Cleavable alkene-containing linkers and supports useful for the solid phase synthesis of chemical compounds, and combinatorial libraries of compounds, are disclosed. Also disclosed are methods of making and using the linkers and supports.

Combinatorial chemistry has recently emerged as an effective method for preparing large numbers of chemical compounds for use, e.g., in the discovery of biologically-active agents such as pharmaceutical drugs. In general, combinatorial chemistry is used to prepare collections of compounds, known as libraries, in which all the members of the library share a common core structural element. Such libraries can be prepared by a variety of methods, including solution-phase synthesis and solid-phase synthesis.
Solid-phase synthesis is usually performed by reaction of compounds which have each been immobilized by a covalent linkage to a solid or insoluble support material. The compounds are attached to the support material, which can be a polymeric resin such as polystyrene or polystyrene copolymer, through a linker, and when the synthesis of compounds is complete, the linker can be cleaved to release the final compound or compounds into solution.
The choice of linker for use in a synthesis depends upon the type of synthetic chemistry to be performed and on the conditions to be employed in the synthesis. In general, a linker is preferably inert to the reaction conditions employed during synthesis of the library, so as to avoid loss of compound by premature cleaving of the compound from the solid support. However, the linker should be selected to permit facile cleavage of the compounds from the solid support when the synthesis has been completed.
Numerous linkers have been proposed for use in solid phase combinatorial synthesis (for reviews, see, e.g., F. Guillier et al. Chem. Rev. (2000) 100(6): 2091-2158). Frequently, such linkers are cleavable under either acidic conditions or basic conditions. However, such linkers are not suitable for the preparation of compounds which are not stable to the acidic or basic conditions required for cleavage.
Other linkers have been developed which can be cleaved under more nearly neutral conditions. However, such linkers may be expensive to prepare and in some cases are not compatible with conditions which may be encountered during synthesis of a combinatorial library.
Accordingly, it would be desirable to provide new linkers which are easily and inexpensively prepared and which are compatible with a variety of reaction conditions.
The present invention relates to compositions and methods useful for performing solid-phase chemical synthesis reactions, including synthesis of combinatorial libraries of compounds. The compositions of the invention include linking moieties that can be cleaved under mild conditions, and are suitable for use with a variety of synthetic reaction conditions.
In one aspect, the invention provides a composition comprising an insoluble support covalently attached to a linker moiety. In this aspect, the linker moiety comprises a group represented by the formula (Formula I):
in which n is 0, 1 or 2; X is CH2, O, S, or NR, in which R is alkyl (which may be substituted) or aryl (which may be substituted); Y is a leaving group, ORxe2x80x2, NHRxe2x80x2, or SRxe2x80x2, in which Rxe2x80x2 is a positively-charged ion, optionally substituted alkyl or optionally substituted aryl; and R1-R5 are each independently selected from the group consisting of H, optionally substituted alkyl or optionally substituted aryl, nitro, alkoxy, aryloxy, cyano, azido, halogen, optionally substituted thioalkyl and optionally substituted thioaryl, and further wherein at least one of R1-R5 is covalently attached to an insoluble support. In certain preferred embodiments, n is 0. In other preferred embodiments, n is 1 and X is CH2. In another preferred embodiment, Y is xe2x80x94OH. In certain embodiments, the insoluble support is agarose; in other embodiments, the insoluble support is polystyrene (including cross-linked polystyrene-divinylbenzene). In other embodiments, the insoluble support can be solubilized in a solvent. In certain preferred embodiments, R2, R3, and R4 are H. In some preferred embodiments, R1 is covalently attached to the insoluble suppor; in other preferred embodiment, R5 is covalently attached to the insoluble support. In certain preferred embodiments, R5 comprises an aminoalkyl group.
In another aspect, the invention provides a method of preparing a chemical compound on an insoluble support. In this aspect, the method comprises the steps of providing a composition of Formula I (in which n, X, Y, and R1-R5 as are defined above); covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; and reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared. In certain preferred embodiments of this method, n is 0. In other preferred embodiments, n is 1 and X is CH2. In another preferred embodiment, Y is xe2x80x94OH, while in other preferred embodiments, Y is a leaving group. In certain embodiments, the insoluble support is agarose; in other embodiments, the insoluble support is polystyrene (including cross-linked polystyrene-divinylbenzene). In other embodiments, the insoluble support can be solubilized in a solvent. In certain preferred embodiments, R2, R3, and R4 are H. In some preferred embodiments, R1 is covalently attached to the insoluble suppor; in other preferred embodiment, R5 is covalently attached to the insoluble support. In certain preferred embodiments, R1 comprises an aminoalkyl group.
In another aspect, the invention provides a method of preparing a chemical compound. This method includes the steps of providing a composition of Formula I; covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared; and cleaving the chemical compound from the insoluble support. In a preferred embodiment, the step of cleaving comprises contacting the chemical compound on an insoluble support with an electrophilic reagent under substantially neutral conditions. In a more preferred embodiment, the electrophilic reagent is I2.
For convenience, certain terms used in the specification and claims are defined below.
The terms xe2x80x9cinsoluble supportxe2x80x9d or xe2x80x9csolid supportxe2x80x9d, as used herein, refer to a solid or insoluble support, commonly a polymeric support, to which a linker moiety can be covalently bonded by reaction with a functional group of the support. Many suitable supports are known, and include materials such as polystyrene resins, polystyrene/divinylbenzene copolymers, agarose, and other materials known to the skilled artisan. It will be understood that an insoluble support can be soluble under certain conditions and insoluble under other conditions; however, for purposes of this invention, a polymeric support is xe2x80x9cinsolublexe2x80x9d if the support is insoluble or can be made insoluble in a reaction solvent and under conditions used to effect the synthesis of chemical compounds on the support, or cleavage of compounds from the support, as described herein.
A variety of supports are known in the art and can be prepared by known techniques. For example, polymers including the carboxylic acid chloride functionality (e.g., xe2x80x94COCl) are known (see, e.g., P. Hodge and D.C. Sherrington, xe2x80x9cPolymer-supported Reactions in Organic Synthesisxe2x80x9d, Chapter 1, (1980)) and can be prepared by treatment of conventional polymer-supported carboxylic acids (e.g., polyacrylic acids) with, e.g., thionyl chloride, oxalyl chloride, and the like. Polymeric supports including sulfonyl chloride functionalities can be obtained by the reaction of a polymer including sulfonic acid moieties with, e.g., thionyl chloride, or by other known methods, for example, the method described in U.S. Pat. No. 5,118,766. Benzyl halide-containing polymers are well known and include chloromethylated polystyrene (e.g., Merrifield resin). Such reactive supports can be reacted with a linker moiety (e.g., through reaction of an amino group of the linker moiety with a resin containing a carboxylic acid chloride) to form a resin-bound linker of the invention. Supports also include materials such as surfaces (e.g., glass or silicon surfaces), beads (such as glass or metallic beads), particles such as microspheres, carbon whiskers or rods, and the like.
In an alternative embodiment, the linker moiety can be attached to a soluble polymeric support such as a polyether moiety (see, e.g., U.S. Pat. No. 5,877,214 to Kim, and references cited therein). Soluble polyether supports have been used for organic synthesis methods in which reactions occur in the solution phase; the polymeric backbone, together with reactive groups, is dissolved in a solvent in which the polymer is soluble. At the conclusion of a given reaction step, a co-solvent (or non-solvent) is added to the reaction mixture, which causes the polymer to become insoluble and to separate from the liquid phase. The polymer, together with the pendant moieties which have been covalently modified, can then be isolated and washed, if desired, as in conventional solid-phase synthesis. Because such polymeric supports are generally handled (e.g., for purposes of purification) through insolubilization as described above, they will be considered to be xe2x80x9cinsolublexe2x80x9d supports for purposes of this invention.
The term xe2x80x9clinkerxe2x80x9d as used herein, refers to a moiety capable of serving as an attachment point for a chemical compound or moiety (i.e., a desired product) that is prepared by solid-phase synthesis. The linker moiety should be capable of retaining the product to the solid support until cleavage of the product from the support is desired, yet permitting cleavage substantially without destruction of the product. Thus, a linker should preferably be substantially inert to reaction conditions used during the synthesis of the product, while being easily cleaved under conditions that do not destroy the product.
The term xe2x80x9ccleavexe2x80x9d or xe2x80x9ccleavingxe2x80x9d, as used herein, refers to the separation of the product from the solid support. In general, a product is cleaved from a solid support when synthesis of the product is complete and the isolation or separation of the product from the solid support is desired. Conditions suitable for cleavage of products from the linkers of the invention are described in more detail, infra.
The term xe2x80x9calkylxe2x80x9d, as used herein, includes cycloalkyl groups and refers to a straight, branched, or cyclic hydrocarbon radical having from 1 to 12 carbon atoms in the carbon chain (3 to 12 ring carbon atoms for cycloalkyl groups). Preferred alkyl groups are lower alkyl groups having 1 to 6 carbons in the carbon chain (3 to 6 ring carbons atoms for cycloalkyls). Alkyl groups also include groups in which the carbon chain is optionally partially unsaturated, as in alkenes and alkynes. Examples of alkyl groups include methyl, ethyl, butyl, isobutyl, sec-butyl, n-octyl, n-decyl, and the like; propenyl, 3-pentenyl, 2-butynyl, and the like. Alkyl groups can also be substituted at one or more positions on the carbon chain with groups such as halogen, hydroxy, amino (including mono- and disubstituted amino groups such as alkyl amino, dialkylamino, arylamino, and diarylamino), C1 to C6 acyloxy, C1 to C6 acyl, C1 to C6 alkoxy, aryloxy, thiol, C1 to C6 alkylthio, thioaryl, alkylcarbonyl, carboxyl, carboxamido, cyano, nitro, and sulfonyl (including alkylsulfonyl, aminosulfonyl and alkoxysulfonyl).
The term xe2x80x9carylxe2x80x9d, as used herein, refers to monocyclic or bicyclic aromatic groups containing from 6 to 12 carbons in the ring portion, preferably 6-10 carbons in the ring portion, such as phenyl, naphthyl or tetrahydronaphthyl. The term xe2x80x9carylxe2x80x9d also includes heteroaryl groups; heteroaryl groups are groups having 5 to 14 ring atoms and 6, 10 or 14 pi electrons shared in a cyclic array; and containing carbon atoms and at least one (optionally two, three, four or five) oxygen, nitrogen or sulfur heteroatoms in the heteroaryl ring system. Examples of heteroaryl groups are: thienyl, benzo[b]thienyl, naphtho[2,3-b]thienyl, thianthrenyl, furyl, pyranyl, isobenzofuranyl, benzoxazolyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, 4H-quinolizinyl, isoquinolyl, quinolinyl, tetrahydroquinolinyl, phthalazinyl, naphthyridinyl, quinazolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, isoxazolyl, furazanyl and phenoxazinyl groups and the like. Aryl groups can optionally be substituted on one to five positions on the aryl ring system with halogen, hydroxy, amino (including mono- and disubstituted amino groups such as alkyl amino, dialkylamino, arylamino, and diarylamino), C1 to C6 acyloxy, C1 to C6 acyl, C1 to C6 alkoxy, thiol, C1 to C6 alkylthio, thioaryl, alkylcarbonyl, carboxyl, carboxamido, cyano, nitro, and sulfonyl (including alkylsulfonyl, aminosulfonyl and alkoxysulfonyl).
The term xe2x80x9caralkylxe2x80x9d or xe2x80x9carylalkylxe2x80x9d as employed herein by itself or as part of another group refers to C1-6 alkyl groups having an aryl substituent, such as benzyl, phenylethyl or 2-naphthylmethyl.
The term xe2x80x9ccycloalkylxe2x80x9d, as used herein, refers to cycloalkyl groups containing 3 to 9 carbon atoms, preferably 4 to 7 carbon atoms. Typical examples are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl.
The term xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d, as used herein, refers to chlorine, bromine, fluorine or iodine with chlorine being preferred.
The term xe2x80x9cleaving groupxe2x80x9d as used herein, is art-recognized and refers to a functionality that upon heterolytic bond cleavage departs with an electron pair. In general, a leaving group will be a functionality that can be readily cleaved from a substrate moiety. One of ordinary skill in the art will be able to select a variety of suitable leaving groups. Examples of leaving groups (or, in some cases, the conjugate acid of a leaving group) include, e.g., carboxylates, halogens, tosylates, mesylates, certain alcohols (including phenols such as pentafluorophenol), N-hydroxysuccinimide (NHS), tetrazoles, triazoles, including 1-hydroxybenzotriazole (HOBT), imidazole, azide, ureas (as the tautomeric form, e.g., from the use of carbodiimide activating agents), cyanide and the like.
In one aspect, the invention provides new linkers and insoluble supports for use in the synthesis of chemical compounds, e.g., for solid-phase synthesis of compounds, including combinatorial synthesis. The synthesized compound(s) are readily released from the linkers of the invention under near-neutral conditions, allowing the preparation of compounds which contain sensitive functional groups that might not survive cleavage conditions which require the use of acids or bases to liberate the desired compounds from the solid support.
In one embodiment, the invention provides a composition comprising an insoluble support covalently attached to a linker moiety, the linker moiety comprising a group represented by the formula (Formula I):
wherein n is 0, 1 or 2; X is CH2, O, S, or NR, in which R is optionally substituted alkyl or optionally substituted aryl; Y is a leaving group, ORxe2x80x2, NHRxe2x80x2 or SRxe2x80x2, in which Rxe2x80x2 is a positively-charged ion (including a proton, an ammonium ion, a metal ion (such as a sodium, potassium, lithium, or other metal ion)), optionally substituted alkyl or optionally substituted aryl; and R1-R5 are each independently selected from the group consisting of H, optionally substituted alkyl or optionally substituted aryl, nitro, alkoxy, aryloxy, cyano, azido, halogen, optionally substituted thioalkyl and optionally substituted thioaryl, and further wherein at least one of R1-R5 is covalently attached to an insoluble support. In a preferred embodiment, n is 0 or 1. In another preferred embodiment, R1 is covalently attached to a solid support and R2-R5 are H.
As described above, the compositions of the invention comprise a support for synthesis covalently bonded to the linker moiety of FIG. 1; the support (which can be a resin (such as polystyrene), agarose, or other supports, e.g., as described herein) can be attached to the linker moiety through a chemical bond or through any moiety (such as a carbon or heterocycle-containing chain or even a cyclic moiety) capable of allowing the linker moiety to a) react with reagents for chemical synthesis and b) release a compound when chemical synthesis is complete. Examples of such attachment moieties are described herein, and can be, for example, C1 to C6 alkyl chain, which alkyl chain can be interrupted by one or two heteroatoms selected from S, O, N, P and Si. In certain preferred embodiments, the alkyl chain is interrupted by one N or O atom.
Certain preferred embodiments of the supports of the invention are described in more detail in the (non-limiting) Examples provided herein. For example, in an embodiment described in Examples 1 and 2, infra, the invention provides a support material of Formula I in which Y is xe2x80x94OLi (the lithium salt of the carboxylate), n is 0, R1-R4 are all hydrogen, and R5 is a linking moiety of the structure xe2x80x94(CH2)3NH-SUP, in which SUP is a solid support (such as polystyrene resin or agarose beads). In the example of Example 3, infra, n is 0, Y is xe2x80x94OH (carboxylic acid), R2, R4 and R5 are all hydrogen, R3 is methyl, and R1 is a bond to a solid support (in this Example, polystyrene resin). In Example 4, infra, n is 0, Y is xe2x80x94OH (carboxylic acid), R2-R5 are all hydrogen, and R1 is a bond to a solid support (in this Example, polystyrene resin). In Example 5, infra, n is 0, Y is xe2x80x94OH (carboxylic acid), R1-R4 are all hydrogen, and R5 is a bond to a solid support (in this Example, polystyrene resin). In Example 6, infra, n is 0, Y is xe2x80x94OH (carboxylic acid), R2-R4 are all hydrogen, R5 is methyl, and R1 is an N-atom-containing attachment to a solid support (in this Example, polystyrene resin). In Example 7, infra, n is 0, Y is xe2x80x94OH (carboxylic acid), R2-R4 are all hydrogen, R5 is methyl, and R1 is an O-containing attachment to a solid support (in this Example, polystyrene resin). In Example 8, infra, n is 1, X is xe2x80x94CH2xe2x80x94, Y is xe2x80x94OH (carboxylic acid), R2-R5 are all hydrogen, and R1 is a bond to a solid support (in this Example, polystyrene resin).
Compositions of Formula I can be prepared according to a variety of methods, including those described herein and other methods which are known to one of ordinary skill in the art. In general, the compositions can be prepared in at least two ways: (A) by preparing the linker moiety and attaching it to a suitable support; and (B) preparing a linker moiety that can be polymerized to form a linker-support composition of the invention.
In general, a linker moiety of the invention will include a carbonyl group spaced, by a distance of 2, 3 or 4 atoms (more preferably, 2 or 3 atoms), from a carbonxe2x80x94carbon double bond. This arrangement permits the cleavage (or release) of a product from the linker by treatment of the linker with an electrophilic reagent. Without wishing to be bound by any theory, it is believed that an oxygen atom of the carbonyl group can, through intramolecular attack upon the carbonxe2x80x94carbon double bond, form a 5-, 6-, or 7-membered ring (a lactone) with concomitant release of the product from the linker. Certain chemical protecting groups are known which are believed to be cleaved through this mechanism; see, e.g., Madsen, R. et al. J. Org. Chem. (1995) 60:7920; Guo, M J et al. Bioorg. Med. Chem. Lett. (1998) 8:2539-2544; and see generally Greene, T. W. and Wuts, P. xe2x80x9cProtective Groups in Organic Synthesisxe2x80x9d 3rd Ed. (1999), New York: John Wiley and Sons. Conditions suitable for cleavage of products from such linkers are described in more detail, infra.
A. Attachment of a Linker Moiety to a Support
A linker moiety of the invention can be prepared in a variety of ways. For example, in a preferred embodiment, a side-chain of the linker (e.g., R4 or R5 of Formula I) can be provided with a reactive group suitable for covalent attachment to a solid support. For example, as described in Examples 1 and 2 herein, an aminopropyl sidechain can be attached to a solid support by formation of an amide bond, e.g., by reaction of the nitrogen atom of the aminopropyl group with an activated carboxyl group of the solid support.
In another embodiment, a precursor of the linker moiety (e.g., a group which corresponds to R1 of Formula I) can be provided with a reactive moiety such as an aldehyde or ketone group, which can be reacted with a solid-supported Wittig reagent to covalently link the linker to the solid support. For example, ethyl levulinate (which includes a ketone group) can be reacted with a resin-bound phosphonium salt to create a resin-bound linker (see Example 3, infra). Thus, a pre-formed linker moiety (or a precursor thereof) can be covalently secured to a solid support using a single-step reaction, which can, as described herein, serve both to tether the linker moiety to the support and to provide the olefinic bond necessary for linker cleavage by electrophilic activation. In an analogous fashion, a phosphonium salt can be reacted with a resin-bound aldehyde group to form a composition of the invention (see Example 4, infra).
Another method for attachment of the linker moiety to a solid support involves the use of radical reactions to form a covalent bond. For example, a linker moiety which contains a carbonxe2x80x94carbon double bond (such as a terminal alkenyl moiety or a styryl moiety) can be linked to a solid support, such as a resin, which also contains a carbonxe2x80x94carbon double bond, by using a radical initiator (such as 2,2xe2x80x2-azobisisobutyrylnitrile (AIBN)). Such a radical reaction will result in covalent attachment of the linker moiety to the support; the amount of linker attached to the support can be controlled by varying the number of reactive sites on the resin.
Another method for providing a linker covalently attached to a support is to copolymerize a monomeric precursor linker moiety (e.g., a free linker moiety which includes a terminal alkenyl or styryl group) with one or more monomeric blocks such as styrene or divinylbenzene, preferably under conditions known for the production of copolymer resins (such as free-radical polymerization). The copolymerization of the monomer units will result in incorporation of the linker moiety into the resin product, thereby providing the linker covalently linked to the support.
B. Attachment of Compounds to the Linker
Once the linker moiety is prepared and covalently bound to the support (e.g., a resin), the linker/support can be used for synthesis of organic compounds. In general, the synthesis will require the attachment of a reactive moiety to the linker, with subsequent modification of the reactive moiety to produce the desired product(s). Thus, for example, an amine-containing moiety can be coupled to the linker, e.g., through a carboxylate functionality on the linker, by well-known methods for forming an amide bond. For example, in the synthetic scheme shown for Example 9, below, piperazine is reacted with an activated carboxylic acid (as the NHS ester) to provide a piperazine-based scaffold for further synthetic manipulation. Many other compounds can be attached to the linker in a similar manner; for example, a molecule which contains a hydroxyl group can be esterified to the linker carboxylate, through an ester linkage, to provide a scaffold for synthesis of compounds; similarly, a thiol-containing compound can be attached to the linker (e.g., through a thioester group) to provide a template for synthesis. One of ordinary skill in the art will be aware of other methods for attaching compounds to the linker to provide a functionalized material useful for synthesis.
The functionalized support can then be used for solid-phase synthesis, e.g., according to methods well known to the ordinarily-skilled artisan; also see infra.
C. Detachment of Products from the Linker/Support
Once a desired compound (or compounds) has been prepared on the solid support/linker of the invention, the desired compounds can be released from the support, if desired, e.g., to provide compounds in solution for further purification or testing. It will be appreciated, however, that the compounds need not be released from the support, e.g., if it is desired to screen the compounds for a specific activity while the compounds are still attached to the linker/support.
To release the compounds, it is preferable to use relatively mild conditions, to avoid decomposition or undesired functionalization of the compounds. As described above, it is believed (without wishing to be bound by theory) that an oxygen atom of the carbonyl group of the linker portion can, through intramolecular attack upon the carbonxe2x80x94carbon double bond of the linker, form a 5- or 6-membered ring (or, in certain embodiments, a 7-membered ring) with concomitant release of the product from the linker upon hydrolysis. Thus, any reagent or condition that promotes such intramolecular attack can be employed to release compounds from the linker. Examples of reagents suitable for promoting cleavage are: iodine (I2), bromine, iodine monochoride, N-bromosuccinimide, N-iodosuccinimide, mercuric chloride or other mercury(II) compounds, certain protic or Lewis acids, and the like. Such cleavage reactions will typically be performed by suspending the functionalized support, with the attached compound(s), in a suitable solvent with addition of the cleaving reagents. As noted above, a suitable nucleophilic reagent or solvent (such as water) should be added to facilitate the cleavage process.
Preferably, the release of compounds is performed under substantially neutral conditions (e.g., strong acids or bases are not used). In preferred embodiments, release of the compounds is performed at a pH in the range of 6.0-8.0, more preferably 6.5 to 7.5.
Once the compound has been released from the linker and solid support as described above, the desired compounds can be recovered by standard means. For example, when the cleavage reaction is performed on a suspension of resin in a solvent, the desired compounds will be released into, and preferably dissolved or suspended in, that solvent. Once the cleavage process is substantially complete, the resin can be separated from the liquid phase, e.g., by filtration, and the desired compound(s) can be recovered from the liquid phase by well-known techniques such as evaporation, crystallization, extraction, chromatography (including column chromatography, high-performance liquid chromatography (HPLC), and other chromatographic techniques), and other purification and isolation methods which will be apparent to one of ordinary skill in the art.
One advantage of the resin-bound linkers of the invention is that, in certain embodiments, the resin/linker can be regenerated and recycled after a synthesis is complete and the desired product has been released from the resin. Thus, for example, after a product has been released using iodine to promote intramolecular ring formation (i.e., the released resin will include a lactone ring) as described above, the spent resin (containing a vicinal acyloxyiodoalkyl functionality) can be recovered. The spent resin can be recycled for further use by, for example, treatment with allyltrimethylsilane and tin(IV) chloride or titanium(IV) chloride to ring-open and reduce the vicinal acyloxyiodoalkyl functionality (see, e.g., Yachi, K. et al., Tet. Lett. 38(29):5161-5164 (1997)) to provide a carbonxe2x80x94carbon double bond. Alternatively, the lactone ring of the spent resin can be cleaved (e.g., by basic hydrolysis) to yield an iodohydrin (with a free carboxylate group also liberated). The iodohydrin can then be converted back to a double bond by reduction with a reagent such as zinc or magnesium metal. The resulting regenerated resin can then be used in a further synthesis by coupling reagents to the carboxylate group as described above.
In general, the methods of the invention involve the attachment of chemical compounds or moieties to a solid-supported linker group as described above. Such chemical compounds or moieties can then be modified by stepwise reaction under a selected reaction scheme until a desired product is obtained. The desired compound can then be cleaved from the solid support under mild conditions which do not significantly destroy or modify the desired compound.
In one embodiment, the invention provides a method of preparing a chemical compound on an insoluble support. The method comprises the steps of providing a composition of Formula I; covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; and reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared.
In this embodiment, the first reactant is preferably an amine, an alcohol, or a thiol (or a conjugate base of any of these). For example, an amine can be attached to the linker moiety by formation of an amide bond with a carboxylate moiety of the linker (e.g., where Y is xe2x80x94ORxe2x80x2 of Formula I), preferably through the use of an active ester or coupling reagent as is well known in the art. Similarly, an alcohol can be attached through an ester moiety by use of a suitably-functionalized linker (e.g., a linker of Formula I in which Y is a leaving group such as xe2x80x94Cl) or by use of a coupling agent (e.g., where Y of the linker of Formula I is xe2x80x94ORxe2x80x2).
The step of reacting the support-bound first reactant moiety with a second reactant can include the use of a wide variety of synthetic reactions, such as those described herein or known to the ordinarily-skilled artisan.
The chemical compound can be screened for a desired activity by screening the compound on the bead according to methods known in the art (see, e.g., E. M. Gordon et al. J. Med. Chem. (1994) 37:1385-1401, and references cited therein). Alternatively, the chemical compounds, once prepared, can be cleaved from the support (e.g., as described herein) and screened in solution.
In another embodiment, the invention provides a method of preparing a chemical compound, the method including the steps of providing a composition of Formula I; covalently linking a first reactant to the linker moiety to provide a support-bound first reactant moiety; and reacting the support-bound first reactant moiety with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared; and cleaving the chemical compound from the insoluble support.
The step of cleaving the chemical compound from the support can be performed as described previously. In certain embodiments, the step of cleaving comprises contacting the chemical compound on an insoluble support with an electrophilic reagent under substantially neutral conditions; in a preferred embodiment, the electrophilic reagent is I2.
The reactions of the present invention may be performed under a wide range of conditions, though it will be understood that the solvents and temperature ranges recited herein are not limitative and only correspond to a preferred mode of the process of the invention.
A variety of synthetic methods are compatible with the compositions of the invention. For example, synthetic reactions, such as amidation, nucleophilic substitution, cycloadditions, aldol reactions, and the like, can be used to prepare a wide variety of compounds on the solid support (see, e.g., B. A. Lorsbach and M. J. Kurth, Chemical Reviews (1999) 99(6): 1549-1582; R. E. Sammelson and M. J. Kurth, Chemical Reviews (2001) 101(1): 137-202; P. H. Seeberger and W.-C. Haase Chemical Reviews (2000) 100(12): 4349-4394; and R. G. Franzxc3xa9n J. Comb. Chem. (2000) 2(3): 195-214; and references cited therein). Deprotection steps can be performed if necessary; however, as with all synthetic reactions to be performed, it is preferred that deprotection steps are compatible with the linker moiety (i.e., such reaction steps do not destroy the linker, the solid support, or the compounds being synthesized on solid support). For example, a synthetic step which involves the use of I2 could cause premature release of compounds from the solid support, which would likely result in lower yields of the desired product when synthesis is complete.
In general, it is desirable that reactions are run using mild conditions that will not adversely affect the substrate, the nucleophile, the intermediates, or the product. For example, the reaction temperature influences the speed of the reaction, as well as the stability of the reactants and catalyst. The reactions will usually be run at temperatures in the range of xe2x88x9278xc2x0 C. to 100xc2x0 C., more preferably in the range xe2x88x9220xc2x0 C. to 50xc2x0 C. and still more preferably in the range xe2x88x9220xc2x0 C. to 25xc2x0 C.
In general, the reactions according to the invention will be performed using a liquid phase, e.g., the reaction can take place on a support dissolved or suspended in a liquid phase. The reactions may be run in an inert solvent, preferably one in which at least one of the reaction ingredients (such as the support or, more preferably, at least one of the reagents) is substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butyl methyl ether, tetrahydrofuran (THF) and the like; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, and the like; aliphatic or aromatic hydrocarbon solvents such as benzene, toluene, hexane, pentane and the like; esters and ketones such as ethyl acetate, acetone, and 2-butanone; polar aprotic solvents such as acetonitrile, dimethylsulfoxide, dimethylformamide (DMF) and the like; or combinations of two or more solvents. In certain embodiments, the use of solvents such as water or alcohols (such as methanol, ethanol, propanol, t-butanol, and the like), either alone or in mixtures with other solvents, may be acceptable.
In certain embodiments it is preferable to perform the reactions under an inert atmosphere of a gas such as nitrogen or argon.
The invention also contemplates the synthesis of libraries or collections of chemical compounds. Combinatorial libraries of compounds can be prepared on solid supports by a variety of methods, some of which are known in the art (see, e.g., F. Guillier et al. Chem. Rev. (2000) 100(6): 2091-2158; E. M. Gordon et al. J. Med. Chem. (1994) 37:1385-1401). In general, preparation of a library involves the use of a plurality of supports (e.g., a plurality of resin beads, plastic xe2x80x9cpinsxe2x80x9d, resin crowns, a plurality of spatially-addressable points on a solid surface, etc.); by varying the reagents used to prepare chemical compounds on each of the plurality of supports, a variety of compounds can be prepared. For example, a plurality of supports (e.g., resin beads), each comprising a composition of Formula I, can be derivatized by linking a first reactant to the linker moiety of each support (e.g., resin bead) to provide a plurality of supports having a support-bound first reactant moiety; and each of the plurality of supports having a support-bound first reactant moiety can then be reacted with a second reactant, under conditions such that a chemical compound on an insoluble support is prepared on each support. The process can be continued, if desired, with third, fourth, etc. reactants to provide the desired chemical compounds. The first, second or subsequent reactants need not be the same for each support; generally, at least one of the reactants will differ between at least two supports, such that at least two different chemical compounds are prepared.
For example, in Example 9, infra, a plurality of supports (6) are reacted with piperidine and p-acetylbenzoic acid to provide a plurality of supports having a support-bound first reactant moiety; the derivatized supports are then divided into five separate portions and reacted with five different aldehydes to provide five different chalcone compounds on solid support. The five portions of support were then recombined and reacted with further reagents (an isatin and an amino acid) to produce five different spirocyclic compounds on the mixed resin supports. The compounds were then cleaved from the resin to provide a mixed library of compounds.
It will be appreciated, however, that in the above-described example, by varying the isatin reagent or the amino acid reagent, a combinatorial library of many members could be provided. For example, use of 5 aldehydes, 5 isatins, and 10 amino acids would provide a library having 250 compounds). Thus, the methods of the invention can be used to prepare libraries having at least 5, 10, 50, 100, 250, 500, 1000, 5000, or 10000 (or even more) compounds.
The following Examples are offered by way of illustration and not limitation.

Cleavable linker for solid phase synthesis


One embodiment of the present invention provides a system that facilitates offloading message segmentation from a central processing unit onto a network interface card. The system operates by first receiving a TSO-send message at the network interface card, wherein the TSO-send message contains information about the message to be sent. Next, the system uses a header address from the TSO-send message to access a message header from memory using remote direct memory access. The system then uses a payload address from the TSO-send message to access a payload from memory that contains message data using remote direct memory access. Finally, the network interface card segments the payload into a set of maximum segment size (mss) segments and transmits the set of mss segments on the network.

1. Field of the Invention
The present invention relates to the process of transmitting data across a computer network. More specifically, the present invention relates to a method and an apparatus for offloading the task of message segmentation from a central processing unit to a network interface card
2. Related Art
Modern communication protocols allow applications executing on different computer systems to communicate with each other. Typically, an application desiring to communicate with another application on another computer system passes the message to a communication process associated with a protocol stack. This protocol stack provides many different mechanisms to transport messages between applications. For example, the Transmission Control Protocol/Internet Protocol (TCP/IP) stack provides reliable delivery of messages from one application to another.
Typically, the TCP layer on the sending end segments a message into maximum segment size (mss) units and transmits the segments to the TCP layer on the receiving end. The TCP layer on the receiving end ensures that each segment is reliably received and that the segments are in proper order.
The IP layer, which operates under the TCP layer, passes these segments from the TCP layer on the sending end to a counterpart IP layer on the receiving end. The IP layer supports addressing that allows segments to be delivered to the proper receiver. However, the IP layer is not reliable. Segments may be lost in transit over the physical network, or the segments may be delivered out of order.
A physical layer resides under the IP layer and typically includes an Ethernet interface. The Ethernet interface facilitates addressing for the sending and receiving ends of the physical link. In doing so, an address resolution protocol (ARP) associates the IP address to a corresponding Ethernet address.
Note that the maximum transmission unit (mtu) for the physical layer limits the mss. The mtu for Ethernet, for example, is 1500 octets (eight-bit bytes). Unfortunately, the relatively small mss allowed by this mtu can cause a performance bottleneck for high-bandwidth communications over modem high-speed networks. This is because performing the segmentation at the central processing unit (CPU) of a computer system causes the CPU to spend considerable time segmenting the messages, which can significantly limit the availability of the CPU to perform mainstream processing.
What is needed is a method and an apparatus for offloading the segmentation process from the CPU, thereby freeing the CPU to do productive work.

Method and apparatus for offloading message segmentation to a network interface card


The reading apparatus is provided with: an optical image forming unit that forms an optical image on a recording medium by irradiating, with light, the recording medium on which an image is formed and which is transported in a slow scan direction; a reading unit that reads a position in a fast scan direction of the image formed on the recording medium transported in the slow scan direction and a position in a fast scan direction of the optical image, by using a minification optical system; and a registration correction unit that corrects a registration error in the fast scan direction of the image read by the reading unit, by using the position in the fast scan direction of the optical image read by the reading unit.

1. Technical Field
The present invention relates to a reading apparatus that reads an image formed on a recording medium, an image forming apparatus that forms an image on a recording medium, and an image forming method.
2. Related Art
In an image forming apparatus such as a printer and the like, there exists a unit performing displacement control (print registration control) for suppressing the displacement of an image by measuring in advance a displacement amount of an image formed on a recording medium such as paper and the like. For example, conventionally, a test image which is called as a registration mark is formed and outputted on a recording medium by an image forming apparatus, the outputted paper is placed on a platen glass of an image reading apparatus for reading, and then the actual forming position of the registration mark relative to the paper is recognized from the reading results, thereby adjusting a parameter used for the displacement control of the recording medium in the image forming apparatus.

Reading apparatus, image forming apparatus and image forming method


A polyimide film according to the present invention can be effectively used as a substrate for a flexible display device without a deterioration in heat resistance even at a temperature of 350° C. or higher since a coefficient of thermal expansion (A) in the section of 100-350° C., of the polyimide film, and a coefficient of thermal expansion (B) in the section of 350-450° C., of the polyimide film, meet 0<B/A<2.

Polyimide (PI) is a polymer having relatively low crystallinity or substantially amorphous structure, and it has advantages such as simple synthesis process, easy process to make a thin film, and no need of cross-linkable moieties for curing, as well as excellent polymeric properties such as transparency, thermal and chemical resistance, mechanical and electrical properties, and dimensional stability due to its rigid chain structure. Polyimide is now widely used as an electrical and electronical material for the field of car and aerospace, a flexible circuit board, a liquid crystal alignment film for LCD, an adhesive as well as a coating agent.
Particularly, polyimide has great attention as a material for flexible display substrates as it is a high performance polymer with excellent thermal stability, mechanical properties, chemical resistance and electrical properties. In order to be used for a display device, polyimide should be transparent and its coefficient of thermal expansion (CTE) should not be a negative value at a temperature of 350° C. or higher so as to lower defect rate caused by residual stress of substrates during heat treatment in the preparation of display devices. Therefore, there are many studies to minimize the change of optical properties and thermal history while maintaining the basic properties of polyimide.
Flexible displays are increasingly in demand due to their free form factor, and lightweight, thin and unbreakable characteristics. In order to implement such a flexible display, a polyimide having excellent heat resistance, BPDA (3,3′,4,4′-Biphenyltetracarboxylic dianhydride)-PDA (phenylene diamine) polyimide is typically used.
A polyimide for a substrate is obtained by polymerization of a diamine monomer and a dianhydride monomer, the diamine being in a relatively excessive amount is known to be favorable in terms of stability of viscosity and molecular weight. However, when the substrate is prepared from a polyimide containing an excessive amount of diamine, it has a negative value of CTE at a temperature of 350° C. or higher and undergoes shrinkage at a high temperature and transparency deterioration due to an amine ending group on curing at a temperature of 450° C. or higher. Also, the negative value of CTE results in residual stress during heat treatment of a TFT process to cause various defects such as film lifting.

Polyimide film for flexible display device substrate


An electronic apparatus includes a thumbnail preparation unit configured to retrieve thumbnail images, each thumbnail image representing a scene of a different time of one or more moving images, a first thumbnail line display unit configured to time sequentially display a first plurality of thumbnail images corresponding to at least a part of one of the moving images as a first thumbnail line, a second thumbnail line display unit configured to display a second plurality of thumbnail images corresponding to a marked part of the moving images as a second thumbnail line, and a thumbnail shifting unit configured to shift a selection of a thumbnail along the second thumbnail line and update the first thumbnail line to display at least one thumbnail image of a temporally adjacent part of the marked part of the moving image corresponding to the newly selected thumbnail in response to a user instruction.

The present disclosure relates to an information processing apparatus, an information processing method, a program, and a surveillance system that present thumbnail images of one or more moving image contents to a user so that the user can grasp contents of scenes.
In recent years, more users view moving images which the users themselves record and moving image contents obtained via the Internet with use of their information terminals. In the environment in which there exist many moving images that can be viewed, such a users' demand as to find, as efficiently as possible, only the scenes that they want to view is expected to increase all the more in the future.
In order to meet such a demand, in various apparatuses, for example, there has been used such a function as to automatically or manually detect highlight scenes in a moving image and add bookmarks thereto. For example, such a technology as to detect moving bodies in a moving image and add bookmarks to the moving bodies thus detected and a frame including the moving bodies is well known. Further, such a method as to recognize a smile of a specific person and similarly add a bookmark thereto, which is achieved by developments of technologies of facial recognition and facial-expression recognition of persons and enhancement of accuracy of the technologies is also well known.
In addition, social bookmark services for sharing the above-mentioned bookmarks with unspecified users have become popular. Sharing of social bookmarks enables users who view a moving image for the first time to view only highlight scenes on their apparatuses. As a result, contents of the moving image can be efficiently grasped.
Incidentally, bookmarks largely contribute to efficiency enhancement also when users search multiple moving images for the scenes that they want to view. However, when users search multiple moving images for such scenes, there is a problem with efficiency, such as necessity for execution of such an operation as to invoke another moving image at each switching of moving images as scene searching objects.
Japanese Patent Application Laid-open No. 2008-312183 (FIG. 3 and paragraphs [0024] and [0025]) (hereinafter, referred to as Patent Document 1) discloses a recording-reproducing apparatus capable of displaying, as a menu screen for selection of moving image contents, a list of thumbnail images of highlight scenes designated from among multiple recorded moving image contents by bookmark operations by a user moving image. When the user designates a target thumbnail image on this menu screen, the corresponding one of the moving image contents is reproduced from a scene added with a bookmark.

Information processing apparatus, information processing method, program, and surveillance system


A packing apparatus which includes a feed conveyor adapted to convey articles to a pick up station and a case conveyor adapted to sequentially convey cases, having an open top and a plurality of flaps, to a feed station. Pick up and grid heads are provided and are adapted to pick up successive slugs of the articles at the pick up station and to sequentially deposit the slugs in each of the cases while they are in the release station. A removal conveyor is provided to successively receive the slug filled cases from the release station and pass them onto a case sealing apparatus which is arranged over the removal conveyor and is operative to apply an adhesive to certain of the flaps and to then move the flaps over the open top into a secured closed position.

The invention relates to an apparatus and method for transferring articles into and out of cases using continuous motion, and particularly, where the continuous motion is basically circular and at higher transfer speeds with a small footprint.
In the art of case packing, large numbers of articles must be grouped and packaged rapidly by an apparatus that will function dependably without damage to the articles processed. When unpacking articles from cases, the articles are already grouped in a pattern in the case reducing some of the problems of article pick up. Case packing apparatus has been generally categorized as either intermittent case packing or continuous case packing. In intermittent case packing the article flow and/or case flow is interrupted during article pick up and/or release. Most recently, attention has been directed to continuous case packing in order to increase production. However, the continuous case packing has brought increased problems with handling the processed articles without breakage, damage, or interruption.
In the continuous case packing apparatus, articles are grouped together in successive slugs at a pick up position. The slugs are typically picked up at the pick up position by article grippers carried by an orbital handling machine rotating about two vertical axes. The slugs are transferred to a case loading position where the grippers release the slug of articles into a case. The articles can be released either simultaneously or sequentially as the case is conveyed beneath the slug of articles. Apparatus of this type may be either of the xe2x80x9cdrop packerxe2x80x9d type or xe2x80x9cplacement packer type.xe2x80x9d In the drop packer type, the articles are allowed to drop at least a small distance into the case after release. In the placement packer type, the drop, if any, is minimal and the articles are essentially placed gently onto the bottom of the case.
Continuous motion machines rotating about a single horizontal axis are shown in U.S. Pat. Nos. 5,375,395, 5,257,888, and 5,313,764 using articulating arms and pickup heads. A set of article grippers is carried on the ends of the articulating arms. However, during the angular descent from the pick up position to the case packing position, both horizontal and vertical accelerations are typically encountered by the articles which are gripped only at their tops or necks. Intermittent circular machines rotating about a single vertical axis are shown in U.S. Pat. Nos. 3,780,492 and 2,807,125.
Various other case packers, generally of the continuous motion type, using a vertical orbital conveyor are shown in U.S. Pat. Nos. 5,212,930; 4,541,524; and 4,294,057. The first patent shows depositing the articles sequentially and individually, rather than as a group or slug, into partitioned cases without positively gripping the articles. The latter two patents use gripper devices to grip and place the articles. U.S. Pat. No. 4,457,121 discloses a continuous motion bottle packer wherein a plurality of grids are mounted individually on spokes of a vertical wheel so that each grid moves through an article in feed position where groups of articles are fed into the grid without interrupting the forward speed. Angular and horizontal accelerations of the articles and their contents are encountered due to the rotary wheel motion during the transfer which may be detrimental to the article and/or contents.
Continuous case packers are also known in which a horizontal rotary carousel is used to move vertically reciprocating gripper sets in a horizontal plane about two vertical axes. The reciprocating gripper sets pick up a slug of articles at one position and transfer the slug of articles to a second position where the gripper set is lowered to deposit the articles into a case. Typically the pickup and release stations are on opposite sides of the carousel, requiring parallel conveyors on each side. However, the disposition of the rotary carousel in a horizontal plane requires an inconvenient floor layout, which also occupies a large amount of floor space. The parallel conveyor arrangements needed for the in feed and out feed of articles adds to the floor space problem. The path of the gripper sets between the slug pick up position and the case packing position is also typically curved producing angular and acceleration forces on the articles. The curved article transfer path intersects the path of the conveyed case only for a brief interval making timing a factor. In various of the rotary carousel types, it is known to deposit the articles by lowering the articles, already gripped by the gripper set, through resilient fingers that guide the articles into partitioned cases.
Case packers, generally of the intermittent type, are shown in U.S. Pat. Nos. 3,553,932 and 3,505,787 which also disclose using combinations of a lifting head having suction cups and bottle grids having pockets for picking up containers and depositing them into cases. The containers and the cases are conveyed on parallel conveyors rather than in-line conveyors, and the transfer from the pick up position to the case loading position is lateral, or transverse, to the flow of containers and cases. U.S. Pat. No. 2,277,688 discloses another case packer using an arrangement of a gripper set and a bottle guide set to package the containers into a case. These type of case packers are generally non-continuous as compared to the continuous motion in-line transfer case packers described above where neither the flow of articles nor the flow of the cases is interrupted during operation of the packer.
Accordingly, an object of the invention is to provide an improved continuous case packing and depacking apparatus having a characteristic circular motion.
Another object of the invention is to provide a continuous motion apparatus and method which moves in a circular motion to provide high speeds of operation.
Another object of the invention is to provide a continuous, circular motion case packing or depacking apparatus and method which rotates about a single axis to provide a small footprint and high speed operation.
Another object of the invention is to provide a continuous, circular motion case packing apparatus and method in which slugs or groups of articles are picked up and transferred to a release station where the motion of the pickup heads is converted to a substantially straight-line motion along a pick up section during which time the articles are picked up.
Still another object of the invention is to provide a continuous, circular motion case packing or depacking apparatus and method wherein the articles are either picked up or released over a circular plate disposed below the path of the pickup heads and rotating about the same axis.
Yet another object of the invention is to provide a continuous motion apparatus and method in which a revolving turret moves a plurality of transfer arms and a transfer plate in a circular path about a single vertical axis as reciprocating article pickup heads and grid heads, carried by the transfer arms, pick up and release the articles wherein either the pick up or release occurs over a circular plate disposed below the pickup heads moving in a circular motion for high speed, reliable operation.
Still another object of the invention is to provide a packing apparatus with a continuous motion circular plate which moves through a case pick up position, an article pick up position, an article deposit position and a case removal position.
Still another object of the invention is to provide a continuous motion packing apparatus which includes a plurality of conveyor belts separated by a rotating plate.
Yet another object of the invention is to provide a continuous motion apparatus and method in which a revolving plate moves successive filled cases onto a sealing section where each case is closed and sealed.
Yet another object of the invention is the provision of a continuous operation of packing articles into cases, removing the packed cases onto a closure section where the case flaps are moved into sealed positions.
The invention is directed to a packer which includes a delivery for moving articles into a pick up position and a take-away for removing cases filled with the articles. A plate is located between the delivery and the take-away and is arranged to rotate about a single axis. The plate is operative to move sequentially the cases into a deposit or release position for receiving the article from the pick up position and to move the cases to the take-away. A rotating tower which carries the plate is supported by a frame member.
Pickup and grid heads are carried by the tower for movement about the axis and for relative vertical movement. A cam is carried by the frame and is operative to control pickup and grid heads through their relative vertical movements.
A third delivery is provided for moving the case to a dispensing position. The third delivery includes a rotating belt and a dispenser. The belt is operative to move the cases to the dispensing position where they are held and released in timed sequence onto the rotating plate. A plurality of radially spaced pins secured with the upper surface of the plate engage and circumferentially locate the cases on the plate. The tower includes a support frame which acts to support the plate. An adjusting member which is carried by the tower is provided for adjusting the plate circumferentially relative to the support frame and pickup and grid heads. Preferably the adjusting member is a rack and pinion arrangement.
Arcuate inner and outer guide rails are positioned above and adjacent the edges of the plate. The guide rails are operative to engage and individually position each case radially on the plate during movement toward and through the deposit position. The guide rails are adjustably mounted with the frame. Adjustment of the guide rails allows the apparatus to accommodate different case sizes.
An apparatus for transferring articles which includes a frame which supports a tower for rotation about a single axis. The tower carries a plurality of paired grid and pickup heads for vertical and rotational movement between a pick up and a release or deposit position. A circular plate is carried by the tower for movement about the tower and through the deposit position.
A first conveyor is provided for moving articles into a pick up position adjacent the plate in the form of article slugs. A second conveyor is provided for moving the cases sequentially onto the plate.
The paired grid and pickup heads are controlled to move onto and to the pick up of a slug of the articles when moving through the pick up position to then move to the deposit position to deposit the slug of articles into a case when both the case and the pickup and guide grids are moving through the deposit or release position.
A third conveyor is provided to receive and remove the filled cases away from the plate.
A plurality of positioning pins carried by the plate in spaced circumferential positions and radially spaced from the axis. The pins are adapted to circumferentially position the cases during movement on the plate. An adjusting member is provided for circumferentially adjusting the positioning pins relative to the pickup and grid heads.
Inner and outer guide rails are provided and are carried by the frame in radially spaced positions above the plate. Adjustable mounting members secure the guide rails in radially adjustable positions.
A packer apparatus comprising a frame carrying a rotating plate which is adapted to receive successive cases. Each of the cases includes front, rear and side flaps which are in folded position adjacent vertical sides of the case. The plate moves the cases through a deposit position and a removal position.
Pickup and grid heads which are carried by the frame are moved along vertical and circular paths between a lower position to deposit or release a slug of articles into each case as it passes through the deposit ore release position. The apparatus includes flap separators which are carried by the frame and are operative to move to separate and lift the flaps of the case during movement of the pickup and grid heads vertically away from the lower release position.
Positioning members are provided to fold down and hold the front and rear flaps from their lifted position as the filled cases are moved from the deposit position and into a take-away or removal position.
The separators are pivotally mounted with the grid head. A control mechanism which is carried by the pickup and grid heads is operative to locate each separator in selective positions relative to the vertical sides of the case during movement of the pickup and grid heads which allows the separators to first separate the flaps and secondly to elevate the front and rear flaps. The control mechanism comprises a cam carried by the pickup head and a spring carried by the grid head.
The positioning members include a positioning rail arranged adjacent the removal position which acts to fold said front flap down. The positioning members also include a rotating positioning disk which is operative to engage and fold down the rear flap as the carton moves through the removal position.
Case sealing apparatus is located over the removal conveyor adjacent the removal position. The sealing apparatus includes guide and support rails which are arranged adjacent the removal conveyor. The guide and support rails include a support zone and a positioning zone. The sealing apparatus also includes adhesive applicators which apply adhesive onto the side flaps as they are supported by the guide and support rails in the support zone. The guide and support rails are operative to elevate the side flaps of the case in the positioning zone. The case sealing apparatus includes side flaps depressing arms which engage the elevated side flaps leaving the positioning zone and urge them into a closed position. The case sealing apparatus also includes a press zone which is located over the removal conveyor adjacent the positioning zone, the sealing apparatus acts to press and hold down the side flaps in position against the front and rear flaps until the adhesive secures them in position. The sealing apparatus is preferably an, elongated flexible weight.
The invention further includes the method of moving pickup and grid heads in an article handling machine to include the steps of providing a pickup station and continuously moving articles into the pickup station; providing a circular plate and rotating the plate about an axis; rotating said pickup and grid heads in a circular path about the axis, through the pickup station and causing the pickup heads to also move in a generally straight line during rotational movement through the pickup station.

Continuous circular motion case packing and closure apparatus and method


A kit-of-parts for assembling an apparatus for verifying Explosive Trace Detector responses includes an alignment tool and a dispenser. The alignment tool has a body with a top cavity open on a top side and configured to receive the dispenser housing or a sampling medium head of a sampling medium. The sampling medium head has a sample collection area. The body has a bottom cavity to receive a hammer arm. The body has one or more sampling media cavities disposed between the top cavity and the bottom cavity, each configured to receive another sampling medium having a respective sample collection area. The top cavity and sampling media cavities are in communication with each other via a common slot. The top cavity and sampling media cavities are configured to receive different sampling media and to align the dispenser housing with the sample collection area of each of the different sampling media.

Trace analyte detection has numerous applications. For example, trace analyte detection may be used for screening individuals or baggage at transportation centers, or screening pieces of mail. Trace analyte detection may be used to provide security at facilities requiring advanced security applications. Trace analyte detection has numerous other applications, e.g., military applications, forensics applications, narcotics detection and identification, cleaning validation, quality control, and raw material identification. Generally speaking, trace analyte detection may be used for the detection of small amounts of analytes, including detection at nanogram to picogram levels. Trace analyte detection can be particularly useful for security applications such as screening individuals or items for trace components in explosive materials, narcotics, or biological contaminants where small amounts of these components are deposited on an individual, the surface of a package, a piece of mail, an animal, a table surface, a bag, or the like.
Trace analysis can be important in the pharmaceutical industry. For example, from time to time equipment must be checked for contamination to ensure pharmaceutical ingredients do not come in to contact with unclean equipment surfaces. Equipment surfaces can be sampled and analyzed for trace contaminants in accordance with manufacturing specifications and safety standards.
A variety of different techniques can be used for trace analyte detection. Ion mobility spectrometry (IMS), mass spectrometry, gas chromatography, liquid chromatography, and high performance liquid chromatography (HPLC) are examples of trace analyte detection techniques.
IMS, as an example technique, is a useful technique for rapid, accurate detection and identification of trace analytes such as narcotics, explosives, and chemical warfare agents. IMS detects and identifies known analytes by detecting a signal which is unique for each analyte. IMS measures the drift time of ions through a fluid, such as clean, dry ambient air at atmospheric pressure. Generally, to perform an analysis a sample is collected and transferred to the sampling medium. The sampling medium containing the analyte is inserted into the inlet of the spectrometer. The sample is heated to transform an analyte from solid, liquid or vapor preconcentrated on the media into a gaseous state. Analyte molecules are ionized in the reaction region of the ion mobility spectrometer. Ions are then spatially separated in the IMS drift region depending on their ion mobility, an intrinsic property of an ion. An induced current at a collector generates a signature for an ion as a function of the time required for that ion to reach the collector. This signature can be used to identify a specific analyte.
It is important to properly align the sample collection area of the sampling substrate material or swab within an analyzer. This is to ensure the portion of the substrate material containing the sample is analyzed by the analytical device. For example, for the IMS technique the collected sample must be properly aligned on the sample desorber so the collected sample is desorbed and analyzed by the IMS. When the sample area of the substrate is not properly aligned within the analyzer, the collected sample may not be completely desorbed. Therefore, the test results of the sample can be affected by how the sample area of the substrate is aligned within the analyzer. While the discussion below focuses on the IMS technique, other trace detection techniques have analogous requirements for accurate analysis.
A variety of sample collection devices (media) of different configurations are used with different IMSs and other detection devices. Typically, sample collection devices (substrates) have a target sample area for collecting or holding a sample. It is important to align the sample in the sample area of the sample collection device (also referred to herein as "sampling medium" or "vendor medium"). The detection system is more sensitive to an analyte aligned in the target sample area. When an analyte is properly aligned in the target sample area it is more readily desorbed when heated, for techniques using heat, as an example. Accordingly, accuracy is improved.

This patent is subject to a terminal disclaimer.

Alignment tool for dry-deposition and kit for assembling apparatus for verifying explosive trace detector responses

The Government of the United States of America, as represented by the Secretary of Homeland Security


A combination play pen, bassinet and changing table includes a bassinet assembly removably supported on the upper frame assembly of the play pen. The bassinet assembly includes a pair of bassinet frame assemblies, each consisting of a pair of J-tube assemblies joined by a cross tube. The J-tube assemblies include outer ends adapted to overly the upper frame. Bassinet side panels and end panels extend upwardly from the floor panel to form a coffer-like enclosure. An adapter supports the J end of the bassinet tube that overlies a collapsible joint assembly at the midpoint of one upper rail assembly. A changing table assembly includes a tubular frame comprised of paired side tubes and end tubes joined in a rectangular configuration. Two vertices of the changing table frame are adjacent to the adapters of the bassinet assembly. A keyed elbow connector at each vertex includes a T-shaped key received in a key slot of an adapter in supporting fashion. The changing table frame includes a pair of second elbow connectors, each including a pair of lugs projecting therefrom. Each second elbow connector impinges on the web of the adjacent upper corner bracket in supported relationship, and the lugs are received in the concave pocket of the web to retain the vertex of the changing table frame in the upper corner of the play pen frame assembly.

This invention generally relates to a collapsible play yard or play pen apparatus, and more particularly to an improved play pen that may be converted to accomplish other baby caretaking functions. One exemplary apparatus in the prior art is described in U.S. Pat. No. 5,381,570 to Cheng, which is incorporated herein by reference in its entirety.
Folding play pens are well known in the prior art and comprise a standard item in parenting and baby caretaking. A play pen enables a baby or toddler to play within a controlled and protected space without requiring continual attention by a responsible adult. Such play pens can be folded into a small space for easy storage and transport and are therefore convenient items for use in high mobility situations.
However, the standard play pen does not address other baby caretaking functions, such as the continual need for changing diapers and dressing, and the need to provide adequate nap space for the child. As a result, parents or caretakers in mobility situations must transport other portable baby furniture, or must improvise these functions with whatever furniture is found at hand. For example, the changing and dressing function may be accomplished on top of an adult bed or table, or on a bathroom sink countertop. These improvisations are fraught with unknown and unseen perils for the child, such as exposure to falling hazards, soaps and chemicals, electrical hazards, and the like. In addition, the frequent naps which small children require are often taken on the floor of the play pen, which is not designed for comfort in such use. Moreover, many small children sleep best in a smaller, cozier space, which the standard play pen does not provide.
There are known in the prior art various forms of play pens that may be combined with a removable bassinet structure. These structures generally are suspended over the upper opening of the play pen and fill the entire opening. A bassinet of such size may be unsuitable for newborn and infant use, due to the fact that a smaller, cozier sleeping space is preferred for such young children. Moreover, the large prior art bassinet structures do not allow any opportunity to provide a changing table in addition to the bassinet itself.
The choice for many traveling parents or caretakers often is to transport a portable play pen, portable changing table or pad, and folding bed or the like for naps. This is a daunting logistical problem, and a discouragement for many parents who would otherwise wish to have greater mobility. Clearly there is a need in the prior art for meeting these disparate apparatus requirements in a more compact, transportable form.
The invention generally comprises an improved play pen or play yard apparatus. A significant feature of the invention is that it is easily converted to use as a baby bassinet and a changing table, whereby it may be used to carry out many of the typical baby caretaking functions.
A typical play pen collapsible frame structure generally includes an upper frame assembly comprised of two pair of parallel collapsible rail assemblies which are supported by corner leg assemblies. The rail assemblies support the side panels of the play pen, while a lower frame assembly is secured to the leg assemblies to support the floor portion of the apparatus. The particular construction of these frame assemblies does not form part of the invention, except for the components described hereinafter.
At each corner of the upper frame assembly, the invention provides an upper corner bracket, each upper corner bracket including diverging body portions extending in orthogonal relationship and adapted to engage a respective collapsible rail assembly. A web extends across the included angle between the diverging body portions, and a concave pocket is formed in the top surface of the arcuate web.
In one aspect of the invention, there is provided a bassinet assembly that is removably supported on a portion of the upper frame assembly. The bassinet assembly includes a pair of bassinet frame assemblies, each consisting of a pair of J-tube assemblies joined by a cross tube. The J-tube assemblies include outer ends that are adapted to overly the upper rail assemblies and be suspended therefrom. The bassinet floor panel is disposed below the upper rail assembly and above the floor of the play pen, and is supported on the cross tubes. Bassinet side panels and end panels of soft fabric extend upwardly from the bassinet floor panel to form a coffer-like enclosure that is sufficiently small and cozy for the resting and napping functions of a bassinet. Sleeves formed in the end panels and floor panel secure portions of the cross tubes and J-tube assemblies.
Regarding the pair of J-tube assemblies that comprise each bassinet frame assembly, one outer J end overlies a respective upper corner bracket. The other outer J end is secured in a hub adapter that supports the J end of the bassinet tube, the hub adapter being configured to rest on and be supported by a collapsible joint assembly located generally at the midpoint of a respective upper rail assembly of the playpen frame structure. Thus the bassinet assembly is supported entirely by suspension from the upper frame portion of the playpen, and may be installed and removed as a single unit. The bassinet assembly is also readily disassembled and collapsed for easy transport.
In another aspect of the invention, there is provided a changing table assembly that is removably supported on a portion of the upper frame assembly adjacent to the bassinet assembly. The changing table assembly includes a tubular frame comprised of paired side tubes and paired end tubes joined in a rectangular configuration. Two vertices of the rectangular changing table frame are disposed adjacent to the hub adapters of the bassinet assembly. The changing table frame includes a pair of first elbow connectors, each disposed at a respective vertex of the rectangular frame and adapted to join a side tube and end tube in orthogonal relationship. Each first elbow connector further includes a T-shaped key extending outwardly therefrom, and each hub adapter is provides with a key slot to receive the key of the adjacent first elbow connector, whereby the hub adapter of the bassinet assembly supports the adjacent vertex of the changing table frame.
The changing table frame further includes a pair of second elbow connectors, each disposed adjacent to one upper corner bracket of the play pen and adapted to join a side tube and end tube in orthogonal relationship. Each second elbow connector includes a pair of lugs projecting therefrom in opposed fashion along an axis generally transverse to the changing table frame. Each second elbow connector is disposed to impinge on the web of the adjacent upper corner bracket in supported relationship, and the lugs are each configured to be received in the concave pocket of the web to locate and retain the vertex of the changing table frame with respect to the upper corner of the play pen frame assembly. Thus the changing table frame is supported at two corners by the upper corner brackets of the play pen frame assembly and at the other two corners by the adjacent hub adapters of the bassinet assembly.
The changing table assembly further includes a horizontal table panel joined to fabric side panels and end panels, which in turn are provided with sleeves to engage the changing table frame in suspended relationship. The table panel is supported slightly below the upper frame assembly of the play pen, and significantly higher than the floor of the bassinet assembly. The table panel provides a changing and dressing surface at a height convenient for those purposes. Due to the fact that changing and dressing often occurs before and after napping, which takes place in the bassinet, the changing table is placed in the most convenient possible location. And, like the bassinet assembly, the changing table assembly may be removed as a unit from its supported position on the play pen, and may be readily disassembled and collapsed for easy transport. When both the bassinet assembly and changing table assembly are removed, the upper opening of the play pen is unobstructed and the play pen is available for the purpose of permitting a baby or toddler to play within its controlled and protected interior space.

Combination folding play pen with changing table and bassinet


A sucrose polyester composition that imparts a coating providing a slickness to teeth when delivered from an oral care composition.

Oral Care products that coat tooth surfaces can provide stain prevention, protection from bacterial and food acids, and a sensorial benefit of tooth slickness or perception surface smoothness.
Prevention of dental caries by coating a tooth with a casein phosphopeptide-amorphous calcium phosphate complex was disclosed in US Pub. No. 2011/0076241. Though they were able to show tooth coating, they had to deliver the material from a water-free composition, thus imposing a barrier to delivery from a toothpaste. In the presence of water, they were unable to deliver a stable film to the tooth's surface and thus were required to have a non-aqueous composition.
Coating the teeth with an antimicrobial varnish (U.S. Pat. No. 4,883,534, and U.S. Pat. No. 4,496,322) or preventative resin has been a means to combat dental caries by a variety of technologies, such as shellac resin (U.S. Pat. No. 6,524,559) or a methacrylate resin to repair caries lesions (U.S. Pat. No. 5,430,074). The inventions related to these coating compositions have to be delivered from a solvent based system that is brushed on, where the resin is the residual after the solvent dries.
For aesthetic purposes, teeth have been coated with reactive glass ionomers (U.S. Pat. No. 6,036,494) or etching the teeth to deliver a non-removable polymer (U.S. Pat. No. 4,512,743). A coating composition is needed that can be added to oral care products, so the composition can be applied to the teeth during a user's normal oral care product usage.

Compositions for deposition on biological surfaces


A thin film transistor includes a thin film transistor layer having a source region, a channel region and a drain region. In one implementation, a gate of the transistor is disposed laterally proximate the thin film channel region and comprises an annulus which laterally encircles the laterally proximate thin film channel region. In another implementation, a channel region of a thin film transistor extends elevationally away from a substrate. Source and drain regions are operatively associated with the channel region and are elevationally spaced therealong and apart from one another. A gate is disposed over the substrate and laterally proximate the channel region.

As circuit density continues to increase, there is a corresponding drive to produce smaller and smaller field effect transistors. Field effect transistors have typically been formed by providing active areas is within a bulk substrate material or within a complementary conductivity type well formed within a bulk substrate. One additional technique finding greater application in achieving reduced transistor size is to form field effect transistors with thin films, which is commonly referred to as "thin film transistor" (TFT) technology. These transistors are formed using thin layers which constitute all or a part of the resultant source and drain regions, as opposed to providing both regions within a bulk semiconductor substrate.
Specifically, typical prior art TFT's are formed from a thin film of semiconductive material (typically polysilicon). A central channel region of the thin film is masked by a separate layer, while opposing adjacent source/drain regions are doped with an appropriate p or n type conductivity enhancing impurity. A gate insulator and gate are provided either above or below the thin film channel region, thus providing a field effect transistor having active and channel regions formed within a thin film as opposed to a bulk substrate.
It would be desirable to improve upon methods of forming thin film transistors and in improving thin film transistor constructions.


A dual emitter light assembly employs a reflector having a pair of adjoining concave reflector dishes. Each dish comprises a pair of angularly related parabolic reflective surfaces. The dishes intersect along a central parabolic path which lies in a plane perpendicular to a plane defined by the parallel axes of light emitter receiving sockets which are integral with each dish.

(1) Field of the Invention
The present invention relates to lights and, more particularly, warning lights having a wide angle radiation pattern, particularly in a single plane. Accordingly, the general objects of the present invention are to provide novel and improved devices of such character.
(2) Description of the Prior Art
Warning light systems which are employed on emergency vehicles, such as police cars, ambulances, fire trucks and the like, are often required to emit bursts of light which are readily visible from all sides of the vehicle. The warning lights of such systems may comprise a revolving incandescent lamp assembly, a moving mirror and cooperating lamp or a flash tube and cooperating lens and reflector. The prior art warning lights can be relatively expensive to manufacture. Additional drawbacks of many prior art warning lights is poor volumetric efficiency and high wind resistance.
A number of improved lights having particular applicability to emergency vehicle warning light systems have recently been introduced. Many such lights employ xenon flash tubes and have found wide popularity. For example, U.S. Pat. No. 4,792,717, which is assigned to the assignee of the present invention, discloses a compact wide-angle warning light. This warning light employs a concave reflector, a lens and a light emitter in the form of a specially designed xenon flash tube. The reflector comprises a linear section having parabolic side walls which are disposed between parabolic dish end sections.
In co-pending application Ser. No. 312,479 now U.S. Pat. No. 4,954,958, which is also assigned to the assignee of the present invention, a lamp assembly comprising a single light emitter, a reflector body and a lens cover which mounts over the reflector body is disclosed. The reflector body comprises a first parabolic dish-like reflector surface which forms a surface of revolution about a central axis. A mounting base projects from the first reflector surface for mounting a light emitter such as a halogen lamp or a gaseous discharge tube. The central axis extends through the emitter mounting base. A pair of reflector wings are located at equidistantly-spaced diametral positions from the central axis. The wings each define a parabolic reflector surface which has its axis canted in relation to the first reflector surface, i.e., the surfaces from which light is reflected are defined by three parabolas and these three parabolas have, to the extent manufacturing tolerances permit, a common focal point. The lens cover preferably includes a multiplicity of light spreaders which project interiorly from the cover surface. A pair of recesses are formed in the cover interior for mating with the outwardly disposed shoulder portions of the wings so as to mount the lens to the reflector body and to angularly fix the orientation of the axes of the spreaders relative to the reflector body. A source of radiation, optionally in the form of a halogen lamp or a gas discharge tube, is positioned in the envelope between the lens cover and the reflector body at the common focal point of the reflector defined parabolas and produces a generally uni-directional, wide angle beam pattern which radiates through the lens.

Warning light with quadruple reflective surfaces


A technique performs an authentication operation using pulse and facial data from a user. The technique involves obtaining current pulse data from a user, and performing a comparison between the current pulse data from the user and expected pulse data for the user. The technique further involves generating an authentication result based on the comparison between the current pulse data and the expected pulse data. The authentication result may control user access to a computerized resource. Since such a technique uses pulse data, a perpetrator cannot simply submit a static image of a subject's face to circumvent the authentication process. In some arrangements, the technique involves obtaining videos of human faces and deriving cardiac pulse rates from the videos. For such arrangements, a standard webcam can be used to capture the videos. Moreover, such techniques are capable of factoring in circadian rhythms and/or aging adjustments to detect and thwart video replay attacks.

A conventional facial recognition system analyzes images of human faces. In particular, when the system receives a first image of a human face, the system measures the sizes, shapes, and/or positions of the subject's eyes, nose, mouth, and cheeks, among other features. The system then saves these face geometry measurements for later matching.
When the conventional facial recognition system receives a second image of a human face in the future, the system performs this measurement operation again. That is, in the same manner as for the first image, the system measures the sizes, shapes, and/or positions of eyes, nose, mouth, and cheeks of the subject's face, etc. in the second image. The system then matches these face geometry measurements taken from the second image against the saved face geometry measurements taken from the first image.
If the system determines that the face geometry measurements match within a predefined threshold of certainty, the system outputs a result indicating that the subject in the second image is the same as the subject in the first image. However, if the system determines that the face geometry measurements do not match within the predefined threshold of certainty, the system outputs a result indicating that the subject in the second image is not the same as the subject in the first image. Such results may be used to manage access to a protected asset such as a room, or an account on a computer.

Controlling access to a computerized resource based on authentication using pulse data


Polymers of olefins such as ethylene and propylene, having functional groups introduced into both the ends thereof, can be provided which are useful as macromonomers for polycondensation. This new polymer comprises a recurring unit represented by the general formula --(--CH.sub.2.CHR--)-- and having functional groups bonded to both the ends of the polymer and a number average molecular weight of 300 to 500,000, the functional groups being selected from the group consisting of H.sub.2 C.dbd.CH-- group and ##STR1## wherein X is --OH, --OR.sup.1, a halogen atom or --SO.sub.3 R.sup.2, R.sup.1 is a hydrocarbon group of 1 to 5 carbon atoms and R.sup.2 is a halogen-substituted or non-substituted hydrocarbon group of 1 to 20 carbon atoms.

1. Field of the Invention
This invention relates to ethylene or propylene polymers each having functional groups such as vinyl groups or carbonyl groups at both the ends thereof, and a process for the production of the same.
2. Description of the Prior Art
An ethylene polymer having a functional group introduced into one end of the polymer obtained by living anion polymerization of ethylene has been known, but an ethylene polymer having functional groups introduced into both the ends thereof has not been known.
Moreover, a method comprising polymerizing propylene using a polymerization catalyst consisting of a vanadium chelate compound and a dialkylaluminum halide and modifying the end of the resulting polypropylene with a functional group has been known, but only one end of tile polymer can be modified by the prior art method.
If functional groups can be introduced into both ends of polymers of olefins such as ethylene, propylene, etc., broad applications thereof can be expected to uses, e.g. macromonmomers of polycondensation.

Both ends-modified olefin polymers and processes for the production thereof


Disclosed is a binder composition for secondary batteries including composite latex comprising conjugated diene latex particles (A) and copolymer latex particles (B), each present in an independent phase, wherein the composite latex has a pH of 7 or less.

Recently, technological development and increased demand associated with portable equipment such as portable computers, cellular phones and cameras have brought about an increase in the demand for secondary batteries as energy sources. Among these secondary batteries, lithium secondary batteries having high energy density and operating voltage, long lifespan and low self-discharge rates have been actively researched and are commercially available and widely used.
In general, as lithium ions of a positive electrode are repeatedly intercalated into and de-intercalated from a negative electrode, lithium secondary batteries are charged and discharged. Repeated intercalation and deintercalation of lithium ions causes bonding between electrode active materials and conductive materials to weaken and contact resistance between particles to be increased. As a result, ohmic resistance of electrodes is increased and battery characteristics may thus be deteriorated. Accordingly, a binder is preferably an elastic polymer because it should offset expansion and shrinkage of electrode active materials resulting from intercalation and deintercalation of lithium ions on the electrodes.
In addition, the binder should have adhesivity to maintain binding strength between the electrode active material and the current collector in the process of drying electrode plates. In particular, in order to improve discharge capacity, in the case where natural graphite having a theoretical discharge capacity of 372 mAh/g is used in combination with a material such as silicon, tin or silicon-tin alloys having high discharge capacity, volume expansion of the material considerably increases, in the course of charging and discharging, thus causing separation of the negative electrode material. As a result, battery capacity rapidly decreases over repeated cycling.
Accordingly, there is an increasing demand in the art for binder and electrode materials which can improve structural stability of electrodes and thus performance of batteries even after several hundred cycles by preventing separation between the electrode active materials, or between the electrode active material and the current collector upon fabrication of electrodes via strong adhesion and controlling volume expansion of electrode active materials upon repeated charge/discharge via strong physical properties.
Furthermore, since a binder may act as resistance itself, it should not greatly affect resistance and ionic conductivity. Resistance is an important property of batteries because most medium and large batteries require high power. There is increasing demand for research on binders having low resistance as well.
Accordingly, there is a high need for development of binders having excellent adhesivity and low resistance.

Binder composition for secondary batteries, and electrode and lithium secondary battery including the same