The present invention relates to oxygenated esters of 4-substituted-phenylamino benzhydroxamic acid derivatives, pharmaceutical compositions, and methods of use thereof.

The present invention relates to oxygenated esters of 4-substituted-phenylamino benzhydroxamic acid derivatives, pharmaceutical compositions, and methods of use thereof.
MAPK/ERK Kinase (xe2x80x9cMEKxe2x80x9d) enzymes are dual specificity kinases involved in, for example, immunomodulation, inflammation, and proliferative diseases such as cancer and restenosis.
Proliferative diseases are caused by a defect in the intracellular signaling system, or the signal transduction mechanism of certain proteins. Defects include a change either in the intrinsic activity or in the cellular concentration of one or more signaling proteins in the signaling cascade. The cell may produce a growth factor that binds to its own receptors, resulting in an autocrine loop, which continually stimulates proliferation. Mutations or overexpression of intracellular signaling proteins can lead to spurious mitogenic signals within the cell. Some of the most common mutations occur in genes encoding the protein known as Ras, a G-protein that is activated when bound to GTP, and inactivated when bound to GDP. The above-mentioned growth factor receptors, and many other mitogenic receptors, when activated, lead to Ras being converted from the GDP-bound state to the GTP-bound state. This signal is an absolute prerequisite for proliferation in most cell types. Defects in this signaling system, especially in the deactivation of the Ras-GTP complex, are common in cancers, and lead to the signaling cascade below Ras being chronically activated.
Activated Ras leads in turn to the activation of a cascade of serine/threonine kinases. One of the groups of kinases known to require an active Ras-GTP for its own activation is the Raf family. These in turn activate MEK (e.g., MEK1 and MEK2) which then activates the MAP kinase, ERK (ERK1 and ERK2). Activation of MAP kinase by mitogens appears to be essential for proliferation; constitutive activation of this kinase is sufficient to induce cellular transformation. Blockade of downstream Ras signaling, for example, by use of a dominant negative Raf-1 protein, can completely inhibit mitogenesis, whether induced from cell surface receptors or from oncogenic Ras mutants. Although Ras is not itself a protein kinase, it participates in the activation of Raf and other kinases, most likely through a phosphorylation mechanism. Once activated, Raf and other kinases phosphorylate MEK on two closely adjacent serine residues, S218 and S222 in the case of MEK-1, which are the prerequisite for activation of MEK as a kinase. MEK in turn phosphorylates MAP kinase on both a tyrosine, Y185, and a threonine residue, T183, separated by a single amino acid. This double phosphorylation activates MAP kinase at least 100-fold. Activated MAP kinase can then catalyze the phosphorylation of a large number of proteins, including several transcription factors and other kinases. Many of these MAP kinase phosphorylations are mitogenically activating for the target protein, such as a kinase, a transcription factor, or another cellular protein. In addition to Raf-1 and MEKK, other kinases activate MEK, and MEK itself appears to be a signal integrating kinase. Current understanding is that MEK is highly specific for the phosphorylation of MAP kinase. In fact, no substrate for MEK other than the MAP kinase, ERK, has been demonstrated to date and MEK does not phosphorylate peptides based on the MAP kinase phosphorylation sequence, or even phosphorylate denatured MAP kinase. MEK also appears to associate strongly with MAP kinase prior to phosphorylating it, suggesting that phosphorylation of MAP kinase by MEK may require a prior strong interaction between the two proteins. Both this requirement and the unusual specificity of MEK are suggestive that it may have enough difference in its mechanism of action to other protein kinases that selective inhibitors of MEK, possibly operating through allosteric mechanisms rather than through the usual blockade of the ATP binding site, may be found.
It has been found that the compounds of the present invention are inhibitors of MEK and are useful in the treatment of a variety of proliferative disease states, such as conditions related to the hyperactivity of MEK, as well as diseases modulated by the MEK cascade.
The present invention provides a compound of Formula
wherein
W is
R2 is hydrogen, methyl, fluorine, or chlorine;
R3 is hydrogen or fluorine;
R4 is xe2x80x94CH2S(CH2)m(CH3), xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)qNHCH3, xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3, (Z)xe2x80x94CHCHCH2OCH3, xe2x80x94(CH2)nCO2R6, xe2x80x94(CF2)pCF3, xe2x80x94CH2(CF2)qCF3, xe2x80x94(CH2)mCF(CF3)2, xe2x80x94CH(CF3)2, xe2x80x94CF2CF(CF3)2, xe2x80x94C(CF3)3, xe2x80x94Cxe2x89xa1Cxe2x80x94(CH2)qN(CH3)2, xe2x80x94(Z)xe2x80x94CHCHxe2x80x94(CH2)qNHCH3, (Z)xe2x80x94CHCHxe2x80x94(CH2)qN(CH3)2, or C(O)C1-3 alkyl;
m is 0 to 1;
n is 0 to 2;
p is 1 to 5;
q is 1 to 2;
R5 is hydrogen, fluorine, bromine, or chlorine;
R6 is hydrogen, methyl or ethyl;
and pharmaceutically acceptable salts, (C1-6) amides and (C1-6) esters thereof.
The present invention provides compounds of Formula I wherein W is
R2 is hydrogen, fluorine, or chlorine; R3 is fluorine; R4 is xe2x80x94(CH2)nCO2R6 where n is 0; R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3; or R4 is C(O)C1-3 alkyl; and R5 is hydrogen.
The invention also provides a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier.
Additionally, the invention provides a method of treating a proliferative disease in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
The invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of a proliferative disease.
Furthermore, the invention provides methods of treating cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain, and neuropathic pain in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I.
The invention also provides the use of a compound of Formula I for the manufacture of a medicament for the treatment of cancer, restenosis, psoriasis, autoimmune disease, atherosclerosis, osteoarthritis, rheumatoid arthritis, heart failure, chronic pain, and neuropathic pain.
In addition, the invention provides a method for treating cancer in a patient in need thereof comprising administering a therapeutically effective amount of a compound of Formula I in combination with radiation therapy or at least one chemotherapeutic agent.
Certain terms are defined below and by their usage throughout this disclosure.
The terms xe2x80x9chalogenxe2x80x9d or xe2x80x9chaloxe2x80x9d in the present invention refer to a fluorine, bromine, chlorine, and iodine atom or fluoro, bromo, chloro, and iodo. The terms fluorine and fluoro, for example, are understood to be equivalent herein.
Alkyl groups, such as xe2x80x9cC1-6 alkylxe2x80x9d, include aliphatic chains (i.e., hydrocarbyl or hydrocarbon radical structures containing hydrogen and carbon atoms) with a free valence. Alkyl groups are understood to include straight chain and branched structures. Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, hexyl, and the like. The term xe2x80x9cC1-6 alkylxe2x80x9d includes within its definition the terms xe2x80x9cC1-4 alkylxe2x80x9d and xe2x80x9cC1-2 alkylxe2x80x9d.
Alkenyl groups are analogous to alkyl groups, but have at least one double bond (two adjacent sp2 carbon atoms). Depending on the placement of a double bond and substituents, if any, the geometry of the double bond may be entgegen (E), or zusammen (Z), cis, or trans. Similarly, alkynyl groups have at least one triple bond (two adjacent sp carbon atoms). Unsaturated alkenyl or alkynyl groups may have one or more double or triple bonds, respectively, or a mixture thereof. Like alkyl groups, unsaturated groups may be straight chain or branched. Examples of alkenyls and alkynyls include vinyl, allyl, 2-methyl-2-propenyl, cis-2-butenyl, trans-2-butenyl, and acetyl.
The present invention includes the hydrates and the pharmaceutically acceptable salts and solvates of the compounds defined by Formula I. The compounds of this invention can possess a sufficiently basic functional group, and accordingly react with any of a number of inorganic and organic acids, to form a pharmaceutically acceptable salt.
The term xe2x80x9cpharmaceutically acceptable saltxe2x80x9d as used herein, refers to salts of the compounds of Formula I which are substantially nontoxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid. Such salts are also known as acid addition salts. Such salts include the pharmaceutically acceptable salts listed in J of Pharm Sci. 1977;66:2-19, which are known to the skilled artisan.
Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, benzenesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Example of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, hydrobromide, iodide, acetate, propionate, decanoate, caprate, caprylate, acrylate, ascorbate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, glucuronate, glutamate, propionate, phenylpropionate, salicylate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, maleate, hydroxymateate, mandelate, mesylate, nicotinate, isonicotinate, cinnamate, hippurate, nitrate, stearate, phthalate, teraphthalate, butyne-1,4-dioate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydrozybenzoate, methoxybenzoate, dinitrobenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, phthalate, p-toluenesulfonate, p-bromobenzenesulfonate, p-chlorobenzenesulfonate, xylenesulfonate, phenylacetate, trifluoroacetate, phenylpropionate, phenylbutyrate, citrate, lactate, xcex1-hydroxybutyrate, glycolate, tartrate, hemitartrate, benzenesulfonate, methanesulfonate, ethanesulfonate, propanesulfonate, hydroxyethanesulfonate, 1-naphthalenesulfonate, 2-naphthalenesulfonate, 1,5-naphthalenedisulfonate, mandelate, tartarate, and the like. A preferred pharmaceutically acceptable salt is hydrochloride.
It should be recognized that the particular counterion forming a part of any salt of this inventions is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. It is further understood that such salts may exist as a hydrate.
As used herein, the term xe2x80x9cstereoisomerxe2x80x9d refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures which are not interchangeable. The three-dimensional structures are called configurations. As used herein, the term xe2x80x9cenantiomerxe2x80x9d refers to each of two stereoisomers whose molecules are nonsuperimposable mirror images of one another. The term xe2x80x9cchiral centerxe2x80x9d refers to a carbon atom to which four different groups are attached. As used herein, the term xe2x80x9cdiastereomersxe2x80x9d refers to stereoisomers which are not enantiomers. The terms xe2x80x9cracematexe2x80x9d or xe2x80x9cracemic mixturexe2x80x9d refer to a mixture of enantiomers.
The enantiomers of compounds of the present invention can be resolved by one of ordinary skill in the art using standard techniques well-known in the art, such as those described by J. Jacques, et al., xe2x80x9cEnantiomers, Racemates, and Resolutionsxe2x80x9d, John Wiley and Sons, Inc. 1981. Examples of resolutions include recrystallization techniques or chiral chromatography.
Some of the compounds of the present invention have one or more chiral centers and may exist in a variety of stereoisomeric configurations. As a consequence of these chiral centers, the compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All such racemates, enantiomers, and diastereomers are within the scope of the present invention.
The compounds of Formula I can be prepared by techniques and procedures readily available to one of ordinary skill in the art, for example, by following the procedures as set forth in the following Schemes, or analogous variants thereof. These synthetic strategies are further exemplified in Examples below. These Schemes are not intended to limit the scope of the invention in any way.
As used herein, the following terms have the meanings indicated: xe2x80x9cBOCxe2x80x9d refers to tert-butoxycarbonyl; Celite(copyright) refers to a filter agent which is acid washed and approximately 95% SiO2; xe2x80x9cDMAxe2x80x9d refers to N,N-dimethylacetamide; xe2x80x9cDMT-MMxe2x80x9d refers to 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride; xe2x80x9cEtOAcxe2x80x9d refers to ethyl acetate; xe2x80x9cEtOHxe2x80x9d refers to ethanol; xe2x80x9cEt2Oxe2x80x9d refers to diethyl ether; xe2x80x9chxe2x80x9d refers to hours; xe2x80x9cLiHMDSxe2x80x9d refers to lithium 1,1,1,3,3,3-hexamethyldisilazane or lithium bis(trimethylsilylamide); xe2x80x9cLindlar catalystxe2x80x9d refers to a Pd/CaCO3 catalyst washed with Pb(OAc)2; xe2x80x9cMexe2x80x9d refers to methyl; xe2x80x9cMeOHxe2x80x9d refers to methanol; xe2x80x9cMsClxe2x80x9d refers to methane sulfonyl chloride; xe2x80x9cPd/Cxe2x80x9d refers to palladium on carbon; xe2x80x9c(Ph3P)2PdCl2xe2x80x9d refers to dichlorobis(triphenylphosphine)palladium(II); xe2x80x9c(Ph3P)4Pdxe2x80x9d refers to tetrakis(triphenylphosphine)palladium(0); xe2x80x9cPyBopxe2x80x9d refers to benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate; xe2x80x9cRTxe2x80x9d refers to room temperature; xe2x80x9cTEAxe2x80x9d refers to triethylamine; xe2x80x9cTFAxe2x80x9d refers to trifluoroacetic acid; xe2x80x9cTHFxe2x80x9d refers to xe2x80x9ctetrahydrofuran; xe2x80x9cTLCxe2x80x9d refers to thin layer chromatography; and xe2x80x9cTMSxe2x80x9d refers to trimethylsilyl. All other terms and substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are readily available to one of ordinary skill in the art. Schemes 1 and 2 provide syntheses of the compounds of Formula I.
In Scheme 1, Step A, a 2-(arylamino)-benzoic acid or diphenylamine (3) is prepared from the coupling of a suitable benzoic acid (1) and a suitable aniline (2) in the presence of a strong base, for example, lithium 1,1,1,3,3,3-hexamethyldisilazane (LiHMDS), in a polar aprotic solvent such as tetrahydrofuran, acetonitrile or dimethylformamide. For example, the aniline (2) and the benzoic acid (1) are dissolved in a suitable organic solvent and cooled to about xe2x88x9278xc2x0 C. under nitrogen. The suspension is treated with an excess of a suitable base, such as LiHMDS, and allowed to warm to room temperature. The reaction is typically complete within about 2 hours to about 5 days. The resulting benzoic acid (3) can be isolated by removing the solvent, for example by evaporation under reduced pressure or by filtering the precipitated solid through Celite(copyright) and washing with a suitable solvent. The benzoic acid (3) can be further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
In Scheme 1, Step B, the compounds of Formula I are generally obtained by the union of 2-(arylamino)-benzoic acid (3) with an alkoxylamine (4) by the action of a peptide coupling agent in the presence of a base, if necessary. It is understood that the alkoxylamine (4) may be suitably protected. In such instances, Scheme 1 may be modified to include a removal of the protecting group by a procedure known in the art. Preferred coupling agents include 1,1xe2x80x2-carbonyldiimidazole (CDI), lithium bis (trimethylsilylamide) (LiHMDS), diphenylphosphinic chloride (DPP-Cl), benzotriazol-yl-oxy-tripyrolidinophosphonium hexafluorophosphate (PyBOP), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), N,Nxe2x80x2-dicyclohexylcarbodiimide (DCC), or 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI). Preferred bases include diisopropylethylamine, triethylamine, 4-methylmorpholine, or pyridine or a substituted pyridine, for example, 4-dimethyaminopyridine or 2,6-dimethylpyridine. Preferred solvents are polar aprotic solvents such as dichloromethane, tetrahydrofuran, or dimethylformamide. The reactions are generally carried out at a temperature between about xe2x88x9278xc2x0 C. to about 25xc2x0 C., and are normally complete within about 1 hour to about 5 days. The product amide can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
It would be understood by one of skill in the art that the substituent at R4 on the diphenylamine (3) or the substituent at R4 on the compound of Formula I can be reduced before the coupling reaction. The reduction is performed on alkene or alkyne derivatives under conditions known in the art, such as through hydrogenation, for example with Pd/C under an atmosphere of hydrogen.
Alternately, the compounds of formula I are generally prepared as shown in Scheme 1, steps C and D by the contact of alkoxyamine (4) with xe2x80x9cactivatedxe2x80x9d benzoic acid derivatives (3a), wherein the activating group xe2x80x9cXxe2x80x9d completes an acid halide, anhydride, mixed anhydride, or an activated ester, such as a pentafluorophenyl ester, nitrophenyl ester or thioester. Preferred bases include diisopropylethylamine, triethylamine, 4-methylmorpholine, imidazole, pyridine or a substituted pyridine, for example, 4-dimethyaminopyridine or 2,6-dimethylpyridine. Preferred solvents are polar aprotic solvents such as dichloromethane, tetrahydrofuran, or dimethylformamide.
In Scheme 2, Step A, a 4-iodo phenylamino benzoic acid (3xe2x80x2) is prepared from the union of a suitable benzoic acid (1) and a suitable 4-iodoaniline (5), according to the general procedure of Scheme 1, Step A.
In Scheme 2, Step B, the 4-iodo phenylamino benzoic acid (3xe2x80x2) is coupled with an alkoxylamine (4) according to the general procedure of Scheme 1, Step B or Scheme 1, Steps C and D.
In Scheme 2, Step C, the compounds of Formula I are prepared from the 4-iodo-phenylamino benzamide (6), by transition metal-promoted coupling with reagent M-R4 (7) in a suitable solvent such as triethylamine. The entire mixture is stirred from about 2 to 24 hours at room temperature. The transition metal-promoted coupling may be carried out with a palladium(0) or palladium (II) coupling agent, such as (Ph3P)4Pd or (Ph3P)2PdCl2 and cuprous iodide. M is defined as a functional group known to transfer a carbon radical fragment in transition metal-promoted coupling processes. Examples of a suitable M group include trialkylstannyl, trialkylsilyl, trimethylsilyl, zinc, copper, boron, magnesium and lithium. It would be understood by one of skill in the art that the substituent R4 may be further transformed, such as by oxidation, reduction, deprotection, or hydrogenation. The substituent R4 may also be transformed into a different R4 through standard synthetic procedures known to one of skill in the art. The resulting compound of formula I, as well as the protected Formula I compound, can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation.
The aniline (2) can be prepared by techniques and procedures readily available to one of ordinary skill in the art and by following the procedures as set forth in the following Schemes, or analogous variants thereof. These Schemes are not intended to limit the scope of the invention in any way.
In Scheme 3, Step A, a suitable thiolate (11) is reacted with a 4-tert-butoxycarbonylamino-3-substituted-benzyl bromide, such as 4-tert-butoxycarbonylamino-3-fluorobenzyl bromide (J Med Chem. 2000;43:5017) to provide a compound of structure (12). In Step B, the BOC protecting group of compound (12) is hydrolyzed with, for example, TFA to provide the desired aniline (2a).
In Scheme 4, Step A, a suitable acetylene (14) such as methylpropargyl ether, and a suitable 4-iodoaniline (13) are coupled via the Sonogashira reaction. For example, a 4-iododaniline (13), such as 2-fluoro-4-iodoaniline, is combined with CuI and (Ph3P)2PdCl2 under nitrogen. An acetylene derivative (14) is added in a suitable solvent, such as TEA, and the entire mixture is stirred for about 2 to 24 hours at room temperature.
After reaction of the aniline (2b) with a suitable benzoic acid (1) under the standard conditions to form the diphenylamine, as in Scheme 1, Step A above, the alkynyl diphenylamine (3a) is dissolved in a suitable solvent, such as tetrahydrofuran, in the presence of a catalyst, such as Lindlar catalyst or palladium on carbon and, if desired, a suitable compound which disrupts the action of the catalyst, such as quinoline or pyridine. The mixture is stirred under an atmosphere of hydrogen from about 1 to 24 hours at room temperature. The resulting alkenyl diphenylamine (3b) can be isolated by removing the solvent, for example by evaporation under reduced pressure, and further purified, if desired, by standard methods such as chromatography, crystallization, or distillation. Reaction with a suitable alkoxylamine, with the 2-(arylamino)benzoic acids (3a and 3b) under the conditions of Scheme 1, Step B gives the desired compounds of Formula I, wherein R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3 or xe2x80x94Cxe2x95x90Cxe2x80x94CH2OCH3.
In Scheme 6, Step B, a suitable acetylene derivative (16), which has been protected, for example with a tetrahydropyranyl ether, and a suitable 4-iodoaniline (13) such as 2-fluoro-4-iodoaniline are coupled via the Sonogashira reaction as in Scheme 4, Step A, to provide the desired aniline (2c).
In Scheme 7, Step A, the propargyl alcohol compound (20) is prepared from the iodide compound (18) by transition metal-promoted coupling according to the general procedure of Scheme 2, Step C.
In Scheme 7, Step B, the propargyl alcohol compound (20) is converted to a fully saturated substituent through hydrogenation, for example with Pd/C under an atmosphere of hydrogen to provide the methyl 4-substituted-phenylamino benzoate (22).
In Scheme 7, Step C, methyl 4-substituted-phenylamino benzoate (22) is deprotected in a manner known to one of skill in the art, for example, aqueous NaOH in EtOH, then coupled with an hydroxylamine according to the general procedure of Scheme 1, Step B.
In Scheme 7, step D, the compound (24) is dissolved in a suitable solvent such as tetrahydrofuran and reacted with methanesulfonyl chloride to give the intermediate mesylate, then NaI in EtOAc to give the iodide compound (26).
In scheme 7, steps E and F, the iodide compound (26) is reacted with methylamine and dimethylamine respectively to give compounds of formula I wherein m is 3 and R4 is xe2x80x94(CH2)mNHCH3 (28) and xe2x80x94(CH2)mN(CH3)2 (30).
In Scheme 8, Step A, the desired perfluoroalkyl anilines (2d) are prepared by an Ullmann condensation of a suitable 4-iodoaniline (5), such as 2-fluoro-4-iodoaniline, with a perfluoroalkyl iodide (24), such as CF3(CF2)nI (e.g. N. Yoshino et. al., Bull Chem Soc Jpn, 1992;65:2141).
In Scheme 8, Step B, the desired anilines (2e) are prepared from perfluoroalkyl anilines (2d) by reductive removal of the benzylic fluorine atoms with a suitable reducting agent, such as LiAlH4 (Tetrahedron Letters, 1996;37:4655).
The anilines (5) wherein R4 is xe2x80x94(CH2)nCO2R6, n is 1, and R6 is hydrogen or ethyl are commercially available or can be prepared by one of skill in the art. The anilines (5) wherein R4 is xe2x80x94(CH2)nCO2R6, n is 1, and R6 is methyl are prepared from esterification of the commercially available corresponding aniline with diazomethane. The aniline (5) wherein R4 is xe2x80x94(CH2)nCO2R6, n is 2, and R6 is hydrogen is commercially available or can be prepared by one of skill in the art. The anilines (5) wherein R4 is xe2x80x94(CH2)nCO2R6, n is 2, and R6 is methyl or ethyl are prepared from esterification of the commercially available corresponding aniline with diazomethane.
The anilines of Scheme 9 are used in the preparation of compounds of formula I wherein R4 is xe2x80x94(CH2)nCO2R6, n is 0, and R6 is methyl. The aniline where R2 is hydrogen is commercially available and the aniline where R2 is fluorine can be prepared according to literature procedures available to one of ordinary skill in the art.
Provided by the present invention are compounds of formula I wherein:
W is
xe2x80x83; or
W is
xe2x80x83; or
W is
xe2x80x83or
W is
xe2x80x83;
R2 is hydrogen, fluorine or chlorine; or R2 is hydrogen or fluorine; or R2 is hydrogen; or R2 is fluorine;
R3 is fluorine;
R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3, xe2x80x94(CH2)nCO2R6 or C(O)CH3 alkyl; or R4 is xe2x80x94(CH2)nCO2R6 where n is 0 and R6 is hydrogen or methyl; R4 is CO2H; or R4 is CO2CH3; or R4 is C(O)CH3; or R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3; or
R5 is hydrogen.
Also provided by the present invention are compounds of Formula
wherein
xe2x80x83W is
R2 is hydrogen, fluorine, or chlorine;
R3 is fluorine;
R4 is xe2x80x94CH2S(CH2)m(CH3), xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3, (Z)xe2x80x94CHCHCH2OCH3, xe2x80x94(CH2)nCO2R6, xe2x80x94(CF2)pCF3, xe2x80x94CH2(CF2)qCF3, xe2x80x94(CH2)mCF(CF3)2, xe2x80x94CH(CF3)2, xe2x80x94CF2CF(CF3)2, xe2x80x94C(CF3)3, xe2x80x94(Z)xe2x80x94CHCHxe2x80x94(CH2)qNHCH3, or (Z)xe2x80x94CHCHxe2x80x94(CH2)qN(CH3)2, or C(O)CH3;
n is 0;
R5 is hydrogen;
R6 is hydrogen or methyl;
and pharmaceutically acceptable salts thereof.
Also provided by the present invention are compounds of Formula
wherein
xe2x80x83W is;
R2 is hydrogen, fluorine, or chlorine;
R3 is fluorine;
R4 is xe2x80x94Cxe2x89xa1Cxe2x80x94CH2OCH3, xe2x80x94(CH2)nCO2R6 or C(O)CH3;
n is 0;
R5 is hydrogen;
R6 is hydrogen or methyl;
and pharmaceutically acceptable salts thereof.
Particularly, the present invention provides the compounds which are
Methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]-phenyl]amino]benzoate;
4-[[2,3-Difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]-amino]benzoic acid;
3,4-Difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]-amino]-N-(2-hydroxyethoxy)benzamide;
Methyl 4-(2,3-difluoro-6-{[(2-hydroxyethoxy)amino]carbonyl}anilino)-3-fluorobenzoate;
4-(2,3-Difluoro-6-{[(2-hydroxyethoxy)amino]carbonyl}anilino)-3-fluorobenzoic acid;
2-(4-Acetyl-2-chloro-phenylamino)-3,4-difluoro-N-(2-hydroxyethoxy)-benzamide and
2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-3,4-difluoro-N-(2-hydroxyethoxy)benzamide.
Compounds of the present invention include, but are not limited to the following compounds:
Methyl 4-[[2,3-difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]-phenyl]amino]benzoate;
4-[[2,3-Difluoro-6-[[(2-hydroxyethoxy)amino]carbonyl]phenyl]-amino]benzoic acid; and
3,4-Difluoro-2-[[2-fluoro-4-(3-methoxy-1-propynyl)phenyl]amino]-N-(2-hydroxyethoxy)benzamide.
Also provided by the present invention are compounds which include, but are not limited to the following compounds:
3,4-Difluoro-2-(2-fluoro-4-methylsulfanylmethyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
2-(4-Ethylsulfanylmethyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(3-methylamino-prop-1-ynyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(3-methoxy-prop-1-ynyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-((Z)-3-methoxy-propenyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluorobenzoic acid;
4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluorobenzoic acid methyl ester;
4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluorobenzoic acid ethyl ester;
{4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluoro-phenyl}-acetic acid;
{4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluoro-phenyl}-acetic acid methyl ester;
{4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluoro-phenyl}-acetic acid ethyl ester;
3-{4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-2-fluoro-phenyl}-propionic acid;
3-{4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluoro-phenyl)-propionic acid methyl ester;
3-(4-[2,3-Difluoro-6-(2-hydroxy-ethoxycarbamoyl)-phenylamino]-3-fluoro-phenyl}-propionic acid ethyl ester;
3,4-Difluoro-2-(2-fluoro-4-pentafluoroethyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-(2-fluoro-4-heptafluoropropyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-(2-fluoro-4-nonafluorobutyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-(2-fluoro-4-undecafluoropentyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-(2-fluoro-4-tridecafluorohexyl-phenylamino)-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(2,2,3,3,3-pentafluoro-propyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(2,2,3,3,4,4,4-heptafluoro-butyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(2,3,3,3-tetrafluoro-2-trifluoromethyl-propyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(1,2,2,2-tetrafluoro-1-trifluoromethyl-ethyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
2-(4-Acetyl-2-fluoro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(2,2,2-trifluoro-1-trifluoromethyl-ethyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(1,1,2,3,3,3-hexafluoro-2-trifluoromethyl-propyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
3,4-Difluoro-2-[2-fluoro-4-(2,2,2-trifluoro-1,1-bis-trifluoromethyl-ethyl)-phenylamino]-N-(2-hydroxy-ethoxy)-benzamide;
Methyl 4-(2,3-difluoro-6-{[(2-hydroxyethoxy)amino]carbonyl}anilino)-3-fluorobenzoate;
4-(2,3-Difluoro-6-{[(2-hydroxyethoxy)amino]carbonyl}anilino)-3-fluorobenzoic acid;
2-(4-Acetyl-2-chloro-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethoxy)-benzamide and
2-{2-fluoro-4-[(methylamino)carbonyl]anilino}-3,4-difluoro-N-(2-hydroxyethoxy)benzamide.
As used herein, the term xe2x80x9cpatientxe2x80x9d refers to any warm-blooded animal such as, but not limited to, a human, horse, dog, guinea pig, or mouse. Preferably, the patient is human.
The term xe2x80x9ctreatingxe2x80x9d for purposes of the present invention refers to treatment, prophylaxis or prevention, amelioration or elimination of a named condition once the condition has been established.
Selective MEK 1 or MEK 2 inhibitors are those compounds which inhibit the MEK 1 or MEK 2 enzymes, respectively, without substantially inhibiting other enzymes such as MKK3, PKC, Cdk2A, phosphorylase kinase, EGF, and PDGF receptor kinases, and C-src. In general, a selective MEK 1 or MEK 2 inhibitor has an IC50 for MEK 1 or MEK 2 that is at least one-fiftieth ({fraction (1/50)}) that of its IC50 for one of the above-named other enzymes. Preferably, a selective inhibitor has an IC50 that is at least {fraction (1/100)}, more preferably {fraction (1/500)}, and even more preferably {fraction (1/1000)}, {fraction (1/5000)}, or less than that of its IC50 or one or more of the above-named enzymes.
The disclosed compositions are useful as both prophylactic and therapeutic treatments for diseases or conditions related to the hyperactivity of MEK, as well as diseases or conditions modulated by the MEK cascade. Examples include, but are not limited to, stroke, septic shock, heart failure, osteoarthritis, rheumatoid arthritis, organ transplant rejection, and a variety of tumors such as ovarian, lung, pancreatic, brain, prostatic, and colorectal.
The invention further relates to a method for treating proliferative diseases, such as cancer, restenosis, psoriasis, autoimmune disease, and atherosclerosis. Other aspects of the invention include methods for treating MEK-related (including Ras-related) cancers, whether solid or hematopoietic. Examples of cancers include brain, breast, lung, such as non-small cell lung, ovarian, pancreatic, prostate, renal, colorectal, cervical, acute leukemia, and gastric cancer. Further aspects of the invention include methods for treating or reducing the symptoms of xenograft (cell(s), skin, limb, organ or bone marrow transplant) rejection, osteoarthritis, rheumatoid arthritis, cystic fibrosis, complications of diabetes (including diabetic retinopathy and diabetic nephropathy), hepatomegaly, cardiomegaly, stroke (such as acute focal ischemic stroke and global cerebral ischemia), heart failure, septic shock, asthma, Alzheimer""s disease, and chronic or neuropathic pain. Compounds of the invention are also useful as antiviral agents for treating viral infections such as HIV, hepatitis (B) virus (HBV), human papilloma virus (HPV), cytomegalovirus (CMV), and Epstein-Barr virus (EBV). These methods include the step of administering to a patient in need of such treatment, or suffering from such a disease or condition, a therapeutically effective amount of a disclosed compound of Formula I or pharmaceutical composition thereof.
The term xe2x80x9cchronic painxe2x80x9d for purposes of the present invention includes, but is not limited to, neuropathic pain, idiopathic pain, and pain associated with chronic alcoholism, vitamin deficiency, uremia, or hypothyroidism. Chronic pain is associated with numerous conditions including, but not limited to, inflammation, arthritis, and postoperative pain.
As used herein, the term xe2x80x9cneuropathic painxe2x80x9d is associated with numerous conditions which include, but are not limited to, inflammation, postoperative pain, phantom limb pain, burn pain, gout, trigeminal neuralgia, acute herpetic and postherpetic pain, causalgia, diabetic neuropathy, plexus avulsion, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain, and nerve injury between the peripheral nervous system and the central nervous system.
The invention also features methods of combination therapy, such as a method for treating cancer, wherein the method further includes providing radiation therapy or chemotherapy, for example, with mitotic inhibitors such as a taxane or a vinca alkaloid. Examples of mitotic inhibitors include paclitaxel, docetaxel, vincristine, vinblastine, vinorelbine, and vinflunine. Other therapeutic combinations include a MEK inhibitor of the invention and an anticancer agent such as cisplatin, 5-fluorouracil or 5-fluoro-2-4(1H,3H)-pyrimidinedione (5FU), flutamide, and gemcitabine.
The chemotherapy or radiation therapy may be administered before, concurrently, or after the administration of a disclosed compound according to the needs of the patient.
Those skilled in the art will be able to determine, according to known methods, the appropriate therapeutically-effective amount or dosage of a compound of the present invention to administer to a patient, taking into account factors such as age, weight, general health, the compound administered, the route of administration, the type of pain or condition requiring treatment, and the presence of other medications. In general, an effective amount or a therapeutically-effective amount will be between about 0.1 and about 1000 mg/kg per day, preferably between about 1 and about 300 mg/kg body weight, and daily dosages will be between about 10 and about 5000 mg for an adult subject of normal weight. Commercially available capsules or other formulations (such as liquids and film-coated tablets) of 100, 200, 300, or 400 mg can be administered according to the disclosed methods.
The compounds of the present invention are preferably formulated prior to administration. Therefore, another aspect of the present invention is a pharmaceutical composition comprising a compound of Formula I and a pharmaceutically acceptable carrier. In making the compositions of the present invention, the active ingredient, such as a compound of Formula I, will usually be mixed with a carrier, or diluted by a carrier or enclosed within a carrier. Dosage unit forms or pharmaceutical compositions include tablets, capsules, pills, powders, granules, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers adapted for subdivision into individual doses.
Dosage unit forms can be adapted for various methods of administration, including controlled release formulations, such as subcutaneous implants. Administration methods include oral, rectal, parenteral (intravenous, intramuscular, and subcutaneous), intracisternal, intravaginal, intraperitoneal, intravesical, local (drops, powders, ointments, gels, or cream), and by inhalation (a buccal or nasal spray).
Parenteral formulations include pharmaceutically acceptable aqueous or nonaqueous solutions, dispersion, suspensions, emulsions, and sterile powders for the preparation thereof. Examples of carriers include water, ethanol, polyols (propylene glycol, polyethylene glycol), vegetable oils, and injectable organic esters such as ethyl oleate. Fluidity can be maintained by the use of a coating such as lecithin, a surfactant, or maintaining appropriate particle size. Carriers for solid dosage forms include (a) fillers or extenders, (b) binders, (c) humectants, (d) disintegrating agents, (e) solution retarders, (f) absorption acccelerators, (g) adsorbants, (h) lubricants, (i) buffering agents, and (j) propellants.
Compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispensing agents; antimicrobial agents such as parabens, chlorobutanol, phenol, and sorbic acid; isotonic agents such as a sugar or sodium chloride; absorption-prolonging agents such as aluminum monostearate and gelatin; and absorption-enhancing agents.
The following examples represent typical syntheses of the compounds of the present invention as described generally above. These examples are illustrative only and are not intended to limit the invention in any way. The reagents and starting materials are readily available to one of ordinary skill in the art.
Step A: Preparation of 1,2:5,6-di-O-isopropylidene-D-mannitol
To a stirring suspension of D-Mannitol (1.82 g, 10.0 mmol) in tetrahydrofuran (21 mL) and dimethylformamide (9 mL) was added p-toluenesulfonic acid monohydrate (0.02 g, 0.1 mmol,) at ambient temperature, followed by 2,2-dimethoxypropane (2.8 mL, 0.023 mol). The reaction mixture was stirred for 18 hours at room temperature, then additional 2,2-dimethoxypropane (0.3 mL, 2.4 mmol) was added. The suspension was heated to 40xc2x0 C. to 45xc2x0 C., and stirred for 2 hours. Sodium bicarbonate (1.8 g, 0.016 mol) was added to neutralize the acid and the mixture was stirred for 30 minutes. The excess Na2CO3 was filtered and washed with tetrahydrofuran (5 mL). The filtrate was concentrated. To the remaining light yellow oil was added toluene (15 mL) and the mixture was stirred at 3xc2x0 C. to 5xc2x0 C. until a light-yellow gelatinous solid formed. The solid was filtered and washed with hexane (2xc3x975 mL). The product was dried in a vacuum oven for 18 hours to give 1,2:5,6-di-O-isopropylidene-D-mannitol (1.24 g, 47.3%) as an off-white solid, mp 110-113xc2x0 C.
Step B: Preparation of (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol
To a solution of the product of Preparation 1, Step A, 1,2:5,6-di-O-isopropylidene-D-mannitol (50 g, 0.191 mol), in water (700 mL), was added solid sodium bicarbonate (20 g). The resultant solution was stirred until all the solid dissolved, and then cooled in an ice-water bath. Solid sodium periodate (81.5 g, 0.381 mol) was slowly added to the solution portionwise. Gas evolution observed. The white mixture was stirred at ambient temperature for 2 hours. Solid sodium chloride (30 g) was added, and the mixture was stirred for 15 minutes. The white solid was filtered. The filtrate was cooled in an ice-water bath. Solid sodium borohydride was added slowly. Gas bubble evolved. The mixture was warmed to ambient temperature, and stirred overnight. The milky mixture turned to a clear solution. The aqueous solution was extracted with dichloromethane (3xc3x97). The organic solution was washed with brine, and dried over magnesium sulfate. The solvent was removed in vacuo to give (S)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol as a colorless oil, which was dried under high vacuum at ambient temperature overnight, 34.82 g (60%); MS (APCI+)=133 (M++1).
Step C: Preparation of (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and the product of Preparation 1, Step B, (S)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3xc2x0 C. to 5xc2x0 C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15xc2x0 C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3xc2x0 C. to 5xc2x0 C. The white solid was filtered, washed with a small amount of cold ETOH, and dried in vacuum oven at 40xc2x0 C. to give (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): xcex4 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Step D: Preparation of (R)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine
To a stirring solution of the product of Preparation 1, Step C, (R)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (74.9 g, 0.27 mol) in dichloromethane (480 mL) at 3xc2x0 C. to 5xc2x0 C. was added methylhydrazine (15.8 mL, 0.29 mol) dropwise. The color of the suspension turned from yellow to white. The cooling bath was removed and the mixture was stirred for 2 hours at ambient temperature. The resulting suspension was concentrated on a rotary evaporator. To the white solid was added ether (0.5 L) and the resulting mixture was stirred for 1.5 hours at ambient temperature. The white precipitate was filtered and washed with ether (0.2 L). The filtrate was concentrated on rotary evaporator to give (R)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (39.0 g, 98.3%): 1H NMR (CDCl3): xcex4 1.35 (s, 3H), 1.42 (s, 3H), 3.73 (m, 3H), 4.05 (m, 1H), 4.33 (m, 1H), 5.39 (m, 2H); MS (APCI+)=148.1 (M++1).
Step A: Preparation of L-gulonic xcex3-lactone
To a solution of L-ascorbic acid (83.9 g, 0.477 mol) in water (600 mL) was added Pd/C (10%, 8.3 g). The mixture was subjected to hydrogenation in a Parr hydrogenator at 48 psi, 18xc2x0 C. for 62 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to afford L-gulonic xcex3-lactone (81.0 g, 96%) as an off-white solid, after drying at 50xc2x0 C. in a vacuum oven for 18 hours: mp 182-184xc2x0 C.
Step B: Preparation of 5,6-isopropylidene-L-gulonic Acid xcex3-lactone
The product of Preparation 2, Step A, L-gulonic xcex3-lactone (25.0 g, 140.3 mmol) was dissolved in mixture of tetrahydrofuran (140 mL) and dimethylformamide (200 mL). p-Toluenesulfonic acid monohydrate (2.67 g, 14.0 mmol) was added and the reaction mixture was cooled to 0xc2x0 C. to 5xc2x0 C. in an ice-water bath. 2,2-Dimethoxypropane (22.4 mL, 182.4 mmol) was added dropwise and the reaction mixture was stirred at ambient temperature for 18 hours. The mixture was neutralized with solid sodium carbonate (24.0 g) and stirred for 1 hour. The solid was filtered and washed with tetrahydrofuran. The THF was removed under vacuo, and DMF by distillation under high vacuum. The resulting orange solid was triturated with toluene (300 mL), filtered, washed with toluene (20 mL), and dried in a vacuum oven at 40xc2x0 C. for 3 days, to yield 5,6-isopropylidene-L-gulonic acid xcex3-lactone (28.9 g, 94%) as a pale orange solid: mp 155-158xc2x0 C.; MS (APCI+)=219.0 (M++1).
Step C: Preparation of (R)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol
To a stirring suspension of the product of Preparation 2, Step B, 5,6-O-isopropylidene-L-gulono-1,4-lactone (15.16 g, 69.5 mmol) in water (0.3 L) was added solid sodium periodate in small portions at 3xc2x0 C. to 5xc2x0 C. The pH of the mixture was adjusted to 5.5 with 1N aqueous sodium hydroxide. The suspension was stirred for 2 hours at ambient temperature, then saturated with sodium chloride (20.0 g) and filtered. To the filtrate, at 3xc2x0 C. to 5xc2x0 C., was added sodium borohydride (10.5 g, 0.278 mol) in small portions. The reaction mixture was stirred for 18 hours at ambient temperature. Acetone (100 mL) was added to destroy the excess of sodium borohydride, and the stirring was continued for 30 minutes. The acetone was removed under reduced pressure, and the aqueous residue was extracted with dichloromethane (3xc3x97300 mL) and EtOAc (3xc3x97300 mL). The combined organic layers were dried over magnesium sulfate, filtered, and evaporated to give (R)-(+)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (5.07 g, 55.7%) as a colorless clear liquid: MS (APCI+)=132.9 (M++1).
Step D: Preparation of (S)-2-(2,2-Dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione
A 3-L round-bottomed flask equipped with mechanical stirrer and additional funnel was charged with N-hydroxyphthalimide (68.0 g, 0.416 mol) and tetrahydrofuran (1.2 L) under nitrogen atmosphere. To this solution was added triphenylphosphine (109.2 g, 0.416 mol) and (R)-(2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (55.0 g, 0.416 mol). The mixture was cooled to 3xc2x0 C. to 5xc2x0 C. and diethyl azodicarboxylate (85.2 mL, 0.541 mol) was added dropwise, while keeping the inner temperature below 15xc2x0 C. The reaction mixture was warmed to ambient temperature, and stirred for 18 hours. The tetrahydrofuran was evaporated under reduced pressure. To the remaining orange solid was added dichloromethane (0.5 L) and the mixture was stirred for 1 hour. The white solid (Ph3PO) was filtered and washed with dichloromethane (0.1 L). The solvent was removed and ethanol (0.5 L) was added to the resulting solid. The mixture was stirred for 2 hours at 3xc2x0 C. to 5xc2x0 C. The white solid was filtered, washed with a small amount of cold EtOH and dried in vacuum oven at 40xc2x0 C. to give (S)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (112.5 g, 97%) as a white solid: 1H NMR (CDCl3): xcex4 1.33 (s, 3H), 1.99 (s, 3H), 3.96 (m, 1H), 4.15 (m, 2H), 4.30 (m, 1H), 4.48 (m, 1H), 7.59 (m, 2H), 7.84 (m, 2H); MS (APCI+)=278 (M++1).
Step E: Preparation of (S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine
To a stirring solution of (S)-2-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-isoindole-1,3-dione (74.9 g, 0.27 mol) in dichloromethane (480 mL) at 3xc2x0 C. to 5xc2x0 C. was added methylhydrazine (15.8 mL, 0.29 mol) dropwise. The color of the suspension turned from yellow to white. The cooling bath was removed and the mixture was stirred for 2 hours at ambient temperature. The resulting suspension was concentrated on a rotary evaporator. To the white solid was added ether (0.5 L) and the resulting mixture was stirred for 1.5 hours at ambient temperature. The white precipitate was filtered and washed with ether (0.2 L). The filtrate was concentrated on rotary evaporator to give (S)-(2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-hydroxylamine (39.0 g, 98.3%): 1H NMR (CDCl3): xcex4 1.35 (s, 3H), 1.42 (s, 3H), 3.73 (m, 3H), 4.05 (m, 1H), 4.33 (m, 1H), 5.39 (m, 2H); MS (APCI+)=148.1 (M++1).
Step A: Preparation of 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione 2,2-Dimethyl-[1,3]dioxan-5-ol was Prepared as Described Previously
(Forbes, D. C. et. al. Synthesis, 1998;6:879-82). 1H NMR (400 MHz; DMSO-d6) xcex4 4.91 (d, 1H, J=5.1), 3.70-3.75 (m, 2H), 3.41-3.46 (m, 3H), 1.30 (s, 3H), 1.24 (s, 3H); MS (APCI+)=132.9. To a stirring solution of 2,2-dimethyl-[1,3]dioxan-5-ol (1.50 g, 11.35 mmol), N-hydroxyphthalimide (1.85 g, 11.35 mmol) and triphenylphosphine (2.98 g, 11.35 mmol) in anhydrous tetrahydrofuran (30 mL) at 0xc2x0 C. was added diethyl azodicarboxylate (2.3 mL, 14.75 mmol). The resultant solution was allowed to warm to room temperature. After stirring for 3 hours, the mixture was concentrated in vacuo and charged with chloroform affording white solids. The solids were filtered off and filtrate was collected and concentrated. The residue was purified via silica column chromatography (4:1 hexanes/ethyl acetate) affording 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione as clear crystals (1.74 g, 55% over 2 steps): 1H NMR (400 MHz; DMSO-d6) xcex4 7.83 (s, 4H), 4.11-4.12 (m, 1H), 4.04-4.09 (m, 2H), 3.92-3.96 (m, 2H), 1.32 (s, 3H), 1.25 (s, 3H); MS (APCI+)=278.0.
Step B: Preparation of O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine
To a stirring solution of the product of Example 13, Step A, 2-(2,2-dimethyl-[1,3]dioxan-5-yloxy)-isoindole-1,3-dione (1.72 g, 6.20 mmol) in dichloromethane (15 mL) at 0xc2x0 C. under nitrogen was added methylhydrazine (0.36 mL, 6.82 mmol) and allowed to warm to room temperature. After stirring for 2 hours the reaction mixture was concentrated in vacuo and charged with diethylether. The solids were filtered off and the filtrate was collected and concentrated to afford O-(2,2-dimethyl-[1,3]dioxan-5-yl)-hydroxylamine as a yellow oil (0.97 g, 100%). 1H NMR (400 MHz; DMSO-d6) xcex4 5.98 (bs, 2H), 3.84-3.87 (m, 2H), 3.66-3.68 (m, 2H), 3.30-3.35 (m, 1H), 1.29 (s, 3H), 1.22 (s, 3H); MS (APCI+)=147.9.

N-(4-substituted phenyl)-anthranilic acid hydroxamate esters


Membrane switches are manufactured by electrically conductive pastes consisting of 55 to 65% by weight of metal powder in the shape of flake (silver, aluminum, copper or the alloy thereof), 35 to 60% by weight of an organic solvent at high boiling point, 5 to 15% by weight of organic thermal plastic, including mainly saturation polyester polymer, and 0.5 to 5% by weight of additives, including trietheanolamine, adhesion promoter, defoamer, leveling agent, thixotropic agent etc. The silver paste is of excellent adhesion on ITO film or ITO glass, delivers conductivity high up to 20 mΩ/□ with less than 65% by weight of silver, and passes test under the conditions (85□, 85% RH, 1000 hours).

1. Field of the Invention
The present invention relates to electrically conductive materials, more particularly, the present invention relates to an electrically conductive paste for conductive substrate or conductive film.
2. Description of Related Arts
The electrically conductive paste is made of low molecular weight liquid epoxy resin and according hardening agent in the U.S. Pat. No. 3,746,662. However, the hardening agent is flaky and hard; it is not applicable to manufacturing membrane keyboards. In the U.S. Pat. No. 4,425,263, the electrically conductive paste is made of metal powder, organic solvent and aromatic polyester resin adhesive. However, the disadvantage of the electrically conductive paste is insufficient flexibility. As a result, the membrane keyboard made of the electrically conductive paste is likely to crack. In order to enhance the flexibility of the electrically conductive paste, polyvinyl dichloride polymer is added to aromatic polyester resin in the U.S. Pat. No. 4,592,961. However, the electrically conductive paste is prone to form gel after kept in storage for a long time. In the U.S. Pat. No. 4,595,605, the soft welding electrically conductive paste is provided, where the electrically conductive paste consists of 88 to 93 wt % by weight of metal powder, and 7 to 12 wt % by weight of plastic vinyl chloride/vinyl ethylene resin polymer with total molecular weight of 14,000 to 35,000. The disadvantage of the electrically conductive paste is that the conductive cannot be attached to indium-tin oxide (ITO) films. In the U.S. Pat. No. 5,011,627, the electrically conductive paste consists of 40 to 75 wt % by weight of metal powder, 5 to 20 wt % by weight of solvent, plastic epoxy resin and phenolic resin (with molecular weight of 10,000 to 25,000). Though the flexibility of the electrically conductive paste is enhanced, but the electrically conductive paste is not as flexible as polyester membrane. In addition, the metal powder used in the electrically conductive paste is spherical, irregular and flake shaped, which delivers less conductivity in the U.S. Pat. No. 5,011,627. In the U.S. Pat. No. 5,089,173, the electrically conductive paste consists of three components polymer plastic vinyl chloride/vinyl ethylene resin/dicaboxylic acid is provided, where the electrically conductive paste consists of 3 to 15 wt % by weight of plastic vinyl chloride/vinyl ethylene resin/dicaboxylic acid and 1 to 6 wt % by weight of polyamide resin, 2 to 10 wt % by weight of polyester alkyd (or 1 to 10 wt % by weight of a mixture of polyamide resin and polyester alkyd), 0.05 to 1.0 wt % by weight of triethanolamine for neutralizing carboxyl group and 50 to 80 wt % by weight of metal powder. The electrically conductive paste is provided for membrane keyboard manufacturing. It should be noted that resin is acidic and therefore may corrode the electronic circuitry. Also, the electrically conductive paste is prone to form gel when the electrically conductive paste is kept in storage for a long time.
In the U.S. Pat. No. 5,653,918, the electrically conductive paste consists of three components polymer, plastic vinyl chloride/vinyl ethylene resin/vinyl alcohol or hydroxyl group, is provided, where the electrically conductive paste consists of 4 to 18 wt % by weight of plastic vinyl chloride/vinyl ethylene resin/vinyl alcohol or hydroxyl group, and 40 to 80 wt % by weight of metal powder. The electrically conductive paste does not have the disadvantage such as gelation, it is not ideal to use in conductive materials such as ITO film or ITO glass.

Conductive paste for conductive substrate or conductive film

Advanced Touch Optics Technology Corporation


Buffer circuits are provided between outputs of a scanning line driver circuit and scanning lines. The buffer circuits each are configured to make rise or fall time of scanning signals at output sides of the buffer circuits substantially the same as or longer than those of the scanning signals at end terminals of the scanning lines when the scanning signals supplied to the scanning lines are rectangular in waveform.

Organic electroluminescence (EL) display apparatus have recently attracted a great deal of attention. Pixels in the display apparatus contain light-emitting devices, i.e., organic EL display elements with thin-film solid-state stacked structures but the display apparatus are not required to have light sources such as rear or front light sources in contrast with liquid crystal display apparatus necessarily provided with them. Thus, the display apparatus are lighter in weight, thinner in thickness and stronger against mechanical shocks than the liquid crystal display apparatus.
The EL display elements are driven by driver transistors of pixel circuits, the gate electrodes of which are supplied with video signals. In other words, electric currents corresponding to the video signals are provided for the EL display elements to emit light with brightness in response to such electric currents.
Voltages at the gate electrodes of the driver transistors are provided by using a voltage or current signal supply system. The voltage-signal supply (or voltage writing) and current-signal supply (or current writing) methods are disclosed in U.S. Pat. Nos. 6,229,506B1 and 6,373,454B1, respectively.
In the pixel circuits, switching transistors are provided to supply voltages to the gate electrodes of the driving transistors. Thus, the gate voltages are controlled for a one frame period, for instance, in response to switching states of the switching transistors. Since the switching transistors turn on or off, the gate voltages are not always set to be accurate, i.e., they do not necessarily correspond to video signals precisely. One of the causes of this effect is "a feed-through (or punch-through) voltage" of the switching transistors, which is influenced by response characteristics of the switching transistors. As the gate voltages fluctuate, output current of the driver transistors also varies so that the display elements cannot always display uniform brightness in accordance with the video signal.
Meanwhile, the applicant has noticed another possible cause of the uneven brightness from the following view point. When a scanning signal is supplied to the switching transistors from the driver circuit though a scanning line, the scanning signal at an output point of the driver circuit is different in waveform from those at middle points of the scanning line (wiring) and an end terminal of the wiring, respectively. This results from the fact that time constant circuits equivalent to the respective pixel portions are different from each other. In other words, the "feed-through (or punch-through) voltage" at the output point of the driver circuit is different in amplitude from those at the middle points of the wiring and the end terminal of the wiring, respectively, to bring about uneven brightness (or uneven display) on a screen.

Toshiba Matsushita Display Technology Co., Ltd.


A HTS-based RF receiver includes a cryocooler and a cryogenic enclosure in thermal communication with the cryocooler. The cryogenic enclosure contains a HTS filter and a LNA therein. A first MEMS bypass switch is positioned between a RF input and the HTS filter, the first MEMS bypass switch operatively coupling the RF input to the HTS filter. A second MEMS bypass switch is positioned between the LNA and RF output, the second MEMS bypass switch operatively coupling the LNA to the RF output. A bypass pathway located within the cryogenic enclosure is connected between the first and second MEMS switches to bypass the HTS filter and LNA when an operating parameter of the RF receiver falls outside a pre-determined range.

The field of the invention relates to high temperature superconducting (HTS) radio frequency (RF) filters for wireless communications. Specifically, the invention relates to a bypass system used in connection with a HTS-based filter and a cryogenically cooled low noise amplifier (LNA).
The increase in the number of mobile telecommunication devices in recent years and the corresponding increase in the amount of data capacity required for such devices has led to the development and implementation of HTS-based RF filters used in connection with RF front-end devices. HTS filters are highly selective, low loss filters that substantially decrease interference between adjacent channels. One of the benefits of the decrease in interference between adjacent channels is the reduction of the number of calls that are dropped. This is particularly advantageous when an ever increasing number of users are occupying frequencies that are very close together. HTS-based filters also provide better mobile-to-base call quality due to the filter""s increased sensitivity. Another important benefit of HTS-based front-end RF filters is that wireless providers can increase the capacity (i.e., call capacity) of existing, non HTS-based base stations. Wireless providers can also deploy wireless networks having fewer base stations when such base stations include HTS-based filters.
HTS front-end RF filters require the use of a cryocooler to cool the filters and any associated electronics, such as LNAs, to around 77K. Accordingly, it is preferable that the cryocooler used to cool the filters be able to operate for long periods of time and in a variety of environmental conditions without failing. Stirling cycle cryocoolers, for example, have been developed and used to cool HTS components for extended periods of time without interruption. In some applications, however, a bypass feature is needed in case one or more of the HTS filters contained in the RF front-end fails to perform properly, as would be the case if the cryocooler failed. It is known, for example, to include a bypass feature on a cryogenically cooled receiver front-end that uses two conventional RF relays to bypass the HTS circuitry to direct the antenna signal directly to an output that proceeds to the base station.
Bypass systems that use conventional RF relays, however, have a number of limitations. First, the conventional RF relays have a relatively high insertion loss, which degrades the overall noise figure of the RF receiver. Consequently, when the system is in bypass mode, reverse channel (i.e., mobile-to-base) coverage is reduced. Second, conventional RF relays dissipate power even in their quiescent state when operated in a fail-safe mode (i.e., if there is a power failure, the relays default to the bypass mode). Consequently, conventional RF relays must be located external to the cryogenic enclosure to avoid the relays using up the finite thermal budget of the cryocooler. Third, conventional RF relays are rather large devices that increase the overall size and weight of the RF receiver.
Accordingly, there is a need for a bypass system for an HTS-based filter/LNA RF front-end receiver that has a very low insertion loss, i.e., a very low contribution to the noise figure of the overall receiver. There also is a need for a bypass system in which the individual switching elements can be located inside the cryogenic enclosure. Accordingly, the individual switching elements need to have little or no power dissipation when switches are in their quiescent state.
In a first aspect of the invention, an HTS-based RF receiver includes a cryocooler, a cryogenic enclosure in thermal communication with the cryocooler, a RF input, and a RF output. The receiver also includes a HTS filter having an input and an output, the input of the HTS filter being operatively coupled to the RF input, the output of the HTS being coupled with a LNA, the LNA having an output that is operatively coupled the RF output. The HTS filter and the LNA are disposed within the cryogenic enclosure. A first Micro-Electro-Mechanical System (MEMS) bypass switch is provided between the RF input and the HTS filter, the first MEMS bypass switch operatively coupling the RF input to the HTS filter. A second MEMS bypass switch is provided between the LNA and the RF output, the second MEMS bypass switch operatively couples the LNA to the RF output. A bypass pathway located in the cold space of the cryogenic enclosure is connected between the first and second MEMS bypass switches.
In a second, separate embodiment, the HTS RF receiver of the first embodiment is modified such that the output of the HTS filter is operatively coupled with the LNA. The second MEMS bypass switch is positioned between the HTS filter and the LNA to operatively couple the HTS filter and LNA.
In another embodiment of the-invention, a method of bypassing a HTS filter in a RF receiver containing a HTS filter and a LNA includes the steps of measuring an operating parameter of the RF receiver, and switching the RF receiver to a bypass mode when the measured operating parameter is outside a pre-determined operating range, the step of switching the RF receiver to the bypass mode includes the step of switching two MEMS switches to a bypass pathway around the HTS filter.
In still another embodiment, the method of bypassing described above includes the step of switching two MEMS switches to a bypass pathway around the HTS filter and the LNA.
It is an object of the invention to provide a HTS-based RF receiver with a bypass capability. It is another object of the invention to provide a MEMS-based bypass solution that reduces the overall size of the device and permits the bypass switches to be placed inside a cryogenic environment. It is yet another object of the invention to provide a low insertion loss bypass system that is used with HTS-based RF receivers.

MEMS-based bypass system for use with a HTS RF receiver


Multistage hydraulic systems and methods for converting the potential energy of a pressurized gas, particularly air, into mechanical work when operating in motor, and for producing compressed gas from the mechanical work of the rotating shaft when rotating when operating in compressor mode, by performing a successive expansion/compression of the said gas. Each of the systems comprises: a multistage Compression-Expansion Unit made of several hydraulic Compression-Expansion Modules having different capacity and integrating a gas/liquid separating heat exchanger, designed to convert pressure power into a hydraulic power and vice-versa, by performing an essentially isothermal compression/expansion of the gas; a single stage or multistage, direct or indirect, external forced-air Heat Exchanger for maintaining the active liquid at ambient temperature; and a multi-circuit, multi-displacement Hydraulic Motor/Pump for converting hydraulic power into mechanical power and vice-versa.

A list of the references quoted in this section is given at the end of the Description.
This invention is related to the production of high pressure air to be used for breathing purposes (medical, diving, etc) or as power source or power transmission for various air-powered tools and industrial processes. It is also related to the use of compressed air as energy storage media like in the case of compressed-air-powered cars or for example to circumvent the intermittency of some renewable energy sources such as solar and wind sources.
The potential energy of compressed air is generally exploited by firstly converting it into mechanical work. Two main categories of energy conversion systems have been proposed for that purpose: pure pneumatic conversion systems where the only active fluid is air and hydro-pneumatic conversion systems that use at least one liquid (oil, water) as active fluid.
Pneumatic Conversion Systems
Pneumatic conversion was the first (and still is the only commercially available) conversion solution used to exploit compressed air for the purpose of energy conversion. It consists, for low and medium power ranges or high compression ratios, in using mainly positive displacement (or volumetric) air machines to produce compressed air and later withdraw energy from it. In these machines, the variations of the working fluid's volume in a work-chamber produce equivalent displacements of the mechanical member, transmitting thus the energy and vice versa. The dynamic effect of the fluid is therefore of minor importance, unlike in kinetic (or turbo) machines where the kinetic energy of the working fluid is transformed into mechanical motion and vice versa. There are two main families of volumetric machines:                Rotary machines like lobe, vane, and screw machines.        Reciprocating machines like diaphragm and piston machines. In most high power and pressure ratio ranges, the piston type is commonly used because of its higher efficiency and pressure ratio.
Since it is difficult to realise an isothermal process in these work-chambers, the compression/expansion process is subdivided into several stages and heat exchangers are inserted in between. Thus the complete cycle is more or less close to an isothermal cycle depending on the performances of the heat exchangers. This principle is as old as the first application of compressed air in propulsion in the 1800s and it is gaining nowadays more interest and improvements with the new developments in compressed-air-powered cars [1]. However, given the difficulties to implement a good heat exchange in the compression/expansion chambers, and the important leakage and friction related to the gaseous nature of air, the pressure ratings and conversion efficiency of this conversion system remain low and make it inefficient for most energy applications.
Hydro-Pneumatic Conversion
The use of hydraulic machines to circumvent the drawbacks of pure air machines has been investigated, as they suffer less from the above problems and therefore exhibit very high conversion efficiencies. One of the main challenges in using hydraulic systems to compress/expand air is the liquid-to-air interface.
A first solution has been proposed by Cyphelly & al. and is described in [2], [3] under the acronym "BOP: Batteries with Oil-hydraulics and Pneumatics". In this system air is compressed/expanded in alternating Liquid-Piston Work-chambers where a "Thin Plate Heat Exchanger" is integrated. During compression, the thin plates transfer the heat from gas top part to the liquid bottom part and the other way round during expansion. However, good heat exchange will require a high density of plate, which is not easy to realise.
Recently, another solution has been patented by Rufer & al. with as main original proposition work-chambers where the compression is performed by injecting the liquid in the form of a "shower" in the chamber, allowing a fast and effective abortion of the compression heat [4]. This solution however requires an external liquid circulating pump to reheat the air during expansion.
In both cases, there is a concern about diffusion of the air into the liquid due to the direct contact between the two fluids. In addition, these hydro-pneumatic systems are somewhat bulky as they are assemblages of several distinct components and machines. Moreover, these split topologies require many ancillary devices for the command and control of the system's operation.
U.S. Pat. No. 1,929,350 discloses an apparatus for compressing gases which has an external heat exchanger circulating external cooling liquid through tubes passing through the expansion/compression chamber.
It would be desirable to provide a hydro-pneumatic conversion system with a simple and efficient integrated heat exchanger that can effectively operate both during compression and expansion. It would be also desirable to have a more compact, flexible and scalable solution that can be easily adapted to stationary as well as mobile applications. The present invention proposes original solutions to achieve these objectives.

Multistage hydraulic gas compression/expansion systems and methods

Ecole Polytechnique Federale de Lausanne (EPFL)


The present application provides a voltage generation circuit and associated capacitor charging method and system. The voltage generation circuit is in a chip and is for generating a first output voltage and a second output voltage. The chip has a first output port and a second output port coupled to a first capacitor and a second capacitor respectively external to the chip. The voltage generation circuit includes a constant current type voltage generation unit and a regulator. When the voltage generation circuit operates in a first mode, the regulator is configured as a unit gain buffer to charge the first capacitor to the first output voltage; and when the voltage generation circuit operates in a second mode, the regulator is configured as a low-dropout regulator to charge the second capacitor to the second output voltage.

For systems that require fast start-up, such as Bluetooth headsets, it is desirable to achieve a stable state as soon as possible after start-up and for the user to use the system normally. For this reason, the system's regulator needs to have a higher driving ability. However, such systems are generally very power-conscious, and a regulator with a higher driving ability will significantly increase the system's overall power consumption. Therefore, how to take care of the start-up speed and power consumption of the regulator at the same time has become one of the most critical issues to be solved in this field.

Voltage generation circuit and associated capacitor charging method and system


A passenger tracking system includes a multiple of sensors for capturing depth map data of objects. A processing module in communication with the multiple of sensors to receive the depth map data, the processing module uses the depth map data to track an object and calculate passenger data associated with the tracked object to generate a passenger tracking list that tracks each individual passenger in the passenger data from an origin lobby to a destination lobby and through an in-car track between the origin lobby and the destination lobby.

The present disclosure relates to a passenger conveyance and, more particularly, to a depth sensor based control for an elevator.
Elevator performance can be derived from a number of factors. To an elevator passenger, an important factor can include travel time. For example, as time-based parameters are minimized, passenger satisfaction with the service of the elevator can improve. Modern elevator systems may still provide opportunities for improved passenger experience and traffic performance.
Typically, in a building with many people inside, efficient elevator usage may be complicated since certain time periods may by high traffic times, while others will be low traffic which may create inconvenience and delay for users, both those in the car and those waiting for a car.
Modern elevator systems may still provide opportunities for improved passenger experience and traffic performance.

Traffic list generation for passenger conveyance


A system that facilitates collecting data is described herein. The system includes a digital camera that is configured to capture images in a visible light spectrum and a near-infrared camera that is configured to capture near infrared images, wherein a field of view of the digital camera and the field of view of the near-infrared camera are substantially similar. The system further includes a trigger component that is configured to cause the digital camera and the near-infrared camera to capture images at a substantially similar point in time, and also includes a mounting mechanism that facilitates mounting the digital camera and the near-infrared camera to an automobile.

Functionality of conventional mapping applications that are accessible by way of the Internet has substantially increased over time. For instance, a user can access a mapping application and be provided with an overhead view of one or more streets. Still further, the user may provide an initial location (e.g., street address) and a destination, and the mapping application can provide the user with detailed directions pertaining to traveling between the initial location and the destination.
Mapping applications have further developed such that an individual can view aerial images of a particular region. For instance, if a user enters a particular location (e.g., address, business name, . . . ), the user can be provided with aerial images pertaining to such entered location. These images may then be subjected to a zooming function, such that the user can be provided with a relatively close aerial view of the entered location. Furthermore, driving directions may be graphically laid on the aerial images, thus providing the user with some context with respect to a route to be traveled between the initial location and the destination.
Some mapping applications have further been adapted to include three-dimensional models of buildings in certain cities. Thus, a user can enter a location into the mapping application, and be placed in a three-dimensional model pertaining to such location. The user may then navigate the three-dimensional model to be provided with context pertaining to the location. For instance, if the user is planning to travel to Paris, France, the user can provide the mapping application with the location of Paris, France, and be provided with a three-dimensional representation of the city. The user could then navigate the provided representation and be provided with a first-person perspective. Thus, the user can "travel" through the city to obtain information pertaining to such city, such as the height of buildings, location of buildings with respect to one or more streets, etc.
Typically, these three-dimensional models are generated first, and thereafter are updated with aerial images, which can be used to provide greater information pertaining to a building or buildings, such as the look of a building façade. Because these images are aerial images, however, the resolution of the images is less than desired. Moreover, the captured aerial images may not be well-suited for adaption to the three-dimensional models.

Vehicle-mounted sensor system that includes cameras and laser measurement systems


A latch is disclosed which is both rugged and economical. The latch includes a flanged housing which acts as a bushing for a journal portion of an operator. The operator includes a narrowed and recessed handle portion. At the inner end of the operator, a generally planar striker is placed to the interior of a door to interact with the frame. The striker rotates with respect to the housing and is limited in rotation by a stop which interacts with the housing. The striker is secured to the operator by connector means to prevent relative movement between them. The housing is fixed to the door by securement means which draws the flange of the housing against the exterior of the door.

This invention relates to the field of door securement devices. More particularly, the present invention relates to door latches particularly suitable for employment with locker doors.
Lockers are purchased by a number of businesses to store employee supplies of various types, uniforms, and employee clothing. Very often, the lockers include a cylinder lock of relatively inexpensive construction. Examples of a typical lock are included in the drawing to this application in FIGS. 2 and 4. Although some manufacturers allegedly try and promote the security of lockers having this type of cylinder lock, the lockers are not in fact very secure and both the employer and employees typically avoid placing anything of value in the locker. Unfortunately, the cylinder locks are prone to malfunction and frequently prevent entry into the locker space. Additionally, employees will lose or forget to carry their key preventing easy entry. When the key is missing, if a master key is not available, the lock will have to be forced and then replaced. Similarly, when a lock malfunctions it will have to be replaced. The replacement generally causes considerable additional inconvenience and expense far in excess of the intrinsic value of the replacement lock.
FIG. 2 illustrates a typical cylinder lock 20 in an exploded view. Lock 20 includes five major components: key 22, cylinder 24, housing 26, bolt 28 and connector means 30. Cylinder 24 includes a plurality of tumblers 32, rotation stop 34, square 36 and thread 38. Cylinder 24 is received within housing interior surface 40.
Housing interior surface 40 includes at least one longitudinal tumbler groove 42 and housing stops 44. If key 22 is not inserted into cylinder 24, tumblers 32 protrude into tumbler grooves 42 to prevent relative rotation between cylinder 24 and housing 26. If a key is inserted into cylinder 24, tumblers 32 are withdrawn into the body of cylinder 24 to allow relative rotation with housing 26. However, this rotation is limited by the interaction between rotation stop 34 and housing stops 44 located at the front or exterior of housing 26. At least one housing flat 46 is provided to interface with corresponding flat on a door orifice to prevent relative rotation between housing 26 and the door. Additionally, at least one housing groove 48 is provided for receiving a tension clip to prevent longitudinal movement of housing 26 with respect to the door by restraining it between the tension clip and housing flange 50. Frequently, both the housing 26 and the cylinder 24 are fabricated from economical cast metal. Bolt 28 defines square orifice 52 in its exterior plane 54 and interfaces with a door frame at its interior plane 56. These exterior 54 and interior 56 planes are joined by offset portion 58. Bolt 28 is fitted over square 36 of cylinder 24 and fastened to cylinder 24 by connector means 30 consisting of star washer 60 and nut 62. Bolt 26, on its exterior plane 54, is brought to bear against the flat interior end 64 of housing 26.
Other locking devices for fastening doors to their frame are described in issued patents.
U.S. Pat. No. 3,876,237 to Hayes, Jr. et al. describes a LOCKING DEVICE incorporating tumbler lock 31 in handle portion 24. Crank assembly 21 consists of crank 21', a journal housing 23 and handle 24. The crank 21' is a metal rod with two 90 degree bends which allows one of the arms 25 to be journaled through the housing 23 and the other arm 26 to releasably engage receiver 22.
U.S. Pat. No. 4,270,780 to Bernard describes a DOOR FASTENER which may incorporate a standard shaft, a lock cylinder or a shaft having a head of a particular shape. A flanged bearing 2 is made longitudinally fast to a door with the aid of nut 13. A handle 14 includes pin 71 which is selectively received by bearing 2 in a position to allow relative rotation or prevent relative rotation. In FIG. 6, an embodiment is shown which includes lateral stop 67 moving in angular cutaway 69 formed at the end 68 of the bearing 2.
U.S. Pat. No. 4,186,952 to Glass describes a TURN BUTTON LATCH. The latch assembly 10 includes latch member 14 which cooperates with housing 16. Housing 16 in turn cooperates with retainer clip 18. Cylinder 60 is received within housing 16. Plate 62 including detent member 64 is placed between thumb latch 58 and cylinder 60 to cooperate with recesses 34-37. Bolt 20 is fastened to cylinder 60 through cooperation of arms 66 and 68 and pin 78. The embodiments of FIG. 12 include a locking cylinder.
Other fasteners described in patents dispense with locks.
U.S. Pat. No. 4,153,284 to Wright describes a PAWL LATCH. The Wright latch includes bush 1 and integral transverse channel shape extension 4. In head 2 an arrow shaped recess 7 points in the direction of the transverse channel to indicate the orientation of the latching arm or pawl which is partly formed by channel 4 but also by metal spring clip 8. Although principally fabricated from plastics, the latch is particularly useful to ensure electrical continuity of a wiring enclosure.
U.S. Pat. No. 4,105,230 to Amann et al describes a CLOSURE FOR PIVOTABLE FLAPS, COVERS OR THE LIKE. The closure includes locking member 4 which is approximately L-shaped and fastened to shaft 5 which receives a handle 11 to the opposite side of flap 10. A spring 6 is interposed between locking member 4 and flap 10. The closure does not appear to include a bushing or housing for shaft 5.
U.S. Pat. No. 1,662,907 to Shilling et al. describes a DOOR LATCH of relatively elaborate construction. In FIG. 5, a less elaborate embodiment is illustrated which includes a block 45 which longitudinally moves in and out of engagement with bars 20.
None of the foregoing describe or suggest a simple, economical device which avoids the drawbacks associated with the cylinder locks previously employed.


Platelets are collected from blood by delivering blood from a blood source to a centrifugal separator and operating the separator to separate plasma from the blood. The separated plasma is collected in a plasma collecting bag. After a predetermined amount of plasma has been collected in the bag, the plasma is circulated between the bag and the separator. That procedure is repeated at least once to build-up the amount of collected blood. Then platelets are collected by delivering additional blood to the separator and circulating plasma between the separator and the plasma collecting bag at an accelerating circulation rate while rotating the rotor to remove platelets from the separator. The platelets are collected in a platelet collecting bag. Then, blood remaining in the separator is returned to the blood source.

The present invention relates to a blood component collecting apparatus and a blood component collecting circuit for separating predetermined blood components from the blood.
For effectively utilizing the blood and reducing the burden on the blood donor in the blood-collection, the collected blood is separated into various blood components centrifugally to extract only the components required for the donee, and the remaining components are returned to the donor.
In the case where a platelet product is produced from this blood component collection process, the blood donated from the donor is introduced to a blood component collecting circuit, separated into four components of plasma, white cells, platelets and red cells by a centrifugal separator called the centrifugal bowl installed in the blood component collecting circuit. Among these blood components, the platelets are recovered in a container to produce a platelet product. Meanwhile the remaining components including the plasma, white cells and red cells are returned to the donor.
Methods of collecting the platelets, first and second methods, are disclosed in WO 94/25086. In the first method, a liquid is sent to the centrifugal bowl and added to the whole blood while being diluted at a predetermined flow rate. According to the second method, the whole blood is sent to the centrifugal bowl and centrifugally separated into a low-density component, a middle-density component and a high-density component. The low-density component is retrieved in a first container, and the circuit is switched to circulate the low-density component at a first flow rate (fixed rate) to expand the middle-density component area in the centrifugal bowl, and the middle-density component, while being recirculated at a second flow rate (acceleration), is retrieved.
The first method, however, requires three pumps including an ACD pump, a blood collecting-returning pump and a circulation pump, and thus enlarges the apparatus size. In the second method, on the other hand, the platelets can be collected by two pumps, thus reducing the apparatus size. Nevertheless, the collected platelets are likely to be mixed with white cells, which fails to meet the requirement of the liquid containing platelets for a platelet product demanded to contain as few white cells as possible.
Accordingly, the object of the present invention is to provide a compact blood component collecting apparatus and a blood component collecting circuit used therein which is capable of producing a high-concentration platelets-contained liquid with low content of white cells at a high platelet collecting efficiency.
The aforementioned object of the invention can be achieved by a blood component collecting apparatus which comprises a blood component collecting circuit including: a centrifugal separator having a rotor having an internal blood storage space, an inlet and an outlet communicating with said blood storage space for centrifugally separating the blood introduced therein through said inlet by rotation of said rotor; a first line for connection between a blood-collection needle or a blood-collection unit connector and said inlet of said centrifugal separator; a second line connected to said outlet of said centrifugal separator; a third line connected to said first line for injecting an anticoagulant; a plasma collecting bag having a first tube connected to a middle point of said first line and a second tube connected to said second line; and a platelet collecting bag connected to said second line; said blood component collecting apparatus further comprising a centrifugal separator drive unit for rotating said rotor of said centrifugal separator, a first liquid supply pump for said first line arranged at a position of said first line between said centrifugal separator and a connecting portion for connecting said first tube to said first line, a second liquid supply pump for said third line, a plurality of flow path shutter means for opening/closing the flow paths of said blood component collecting circuit; and a controller for controlling said centrifugal separator drive unit, said first liquid supply pump, said second liquid supply pump and said plurality of flow path shutter means; wherein said controller controls said centrifugal separator drive unit, said first liquid supply pump, said second liquid supply pump and said plurality of flow path shutter means so as to execute a platelet collecting operation which includes at least twice of plasma collecting-circulation steps including a plasma collecting step for collecting blood added anticoagulant by starting said first and second liquid supply pumps and collecting said plasma obtained from said blood in said plasma collecting bag by activating said centrifugal separator drive unit and a plasma circulation step for temporarily suspending blood-collection subsequent to said plasma collecting step and circulating said plasma contained in said plasma collecting bag to said centrifugal separator by activating said centrifugal separator drive unit, subsequent to said plasma collecting-circulation steps, a platelet collecting step for collecting platelet released from said centrifugal separator into said platelet collecting bag by accelerating a plasma circulation rate by said first liquid supply pump; and to execute a blood returning step, subsequent to said platelet collecting step, for returning said blood contained in said centrifugal separator.
Further, the aforementioned object of the invention can be achieved by a blood component collecting circuit which comprises a centrifugal separator having an inlet and an outlet; a blood-collection needle or a blood-collection unit connector; a first line having a first pump tube for connection between said blood-collection needle or said blood-collection unit connector and the inlet of said centrifugal separator; a second line connected to the outlet of said centrifugal separator; a third line having a second pump tube connected to a portion near said blood-collection needle or said blood-collection unit connector of said first line; a plasma collecting bag having a first tube connected to a portion of said first line between said blood-collection needle or said blood-collection unit connector and said first pump tube and a second tube connected to said second line; a platelet collecting bag having a third tube connected to said second line; and a cassette housing for partially containing and partially holding said first line, said second line, said third line, said first tube, said second tube and said third tube; wherein said first pump tube and said second pump tube are fixed on said cassette housing so as to extend therefrom; wherein said cassette housing includes a first opening for exposing the portion of said first line between said blood-collection needle or said blood-collection unit connector and said first pump tube and capable of being intruded by a flow path shutter means, a second opening for exposing said first pump tube and capable of being intruded by a flow path shutter means, a third opening for exposing said second tube and capable of being intruded by a flow path shutter means, a fourth opening for exposing said third tube and capable of being intruded by a flow path shutter means, a fifth opening for exposing the portion of said second line between said centrifugal separator and a connecting portion for connecting said fourth tube to said second line and capable of being intruded by a flow path shutter means.
Further, the aforementioned object of the invention can be achieved by a blood component collection apparatus comprising a blood component collection circuit including: a centrifugal separator having a rotor, an internal blood storage space, an inlet and an outlet communicating with said blood storage space and centrifugally separating blood introduced thereinto through said inlet by a rotation of said rotor; a first line for connecting a connecting portion of a blood collection needle or a blood collection instrument and said inlet of said centrifugal separator with each other; a second line connected to said outlet of said centrifugal separator; a third line connected to said first line, for injecting an anticoagulant to said blood; a plasma collection bag having a first tube connected with said first line and a second tube connected with said second line; and a platelet collection bag connected with said second line; said blood component collection apparatus further comprising: a centrifugal separator drive unit for rotating said rotor of said centrifugal separator; a first liquid supply pump which is used for said first line and located at a position of said first line between said centrifugal separator and a connecting portion for connecting said first tube to said first line; a second liquid supply pump which is used for said third line; a plurality of flow path shutter means for opening/closing flow paths of said blood component collection circuit; and a controller for controlling said centrifugal separator drive unit, said first liquid supply pump, said second liquid supply pump, and a plurality of said flow path shutter means; wherein said controller controls said centrifugal separator drive unit, said first liquid supply pump, said second liquid supply pump, and a plurality of said flow path shutter means to execute a platelet collection operation including: a plasma collection/constant-speed circulation step including a first plasma collection step of collecting anticoagulant-added blood by starting said first and second liquid supply pumps and collecting a predetermined amount of plasma into said plasma collection bag by activating said centrifugal separator drive unit; and a constant-speed plasma circulation step which is executed after said execution of said first plasma collection step terminates to temporarily suspend a blood collection and circulate said plasma contained in said plasma collection bag to said centrifugal separator at a constant speed by activating said centrifugal separator drive unit; a plasma collection/acceleration circulation step including a second plasma collection step which is executed after said execution of said plasma collection/constant-speed circulation step terminates to collect said anticoagulant-added blood by starting said first and second liquid supply pumps and collect said plasma by activating said centrifugal separator drive unit; and an acceleration plasma circulation step which is executed after said execution of said second plasma collection step is executed to temporarily suspend said blood collection and circulate said plasma contained in said plasma collection bag to said centrifugal separator at an accelerated speed by activating said centrifugal separator drive unit, a platelet collection step which is executed after said execution of said plasma collection/acceleration circulation step terminates to flow out platelets from said centrifugal separator and collect said platelets into said platelet collection bag by accelerating a plasma circulation rate by means of said first liquid supply pump, and a blood return step which is executed after said execution of said platelet collection step terminates to return said blood inside said centrifugal separator to a donor.