antitumor activity. Id. Maximum antitumor activity was observed for compounds with pKa""s in the range of 6-7. Id.
Analysis of structure-activity relationships has led to attempts to obtain compounds with more potent antitumor activity by chemical modification of asterriquinone and related compounds isolated from natural sources (Shimizu et al., 1982, xe2x80x9cAntitumor Activity of Asterriquinones from Aspergillus Fungil IV. An Attempt to Modify the Structure of Asterriquinones to Increase the Activity,xe2x80x9d Chem. Pharm. Bull. 30(5): 1896-1899). Although benzoquinone derivatives having aziridinyl groups in the molecule such as mitomycin C, carbazilquinone or xe2x80x9cE 39xe2x80x9d are well known potent anticancer agents, replacement of the functional groups at the 3 and 6 positions in the benzoquinone moiety of asterriquinone failed to enhance its antitumor potency. Id. Similarly, the introduction of an ethyleneimino group into the molecule did not increase antitumor activity. A dimethylallyl derivative of asterriquinone showed moderate activity against the ascites and solid tumors of Ehrlich carcinoma, while an allyl derivative did not. It was suggested that in order to enhance the antitumor activity, it may be necessary not only to alter the pKa value by alkylation, but also to introduce hydrophilic groups into the molecule.
Most recently, in addition to their demonstrated antitumor activity, asterriquinone and some of its analogues have also been shown to be strong inhibitors of HIV-reverse transcriptase (Ono et al., 1991, xe2x80x9cInhibition of HIV-Reverse Transcriptase Activity by Asterriquinone and its Analogues,xe2x80x9d Biochem. Biophys. Res. Commun. 174(1): 56-62).
2.2 Cancer and Signal Transduction
As mentioned above, indolylquinones have utility as antitumor agents for the treatment of cancer and other cell proliferative disorders. These compounds are believed to arrest the growth of tumors by interfering with the signal transduction pathways that regulate cell proliferation and differentiation
Protein phosphorylation is a common regulatory mechanism used by cells to selectively modify proteins carrying signals that regulate cell proliferation and differentiation. The proteins that execute these biochemical modifications are a group of enzymes known as protein kinases. They may further be defined by the amino acid that they target for phosphorylation. One group of protein kinases are the tyrosine kinases (PTKs) which selectively phosphorylate a target protein on its tyrosine residues.
Protein tyrosine kinases comprise a large family of proteins, including many growth factor receptors and potential oncogenes. Tyrosine kinases can be cytoplasmic, non-receptor-type enzymes and act as a key component of a signal transduction pathway which regulates cell functions such as cell division, differentiation and survival.
Adaptor proteins are intracellular proteins having characteristic conserved peptide domains (SH2 and/or SH3 domains, as described below) which are critical to the signal transduction pathway. Such adaptor proteins serve to link protein tyrosine kinases, especially receptor-type protein tyrosine kinases to downstream intracellular signalling pathways such as the RAS signalling pathway. It is thought that such adaptor proteins may be involved in targeting signal transduction proteins to the correct site in the plasma membrane or subcellular compartments, and may also be involved in the regulation of protein movement within the cell.
The profound cellular effects mediated by tyrosine kinases and adaptor molecules have made them attractive targets for the development of new therapeutic molecules. It is known, for example, that the overexpression of tyrosine kinases, such as HER2, can play a decisive role in the development of cancer (Slamon, D. J., et al., 1987, Science, 235:177-182) and that antibodies capable of blocking the activity of this enzyme can abrogate tumor growth. (Drebin, et al. 1988, Oncoqene 2:387-394). Blocking the signal transduction capability of tyrosine kinases such as Flk-1 and the PDGF receptor have been shown to block tumor growth in animal models (Millauer, B., et al. 1994, Nature 367:577; Ueno, H., et al. 1991, Science 252:844-848).
Despite great interest in the various therapeutic and other utilities of indolylquinones such as asterriquinones, research into the therapeutic activities of indolylquinones and efforts to obtain indolylquinones with enhanced therapeutic activity have both been limited by the lack of reliable sources for these compounds. Indeed, isolation of indolylquinones from natural sources requires multiple steps and produces only milligram quantities of the target molecules. Further, evaluation of the activities of novel indolylquinones has necessarily been confined to those compounds which can be obtained by chemical modification of known compounds that can be isolated from natural sources. Clearly, a synthetic routine to these compounds would be invaluable to the art.
2.3 Synthesis of Cochliodinol
A synthetic route to an indolylquinone, cochliodinol, has been reported by Hxc3x6rcher et al. This route is a complex, multi-step, low-yield process for the total synthesis of cochliodinol (1986, xe2x80x9cTotalsynthese des Cochliodinolsxe2x80x9d, Liebigs. Ann. Chem. 1765-1771). The Hxc3x6rcher method involves an unusual solid state reaction of bromanil (2,3,5,6-tetrabromo-1,4-quinone) with 5-bromoindole in the presence of aluminum oxide and potassium carbonate in a dry box at 105xc2x0 C. This solid state reaction yields about 11% of 2,5-dibromo-5,6-bis(5-bromo-3-indolyl)-1,4-quinone. The 2,5-dibromo-5,6-bis(5-bromo-3-indolyl)-1,4quinone is then treated with benzalcohol and sodium hydroxide to give 2,5-bis(benzyloxy)-3,6-bis(5-bromo-3-indolyl)-1,4-quinone in 45% yield. This product is then reacted with hydrogen gas in the presence of a 10% Pd on activated charcoal catalyst, followed by treatment with acetic anhydride in pyridine to give 1,2,4,5-tetracetoxy-3,6-bis(5-bromo-3-indolyl)benzene. Reaction of this compound with a complex of isopentenyl bromide and tetracarbonyl nickel gives 1,2,4,5-tetracetoxy-3,6-bis[5-(3-methyl-2-butenyl)3-indolyl]benzene. This compound is then reacted with sodium hydroxide and oxygen to give cochliodinol.
According to Hxc3x6rcher et al., the reaction of bromanil with certain substituted indoles is problematic. Hxc3x6rcher et al. report that earlier attempts to react a p-benzoquinone with 2-methylindole resulted in only monoindolequinones in very low yields. Attempts to react bromanil with 5-(2-methylbut-2-en-4-yl)-indole were also reported by Hxc3x6rcher to be unsuccessful due to the instability of the unsaturated side chain vis-a-vis the dehydrogenating bromanil. To overcome this difficulty, Hxc3x6rcher reacted bromanil with 5-bromoindole instead of 5-(2-methylbut-2-en-4-yl), followed by introduction of the 2-methylbut-2-en-4-yl group at the end of the synthesis, requiring the additional step of reacting the 5,5xe2x80x2-dibromo-bis-indolylquinone with the complex of isopentenyl bromide and tetracarbonyl nickel, which substitutes the bromine atoms with 2-methylbut-2-en-4-yl groups.
Hxc3x6rcher et al. report that this method resulted in isolation of only milligram quantises of cochliodinol in a very low overall yield. However, Hxc3x6rcher et al. indicate that conducting the initial reaction of bromanil with 5-bromoindole in smaller batches results in better yields. This suggests that the methods of Hxc3x6rcher et al. are unsuited for production of bis-indolylquinones on a large stale. In addition, as applied to the production of bis-indolylquinones in general, the methods of Hxc3x6rcher et al. would be prohibitively multistep, and would likely result in isolation of only milligram quantities of the target indolylquinones. Moreover, these methods require high temperature and manipulation in dry box.
Accordingly, despite the great interest in indolylquinones, there is a lack of feasible large scale synthetic routes for obtaining these compounds. Thus, there is a need in the art for a fast, efficient synthetic method for making indolylquinones in preparative quantities. Further, there is a need for synthetic means of producing known indolylquinones previously available only in milligram quantities from natural sources. Moreover, there is a need in the art for a synthetic method that may be manipulated easily to produce a wide variety of structurally diverse novel indolylquinones, so that structure-activity relationships may be further elucidated, and new, perhaps more therapeutically useful indolylquinones may be developed.
The present invention provides a method for the synthesis of indolylquinones which comprise reacting a substituted or unsubstituted 2,5-dihalo-1,4-benzoquinone with one or more substituted or unsubstituted indoles in a polar organic solvent and in the presence of metal carbonate.
In one embodiment, the present invention provides a method for preparing a symmetrical indolylquinone compound of the formula I:
wherein: R1 and R2 are each independently Br, Cl, F, I, H, OH or xe2x80x94OCOR, wherein R is, lower alkyl, aryl or alkylaryl; Rxe2x80x31 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, arylalkyl or aryl; and R3 to R7 are each independently hydrogen, branched or unbranched C2-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, C2-Cm alkynyl, alkenylcarboxy, aryl, alkylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer from 0 to 12, preferably 1-7, and m is an integer from 0 to 12, preferably 1-7. R1 and R2 are preferably Br, Cl, F or H; and least preferably OH. The. method comprises reacting a substituted or unsubstituted 2,5-dihalo-1,4-benzoquinone, preferably a 2,5-dibromo-1,4-benzoquinone compound of the formula II:
wherein R1 and R2 are as defined above; with at least one indole of the formula III:
wherein Rxe2x80x31 and R3-R7 are as defined above. The reaction is carried out in a polar organic solvent and in the presence of metal carbonate under mild conditions which are further discussed below.
The method may further comprise reacting the indolylquinone compound of formula I with an alkali metal hydroxide to produce a compound of the formula IV:
Further, the invention encompasses reacting the indolylquinone compound of formula I wherein R1 and R2 are Br with an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH, wherein Rxe2x80x2 is lower alkyl or alkylaryl, to produce an indolylquinone compound of the formula:
wherein Rxe2x80x21 and Rxe2x80x22 are each independently lower alkyl, aryl or alkylaryl.
In another embodiment,, the present invention provides a method for preparing an asymmetrical indolylquinone compound of the formula VI:
wherein: R1 and R2 are each independently Br, Cl, F, I, H, OH, or xe2x80x94OCOR, wherein R is lower alkyl, aryl or alkylaryl; Rxe2x80x31 and Rxe2x80x32 are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, arylalkyl or aryl; and R3 to R12 are each independently hydrogen, branched or unbranched C1-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, C2-Cm alkynyl, alkenylcarboxy, aryl, alkylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer from 0 to 12, preferably 1-7, and m is an integer from 0 to 12, preferably 1-7. R1 and R2 are preferably Br, Cl, F or H; and least preferably OH. The principal steps of the method comprise:
(a) reacting a substituted or unsubstituted 2,5-dibromo-1,4-benzoquinone compound of the formula II:
wherein R1 and R2 are as defined above; with one equivalent of a first indole of the formula III:
wherein Rxe2x80x31 and R3-R7 are as defined above; in a polar organic solvent and in the presence of metal carbonate;
(b) reacting the intermediate product of step (a) with one equivalent of a second indole of the formula IV:
wherein Rxe2x80x32 and R8-R12 are as defined above. Both reactions are carried out in a polar organic solvent and in the presence of metal carbonate under mild conditions which are further discussed below.
The invention also encompasses further reacting the indolylquinone compound of formula VI with an alkali metal hydroxide to produce a compound of the formula VIII:
wherein Rxe2x80x31, Rxe2x80x32 and R3-R12 are as defined above.
Further, the invention encompasses reacting the indolylquinone of formula VI wherein R1 and R2 are Br, F, Cl or I with an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH, wherein Rxe2x80x2 is lower alkyl or alkylaryl, to produce an indolylquinone compound of the formula IX:
wherein Rxe2x80x21 and Rxe2x80x22 are each independently lower alkyl, aryl or alkylaryl.
In yet another embodiment, the present invention provides a method for preparing an indolylquinone compound of the formula X:
wherein: Rxe2x80x31 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, arylalkyl or aryl.; and R3 to R7 are each independently hydrogen, branched or unbranched C1-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, C2-Cm alkynyl, alkenylcarboxy, aryl, alkylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer of 0 to 12, preferably 1-7, and m is an integer of 0 to 12, preferably 1-7. This embodiment of the inventive method involves reacting 2,3,5,6-tetrabromo-4-benzoquinone with at least one indole of the formula:
wherein Rxe2x80x31 and R3-R7 are as defined above. The reaction is carried out in a polar organic solvent in the presence of metal carbonate.
The method also encompasses further reacting the indolylquinone compound of formula X with an alkali metal hydroxide to produce a compound of the formula:
wherein R3-R7 are as defined above. Further, the invention also encompasses a method which further comprises reacting the indolylquinone compound of formula X with an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH, wherein Rxe2x80x2 is lower alkyl or alkylaryl, to produce an indolylquinone compound of the formula:
wherein Rxe2x80x21 and Rxe2x80x22 are each independently lower alkyl, aryl or alkylaryl.
In yet another embodiment, the present invention provides a method for preparing an indolylquinone compound of the formula XIV:
wherein: Rxe2x80x31 and Rxe2x80x32 are each independently H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, arylalkyl or aryl; and R3 to R12 are each independently hydrogen, branched or unbranched C1-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, C2-Cm alkynyl, alkenylcarboxy, aryl, alkylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer of 0 to 12, preferably 1-7, and m is an integer of 0 to 12, preferably 1-7. This embodiment of the inventive method involves reacting 2,3,5,6-tetrabromo-1,4-benzoquinone with one equivalent of a first indole of the formula III:
wherein
Rxe2x80x31 and R3-R7 are as defined above; in a polar organic solvent and in the presence of metal carbonate;
reacting the intermediate product of step (a) with one equivalent of a second indole of the formula VII:
wherein Rxe2x80x32 and R8-R12 are as defined above. Both reactions are carried out in a polar organic solvent and in the presence of metal carbonate under mild conditions which are further discussed below.
The invention also encompasses further reacting the indolylquinone compound of formula XIV with an alkali metal hydroxide to produce a compound of the formula VIII:
wherein Rxe2x80x31, Rxe2x80x32 and R3-R12 are as defined above.
Further, the invention encompasses reacting the indolylquinone of formula VI wherein R1 and R2 are Br, F, Cl or I with an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH, wherein Rxe2x80x2 is lower alkyl or alkylaryl, to produce an indolylquinone compound of the formula IX:
wherein Rxe2x80x21 and Rxe2x80x22 are each independently lower alkyl, aryl or alkylaryl.
In still another embodiment, the present invention provides a method for preparing a mono-indolylquinone compound of the formula XI:
wherein
R1, R2 and R30 are each independently Br, Cl, F, I, H, OH or xe2x80x94OCOR, wherein R is lower alkyl, aryl or alkylaryl;
Rxe2x80x31 is H, C1-C7 alkyl, C2-C7 alkenyl, C2-C7 alkynyl, arylalkyl or aryl; and
R3 to R7 are each independently hydrogen, branched or unbranched C1-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, alkynyl, alkenylcarboxy, aryl, alkylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer from 0 to 12 and m is an integer from 0 to 12. This method comprises reacting a substituted or unsubstituted 2,5-dibromo-1,4-benzoquinone compound of the formula:
wherein R1 and R2 are as defined above, with one indole of the formula
wherein Rxe2x80x31 and R3-R7 are as defined above. The reaction is carried out in a polar organic solvent and in the presence of metal carbonate.
The method of the present invention may further comprise reacting the indolylquinone compound of formula XI with an alkali metal hydroxide to produce a compound of the formula:
wherein R30 and R3-R7 are as defined above.
The method may further comprise reacting the indolylquinone compound of formula XI wherein R1, R2and R30 are Br, F, Cl or I with a mixture of an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH, wherein Rxe2x80x2 is lower alkyl or alkylaryl, to produce an indolylquinone compound of the formula:
wherein Rxe2x80x21 and Rxe2x80x22 are each independently lower alkyl, aryl or alkylaryl.
In another embodiment, the present invention further encompasses methods for producing large quantities of known, naturally occurring asterriquinones in high purity and in high yield. In yet another embodiment, the present invention is directed to known, synthetically prepared naturally occurring asterriquinones of high purity which are obtainable in large quantities and in high yield. The invention also encompasses the preparation of novel monoindolylquinones, i.e., compounds substituted with only one indole, and the monoindolylquinone compounds, as described below.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
As mentioned above, the present invention relates to a synthetic route for the preparation of a wide variety of indolylquinones including asterriquinone compounds having interesting antitumor activity. As a result, the invention provides a major contribution to the art in that naturally occurring compounds with important therapeutic properties can be prepared in large quantities, e.g., quantities of about 1 gram or more, with purity in excess of about 95% and in high yield. The availability of large quantities allows the skilled artisan to more quickly and easily test these naturally occurring compounds. Prior to the present invention, such compounds were isolated from natural sources in limited quantities (e.g., about 750 mg or less) and low purity (e.g., lessthan about 95%). With the present invention, large quantities can more easily be obtained and the purification of complex natural product mixtures is avoided. Finally, the present invention provides a means for preparing novel analogues of the naturally occurring indolylquinones, which analogues may prove to be of greater interest than the naturally occurring compounds for their therapeutic activity or other properties.
More specifically, the present invention provides a solvent based reaction of indoles and haloquinones in the presence of metal carbonate. It has been discovered that the reaction of indoles and halo-quinones using a polar organic solvent and metal carbonate provides a rapid and efficient reaction under mild conditions, which include but arenot limited to mild temperatures, short reaction times and standard/ambient pressures. Thus, the present method is well suited for large scale and commercial production of indolylquinones.
More specifically, the present invention provides methods for the preparation of indolylquinones which involve the reaction of a 2,5-dihalo-1,4-benzoquinone of the formula II with at least one indole of the formula III. When one indole is used, a symmetrical bis-indolylquinone of the formula I is obtained as the product. In the alternative, step-wise or concurrent addition of two different indoles may be used to obtain an asymmetrical bis-indolylquinone of the formula VI. For example, an asymmetrical bis-indolylquinone may be made by the reaction of a 2,5-dihalo-1,4-benzoquinone with about one equivalent of a first indole, followed by addition of about 1.5 equivalents of a second indole. Preferably, the preparation of asymmetrical bis-indolylquinones is carried out in the presence of about 3 equivalents of metal carbonate. As another alternative, mixtures of two or more indoles may be reacted with the starting quinone to give a mixture of symmetrical and asymmetrical bis-indolylquinones. Finally, the controlled addition of one equivalent of at least one indole to the starting quinone in the presence of about one equivalent of metal carbonate can be used to obtain one or more mono-indolylquinones.
The preferred 2,5-dihalo-1,4-quinones useful in the present invention are the 2,5-dibromo-1,4-benzoquinones of formula II, which may be substituted or unsubstituted, wherein R1 and R2 are each independently Br, Cl, F, I, OH, H or xe2x80x94OCOR, wherein R is lower alkyl, aryl or alkylaryl. Alternatively, the 2,5-dichloro-, difluoro- or diiodo-1,4-benzoquinones may be used in the methods of the invention. A particularly preferred 2,5-dibromo-1,4-quinone is 2,3,5,6-tetrabromo-1,4-benzoquinone.
The indoles useful in the present invention may be substituted at the 1, 2, 3, 4, 5 or 7 positions with hydrogen, branched or unbranched C1-Cn alkyl, alkylcarboxy, C2-Cm alkenyl, C2-Cm alkynyl, alkenylcarboxy, aryl, akylaryl, hydroxy, hydroxyalkyl, C1-Cn alkoxy, nitro, halo, trihalomethyl, amido, carboxamido, carboxy, sulfonyl, sulfonamido, amino, mercapto, or 2-methylbut-2-en-4-yl, wherein n is an integer from 0 to 12, preferably 1-7, and m is an integer from 0 to 12, preferably 1-7. Preferably, the indoles used in the present invention are substituted at the 2 position. Least preferred indoles are the unsubstituted indoles. Certain indoles useful in the present invention are available from commercial sources such as the Aldrich Chemical Company, Milwaukee, Wis. Alternatively, the indoles may be prepared via a cyclization procedure according to the method of Verley and Bedure, 1925, Bull. Soc. Chim. Fr. (37): 190.
Any non-nucleophilic, aprotic solvent may be used in the methods of the invention. Mixtures of solvents may also be used. Preferred solvents are inert or non-reactive, polar organic solvents including but not limited to acetonitrile, dimethyl formamide (DMF) and tetrahydrofuran (THF). A particularly preferred solvent is acetonitrile. The solvent volume will depend upon the scale of the reactors, and may range from a few milliliters up to a multi-liter volumes useful in large-scale production. Reactant concentrations are set forth below.
It is believed that the metal carbonate used in the methods of the present invention assists the reaction of the 2,5-dihalo-1,4-quinone and the indole by scavenging the hydrogen bromide by-product formed in the reaction. Any metal carbonate or mixture of metal carbonates may be used; however, cesium carbonate, potassium carbonate, sodium carbonate, lithium carbonate and mixtures thereof are preferred. A particularly preferred metal carbonate is cesium carbonate. The amount of metal carbonate used in the method ranges from about 2 to about 10 equivalents based on the haloquinone; preferably 2 to 5 equivalents; and most preferably 3 to 4 equivalents.
The reaction may be run at any concentration ranging from about 0.1M to about 5M (molarity based on the haloquinone). Preferably the reaction is run at a concentration of about 1M.
As mentioned above, the reaction to produce a mono-indolylquinone is preferably carried out in the presence of about two equivalents of metal carbonate. Reactions to produce symmetrical or asymmetrical bis-indolylquinones are preferably carried out in the presence of about 3 equivalents of metal carbonate.
According to the methods of the invention, the reaction of the 2,5-dihalo-1,4-quinone with the indole nay be run at temperatures ranging from about xe2x88x9210xc2x0 C. to about 100xc2x0 C. However, a particularly beneficial aspect of the present invention is that harsh conditions and high temperatures are not required to effect this reaction. Preferably the reaction of the 2,5-dihalo-1,4-quinone is run at a temperature in the range of about 0xc2x0 C. to about 30xc2x0 C. More preferably, the reaction is run at about room temperature.
The reaction of the 2,5-dihalo-1,4-quinone with the indole may be conducted under an inert atmosphere such as nitrogen or argon; however, the reaction may also be run in atmospheric air. The reaction may be run at any pressure up to 500 psig; however, it is preferable to conduct the reaction at atmospheric pressure.
The reaction time will vary according to the specific reactants and reaction conditions used, but generally will be from about 2 hours to about 72 hours.
After reaction of the 2,5-dihalo-1,4-quinone and the indole, the product indolylquinones are typically isolated according to standard workup procedures. For example, the crude reaction mixture nay be diluted with 1N hydrochloric acid, followed by extraction with an organic solvent such as ethyl acetate. Typically, the organic layer is washed with brine and then dried over anhydrous sodium sulfate. As an alternative to extraction, the crude reaction mixture may simply be filtered to remove solids. The solvent is removed under reduced pressure, and the crude residue is purified by recrystallization, flash chromatography, High Pressure Liquid Chromatography (HPLC) or a combination thereof. Preferably, the residue is purified using flash chromatography and/or High Pressure Liquid Chromatography (HPLC).
In a preferred embodiment, the symmetrical bis-indolylquinone of formula I is further reacted with an alkali metal hydroxide to give a bis-indol-2,5-dihydroxy-1,4-quinone of formula IV. Preferred alkali metal hydroxides are sodium and potassium hydroxide, or mixtures thereof. Preferably, this reaction is carried out in a mixture of ethanol and tetrahydrofuran using concentrated aqueous KOH at a reflux temperature of about 85xc2x0 C. for up to 20 hours. The bis-indol-2,5-dihydroxy-1,4-quinone of formula IV maybe isolated according to standard workup and purification procedures as described above.
In other embodiments, the methods of the present invention comprise reacting a symmetrical compound of formula wherein R1 and R2 are Br, or an asymmetrical compound of formula VI wherein R1 and R2 are Br, with an alkali metal hydroxide and an alcohol of the formula Rxe2x80x2OH wherein Rxe2x80x2 is lower alkyl or alkylaryl, to a produce symmetrical indolylquinone of the formula V or an asymmetrical indolylquinone of formula XI.
As used herein the term xe2x80x9csubstituted or unsubstitutedxe2x80x9d means that the group in question can be substituted with one or more substituents as desired; for example, substituents other than hydrogen such as Br, Cl, F, I, NH2, NR2, NO2, CN, COR, OH, OR, SO2, alkyl, aryl, alkylaryl and the like may be used. On the contrary, unsubstituted groups do not contain any substituents.
By the term xe2x80x9calkylxe2x80x9d as used herein is meant a straight or branched chain saturated hydrocarbon group having from 1 to 12 carbons such as methyl, ethyl, isopropyl, n-butyl, s-butyl, t-butyl, n-amyl, isoamyl, n-hexyl, n-octyl and n-decyl; xe2x80x9calkenylxe2x80x9d and xe2x80x9calkynylxe2x80x9d are used to mean straight or branched chain hydrocarbon groups having from 2 to 12 carbons and unsaturated by a double or triple bond respectively, such as vinyl, allyl, propargyl, 1-methylvinyl, but-1-enyl, but-2-enyl, but-2-ynyl, 1 methylbut-2-enyl, pent-1-enyl, pent-3-enyl, 3-methylbut-1-ynyl, 1,1-dimethylallyl, hex-2-enyl and 1-methyl-1-ethylallyl; xe2x80x9calkylarylxe2x80x9d means the aforementioned alkyl groups substituted by a phenyl group such as benzyl, phenethyl, phenopropyl, 1-benzylethyl, phenobutyl and 2-benzylpropyl; xe2x80x9carylxe2x80x9d as used herein includes a monocyclic or bicyclic rings, wherein at least one ring is aromatic including aromatic or hetero-aromatic hydrocarbons; the term xe2x80x9chydroxy-alkylxe2x80x9d means the aforementioned alkyl groups substituted by a single hydroxyl group such as 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 4-hydroxybutyl, 1-hydroxybutyl and 6-hydroxyhexyl.
Specific compounds which can be made according to the methods of the present invention are described by formula (XII) below. R1-R12 of the formula can be as listed in Table I following the formula. Illustrative preparations of these compounds are found in the working examples.
The mono-indolylquinone compounds which can be made according to the methods of the present invention are described by formula (XI) below. R1-R7 and R30 can be as listed in Table II below.
The following is a general experimental procedure for the synthesis of the trihalo-monoindolyl quinones of formula XI using the appropriate indoles. As discussed above, the indoles may be commercially available or may be prepared according to the method of Verley and Bedure, 1925, Bull. Soc. Chim. Fr. (37): 190.
Preparation of 6-(2-phenylindol-3-yl)-2,3,5-tribromo-1,4-quinone [Compound (48a)]: To a 25 ml round bottom flask equipped with a magnetic stir bar and a drying tube was placed 2-phenylindole (2.28 g), cesium carbonate (7.69 g), bromanil (5 g), and acetonitrile (11.8 ml). After stirring the mixture at room temperature for 3 hours, 1N hydrochloric acid (150 ml) was added and the aqueous layer extracted with ethyl acetate (300 ml). The organic layer was washed with brine (150 ml) and dried with sodium sulfate. Following removal of the solvent under reduced pressure, the crude residue was purified by flash chromatography (10% ethyl acetate/hexane) to yield 6-(2-phenylindol-3-yl)-2,3,5-tribromo-1,4-quinone (1.88 g, 30%) as a blue crystalline solid.
As mentioned above, the compounds of Tables I and II have therapeutic activity for example as antifungal agents, antibacterial agents, and antitumor agents. In addition, these compounds may be useful in the dye industry.


A golf ball 2 has, on a surface thereof, a plurality of types of dimples 10 having different diameters from each other. The standard deviation of the curvature radii of cross sections of all the dimples 10 is 0.90 mm or less. The average of the curvature radii of the cross sections of all the dimples 10 is 20% or greater but 40% or less of the diameter of the golf ball. The sum of the volumes of all the dimples is 300 mm3 or greater but 370 mm3 or less. The average of the diameters of all the dimples is 3.5 mm or greater but 4.5 mm or less. The ratio of the sum of the areas of all the dimples to the surface area of a phantom sphere of the golf ball is 75% or greater but 95% or less.

1. Field of the Invention
The present invention relates to golf balls. Specifically, the present invention relates to improvement of dimples of golf balls.
2. Description of the Related Art
Golf balls have a large number of dimples on the surfaces thereof. The dimples disturb the air flow around the golf ball during flight to cause turbulent flow separation. This phenomenon is referred to as "turbulization". Due to the turbulization, separation points of the air from the golf ball shift backwards leading to a reduction of drag. The turbulization promotes the displacement between the separation point on the upper side and the separation point on the lower side of the golf ball, which results from the backspin, thereby enhancing the lift force that acts upon the golf ball. Excellent dimples efficiently disturb the air flow. The excellent dimples produce a long flight distance.
The ratio of the sum of the areas of dimples to the surface area of a phantom sphere of a golf ball is referred to as an occupation ratio. In general, in a golf ball having a high occupation ratio, the degree of turbulization is great. A golf ball having a high occupation ratio has excellent flight performance.
It is known that the degree of turbulization is great in a golf ball in which the diameters of dimples are less variable. The golf ball has excellent flight performance.
In order to increase an occupation ratio, it is necessary to locate a small-diameter dimple in a narrow zone surrounded by a plurality of dimples. The presence of the small-diameter dimple causes an increase in variation of the diameters of dimples. Increasing an occupation ratio and suppressing the variation of the diameters are incompatible with each other.
The degree of turbulization also depends on the cross-sectional shapes of dimples. In a golf ball in which dimples are too deep, turbulization is insufficient. Also in a golf ball in which dimples are too shallow, turbulization is insufficient.
There have been various proposals for the cross-sectional shapes of dimples. JPS62-192181 (U.S. Pat. No. 4,813,677) discloses a golf ball that has dimples having large diameters and large depths and dimples having small diameters and small depths.
JPH2-134175 (U.S. Pat. No. 5,033,750) discloses a golf ball in which the difference between a value obtained by dividing the diameter of a dimple by the depth thereof and a value obtained by dividing the diameter of another dimple by the depth thereof is equal to or less than 0.3.
JPH3-198875 (U.S. Pat. No. 4,979,747) discloses a golf ball that has dimples having large diameters and small depths and dimples having small diameters and large depths.
JPH4-231079 (U.S. Pat. No. 5,016,887) discloses a golf ball in which values obtained by dividing the depths of all dimples by the diameters thereof are the same.
JPH5-237202 (U.S. Pat. No. 5,158,300) discloses a golf ball in which the edge angles of all dimples are the same.
The greatest interest to golf players concerning golf balls is flight distance. In light of flight performance, there is room for improvement in the shapes of dimples. An object of the present invention is to provide a golf ball having excellent flight performance.


A developing roller includes a roller main body disposed to face, without contact, an outer circumferential surface of an image carrier. A resin coat layer has been formed on an outer circumferential surface of the roller main body, the resin coat layer being made of a resin material having electric conductivity. A product of resistance component Rs [Ω] and electrostatic capacitance component Cs [F] in AC impedance Z of the roller main body is in a range from 2.79×10−7 to 6.77×10−5, the AC impedance Z being obtained when an AC voltage of a predetermined frequency f is applied.

The present disclosure relates to a technology of a developing roller that is disposed to face, without contact, the outer circumferential surface of the image carrier.
A developing device is installed in an image forming apparatus which is a copier, a printer or the like and forms an image on a paper sheet based on the electrophotography. The developing device develops, by toner, an electrostatic latent image formed on an image carrier such as a photoconductor drum. As the developing method, a so-called two-component developing method is known which uses two-component developer including magnetic carrier and toner to develop a toner image on the image carrier. As an example of the two-component developing method, there is conventionally known a contactless developing system called "interactive touchdown developing system". In the interactive touchdown developing system, a developing roller and a magnetic roller are used. The developing roller is disposed at a predetermined distance from the image carrier. A magnet is embedded in the magnetic roller. The magnetic roller draws up the magnetic carrier as well as the toner, and holds them on the surface thereof. The magnetic roller forms a magnetic brush thereon to transfer only the toner to the developing roller, and form a toner thin layer on the developing roller. An AC electric field is generated by a developing bias including an AC component applied to the developing roller, and the AC electric field flies the toner from the developing roller and causes the toner to adhere to the electrostatic latent image on the image carrier.
Meanwhile, the developing device is required to have high developability. That is, the developing device is required to surely cause toner to be flown from the developing roller and adhered to the electrostatic latent image on the image carrier. To improve the developability, the resistance of the developing roller may be decreased to increase the magnitude of the developing electric field (an electric field between the developing roller and the photoconductor drum). However, when the resistance of the developing roller is decreased, the adhesion (image force) of toner not having been used in the developing to the surface of the developing roller increases, thereby it becomes difficult for the not-used toner to separate from the developing roller. When the toner carried on the surface of the developing roller is held there for a long time without being separated, a toner filming occurs to the surface of the developing roller, resulting in a roller contamination. On the other hand, when the image force is reduced, it becomes easy for the toner to separate, the roller contamination by the toner filming is restricted, and the contamination resistance is improved. However, when the image force is reduced, the toner easily separates from the developing roller and unnecessarily adheres to the image carrier. In that case, a toner fogging occurs and the developability by the toner is decreased.

Developing roller, developing device, and image forming apparatus including developing device


An electric drive comprises a base (1), an electric motor including a frame (2) and, mounted therein, a stator (3) and a rotor (4), a lead screw (5), an axial force limiter disposed between a bearing surface (12) of the base (1) and a pressure surface (13) of the frame (2) of the electric motor and comprising washers (9) and (10) with a resilient member (11) placed therebetween. The electric motor frame (2) is axially displaceable and kinematically coupled with the axial force limiter. The base (1) is provided with a stop (14) facing the pressure surface (13) of the frame (2), and the frame (2) is provided with a stop (15) facing the bearing surface (12) of the base (1).

The electric drives mounted on the actuators of pipe valves must be provided with limiters of the axial force (torque) transmitted to the actuator. It is generally preferred that this axial force limiter be available both when opening the stop valves and when closing the same. This necessitates the provision of a pair of limiters, resulting in increased overall dimensions of the electric drive.
Known in the art is an electric drive comprising an electric motor, a lead screw coupled to the actuator and connected with the shaft of the electric motor by a helical gearing, an axial force limiter formed by a pair of springs disposed along the electric motor shaft, with the drive gear of said gearing interposed therebetween and capable of being axially displaced. Each of said springs is connected with the corresponding microswitch (DE, C, 155950).
With an excessive axial force acting on the lead screw, the displacement of the screw is slowed down, and the driven gear of the gearing mounted thereon also slows down its rotation, while the drive gear keeps rotating. Due to the force component directed along the axis, the drive gear moves axially to either side, depending on the direction of the lead screw motion, against the pressure of the corresponding spring which is compressed to open the corresponding microswitch, and the electric motor is stopped.
Said electric drive suffers from a disadvantage consisting in its larger size as a result of the two springs provided in the axial force limiter and disposed along the electric motor shaft, for two opposite moving directions of the lead screw.
Known is an electric drive comprising a base, an electric motor including a frame with a stator and a hollow rotor mounted therein, a lead screw located in the hollow rotor, an axial force limiter comprising a washer and a resilient member with one end thereof contacting the washer, an assembly kinematically coupled with the axial force limiter and capable of being axially displaced, the axial force limiter being interposed between the bearing surface of the base and the pressure surface of the assembly kinematically coupled with the axial force limiter (FR, B, 2274859). In this apparatus, the assembly kinematically coupled with the axial force limiter is represented by a sliding nut locked against rotation relative to the rotor by means of a key and capable of being axially displaced, to some extent, with respect to the rotor. The extent of this displacement is limited by a pair of axial force limiters disposed on either side of the sliding nut, in its moving direction. When the axial force transmitted to the actuator is exceeded, the lead screw stops, and the sliding nut working against the force of the resilient member in a particular axial force limiter (depending on the direction of the lead screw motion) starts moving axially along the thread of the lead screw that has stopped, with respect to the rotor, thus limiting the axial force transmitted to the actuator.
One drawback of the apparatus described consists in considerable longitudinal dimensions of the electric drive due to the presence of two axial force limiters disposed on either side of the sliding nut. Besides, the two axial force limiters present in the apparatus result in its complicated design.

prospekt Nastavnikov, 25, Korpus 3, kv. 101

ulitsa Proletarskaya, 107, kv. 76, Kolpino


A thin film transistor substrate, a display apparatus using the same and a manufacturing method thereof are provided. The display apparatus includes a thin film transistor substrate, a top substrate and a display medium layer. The thin film transistor substrate includes a composite plate and several thin film transistors. The composite plate includes a core material structure and two insulation structures. The core material structure includes a metal layer. The two insulation structures are respectively disposed at two sides of the core material structure so as to sandwich the core material structure therebetween. The thin film transistors are disposed on the composite plate. The display medium layer is disposed between the thin film transistor substrate and the top substrate.

1. Field of the Invention
The invention relates in general to a thin film transistor substrate, a display apparatus using the same and a manufacturing method thereof, and more particularly to a thin film transistor substrate with a composite plate, a display apparatus using the same and a manufacturing method thereof.
2. Description of the Related Art
As the application of display apparatus is getting more and more popular, the research and development in the elements has become one of the prominent tasks for manufacturers. Originally, most display apparatus adopts glass substrate due to its excellent performance in transparency, surface flatness, water/oxygen resistance and dimension stability (that is, low coefficient of thermal expansion). However, glass substrate is not suitable for flexible or impact resistant display apparatus for its poor strength, fragility and poor flexibility. Currently, some display apparatus replace glass substrate with plastic substrate to achieve better performance in toughness, strength, specific weight and flexibility.
However, plastic substrate cannot achieve the same performance with glass substrate in temperature resistance, chemical resistance, water/oxygen resistance and dimension stability. Particularly, the performance of plastic substrate requires low-temperature or other specific manufacturing ways for passing existing manufacturing specifications. Besides, since water and oxygen are critical to stability and lifespan of electronic elements, poor water/oxygen resistance makes the properties of the product hard to maintain. In addition, the plastic substrate has poor rigidity, the bending level of the plastic substrate hard to meet the operation specifications of existing manufacturing machines even when the thickness is close to glass substrate. Therefore, the plastic substrate must be combined with a rigidity carrier in process. After process finished, the rigidity carrier and the plastic substrate need to be separated, incurring additional materials and costs.
Some manufacturers try to replace glass substrate with metal foil to provide excellent performance in terms of rigidity, strength, toughness, flexibility, temperature resistance, chemical resistance, water/oxygen resistance and dimension stability. However, metal having large specific weight, metal plate cannot meet the lightweight requirement of display. In order to reduce the weight, after process finished, thin film transistors are covered by a protection layer and the bottom surface of metal plate is etched and thinned to obtain a metal foil. Thus, using metal foil incurs high cost and transistors may be damaged during the etching/thinning process. Thus, find some material to replace glass substrate has become a prominent task for the industries.

Thin film transistor substrate and display apparatus using the same and manufacturing method thereof


Economic development and workforce development information, such as historical and forecasted economic data regarding economic variables including but not limited to jobs, unemployment, wages, and/or productivity, etc., and/or any changes therein are stored in a database. Access to the data stored in the database is provided via a web portal running on a data server coupled to the Internet. Users access the data using a web browser client. Data stored in the database are updated from time to time, such as, for example, monthly and/or quarterly. User tools are provided for assembling and processing the data in ways meaningful to the user.

In a dynamic economy, the fortunes of industries adjust because of changes in preferences, technology, international trade, and government regulations. As industries change, demand for occupations and skills adjust as does the need for various training and instructional programs. Accordingly, an information system is needed to help economic and workforce developers, policymakers, educators, incumbent workers, jobseekers, and students assess alternative paths that take into account the expected need for occupations and skills.
The systems and methods described herein provide a comprehensive arrangement for gathering raw data such as economic development and workforce development information including historical and forecasted economic data, organizing that data in a database in a manner in which it can be usefully mined, analyzing the data with a plurality of user selectable analytical tools and presenting mined and organized data to an end user in a way that answers a user's inquiry via a web-based interface. Inventions described herein relate to the manner of gathering the data, the manner of organizing it, the manner of mining that data, the tools that can be selected and utilized by the end user and the overall manner of providing these data in a convenient web accessible manner.
In the past, some of this type of information has been obtained from various government documents and websites. However, the process of collecting and linking the data to make it useful has been cumbersome and often required strong analytical skills. Consequently, information seekers either ignored the information or did not ascertain the full implication of the available information. In this environment, analysts were forced to spend hours collecting, manipulating, and analyzing the disparate sources of data. By the time all necessary data were collected, adjusted, and analyzed, the information often became outdated, sometimes leading to incorrect decisions.
In order to provide a system for better-decision making for economic and workforce developers, policymakers, educators, incumbent workers, jobseekers and students, there is now provided a web-based information system including decision support to assist users in considering alternative decision paths. Such alternative decision paths include, for example, whether to offer or take secretarial training in light of expected growth rates and future job opportunities in a local economy. The inventions are collectively referred to as a "system" throughout this document. The system described herein is implemented using a relational database and graphical user interface that allows a user to query the database to mine the appropriate information addressing a question and then report the mined information in the form of reports, charts, tables, and maps. Dynamic decision support (e.g., as to whether or not to offer certain courses at an educational institution or to attract particular industries to a region) provides information and recommendations to decision makers, tailored to the geographic region, industry, and/or occupation required by the user.
The use of the claimed system allows a user to increase productivity and leads to better decision making. Users are able to quickly select and utilize analytic tools that provide answers to questions that formerly took days or weeks, even months to compile. Also, help tools are provided to guide the user with information and guidelines for interpreting and using data mined from the database.
Economic development, workforce development and education key information outputs, such as historical and forecasted economic data regarding economic variables including but not limited to jobs, unemployment, wages, and/or productivity, etc., and/or any changes therein are stored in a database. The presently preferred database is an SQL database. Access to the data stored in the database are provided via a web portal running on a data server coupled to the Internet. Users access the data using a web browser client. Data stored in the database are updated from time to time, such as, for example, monthly and/or quarterly. User tools are provided for assembling and processing the data in ways meaningful to the user.
The user tools allow the historical and/or forecasted economic data to be provided in various forms useful to the end user including, for example, charted and/or rendered forms. The economic data can be correlated to a user-selected economic variable and/or any of a wide variety of user-selectable parameters, such as:                region (e.g., state, metropolitan statistical area (MSA), planning district commission (PDC), workforce investment area (WIA), county, and/or city, etc.);        industry (e.g., 2- through 5-digit standard industrial classification (SIC) and/or North American Industry classification system (NAICS), and/or uncoded industry, etc.);        employer characteristic (e.g., size, legal structure, headquarters location, historical behavior (e.g., rapid growth, local growth, quality of growth, prone to layoffs, etc.), etc.);        occupation (e.g., standard occupational code (SOC), etc.); and/or        worker attribute (e.g., credential, knowledge, experience, skill, and/or ability, etc.);        demographics (e.g., age, gender, education, etc.); etc.
Historical and/or forecasted economic variables include, for example, jobs, occupations, and/or attributes. These historical and/or forecasted economic variables can comprise statements and/or estimates of supply and/or demand, which can utilize and/or integrate any of numerous potential factors. For example, historical and/or forecasted economic variables such as wages, jobs, occupations, worker attributes, employment, and/or unemployment, etc. They can relate to, be determined from, and/or comprise absolute values and/or changes, events, emergences, growths, declines, shifts, trends, and/or patterns relating to factors such as:                macro-economics (e.g., gross domestic product (GDP), per-capita income, prices, inflation, interest rates, exchange rates, balance of trade, government spending, etc.);        population;        demographics;        consumer spending;        travel and/or tourism;        technology (from the broadest to the narrowest sense of the term);        number of employed;        type of employed (e.g., full-time, part-time, hourly, salary, etc.);        number of unemployed;        type of unemployed (e.g., underemployed and/or actively seeking, etc.);        emerging workforce (e.g., arising from academic and/or other training, entry- and/or lower-level positions, horizontally transitioning, in-migration, etc.);        fading workforce (e.g., retiring, expiring, transitioning away (vertically and/or horizontally), out-migration, etc.); and/or        personal characteristics (e.g., education, sex, and/or age, etc.); etc.
Using government-provided data for occupation-related worker attributes, occupations can be automatically mapped into occupation groups using data mining and mapping tools incorporating algorithms. Within each occupation group, training ladders can be generated, the training ladders indicating what worker attributes are needed and/or desired to obtain and/or maintain each occupation, to move from one "rung" to another in a "vertical" progression in a career, and/or to "horizontally" change occupations and/or careers, etc.
A user-selected worker attribute, from among many available worker attributes, can be mapped to degrees, certificates, courses, trainings (including training that is on-the-job, hands-on, and/or experiential, etc.), and/or salaries by industry etc., that are suggested and/or required to obtain and/or maintain that selected worker attribute. This mapping can extend to post-academic, post-graduate, graduate, undergraduate, associate, military, technical, vocation, high school, pre-high school, and/or other degrees, certificates, courses, and/or trainings.
This mapping can be general and/or specific. For example, one or more particular courses of study can be mapped to specific regional academic institutions offering each course, the times the course is offered, the capacity of the course, admission and/or registration procedures, the cost of the course, the availability of and/or requirements for financial aid, textbooks and/or other materials required and/or suggested, etc. Similar mapping can be provided for off-campus coursework, such as on-line and/or correspondence courses. Conversely, such mapping can forecast the demand and/or need to provide various degrees, certificates, courses, and/or trainings, etc.
For any user-selected parameter, performance related to any relevant economic criteria can be determined, measured, estimated, rendered, and/or tracked. Likewise, objectives, goals, and/or plans related to any user-selected economic criteria can be selected, entered, measured, and/or tracked at any desired time and/or frequency. Notifications can be provided if performance deviates by a user-determined value from a goal, average, and/or norm, etc. Examples of economic criteria can include:                entrepreneurial activities;        productivity;        wealth creation;        employer retention;        knowledge base and/or workers;        economic diversity;        utilization of community assets (e.g., academic and/or training resources, such as institutions, facilities, and/or personnel; programs; services, etc.); and/or        commuting patterns; etc.
Thus, for example, for a given region, a goal related to entrepreneurial activities can be set and performance against that goal by the region can be tracked and/or reported in the balanced scorecard. A notification can be provided, such as via an e-mail message to a predetermined individual, if for example, quarterly performance exceeds the goal by more than 5 percent, and/or falls below the goal by more than 3 percent.
For any user-selected parameter, leading and/or lagging indicators can be used to determine performance related to any relevant economic variable and/or criteria. For example, with respect to knowledge base, knowledge workers, worker credentials, and/or worker skill level, a leading indicator such as high school drop-out rates, and/or a lagging indicator such as general educational development (GED) award rates, can be utilized.
For any user-selected region, a desirability index can be generated and/or rendered, the index providing an indication of the desirability of attracting and/or retaining one or more user-selected and/or known industries, employers, and/or occupations, etc. The index can be based on knowledge and/or estimates regarding factors related to each industry, employer, and/or occupation, etc., such as whether it pays above-market wages, whether it is likely to grow, whether it is likely to hire locally, and/or whether it provides worker training, etc. The factors can be filtered, adjusted, and/or weighted as desired.
The database contains a critical mass of workforce and economic development data (refreshed and supplemented regularly), the building blocks to wealth, to users at every level of economic development, workforce development, education reform, partnership consulting, human resources, corporate operations, and so forth. The interactive web-based system described herein provides capabilities that include regional specific economic indicators like employment trends, regional wealth, productivity of a region's workforce, entrepreneurial activities, high-technology trends, and forecasts for occupations and industries for every metropolitan statistical area, planning district commission, workforce area, county and city in a state.
Using the system a user can obtain specialty information by ad-hoc query about the economic trends for the users region in the state. It removes traditional barriers between workforce and economic development analysis by aggregating and mining data for each user to understand the dynamic relationship of key economic indicators on current and future industry and occupation trends unique to their region. Brick and mortar economies undergo chum and the new economy emerges seeking a knowledgeable savvy labor market. The system matches trained workers to available jobs and allows workforce development officials to underpin economic development strategies by providing an inventory of workers who are:                Employed        Unemployed        Underemployed        Emerging
The system delivers secure, responsive, high-quality, customer-oriented services and support fostering a productive web-enabled database capable of mining key economic and workforce development indicators. Analyzed and organized data from the system can be used as building blocks for engineering a vibrant regional workforce aligned to the strategic goals of the economic development communities. The system is easily and rapidly accessed via a web interface and provides seamless data mining of critical analytics that result in a reliable information coordination environment between workforce development officials, economic development practitioners, education reformers, high-technology industries and occupations, and job seekers.
User selectable analytical tools tie together high-quality government and CEA data along with help tutorials to identify and select alternative actions for a region.
Economic Development officials can benefit from using the system. Economic Development agencies can make informed decisions about their regions industry capabilities that include the knowledge and skills attributes of the local workforce. Among the user tools provided, the system includes the following dashboard analytics (vital economic statistics) for the economic developer end user:                Labor Market and Industry Demand Forecasts by Occupation        Entrepreneurial Activities        Labor Market Inventory        Employment and Unemployment trends
The user, via a standard web browser and Internet access, is presented with a "dashboard" of choices from which he can mine data from the SQL database and apply analytical tools. The user can use this dashboard presentation to drilldown to specific data related to questions at hand and obtain more detailed information about a region's economic and workforce metrics. Gaps for skills shortages allow workforce agencies to develop regional training strategies for retooling the local labor market based on the economic development regional and local strategies for the regions. Labor and industry demands offer a roadmap for strategic initiative planning and resource allocation based on the best fit industry to workforce alignments.
The system is useful for Workforce Development officials. Workforce Development (WD) officials supply Economic Development (ED) and Education (EDU) reform process owners with current data about the attributes of the local workforce. The system provides a web-based, interactive method to track a region's changing workforce performance relative to a baseline and goals over time. WD can provide ED with the following important statistics about a region's workforce today and discuss strategies for future workforce initiatives to meet the needs of potential firms desiring to locate in the WD and ED region:                Employed        Unemployed        Underemployed        Emerging
The system can serve as a useful tool in recruiting new firms and employees to a geographical region. It provides information about the current and future economy for the region as it relates to the supply of workers and the demand for workers based on industry needs. Identification of supply and demand results in the occupational and instructional program gap metrics as well as current and projected inventories of occupations and skills.
It has been nearly impossible to find the caliber of data required for understanding the workforce capabilities for all communities in a given state. It is a daunting task for economic development folks to find as complete a source of quality, up-to-date, and objective data that they can use to benchmark their community against any other in the state. The system includes complex analytical tools that calculate the aggregate skills, knowledge and abilities of the region's workforce and compare these profiles to the current and future demands for these attributes by industry and labor market demands using CEA proprietary technology.

System and method for managing economic development, workforce development and education information


A catheter having a balloon (10) which has at least one wing (12) in the undilated state, the balloon having at least one fold element (11, 11′, 31, 32, 41, 42) running essentially in the longitudinal direction for each wing (12), such that in folding the balloon (10), the fold element is arranged in an area of the wing (12) with a minimum in the bending radius, said area running in the longitudinal direction. Also disclosed is a system for introducing an intraluminal endoprosthesis, preferably a stent, into a body cavity consisting of an intraluminal endoprosthesis and a catheter having the balloon as described. Further, disclosed are methods of producing such a catheter and such a system.

Catheters are tubes or tubing of various diameters that can be inserted into the respective body cavity to be treated. So-called balloon catheters, which are used mainly in angioplasty to dilate or reopen a vessel, have a guide wire that is first inserted into the vessel to be treated. Then a tube which has an undilated folded balloon in a predefined area of the tube, is advanced along the guide wire up to the site of the blood vessel to be treated so that the balloon is placed in the area of the site of the blood vessel to be treated, e.g., where there is a stenosis. Then the balloon is dilated, i.e., unfolded and expanded, so that the site to be treated is reopened or dilated and the flow of body fluid through the blood vessel is no longer hindered or is not hindered to the previous extent. Finally, the balloon is deflated and removed from the blood vessel along the guide wire. At the same time or thereafter, the guide wire is also retracted out of the blood vessel.
For insertion of balloon catheters, the balloon must first be introduced in a folded, i.e., undilated state, into the body cavity to be treated. With the balloon catheters currently in use, the balloons are folded after being shaped and then are secured by applying compressive forces (referred to as impressing) to the folded balloon. The steps required to do so as well as the corresponding device are complex because high temperatures and long impressing times are required in the impressing step. Furthermore, the heat treatment often results in shrinkage of a balloon, thereby altering the dimensions of the balloon. Another disadvantage of this procedure is that the wing shape is lost after the initial dilatation i.e., the balloon is refolded in a defective manner to some extent or is folded inconsistent with its pre-inflation configuration. This is due to the fact that a fold produced in the traditional way stores very little energy on inflation of the balloon so that the refolding tendency in deflation is low. On retraction of a defectively refolded balloon, an increased pull-back force is required. Likewise, an increased force is required to redilate a stent, to reach a side branch through a stent segment or to pass through a second stenosis.
With traditional catheters, the balloon has wings which run parallel to the axis of the balloon. These balloons create an anisotropic bending moment of the folded balloon. The disadvantage of such folding is that the catheter in the area of the balloon is more susceptible to kinking of the catheter and the wings stand up in tight curves on insertion into the body cavity to be treated so that insertion is prevented. After deflation, wings running parallel to the axis of the catheter may also cause unwanted transverse folding when the inside shaft expands with the balloon in a non-plastic manner. This also requires an increased pull-back force.
Furthermore, balloons that are integrally furnished with an active pharmaceutical substance may release residues of the substance to the surrounding body fluid at the wrong point in time, e.g., during retraction in the event of uncontrolled refolding. This may cause adverse effects.
For purposes of the present disclosure, the term "active pharmaceutical substance" (also known as "active therapeutic substance") means an active ingredient (medication) of plant, animal or synthetic origin or a hormone which is used in a suitable dosage as a therapeutic agent to influence conditions or functions of the body, as a substitute for active ingredients, such as insulin, that are synthesized naturally by the human or animal body and to eliminate disease pathogens, tumors, cancer cells or exogenous substances or to render them harmless. The release of the substance in the environment of the endoprosthesis has a positive effect on the course of healing or counteracts pathological changes in the tissue due to the surgical procedure and/or serves to render malignant cells harmless in oncology.
Such active pharmaceutical substances have an anti-inflammatory and/or antiproliferative and/or spasmolytic effect, so that, for example, restenoses, inflammations or (vascular) spasms can be prevented. In certain exemplary embodiments, such substances may consist of one or more substances from the group of active ingredients consisting of calcium channel blockers, lipid regulators (such as fibrates), immunosuppressants, calcineurin inhibitors (such as tacrolimus), the antiphlogistics (such as cortisone or diclofenac), anti-inflammatories (such as imidazoles), antiallergics, oligonucleotides (such as dODN), estrogens (such as genistein), endothelializing agents (such as fibrin), steroids, proteins, hormones, insulins, cytostatics, peptides, vasodilators (such as sartans) and substances with an antiproliferative action, such as taxols or taxans, in this case, preferably paclitaxel or sirolimus.
German Patent No. 691 19 753 describes a balloon catheter having a catheter body and a balloon arranged along the length of the catheter body. The balloon is also provided with a device for its inflation and deflation from the outside and a device for supplying a medication or a combination of medications for treatment or diagnosis within a hollow organ of a body when the catheter is positioned in the hollow organ and inflated. The supply device has microcapsules on the outside of the balloon where the microcapsules are secured in folds on the balloon such as those formed when the balloon is shrunk. The microcapsules here are designed so that the microcapsules can be ruptured or degraded. The microcapsules open when they remain on the walls of the hollow organ. The capsules may also rupture due to the application of ultrasonic waves.
The disadvantage of the catheter described in German Patent No. 691 19 753 is that microencapsulated medications must be used to implement the dispensing of medications, but microencapsulated medications are expensive and complicated to produce. Furthermore, microencapsulation is not possible for all medications that may be considered. Additionally, a balloon of such a catheter provided with microcapsules has a comparatively large diameter whose profile cannot be used in practice and which makes the catheter rigid and inflexible. Furthermore, the medication can be rubbed off not only at the site to be treated but also on insertion or dilatation of the balloon. This increases the side effects associated with the treatment.
Balloon catheters may also be used to introduce intraluminal endoprostheses to a site to be treated in a body cavity.
Intraluminal endoprostheses in the form of stents are currently widely used because they allow a simple and inexpensive treatment. These stents often have a tubular or hollow cylindrical basic mesh which is open on both longitudinal ends. The basic mesh of such an endoprosthesis is inserted by means of a catheter into the hollow cavity to be treated and is then dilated or released. After removal of the catheter, the endoprosthesis serves to support the body cavity. Such stents have become established, in particular, for treatment of vascular diseases. Through the use of stents, constricted areas in the vessels can be dilated so that the vascular lumen is enlarged.
Intraluminal endoprostheses are often provided with active pharmaceutical substances which are released in the body over a certain period of time.
These active pharmaceutical substances may serve, for example, to prevent restenoses or agglomerations. Due to the release of active pharmaceutical substances with which such intraluminal endoprostheses are provided, it is possible to perform merely a local treatment, i.e., elution of an active ingredient essentially only in the tissue surrounding the intraluminal endoprosthesis. This process is also known as local drug delivery ("LDD"). The treatment site where the active ingredient should manifest its pharmacological effect is thus directly adjacent to the site of implantation of the intraluminal endoprosthesis.
Intraluminal endoprostheses that consist of a material which is subject to biodegradation are currently also in use. For purposes of the present disclosure, biodegradation means hydrolytic, enzymatic or other metabolic degradation processes in a living organism caused mainly by the body fluids coming in contact with the endoprosthesis and leading to a gradual dissolution of at least large portions of the endoprosthesis. The term "biocorrosion" is often synonymous with the term biodegradation. For purposes of the present disclosure, the term "bioabsorption" includes the subsequent absorption of the degradation products by the living organism. Such biodegradable materials may consist of polymers or metals. The abbreviation AMS (absorbable metal stent) is also often used in conjunction with stents. Such stents contain a biodegradable metal, preferably magnesium and/or a magnesium alloy. Other degradable metals that may be used include iron, zinc, tungsten and alloys thereof.
In intraluminal endoprostheses consisting of a biodegradable material and provided with an active pharmaceutical substance, the problem often arises that the active pharmaceutical substances do not adhere properly to the basic mesh of the endoprosthesis or do not function in the desired manner because, in the biodegradation of the endoprosthesis, the pH of the environment may change and/or the endoprosthesis may undergo uncontrolled corrosion and thereby undergo a high degree of penetration. Release of the active pharmaceutical substance thus does not take place in the desired manner or within the desired time frame.

Catheter, system for inserting an intraluminal endoprosthesis and method for manufacturing same


In certain embodiments, a mobile device includes a sensor, one or more processors, and a memory. The memory stores computer-executable instructions that, when executed by the one or more processors, cause the one or more processors to perform operations including determining a first geographic location based on wireless signals received as part of a wireless-based mobile device positioning system. The operations include accessing a geographic database that includes data representing a number of geographic locations and properties associated with the geographic locations, and a mapping between measureable values of a type and particular geographic locations. The operations include determining, using the geographic database, candidate geographic locations for adjusting the first geographic location. The operations include accessing a particular value of the type determined according to a measurement of the sensor and determining a second geographic location based on the candidate geographic locations and on the particular value and the mapping.

It is often desirable for a mobile device, such as a smartphone or vehicle, to determine its geographic location. The mobile device (or another entity) may use the determined geographic location of the mobile device for a variety of applications. For example, the geographic location may be used by a navigation application on the mobile device to provide routing information to a user of the mobile device. As another example, the geographic location may be used by an application of the mobile device to suggest businesses or services in proximity to the mobile device. As another example, the geographic location may be used to track freight or the progress of a package or other material in transit to a destination such as a residence. As another example, the geographic location may be used to facilitate traffic engineering, such as for self-driving vehicles. A mobile device may determine its geographic location using a global navigation satellite system (GNSS), such as the Global Positioning System (GPS). Other forms of wireless communication, such as BLUETOOTH, Wi-Fi, or cellular communication, may be used to determine the geographic location of the mobile device.

Determining geographic location of a mobile device using sensor data


The present invention is a mono-functional branched organosiloxane compound that is liquid and shown by the following general formula (1)Ma-1MRa-2Db-1DRb-2Tc-1TRc-2Qd-1  (1)wherein M=R13SiO0.5, MR=R12R2SiO0.5, D=R12SiO, DR=R2R1SiO, T=R1SiO1.5, TR=R2SiO1.5, and Q=SiO2, where R1 represents a group selected from an alkyl group having 1 to 30 carbon atoms, and so on, R2 represents a hydrogen atom, and so on, a-1 represents an integer of 1 or more, b-1 and c-1 each represent an integer of 0 or more, and a-2, b-2, c-2, and d-1 each represent 0 or 1, provided that c-1, c-2, and d-1 are not simultaneously 0, a total of a-2, b-2, and c-2 is 1, and when b-1 is 0, a-1 is 2 or more and a total of c-1 and d-1 is 1 or more. There can be provided a novel mono-functional branched organosiloxane compound having a branched structure, and a method for producing the same.

An organosiloxane having a functional group at one terminal of its molecular chain is used as a raw material of a graft organic polymer that has organosiloxane chain branches by reactivity of the functional group. The organic polymer incorporating this organosiloxane has high functions such as powder dispersibility, water repellency, antifouling property, non-adhesiveness, heat resistance, wear resistance, biocompatibility, and oxygen permeability.
It is conventionally known that the organosiloxane having a functional group at one terminal of its molecular chain can be synthesized by ring-opening polymerization of hexamethylcyclotrisiloxane, followed by capping the reaction terminal with terminating agents containing various functional groups (Patent Literature 1 and Patent Literature 2).
It is also known that an organosiloxane having a (meth)acryl group at one terminal can be synthesized by ring-opening polymerization of hexamethylcyclotrisiloxane using trimethyl silanol or 3-methacryloxypropyldimethyl silanol as an initiator in the presence of 5-coordinate silicon catalyst, followed by terminating the reaction by 3-methacryloxypropyldimethylchlorosilane or trimethylchlorosilane.
In the above method, however, the organosiloxane of the main chain is not branched and has inadequate oxygen permeability, sliding property, release property, dispersibility, and so on.
A method for synthesizing a branched siloxane is proposed in Patent Literature 3, which discloses a method for producing a branched tetrasiloxane in high yield by hydrolysis reaction in the presence of an acid catalyst. However, a method for polymerizing the siloxane has not been disclosed. Synthesis methods reported by Hrecaycho and others enable a target product to be obtained in high yield, but require a specific catalyst (Non Patent Literatures 1 and 2).
Patent Literature 4 and Patent Literature 5 propose compounds having a dendrimer structure, which are one-molecular-chain-terminal functionalized organosiloxane compounds having an extremely branched organosiloxane chain. A material using this compound is excellent in coating property, but a method for producing the same requires complicated steps and a specific starting material for synthesis.

Mono-functional branched organosiloxane compound and method for producing the same


Method and apparatus for removing high density particles from a biological fluid such as blood using aphaeresis. The particles are preferably sub-micron in size and denser than normally occurring components of the fluid and can be removed by a modified reverse-flow gradient density centrifuge without damaging the fluid. The particles can be provided to a patient in vivo or added to the fluid after it is removed from the patient. Some particles can carry and deliver oxygen and scavenge carbon dioxide. Other particles are conjugated to capture molecules for attaching to targets such as cancer cells, viruses, pathogens, toxins, or excess concentrations of a drug or element in the fluid. The targets are then removed from the fluid along with the particles by the aphaeresis instrument.

Note that the following discussion refers to a number of publications and references. Discussion of such publications herein is given for more complete background of the scientific principles and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Many adverse health conditions result in the accumulation of abnormal compositions in the blood. For example, excess drugs given to patients, self consumed drugs and alcohol, and other consumables may be reflected in abnormal blood compositions. Some of the components found in the blood of affected individuals are used as diagnostic markers for disease and health conditions, while others may contribute to further problems by causing secondary symptoms and conditions. Medical treatment in such cases aim at reducing, masking or counteracting the effects of specific molecules and toxins, and supporting body processes that facilitate their clearance from the body. When symptoms become severe, the body can no longer handle the abnormal compositions, and facilitated medical intervention may be insufficient. Patients may suffer permanent damage or even death as a result.
Aphaeresis is a well-established clinical method that is used to separate components of blood for treatment or donation. In this method components of the blood which span a relatively narrow range of densities, but a much wider range of molecular weight and size, can be efficiently, rapidly, and continuously separated. Because blood is a heterogeneous non-ideal fluid, and most of the molecules and/or cells that are diagnostic for a disease fall within the density range spanned by the largest and smallest blood components, conventional aphaeresis is often ineffective or inefficient as an exclusive therapeutic device to collect and reduce the body's disease load, except possibly in cases where a major blood component is exchanged for a similar component obtained from healthy individuals (e.g. transfusion of red blood cells, harvesting of stem cells, platelets, white cells, removal of defective cells, etc.). Even some cells like metastatic cancer cells and stem cells are similar enough to normally present blood corpuscles to make separation difficult. Separation by aphaeresis is based on density and many undesirable components cannot be separated by density.
There are many situations where separation of targets from fluids is desirable. For example, patients with malignant cancer are typically treated with radiation and chemotherapeutic agents by scheduled infusion. Despite these efforts for many cancers the frequency of recurrence and metastasis remains significant. In some cases the cancer may be kept at bay if evidence for recurrence or continued malignancy could be caught early and the therapy modified appropriately. However, detecting evidence for metastatic cancer cells at early stages is difficult. By the time imaging and blood chemistry markers are able to reveal a problem the metastatic cancer is advanced and more aggressive treatment is required. Exacerbating this problem is the potential for some cancer cells to change their resistance to drug over time, which suggests that if effective detection and eradication could occur at early stages then patient prognosis could be significantly improved. Moreover, when present in sufficient quantity, certain cancer cells can be isolated from tissues such as blood and detected using immunological methods. Diagnosis therefore relies on the ability to find these diseased cells, which may be present in exceedingly small quantities.
Treatments of some viral diseases are available and preventable by immunization, but others are not. A patient who has not been immunized for a viral disease may be able to develop natural immunity and eventually build resistance to the disease. During this period, however, the patient may suffer from fever, infection and even life threatening symptoms, despite the intervention of indirect treatments to ease symptoms. Thus, being able to directly reduce the proliferation of viruses in the body of patients in crisis situations could bring significant benefits leading to recovery from viral diseases. In addition, it has become evident that methods to remove viruses (e.g., HIV, Ebola, or Hepatitis C) early in the infection greatly impacts prognosis and the effect of therapeutic treatments. Similarly, studies have shown that reducing the initial exposure load to toxins (e.g. snake bites, bacterial, or insect bites) can dramatically affect recovery, even avert death. Whether or not anti-toxin is available, by reducing the initial toxin load by removing toxins from the blood, neurotoxic, hemotoxic, necrotic, and other damage, as well as time spent in the hospital, may be minimized and disfigurement and death prevented.
Chelation therapeutics are drugs that are taken by patients exhibiting signs of excessively high metal levels such as iron. Taken by injection or orally these drugs supplement the transfusion therapy and prolong patient well-being and avoid crisis. Compliance with injection regimes has been difficult, but greatly improved with new oral medications. Bioavailability of oral drugs is still problematic and side effects arising from the larger than needed dosages that must be taken to reach consistent therapeutic levels is still an issue. The ability to lower iron levels in the blood could reduce side effects of transfusion therapy as well as alleviate the suffering of those with excess iron in the blood.
Patients with chronic hemoglobinopathies and other hemolytic diseases are typically treated by regular transfusion to replace lost oxygen carrying function and remove defective cells and their breakdown products. However, unlike the blood cells normally produced in the body, transfused blood cells are more fragile and tend to break down quicker in the blood stream. This leads to release of free iron from hemoglobin into the blood and eventual accumulation of iron in tissues and organs since the normal transferrin/ferritin network becomes overloaded and clearance of iron from the body cannot keep up. In those individual with defective iron clearance systems such as those with iron overload syndrome, the problem is even more acute.
In case of sickle cell anemia, the red blood cells (RBC) of patients are hemolyzed and the hemoglobin (HbS) released in the plasma become a cause of severe oxidative stress. Specifically, intravascular release of the tetrameric Hb results in its disassociation into a dimeric form. As a reactive molecule, hemoglobin can generate oxidant species. Outside a red blood cell, hemoglobin can react with plasma compounds, leading to oxidations. Free hemoglobin (Hb) is linked to the susceptibility of deoxyhemoglobin to oxidation, leading to the production of methemoglobin, which has a peroxidative activity and forms further reactive O2 species. Oxidation of methemoglobin also releases hemin, which rapidly associates with membranes, leading to cytotoxicity. The Hb scavenger Haptoglobin (Hp) will irreversibly bind the dimeric form of Hb. The Hp-Hb complex can associate with the receptor CD163, found on the surface of monocytes and macrophages and then endocytosed for removal by degradation in the liver. However, when the binding capacity of Hp is overwhelmed, the hemoglobin (Hb) can reach and overload the absorptive capacity of the kidney (hemoglobinuria), leading to nephrotoxicity. Plasma free hemoglobin (PFH) is one of the causes of serious oxidative side effects in patients with sickle cell anemia (SCA). The PFH circulating in the blood damages the patient's tissues and organs.
Treatment of these diseases mostly relies on drugs, high energy radiation, temperature, immunity, etc., which usually take place while these pathogens still reside in the body of the patient, which causes unwanted side effects. Thus there is a need for a therapeutic method that removes those pathogens/unwanted molecules from the blood circulation of the patient.
Use of retrievable nanoparticles (rNP) functionalized with a capture molecule (rNP-capture molecule) capable of binding to a target of interest if present in solution is useful for removing molecules of interest from fluid especially biological fluid. Mechanical mixing of the solution containing the rNP-capture molecule and its target of interest decreases the segregation of the rNP-capture molecule and its target in solution and enhances the rate of binding of the rNP-capture molecule and target of interest by increasing the rate of random collision. Common mechanical mixing techniques to decrease segregation of molecules in solution include vortexing, tilt mixing, stirring with paddle or magnet, shaking solution with a shaker plate, and inversion mixing for example to induce turbulence. Turbulence may randomly increase the collision frequency between nanoparticles and molecules.

Therapeutic retrieval of targets in biological fluids