CHEMOLUMINESZENTE 3-(SUBSTITUIERTE ADAMANT-2'-YLIDENE)1,2-DIOXETANE

CHEMILIMINESZENTE 1,2-DIOXETAN-VERBINDUNGEN.

chemiluminescent 3-(substituted adamant-2'-ylidene) 1,2-dioxetanes

CHEMILIMINESZENTE 1,2-DIOXETAN-VERBINDUNGEN

DISUBSTITUIERTE 1,2-DIOXETANVERBINDUNGEN WITH INCREASED WATER SOLUBILITY AND COMPOSITIONS TO the PROOF

PROCEDURE FOR the PRODUCTION OF 1,2 - DIOXETANVERBINDUNGEN AND WITH SULFUR SUBSTITUTED 1,2-DIOXETANE AS INTERMEDIATE CONNECTIONS

IN 6-POSITION BY THIO SUBSTITUTED PACLITAXELE

HYDROPHOBE TAXAN OF DERIVATIVES

Phospholipid ether analogs as cancer-targeting drug vehicles

Chemiluminescent 3-(substituted adamant-2'-ylidene) 1,2-dioxetanes

METHODS OF USING CHEMILUMINESCENT 1,2-DIOXETANES

Processes are disclosed in which light of different wavelengths is simultaneously released from two or more enzymatically decomposable chemiluminescent 1,2-dioxetane compounds, said compounds being configured, by means of the inclusion of a different light emitting fluorophore in each of them, to each emit light of said different wavelengths, by decomposing each of said compounds by means of a different enzyme. Such processes can be used in multi-channel assays --immunoassays, chemical assays and nucleic acid probe assays -- to detect the presence or determine the concentration of chemical or biological substances, and in multi-channel chemical/physical probe procedures for studying the microstructures of macromolecules.

SYNTHESIS OF STABLE WATER-SOLUBLE CHEMILUMINESCENT 1,2-DIOXETANES AND INTERMEDIATES THEREFOR

A novel synthesis of compounds having the formula: (See formula I) wherein T is a stabilizing spiro-linked polycycloalkyli-dene group, R3 is a C1-C20 alkyl, aralkyl or heteroatom containing group, Y is an aromatic fluorescent chromo-phore, and Z is a cleavable group which, when cleaved, induces decomposition of the dioxetane ring and emission of optically detectable light, is disclosed. A tertiary phosphorous acid alkyl ester of the formula: (R1O)3P wherein R1 is a lower alkyl group, is reacted with an aryl dialkyl acetal produced by reacting a corresponding aryl aldehyde with an alcohol of the formula: wherein R3 is as defined above, to produce a 1-alkoxy-1-aryl-methane phosphonate ester of the formula: (See formula II)

CHEMILUMINESCENT 3-(SUBSTITUTED ADAMANT-2'-YLIDENE) 1,2-DIOXETANES

Enzymatically cleavable chemiluminescent 1,2-dioxetane compounds capable of producing light energy when decomposed, substantially stable at room temperature before a bond by which an enzymatically cleavable labile subsituent thereof is intentionally cleaved, are disclosed. These compounds can he represented by formula (I) wherein X and X1 each represent. individually, hydrogen, a hydroxyl group, a halo substituent, an unsubstituted lower alkyl group, a hydroxy (lower) alkyl group, a halo (lower) alkyl group, a phenyl group, a halophenyl group, an alkoxyphenyl group, a hydroxyalkoxy group. a cyano group, a carboxyl or substituted carboxyl group or an amide group, with at least one of X and X1 being other than hydrogen; and R1 and R2 individually or together, represent an organic substituent that does not interfere with the production of light when the dioxetane compound is enzymatically cleaved and that satisfies the valence of the dioxetane compound's 4-carbon atom, with the provisos that if R1 and R2 represent individual substituents the R2 substituent is aromatic, heteroaromatic, or an unsaturated substituent in conjugation with an aromatic ring, and that at least one of R1 and R2 is, or R1 and R2 taken together are, an enzymatically cleavable labile group-substituted fluorescent chromophore group that produces a luminescent substance when the enzymatically cleavable labile substituent thereof is removed by an enzyme. The corresponding dioxetanes which, instead of being substituted at the 5' or 7', or at the 5' and ~ positions, instead contain a 4' methylene group, are also disclosed, as are intermediates for all these 3substituted adamant-2'-ylidenedioxetanes, and their use as reporter molecules in assays.

CHEMILUMINESCENT 3-(SUBSTITUTED ADAMANT-2'-YLIDENE) 1,2-DIOXETANES

PROCESS FOR THE PREPARATION OF 1,2-DIOXETANE COMPOUNDS AND NOVEL SULFUR-SUBSTITUTED 1,2-DIOXETANE COMPOUNDS AS INTERMEDIATES

A process is provided for the preparation of a variety of triggerable dioxetanes bearing alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy substituents from a common intermediate along with sulfur-substituted dioxetanes and vinyl sulfide compounds used as intermediates. Alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy substituted dioxetanes are useful in detecting activating agents and in assays such as immunoassays and nucleic acid hybridization assays. The sulfur-substituted dioxetanes additionally are useful for producing chemiluminescence. The novel process involves conversion of a vinyl sulfide compound to a sulfur-substituted dioxetane, reacting the sulfur-substituted dioxetane with an electrophilic agent and a hydroxylic compound or salt thereof and forming the alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy-substituted dioxetane.

WATER SOLUBLE TRI-SUBSTITUTED 1,2-DIOXETANE COMPOUNDS HAVING INCREASED STORAGE STABILITY, SYNTHETIC PROCESSES AND INTERMEDIATES

Stable, enzymatically triggered chemiluminescent 1,2-dioxetanes with improved water solubility and storage stability are provided as well as synthetic processes and intermediates used in their preparation. Dioxetanes further substituted with two or more water-solubilizing groups disposed on the dioxetane structure and an additional fluorine atom or lower alkyl group provide superior performance by eliminating the problem of reagent carryover when used in assays performed on capsule chemistry analytical systems. These dioxetanes display substantially improved stability on storage. Compositions comprising these dioxetanes, a non-polymeric cationic surfactant enhancer and optionally a fluorescer, for providing enhanced chemiluminescence are also provided.

Fluoro taxols

A prodrug derivatives [...]

Phosphonooxymethyl ethers of taxane derivatives

The present invention concerns novel water-soluble phosphonooxymethyl ethers of taxane derivatives, their use as antitumor agents, and pharmaceutical compositions containing the novel compounds.

Alkene adamantane intermediates and the corresponding 1,2-dioxetanes

Alkene adamantane compounds useful as intermediates for producing the corresponding 1,2-dioxetanes which are useful in chemiluminescent assays.

Process for the preparation of 1,2-dioxetane compounds and novel sulfur-substituted 1,2-dioxetane compounds as intermediates

A process for producing a stable triggerable dioxetane comprising; (a) reacting a vinyl sulfide compound containing a sulfur-substituent SR4, wherein R4 is an organic group containing 1 to 20 carbon atoms and optionally heteroatoms, with oxygen and light in the presence of a photosensitizer to form an intermediate sulfur-substituted dioxetane compound; and (b) reacting the sulfur-substituted dioxetane compound with an electrophilic compound E--Y and a hydroxylic compound R5 OH selected from the group consisting of alcohols, phenols and carboxylic acids or their salts and containing an OR5 group to replace the SR4 group of the dioxetane with the OR5 group.

1,2-dioxetane compounds as chemiluminescent labels for organic and biological molecules

Dioxetanes which couple with organic and biological molecules of the formula: см. иллюстрацию в PDF-документе wherein X is a leaving group which is removed by an `activating agent to produce light, wherein A is a coupling substituent, Ar is a substituent selected from the group consisting of phenyl and naphthyl to provide a label are described. R1 is an optional linker substituent and can have between 1 and 30 carbon atoms with some of the carbon atoms being oxygen, sulfur, nitrogen or phosphorus. Ar as phenyl is preferred. The dioxetane coupled molecules are useful in assays of all types where luminescence can be used as an indicator.

Kit for conducting an assay to detect a substance using enzymatically-induced decomposition of dioxetanes

A kit for detecting a first substance in a sample including a stabilized 1,2-dioxetane bearing an enzyme-labile substituent, which is destabilized and caused to decompose by contacting the 1,2-dioxetane with an enzyme under conditions which cause the enzyme to cleave the enzyme-labile group from the dioxetane, thereby yielding a negatively charged oxygen anion bonded to the 1,2-dioxetane, which causes the 1,2-dioxetane to decompose without input from an external excitation energy source, the decomposition being accompanied by chemiluminescence; and a second component selected from the group consisting of a specific affinity substance (e.g., an antigen, an antibody or a nucleic acid probe) and an enzyme which destabilizes said 1,2-dioxetane.

Alkene adamantane intermediates and the corresponding 1,2-dioxetanes

Alkene adamantane compounds useful as intermediates for producing the corresponding 1,2-dioxetanes which are useful in chemiluminescent assays.

Chemiluminescent doubletriggered 1,2-dioxetanes

CHEMILUMINESCENT ELECTRON-RICH ARYL-SUBSTITUTED 1,2-DIOXETANES

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetane compounds are disclosed in which the aryl group is poly-substituted with suitable electron-donating groups such that the light-emitting pattern of the molecule results in a very high luminescent count, thus providing for a sensitive and precise assay for haptens, analytes, polynucleotides and the like. These substituted aryl-containing 1,2-dioxetane compounds can be used as direct labels in an immunoassay or when derivatized with an appropriate leaving group, can be used as a substrate for an enzyme immunoassay. The unusual chemiluminescence of the compounds allows the timing of the luminescent reaction to be exactly controlled.

DIOXETANES FOR USE IN ASSAYS

Desoxy-Taxol-Derivate

MORE PHOSPHONOOXYMETHYLETHER OF TAXAN DERIVATIVES

CHEMOLUMINESZENTE 3 (SUBSTITUTED ONE ADAMANT-2' YLIDENE) 1,2-DIOXETANE

PROCEDURE FOR THE PRODUCTION OF VINYLETHERN.

PROCEDURE AND COMPOSITIONS FOR the PRODUCTION of STRENGTHENING CHEMILUMINESZENZ OF 1,2-DIOXETANEN.

1,2-DIOXETANE WITH IMPROVED CHEMOCLUMINESCENCE

1,2-DIOXETANE WITH MORE IMPROVE CHEMILUMINESZENZ

DESOXY TAXOL DERIVATIVES

HYDROPHOBI TAXAN OF DERIVATIVES

WATER-SOLUBLE TRISUBSTITUTED 1.2 - DIOXETANVERBINDUNGEN WITH INCREASED STABILITY IN STORAGE, SYNTHESIS PROCEDURE AND INTERMEDIATE CONNECTIONS

Heteroaryl substituted benzothiazole dioxetanes

Deoxy taxols

Alkane precursors of chemiluminescent dialkyl-substituted 1,2-dioxetane compounds, methods of synthesis and use

Tri-substituted phenyl 1,2-dioxetanes

Phosphonooxymethyl ethers of taxane derivatives

PROCESS FOR THE PREPARATION OF VINYL ETHERS

Phosphonooxymethyl ethers of taxane derivatives

SYNTHESIS OF 1,2-DIOXETANES AND INTERMEDIATES THEREFOR

SYNTHESIS OF STABLE, WATER-SOLUBLE CHEMILUMINESCENT 1,2-DIOXETANES AND INTERMEDIATES THEREFOR

Pharmaceutical derivatives

PURIFICATION OF STABLE WATER-SOLUBLE DIOXETANES

Methods are disclosed for purifying chemiluminescent water-soluble 1,2-dioxetane derivatives suitable for use as reporter molecules in a variety of biological analytical systems, including enzyme-linked immunoassays, nucleic acid probe techniques, and structural determinations. The methods are based upon high pressure, medium pressure or low pressure liquid chromatography using as the stationary phase alkaline pH-stable compositions with the chromatographic characteristics of reversed-phase adsorbents, at alkaline pH values, and in the absence of acid-forming compounds or compounds with an unshared pair of electrons. Desalting of substantially pure water soluble 1,2-dioxetane derivatives may be accomplished by the same chromatographic systems or by molecular sieve chromatography systems, but in the absence of salt buffers. Under some circumstances, purification and desalting may be combined in a single chromatographic step. Substantially pure chemiluminescent water-soluble 1,2-dioxetane ...

PHOSPHONOOXY AND CARBONATE DERIVATIVES OF TAXOL

CT-2178X A taxol derivative of formula I I or a pharmaceutically acceptable salt thereof, in which Rj is -COR2 in which R2 is t-butyloxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or phenyl, optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; RY is C1-6 alkyl, C2-6 alkeny1, C2-6 alkynyl, C3-6 cycloalkyl, or a radical of the formula -W-RX in which W is a bond, C2-6 alkenediyl, or -(CH2)t-, in which t is one to six; and Rx is naphthyl, furyl, thienyl or phenyl, and furthermore Rx can be optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; Rw is hydrogen, hydroxy, acetyloxy, OC(=O)OY or -OZ; R1 is hydrogen, hydroxy, -OC(=O)OY or -OZ; R2 is hydroxy, -OC(=O)OY, -OC(=O)R or -OZ, with the proviso at least one of R1, R2 or Rw is CT-2178X -OC(=O)OY or -OZ; R is C1-6 alkyl; Z is of the formula or wherein R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken ...

PHOSPHONOOXY AND CARBONATE DERIVATIVES OF TAXOL

A taxol derivative of formula I (see fig I) or a pharmaceutically acceptable salt thereof, in which R j is -COR2 in which R2 is t-butyloxy, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or phenyl, optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; R y is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or a radical of the formula -W-R x in which W is a bond, C2-6 alkenediyl, or -(CH2)t -, in which t is one to six; and R x is naphthyl, furyl, thienyl or phenyl, and furthermore R x can be optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; R w is hydrogen, hydroxy, acetyloxy, -OC(=O)OY or -OZ; R1 is hydrogen, hydroxy, -OC(=O)OY or -OZ; R2 is hydroxy, -OC(=O)OY, -OC(=O)R or -OZ, with the proviso at least one of R1, R2 or R w is -OC(=O)OY or -OZ; R is C1-6 alkyl; Z is of the formula wherein R3 and R4 are independently hydrogen or C1-6 alkyl, or R3 and R4 taken together with the carbon atom to which they are attached form C3-6 cycloalkylidene; R5 is -OC(=O)R, -OP=O(OH)2 or -CH2OP=O(OH)2; R6, R7, R8 and R9 are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen; or one of R6, R7, R8 and R9 is -OC(=O)R, -OP=O(OH)2 or hydroxy, and the others are independently halogen, C1-6 alkyl, C1-6 alkoxy or hydrogen; but when R5 is -OC(=O)R, one of R6, R7, R8 or R9 must be -OP=O(OH)2; Q is -(CH2)q-, optionally substituted with one to six same or different C1-6 alkyl or C3-6 cycloalkyl, or a carbon atom of said -(CH2)q- group can also be a part of C3-6 cycloalkylidene; q is 2 to 6; n is 0, and m is 1 or 0 when R5 is -CH2OP=O(OH)2; n is 1 or 0, and m is 1 when R5 is -OC(=O)R or -OF=O(OH)2; Y is C1-6 alkyl (optionally substituted with -OP=O(OH)2 or one to six same or different halogen atoms), C3-6 cycloalkyl, C2-6 alkenyl, or a radical of the formula in which D is a bond or -(CH2)t-, optionally substituted with one to six same or different C1-6 alkyl; ...

CHEMILUMINESCENT ELECTRON-RICH ARYL-SUBSTITUTED 1,2-DIOXETANES

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetane compounds are disclosed in which the aryl group is polysubstituted with suitable electron-donating groups such that the light-emitting pattern of the molecule results in a very high luminescent count, thus providing for a sensitive and precise assay for haptens, analytes, polynucleotides and the like. These substituted aryl-containing 1,2-dioxetane compounds can be used as direct labels in an immunoassay or when derivatized with an appropriate leaving group, can be used as a substrate for an enzyme immunoassay. The unusual chemiluminescence of the compounds allows the timing of the luminescent reaction to be exactly controlled.

PHOSPHONOOXYMETHYL ETHERS OF TAXANE DERIVATIVES

The present invention concerns novel water-soluble phosphonooxymethyl ethers of taxane derivatives, their use as antitumor agents, and pharmaceutical compositions containing the novel compounds.

ANALOGS OF ETHERS OF PHOSPHOLIPIDS AS CARRIERS OF MEDICINAL AGENTS, TARGETED ON CANCER CELLS

WATER SOLUBLE TRI-SUBSTITUTED 1,2-DIOXETANE COMPOUNDS HAVING INCREASED STORAGE STABILITY, SYNTHETIC PROCESSES AND INTERMEDIATES

Stable, enzymatically triggered chemiluminescent 1,2-dioxetanes with improved water solubility and storage stability are provided as well as synthetic processes and intermediates used in their preparation. Dioxetanes further substituted with two or more water-solubilizing groups disposed on the dioxetane structure and an additional fluorine atom or lower alkyl group provide superior performance by eliminating the problem of reagent carryover when used in assays performed on capsule chemistry analytical systems. These dioxetanes display substantially improved stability on storage. Compositions comprising these dioxetanes, a non-polymeric cationic surfactant enhancer and optionally a fluorescer, for providing enhanced chemiluminescence are also provided.

Chemiluminescent 3-(substituted Adamant-2'-Ylidene) 1,2-dioxetanes

Enzymatically cleavable chemiluminescent 1,2-dioxetane compounds capable of producing light energy when decomposed, substantially stable at room temperature before a bond by which an enzymatically cleavable labile substituent thereof is intentionally cleaved, are disclosed. These compounds can be represented by the formula: см. иллюстрацию в PDF-документе The corresponding dioxetanes which, instead of being substituted at the 5' or 7', or at the 5' and 7' positions, instead contain a 4' methylene group, are also disclosed, as are intermediates for all these 3-substituted adamant-2'-ylidenedioxetanes, and their use as reporter molecules in assays.

Hydrophobic taxane derivatives

This invention provides a taxane derivative of the formula:wherein a hydrophobic organic moiety is attached to a taxane. R and R1 is each indepently H or a hydrophobic organic moiety, as long as at least one of R and R1 is not H. Attachment of a hydrophobic organic moiety to the taxane so as to obtain a taxane derivative generally stabilizes the association of the derivative with a lipid, including a liposomal lipid, carrier in the plasma of animals to which the derivative-carrier association is administered. Also provided herein is a composition containing the taxane derivative and a pharmaceutically acceptable medium; desirably, the medium also contains a lipid carrier, and the derivative is associated with the carrier. Further provided herein is a method of administering taxane derivatives to animals, for example, animals afflicted with cancers.

Improved chemiluminescent 1,2-dioxetanes

STABLE DIOXETANE AND LUMINESCENT COMPOSITION CONTAINING THE SAME

PROBLEM TO BE SOLVED: To obtain a new dioxetane generating chemical luminescence by triggering with an enzyme-containing chemical reagent, also improving solubility to an aqueous solution, having excellent stability, and useful as a substrate for a marker enzyme in the field of immunoassay and a study of gene expression, etc. SOLUTION: This dioxetane is a compound expressed by formula I[R1 is a 1-20C substituted (hetero)alkyl, alkenyl or alkynyl, or a hydrophilic organic group containing at least tow groups enhancing solubility to an aqueous solution and voluntarily at least one oxygen atom; R3 and R4 are each voluntarily substitutable with a hetero atom, or a (non)cyclic or a polycyclic organic group capable of voluntarily forming from a dioxetane ring with combinedly using a spiro-fused (poly)cyclic organic group; R2 is an aryl as an (additively substituted) phenyl or naphthyl; X is a protecting group generating light by removed with an activating reagent ], e.g. a trisodium 4-(3-carboxypropoxy ...

7-ДЕЗОКСИПРОИЗВОДНЫЕ ТАКСОЛА, ПРОИЗВОДНЫЕ БАККАТИНА, 10-ПЕНТАФТОРФЕНИЛБАККАТИН, 7-[(МЕТИЛТИО)КАРБОНОТИОИЛОКСИ]-13-ТРИЭТИЛСИЛИЛОКСИБАККАТИН, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention proposes 7-deoxyderivatives of taxol of the formula (I) where R 1 means a group of the formula -C(O)R z where R z is a group of the formula RO or R and R means C 1 -C 6 --alkyl, phenyl; R g is phenyl or 5-membered heteroaryl containing one atom of oxygen or sulfur; R 2 means hydrogen atom or a group of the formula: -COOR where R means C 1 -C 6 -alkyl. Also, invention relates to derivatives of baccatine-III (II) that are intermediate compounds in synthesis of 7-deoxyderivatives of taxol of the formula (I) and particular intermediate compounds: 10-penta-fluorothioncarbonate-7-triethylsilylhydroxybaccatine-III of the formula (III), 7-[(methylthio)carbonothioylhydroxy]-10- -deacetylhydroxybaccatine-III of the formula (IV) and 7-[(methylthio)carbonothioylhydroxy] -13-triethylsilhydroxy-baccatine-III of the formula (V) using for synthesis of derivatives of baccatine-III of the formula (II). Also, invention proposes a pharmaceutical composition containing a compound of the formula (I) that shows antitumor activity and can be used for treatment of mammals with tumors. EFFECT: improved method of synthesis, enhanced effectiveness. 14 cl, 1 tbl, 42 ex

ФОСФОНООКСИМЕТИЛОВЫЕ ЭФИРЫ ПРОИЗВОДНЫХ ТАКСАНА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ЛЕЧЕНИЯ

Изобретение относится к противоопухолевым соединениям, в частности к новым производным таксана, к фармацевтическим композициям, содержащим указанные производные, а также к их использованию в качестве противоопухолевых средств.

VERFAHREN ZUR HERSTELLUNG VON 1,2-DIOXETANVERBINDUNGEN UND MIT SCHWEFEL SUBSTITUIERTE 1,2-DIOXETANE ALS ZWISCHENVERBINDUNGEN

1,2-DIOXETANE WITH IMPROVED CHEMOCLUMINESCENCE

CHEMILUMINESZENTE DIALKYL-SUBSTITUTED 1.2 - DIOXETANVERBINDUNGEN, SYNTHESIS METHOD AND APPLICATION

ALKENE CONNECTIONS

CHEMILUMINESZENTE 1,2-DIOXETANE WITH IMPROVED ACHIEVEMENT

PHOSPHONOOXYMETHYL OR METHYLTHIOMETHYLETHER OF TAXANDERIVATEN AS ANTI-TUMOR MEANS

PRODRUGS OF PACLITAXEL DERIVATIVES

IMPROVED EMISSION WITH CHEMILUMINESZENZASSAYS

FLUORINE TAXOLE WITH ANTI-TUMOR EFFECT

7,8-ZYKLOPROPATAXANEN WITH ANTI-TUMOR EFFECT

CHEMOLUMINESZENTE 1,2-DIOXETANE

Pharmaceutical derivatives

A method of inhibiting tumor growth

Deoxy taxols

BENZOTHIAZOLE DIOXETANES

Chemiluminescent 1,2-dioxetane compounds capable of producing light energy when decomposed, substantially stable at room temperature, represented by formula (I) or (II), wherein T is (a) or (b).

METHOD AND COMPOSITIONS PROVIDING ENHANCED CHEMILUMINESCENCEFROM 1,2-DIOXETANES

A method and compositions including a 1,2-dioxetane and a fluorescent compound is described. In particular, enzymatic triggering of a triggerable 1,2-dioxetane admixed with a surfactant and the fluorescent compound attached to a hydrocarbon to provide a co-surfactant in a micelle or other structure providing close association of these molecules is described. The method and compositions are useful in immunoassays and in DNA probes used for various purposes.

FLUORO TAXOLS

This invention relates to a fluorinated taxol ~ of formula I (see formula I) in which R1 is -COR2 in which R2 is RO- or R; R8 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or a radical of the formula -W-R x in which W is a bond, C2-6 alkenediyl, or -(CH2)t-, in which t is one to six; and R x is naphthyl, furyl, thienyl or phenyl, and furthermore R x can be optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; R2 is -OCOR, H, OH, -OR, -OSO2R, -OCONRR, -OCONHR, -OCOO(CH2)t R, or -OCOOR; and R and R o are independently C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-6 alkynyl, or phenyl, optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups. Further provided by this invention are pharmaceutical formulations and useful intermediates for the fluorinated taxols ~ of formula I. A method of treating mammalian tumors using a compound of formula I is also provided.

DEOXY PACLITAXELS

ABSTRACT I in which R1 is -CORZ in which RZ is RO- or R; Rg is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, or a radical of the formula -W-Rx in which W is a bond, C2-6 alkenediyl, or -(CH2)t-, in which t is one to six; and Rx is naphthyl, phenyl, or heteroaryl, and furthermore Rx can be optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups; R2 is -OCOR, H, OH, -OR, -OSO2R, -OCONRoR, -OCONHR, -OCOO(CH2),R, or -OCOOR; and R and Ro are independently C1-6 alkyl, C2-6 alkenyl, C3-6 cycloalkyl, C2-6 alkynyl, or phenyl, optionally substituted with one to three same or different C1-6 alkyl, C1-6 alkoxy, halogen or -CF3 groups. Further provided by this invention are pharmaceutical formulations and intermediates for the the preparation of deoxy taxols of formula I. A method of treating mammalian tumors using a compound of formula I is also provided.

CHEMILUMINESCENT DOUBLE-TRIGGERED 1,2-DIOXETANES

A stable 1,2-dioxetane of the formula (I), where R1, R2 and R3 are passive organic groups that allow the dioxetane to decompose and produce light when Z and Y are removed, with the proviso that R1 and R2 may be joined to form a cyclic moiety, Z is a first protecting group that can be removed by a first deprotecting process, Y is a second protecting group that can be removed by a second deprotecting process, and X is an organic group which upon removal of Z and Y renders the dioxetane susceptible to said decomposition, with the proviso that X may be joined to R3 to form a cyclic moiety. These di-oxetanes are useful for generating chemiluminescent output in immunoassays and nucleic acid hybridization assays.

ENHANCED CHEMILUMINESCENCE FROM 1,2-DIOXETANES THROUGH ENERGY TRANSFER TO TETHERED FLUORESCERS

Triggerable dioxetanes with a fluorescent molecule containing group bonded or tethered in the dioxetane so as to produce fluorescence from the group are described. The compounds are useful in immunoassays and in probes using enzymes or other chemicals for triggering the dioxetanes to produce light from the fluorescent molecule in the group as a signal.

Chemiluminescent 1,2-dioxetanes

Spiroadamantyl dioxetanes bearing an alkoxy substituent, and an aromatic substituent of phenyl or naphthyl on the dioxetane ring can be activated to chemiluminesce if the aromatic substituent bears a moiety designated OX, wherein the X is cleaved by an enzyme with which the dioxetane is permitted to come in contact with. The T 1/2 kinetics of the chemiluminescent reaction, as well as the signal intensity, or quantum yield of the chemiluminescent reaction, can be altered by selection of an electron-withdrawing or an electron-donating group Z, at positions on the aromatic substituent other than those adjacent the point of attachment to the dioxetane. Signal strength can further be enhanced by recognized chemiluminescent enhancers.

Phosphate-containing nanoparticle delivery vehicle

A phosphate-containing nanoparticle delivery vehicle includes a nanoparticle, an active ingredient, and a phosphodiester moiety connecting the nanoparticle and the active ingredient and forms a prodrug. The nanoparticle delivery vehicle achieves the function of increasing hydrophilicity of the active ingredient and specificity against tumor cells. Advantages of the nanoparticle material include biocompatibility, magnetism and/or controllable drug release.

Synthesis of 1,2-dioxetanes and intermediates therefor

Compounds having the formula: wherein T is a polycycloalkylidene group (e.g., adamant-2-ylidene); R is a C 1-20 alkyl, aralkyl or cycloalkyl group; and Y is a fluorescent chromophore (e.g., m-phenylene), produced by reacting a compound having the formula: with an R-ylating agent (e.g., R 2 SO 4 ) in the presence of an alkali metal alkoxide in a polar aprotic solvent. Also, compounds having the formula: are produced by reacting a compound having the formula: with wherein X is an electronegative leaving group (e.g., a halogen anion such as chloride ion) in the presence of a Lewis base (e.g., a trialkyl-amine) dissolved in an aprotic organic solvent (e.g., benzene or toluene). Also, compounds having the formula are produced by reacting a compound of the formula with a tetra-O-acylated-O-hexopyranoside halide, then hydrolyzing off the protective acyl groups. The aforementioned compounds and procedures are useful in the synthesis of enzyme-cleavable 1,2-dioxetane ring systems that can serve as members of a binding pair employed, for example, in chemiluminescent immunoassays, DNA probe assays, and direct assays for an enzyme.

In situ chemiluminescent substrates and assays

Methods for generating a chemiluminescent enzyme substrate in situ, in aqueous or other assay conditions. Also disclosed are methods to use the substrates to generate light, detect and/or quantify enzymes, antigens, and/or nucleic acids. Kits relating to these methods are also disclosed.

Improved chemiluminescent 1,2-dioxetanes

Novel 1,2-dioxetanes with improved chemiluminescent properties, such as signal intensity, S/N ratio, T½, etc. are provided by spiroadamantyl 1,2-dioxetanes, wherein the remaining carbon atom of the ring bears an alkoxy, aryloxy, or arylalkoxy substituent, and either a phenyl or naphthyl ring, this aromatic ring bearing, at the meta position on the phenyl group, or a nonconjugated position on the naphthyl ring,an OX moiety wherein X is an enzyme-cleavable group, which when removed from the dioxetane, leaves the oxyanion which decomposes with chemiluminescence, the aryl ring further bearing an electron-active substituent Z. The nature and placement of the Z substituent, at a position not adjacent the point of attachment to the dioxetane ring, strongly influences the properties of the dioxetane. Assays, as well as kits for the performance of those assays, include the dioxetane, an enzyme capable of cleaving the X group, and in certain cases, membranes and chemiluminescent enhancement agents.

ПРОИЗВОДНЫЕ ПАКЛИТАКСЕЛА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ ТОРМОЖЕНИЯ РОСТА ОПУХОЛИ

FIELD: organic chemistry, medicine, oncology, pharmacy. SUBSTANCE: invention describes novel compounds of the formula (I) where R 1 is OC(O)R x ; R 2 is hydroxy-group; R 2 is hydrogen atom; R 6 or hydrogen atom; R 6 is hydrogen atom; R 8 is methyl-group; R 9 is OC(O)R x ; R 7 and R 7 in common form oxo-group; R 4 and R 5 mean phenyl-group; p = 0; R d and R e mean hydrogen atom; R f means hydrogen atom; R x means C 1-6 -alkyl or R x means radical of the formula where D means a bond or C 1-6 -alkyl and R a , R b , R c means hydrogen atom independently, or their pharmaceutically acceptable salts. These compounds show antitumor activity and are used for preparing pharmaceutical composition for inhibition of tumor growth in bearing mammal. EFFECT: new compounds indicated above, improved method of tumor growth inhibition, valuable antitumor activity. 7 cl, 7 ex сз0с9Ес ПЧ с» РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (19) (13) ВИ `” 2 162 082” С2 57 МК’ С 070 305/14, А 61 К 31/337, А 61Р 35/00 (12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 96111012/04, 05.06.1996 (24) Дата начала действия патента: 05.06.1996 (30) Приоритет: 06.06.1995 Ц$ 469,247 (46) Дата публикации: 20.01.2001 (56) Ссылки: ЕР 577083 АЛ, 05.01.1994. ЕР 604910 АЛ, 06.07.1994. ЕР 639577 АЛ, 22.02.1995. \М!О 9420485 А, 15.09.1994. КЦ 2017724 СЛ, 15.08.1994. (98) Адрес для переписки: 129010, Москва, ул. Большая Спасская 25, стр.3, ООО "Городисский и Партнеры", Лебедевой Н.Г. (71) Заявитель: . БРИСТОЛЬ-МЕИЕРЗ СКВИББ КОМПАНИ (0$) (72) Изобретатель: Пол М. СКОЛА (Ц$)}, Джон Ф. КЭДОУ (Ц$), Долатрай М. ВИАС (СА) (73) Патентообладатель: БРИСТОЛЬ-МЕИЕРЗ СКВИББ КОМПАНИ (Ц5$) (54) ПРОИЗВОДНЫЕ ПАКЛИТАКСЕЛА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ И СПОСОБ ТОРМОЖЕНИЯ РОСТА ОПУХОЛИ 57 описываются новые соединения формулы 1, в которой В'-ОС(О)Бх; В? - гидрокси: В?- водород; Вб- водород; Вб - водород; В8 - метил; К3-ОС(О)БХ: В’и В’ вместе образуют оксогруппу; В и БВ? - фенил; р=0; КЗ и Б® - водород ...

1,2-Dioxetane mit verbesserter Chemolumineszenz

VERFAHREN ZUR VERWENDUNG CHEMILUMINESZIERENDER 1,2-DIOXETANE.

WASSERLÖSLICHE TRISUBSTITUIERTE 1,2-DIOXETANVERBINDUNGEN MIT ERHÖHTER LAGERSTABILITÄT, SYNTHESEVERFAHREN UND ZWISCHENVERBINDUNGEN

PHOSPHONOOXY AND CARBONATE DERIVATIVES OF TAXOL

CHEMOLUMINESZIERENDE 1,2-DIOXETAN-VERBINDUNGEN.

INCREASE OF CHEMILUMINESZENZ IN ASSAYS

Water soluble tri-substituted 1,2-dioxetane compounds having increased storage stability, synthetic processes and intermediates

Pharmaceutical derivatives

Prodrugs of paclitaxel derivatives

Inactivation of viruses present in blood components using chemically-activated compounds

PHOSPHATE DERIVATIVES OF PHARMACEUTICAL PRODUCTS

According to the invention, there is provided a complex of a pharmaceutical compound selected from the group consisting of opioids, hormones, anaethetics and chemotherapeutic agents comprising the reaction product of: (a) one or more phosphate derivatives of one or more opioids, steroid hormones, thyroid hormones, anaesthetics or chemotherapeutic agents having a phenolic, primary alcohol, secondary alcohol or tertiary hydroxyl group; and (b) a complexing agent selected from the group comprising amphoteric surfactants, cationic surfactants, amino acids having nitrogen functional groups and proteins rich in these amino acids.

PHOSPHOLIPID ETHER ANALOGS AS CANCER-TARGETING DRUG VEHICLES

The present invention is directed to therapeutic compounds capable of targeting cancer cells and cancer stem cells. The present invention is further directed to compositions comprising these therapeutic compounds and methods of treating cancer comprising administering these therapeutic compounds. A therapeutic compound comprising the formula A-B-D wherein: A is at least one compound of formula (I).

CHEMILUMINESCENT PROBES FOR DIAGNOSTICS AND IN VIVO IMAGING

The present invention provides dioxetane-based chemiluminescence probes, more specifically fluorophore-tethered dioxetane-based chemiluminescence probes and compositions thereof. The chemiluminescence probes disclosed are useful for both diagnostics and in vivo imaging. 3. The conjugate of claim 2 , wherein Rand Rtogether with the carbon atom to which they are attached form adamantyl.4. The conjugate of claim 2 , wherein Xis —(CH)-para-phenylene; and Xis —C(O)—.5. The conjugate of claim 1 , wherein:{'sup': '1', 'sub': 1', '8, 'Ris a linear or branched (C-C)alkyl;'}{'sup': 2', '3, 'Rand Rtogether with the carbon atom to which they are attached form a fused, spiro or bridged polycyclic ring;'}{'sup': 7', '8', '9', '7', '8', '9, 'sub': '2', 'at least one of R, Rand Ris H, and the other of R, Rand Reach independently is an electron acceptor group selected from the group consisting of halogen, —NOand —CN; and'}{'sub': 1', '2', '1', '1', '18', '6', '14', '1', '18', '6', '14', '2', '2', '2', '2', '2', '3', '6', '10', '1', '4', '6', '10', '1', '4', '1', '18', '1', '8', '6', '10', '6', '10', '2, 'X is a linker of the formula —X—X—, wherein Xis (C-C)alkylene, (C-C)arylene-diyl, or (C-C)alkylene-(C-C)arylene-diyl, optionally substituted by one or more groups each independently selected from the group consisting of halogen, —COH, —COOH, —OCOOH, —OCONH, —CN, —NO, —SH, —OH, —NH, —CONH, —SOH, —SOH, —S(═O)H, (C-C)aryl, (C-C)alkylene-(C-C)aryl, heteroaryl, and (C-C)alkylene-heteroaryl, and said (C-C)alkylene being further optionally interrupted by one or more identical or different heteroatoms selected from the group consisting of S, O and N, and/or at least one group each independently selected from the group consisting of —NH—CO—, —CO—NH—, —N(C-Calkyl)-, —N(C-Caryl)-, (C-C)arylene-diyl, and heteroarylenediyl; and Xis —C(O)—.'}6. The conjugate of claim 5 , wherein Ris methyl; Rand Rtogether with the carbon atom to which they are attached form adamantly; Xis —(CH)-para-phenylene; ...

CHEMILUMINESCENT PROBES FOR DIAGNOSTICS AND IN VIVO IMAGING

The present invention provides dioxetane-based chemiluminescence probes, more specifically fluorophore-tethered dioxetane-based chemiluminescence probes and compositions thereof. The chemiluminescence probes disclosed are useful for both diagnostics and in vivo imaging. 2. The compound of claim 1 , wherein:{'sup': '1', 'sub': 1', '8, '(i) Ris a linear or branched (C-C)alkyl; or'}{'sup': 2', '3, '(ii) Rand Rtogether with the carbon atom to which they are attached form a fused, spiro or bridged polycyclic ring; or'}{'sup': 5', '6, 'sub': 1', '8, '(iii) Rand Reach independently is (C-C)alkyl, and together with the oxygen atoms to which they are attached form a heterocyclic ring; or'}{'sup': 7', '8', '9', '7', '8', '9, 'sub': '2', '(iv) at least one of R, Rand Ris H, and the other of R, Rand Reach independently is an electron acceptor group selected from the group consisting of halogen, —NOand —CN; or'}{'sub': 3', '2', '3', '3', '3', '2', '2, '(v) said protecting group is selected from the group consisting of —CH, —CHOCH, —C(═O)C(CH), —CH—CH═CH, TBDMS, TBDPS, benzyl, and 2-nitro-4,5-dimethoxybenzyl.'}3. The compound of claim 2 , wherein Rand Rtogether with the carbon atom to which they are attached form adamantyl.4. The compound of claim 2 , wherein Rand Reach is isopropyl and together with the oxygen atoms to which they are attached form 4 claim 2 ,4 claim 2 ,5 claim 2 ,5-tetramethyl-1 claim 2 ,3 claim 2 ,2-dioxaborolanyl.5. The compound of claim 1 , wherein:{'sup': '1', 'sub': 1', '8, 'Ris a linear or branched (C-C)alkyl;'}{'sup': 2', '3, 'Rand Rtogether with the carbon atom to which they are attached form a fused, spiro or bridged polycyclic ring;'}{'sup': 5', '6, 'sub': 1', '8, 'Rand Reach independently is (C-C)alkyl, and together with the oxygen atoms to which they are attached form a heterocyclic ring; and'}{'sup': 7', '8', '9', '7', '8', '9, 'sub': '2', 'at least one of R, Rand Ris H, and the other of R, Rand Reach independently is an electron acceptor group ...

Chemiluminescent probes for diagnostics and in vivo imaging

Dioxetane-based chemiluminescence probes, more specifically fluorophore-tethered dioxetane-based chemiluminescence probes and π* acceptor group-containing dioxetane based chemiluminescence probes can be included in compositions. The chemiluminescence probes are useful for both diagnostics and in vivo imaging.

In Situ Chemiluminescent Substrates and Assays

Methods for generating a chemiluminescent enzyme substrate in situ, in aqueous or other assay conditions. Also disclosed are methods to use the substrates to generate light, detect and/or quantify enzymes, antigens, and/or nucleic acids. Kits relating to these methods are also disclosed. 2. The method of claim 1 , wherein the oxidant is selected from hydrogen peroxide claim 1 , sodium molybdate claim 1 , hydrogen peroxide and sodium molybdate claim 1 , hypochlorite claim 1 , hypochlorite and hydrogen peroxide claim 1 , aryl endoperoxide claim 1 , calcium peroxide peroxyhydrate claim 1 , and combinations thereof.3. The method of claim 2 , wherein the oxidant is hydrogen peroxide claim 2 , and hydrogen peroxide and sodium molybdate.6. The method of claim 1 , wherein Ris alkyl containing 1 to 2 carbon atoms or trifluoalkyl containing 1 to 2 carbon atoms.12. The method of claim 1 , wherein the enzyme moiety comprises a hydrolytic enzyme.13. The method of claim 12 , wherein the hydrolyic enzyme is alkaline phosphatase claim 12 , β-galactosidase claim 12 , β-glucosidase claim 12 , β-glucuronidase claim 12 , or neuraminidase.14. The method of claim 13 , wherein the enzyme moiety is an enzyme.15. The method of claim 14 , further comprising the step of detecting the light emitted from the reaction mixture after addition of the aqueous solution of the 1 claim 14 ,2-dioxetane enzyme substrate claim 14 , wherein the emission of light is indicative of the presence of the enzyme claim 14 , and the amount of light emitted can be correlated to the amount of the enzyme present in the sample.16. The method of claim 13 , wherein the enzyme moiety is an enzyme-linked antibody comprising a first antibody capable of binding to an antigen and an enzyme capable of cleaving the 1 claim 13 ,2-dioxetane enzyme substrate so that the substrate decomposes and generates light.17. The method of claim 16 , wherein the first antibody is covalently or non-covalently linked to the enzyme.18. The ...

CELL-PENETRATING, GUANIDINIUM-RICH OLIGOPHOSPHOTRIESTERS FOR DRUG AND PROBE DELIVERY

Guanidinium-rich oligophosphotriesters transporter compounds and methods of making and using the same are provided. Also provided are pharmaceutical compositions that include the subject transporter compounds, where the transporter can be joined to a cargo of interest, and is formulated with a pharmaceutically acceptable excipient. Formulations may be provided in a unit dose, where the dose provides an amount of the compound effective to afford a desired therapeutic effect. Methods of using the subject transporter compounds to deliver a cargo moiety to a cell are provided, where the method can include contacting a target cell with the transporter compound. The subject methods can be performed in vitro or in vivo. 3. The transporter compound of claim 2 , wherein:{'sub': '3', 'Ris H;'}X is O;p is 1; andn is 4 to 10.4. The transporter compound of claim 1 , wherein Zis a cargo moiety.5. The transporter compound of claim 4 , wherein the cargo moiety is a chemotherapeutic drug claim 4 , a dye claim 4 , a protein or a polynucleotide.6. The transporter compound of claim 4 , wherein Lis a cleavable linker.8. The method of claim 7 , wherein Lis a cleavable linker and the method further comprises cleaving Lto release the cargo moiety.9. The method of claim 7 , wherein Zis a chemotherapeutic drug or a dye.11. The method of claim 10 , wherein Zis a protected guanidine group and the method further comprises deprotecting Zto produce a guanidine group.12. The method of claim 10 , wherein Zis a cargo moiety.13. The method of claim 6 , wherein Zis a protected thiol.14. The method of claim 13 , further comprising deprotecting Zto produce a reactive functional group and conjugating the reactive functional group to a cargo moiety.15. A pharmaceutical composition comprising the composition of any of - claim 13 , and a pharmaceutically acceptable excipient.16. A method of treating a subject for a disease condition claim 13 , the method comprising administering to the subject an effective ...

Phospholipid Ether Analogs as Cancer-Targeting Drug Vehicles

The present invention is directed to therapeutic compounds capable of targeting cancer cells and cancer stem cells. The present invention is further directed to compositions comprising these therapeutic compounds and methods of treating cancer comprising administering these therapeutic compounds. 2. The therapeutic compound of wherein the linker compound is a bond or a compound of formula (IV) claim 1 , Y—(CH)—Z(IV) claim 1 , wherein:Y is bound to A;Z is bound to D;{'sub': '2', 'Y is selected from the group consisting of a bond, O, NH, C═O, NHSOO, and OC(═O)O;'}{'sub': 2', '2, 'Z is selected from the group consisting of O, NH, C═O, C(═O)O, C(═O)NH, SO, OC(═O)OCH, and —S—S—; and'}n is an integer from 0 to 6.9. A pharmaceutical composition comprising a therapeutic compound of and one or more pharmaceutically acceptable carriers.10. A method of treating cancer comprising administering an effective amount of a therapeutic compound of to a subject with cancer.11. The method of wherein the cancer comprises cancer stem cells.12. The method of wherein the cancer is recurrent.13. A pharmaceutical composition comprising a therapeutic compound of and one or more pharmaceutically acceptable carriers.14. A pharmaceutical composition comprising a therapeutic compound of and one or more pharmaceutically acceptable carriers.15. A method of treating cancer comprising administering an effective amount of a therapeutic compound of to a subject with cancer.16. A method of treating cancer comprising administering an effective amount of a therapeutic compound of to a subject with cancer. In 2012, 14.1 million people were diagnosed with cancer worldwide and 8.2 million died of cancer. In the United States, around 40% of all people will be diagnosed with cancer during their lifetime. Despite receiving the best treatment available, 44% of those Americans will die from cancer.Cancer is the result of a cell dividing without limitation. Healthy cells have checkpoints that prevent unlimited ...

팩리택셀 유도체의 전구약물

Methods of using chemiluminescent 1,2-dioxetanes

Processes are disclosed in which light of different wavelengths is simultaneously released from two or more enzymatically decomposable chemiluminescent 1,2-dioxetane compounds, said compounds being configured, by means of the inclusion of a different light emitting fluorophore in each of them, to each emit light of said different wavelengths, by decomposing each of said compounds by means of a different enzyme. Such processes can be used in multi-channel assays--immunoassays, chemical assays and nucleic acid probe assays--to detect the presence or determine the concentration of chemical or biological substances, and in multi-channel chemical/physical probe procedures for studying the microstructures of macromolecules.

Method of converting a drug to an orally available form by covalently bonding a lipid to the drug

The oral delivery of many classes of drugs is facilitated by converting drugs having suitable functional groups to 1-O-alkyl-, 1-O-acyl-, 1-S-acyl, and 1-S-alkyl-sn-glycero-3-phosphate derivatives. The method confers the ability to be absorbed through the digestive tract to drugs that are not orally bioavailable in the non-derivatized state, and enhances the effectiveness of drugs that are poorly absorbed or rapidly eliminated. The method provides orally bioavailable lipid prodrugs of pharmaceutical compounds having diverse physiological activities, including anticancer and antiviral agents, anti-inflammatory agents, antihypertensives and antibiotics. Potency of the lipid prodrugs is comparable to that of the corresponding non-derivatized drugs.

Methods for generating light with chemiluminescent dioxetanes activated by anchimeric assisted cleavage

Novel assay methods employing compounds which are chemically or enzymatically cleavable and which give rise to an intermediate which further decomposes by an intramolecular anchimeric displacement reaction which releases a signal producing species are disclosed. Also disclosed are probe hybridization assays employing the compounds of the invention employing thermostable enzymes which are not denatured by the hybridization conditions. Such signal producing species may include chemiluminescent dioxetanes and other colored products.

Phosphonohydroxymethyl esters of taxane derivatives, pharmaceutical composition, methods of inhibition

FIELD: organic chemistry. SUBSTANCE: invention proposes phosphonohydroxymethyl esters of taxane derivatives of the general formula (A) where T means taxane moiety carrying substituted 3-amino-2-hydroxypropanoylhydroxy-group on C 13 -carbon atom; m = 0 or 1; n = 1, 2, or its pharmaceutically acceptable salts. Thio-derivatives of baccatin of the formula (D) where txn is taxane moiety, or its C 13 -alkoxide of metal. Thio-derivatives of taxane of the formula (B) where T 1 means T where reactive hydroxy-groups are blocked. Ester derivatives of phosphonohydroxymethyl taxane derivatives of the formula (C) where T 1 , m and n are defined above and R y is a phosphono-protective group. Invention relates to also a pharmaceutical composition showing antitumor activity and methods of inhibition of tumor growth in mammal-host. EFFECT: taxane derivatives indicated above, enhanced antitumor activity. 81 cl, 6 tbl, 41 ex Гээзстс ПЧ Го РОССИЙСКОЕ АГЕНТСТВО ПО ПАТЕНТАМ И ТОВАРНЫМ ЗНАКАМ (19) ВИ” 2 128 661 ' (51) МПК 13) СЛ 305/14, С 07С 323/43 С 07Е 9/09, 9/655, С 070 12) ОПИСАНИЕ ИЗОБРЕТЕНИЯ К ПАТЕНТУ РОССИЙСКОЙ ФЕДЕРАЦИИ (21), (22) Заявка: 94029662/04, 15.08.1994 (30) Приоритет: 17.08.1993 1$ 108,015 24.11.1993 Ц$ 154,840 17.05.1994 4$ 245,119 (46) Дата публикации: 10.04.1999 (56) Ссылки: Ц$ 4942184 А, 07.03.88. 4$ 5059699 А, 22.10.91. 4$ 4960790 А, 09.03.89. КО 2059630 СЛ, 10.05.96. КЦ 94019168 АЛ, 10.11.95. (98) Адрес для переписки: 103735, Москва, ул.Ильинка, 5/2, Союзпатент (71) Заявитель: Бристоль-Мейерз Сквибб Компани (ЦЗ) (72) Изобретатель: Джерзи Голик (ЦЗ), Джон Ф.Кадоу (1$), Муррей А.Каплан (0$), Уэн-Сен Ли (4$), Роберт К.Перроун (0$), Джон К.Тотгатил (1$), Долатрай Вайас (0$), Марк Д.Уиттман (1$), Генри Уонг (0$), Джон Дж.Райт (4$) (73) Патентообладатель: Бристоль-Мейерз Сквибб Компани (ЦЗ) (54) ФОСФОНООКСИМЕТИЛОВЫЕ ЭФИРЫ ПРОИЗВОДНЫХ ТАКСАНА, ФАРМАЦЕВТИЧЕСКАЯ КОМПОЗИЦИЯ, СПОСОБЫ ИНГИБИРОВАНИЯ (57) Реферат: Предложены фосфонооксиметиловые эфиры производных таксана общей ...

Taxol derivative and preparation method and application thereof

本发明涉及医药领域，具体涉及一类水溶性紫杉醇衍生物及其制备方法和用途。一类可在血浆中降解，水溶性明显增加的紫杉醇衍生物。通过共价键将含有磷酸和磺酸基团的小分子羧酸与难溶性药物紫杉醇结合，因磷酸和磺酸基团具有极强的亲水性，得到的紫杉醇衍生物水溶性明显增强；而且此种衍生物可在血浆中降解成原料紫杉醇。

Method for producing vinyl ether

Chemiluminescent 1,2-dioxietanes

本发明提供由取代芳族酯或酮和在环中含有π－电子体系或在螺稠环中含有碳碳双键或叁键的螺稠酮制得的化学发光1,2－二氧丁环。这些1,2－二氧丁环在四元过氧化物环中有给电子或吸电子基团,因此,通过加入的电荷可以影响这些1,2－二氧丁环。

Methylthiomethyl-ether of taxane derivatives

본 발명은 항종양 화합물에 관한 것이다. 보다 구체적으로는, 본 발명은 신규의 탁산 유도체, 그의 약제 조성물, 및 항종양제로서 그들의 용도를 제공한다. The present invention relates to antitumor compounds. More specifically, the present invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetanes

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetane compounds are disclosed in which the aryl group is polysubstituted with suitable electron-donating groups such that the light-emitting pattern of the molecule results in a very high luminescent count, thus providing for a sensitive and precise assay for haptens, analytes, polynucleotides and the like. These substituted aryl-containing 1,2-dioxetane compounds can be used as direct labels in an immunoassay or when derivatized with an appropriate leaving group, can be used as a substrate for an enzyme immunoassay. The unusual chemiluminescence of the compounds allows the timing of the luminescent reaction to be exactly controlled.

Methylthiomethyl ethers of taxane derivatives

1,2-Dioxetane compound and light emitting method using the same

Chemiluminescent probes for diagnostics and in vivo imaging

The present invention provides dioxetane-based chemiluminescence probes, more specifically fluorophore-tethered dioxetane-based chemiluminescence probes and π* acceptor group-containing dioxetane based chemiluminescence probes, and compositions thereof. The chemiluminescence probes disclosed are useful for both diagnostics and in vivo imaging.

1,2 chemiluminescent dioxetanes of improved performance.

Una clase nueva de dioxetanos estables porta un grupo estabilizante policíclico y una porcion ariloxi, el átomo de oxígeno del cual que es proporcionado con un grupo protector el cual puede ser eliminado por un activador enzimático o químico mezclado con el dioxetano. El grupo estabilizante policíclico es preferiblemente espiroadamantano. El grupo tiene una porcion alcoxi, ariloxi, aralquiloxi o cicloalquiloxi la cual es substituida parcial o totalmente con halogenos, particularmente fluor y cloro. La seleccion apropiada de los grupos activos a electrones sobre la porcion estabilizante, el grupo arilo y el grupo OR produce cinéticas enzimáticas mejoradas, intensidad de luz superior y sensibilidad de deteccion excelente en varios ensayos.

METHOD FOR DETECTING A CONNECTION USING THE ENZYMATICALLY INDUCED DECOMPOSITION OF DIOXETHANES.

Inactivation of viruses present in blood components using chemically-activated compounds

A method of inactivating viral molecules present within a blood sample and compounds for use in same. The method involves adding to a virus-containing blood sample an effective quantity of a compound which both has an affinity for viral nucleic acid and which is activatable to an excited state in which the compound covalently binds viral nucleic acid. After permitting the compound to complex with viral nucleic acid, the compound is raised to its excited state by chemical activation. In a first preferred embodiment, psoralen, hypericin or a derivative of psoralen or hypericin is used as the activatable, viral-inactivating compound, and chemical activation of the compound is effected by the decomposition of a dioxetane proximate to the nucleic acid/compound complex. In a second preferred embodiment, the activatable, viral-inactivating compound is incorporated into a dioxetane molecule, and chemical activation of the compound is effected by decomposition of the dioxetane into a pair of carbonyl compounds.

Phospholipid ether analogs as cancer-targeting drug vehicles

Improved use of chemiluminescent 1,2-dioxetanes

Process for the preparation of 1,2-dioxetane compounds and novel sulfur-substituted 1,2-dioxetane compounds as intermediates

A process is provided for the preparation of a variety of triggerable dioxetanes bearing alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy substituents from a common intermediate along with sulfur-substituted dioxetanes and vinyl sulfide compounds used as intermediates. Alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy substituted dioxetanes are useful in detecting activating agents and in assays such as immunoassays and nucleic acid hybridization assays. The sulfur-substituted dioxetanes additionally are useful for producing chemiluminescence. The novel process involves conversion of a vinyl sulfide compound to a sulfur-substituted dioxetane, reacting the sulfur-substituted dioxetane with an electrophilic agent and a hydroxylic compound or salt thereof and forming the alkoxy, alkenyloxy, alkynyloxy, arlyoxy, aralkyloxy or acyloxy-substituted dioxetane.

Improved chemiluminescent 1,2-dioxetanes

Novel 1,2-dioxetanes with improved chemiluminescent properties, such as signal intensity, S/N ratio, T1/2, etc. are provided by spiroadamantyl 1,2-dioxetanes, wherein the remaining carbon atom of the ring bears an alkoxy, aryloxy, or arylalkoxy substituent, and either a phenyl or naphthyl ring, this aromatic ring bearing, at the meta position on the phenyl group, or a non-conjugated position on the naphthyl ring, an OX moiety wherein X is an enzyme-clevable group, which when removed from the dioxetane, leaves the oxyanion which decomposes with chemiluminescence, the aryl ring further bearing an electron-active substituent Z. The nature and placement of the Z substituent, at a position not adjacent the point of attachment to the dioxetane ring, strongly influences the properties of the dioxetane. Assays, as well as kits for the performance of those assays, include the dioxetane, an enzyme capable of cleaving the X group, and in certain cases, membranes and chemiluminescent enhancement agents.

Drugs of paclitaxel derivatives

Palcitaxelderivater med antitumoregenskaper har formelen (I), eller et farmasøytisk akseptabelt salt derav. hvor bl. a. Rer -CO(0)R; Rer hydroksy; R2 er hydrogen; Rer hydroksy eller -OC(0)R; Rer metyl;6 og R6 er hydrogen; Rer -OC(0)R; Rog R7 danner sammen en oksogruppe; Rog Rer uavhengig av hverandre C i--alkyl, C--alkenyl eller -Z-Rhvor Z er en direkte binding eller Q--alkyl og Rer aryl, substituert aryl C--cykloalkyl eller heteroaryl; p er 0; Rd og Re er hydrogen; Rf er hydrogen, Rx er C.-cykloalkyl, C-alkenyl eller C..alkyl, hvor alle eventuelt er substiuert med fra 1 til 6 like eller forskjellige halogenatomer, eller Rx er et radikal med formelen. hvor D er en binding eller C..alkyl, og Ra, Rog R° er uavhengig av hverandre hydrogen,. nitro, amino, C--alkylamino, di C--alkylamino, halogen, C--alkyl eller C--alkoksy. Det omtales også farmasøytiske preparater som inneholder paclitaxelderivater, samt anvendelse av derivatene. Palcitaxel derivatives having antitumor properties have the formula (I), or a pharmaceutically acceptable salt thereof. where, among others. a. Rer -CO (0) R; Rer hydroxy; R 2 is hydrogen; R is hydroxy or -OC (O) R; R 6 is methyl, 6 and R 6 are hydrogen; Rs is -OC (0) R; Rog R7 together form an oxo group; R 6 is independently C 1-4 alkyl, C 1-4 alkenyl or -Z-Rh wherein Z is a direct bond or C 1-4 alkyl and R 11 is aryl, substituted aryl C 1-8 cycloalkyl or heteroaryl; p is 0; Rd and Re are hydrogen; Rf is hydrogen, Rx is C1-cycloalkyl, C-alkenyl or C1-4alkyl, all of which are optionally substituted by from 1 to 6 identical or different halogen atoms, or Rx is a radical of the formula. wherein D is a bond or C 1-4 alkyl, and Ra, Rog R ° are independently hydrogen ,. nitro, amino, C - alkylamino, di C - alkylamino, halogen, C - alkyl or C - alkoxy. Pharmaceutical preparations containing paclitaxel derivatives and the use of the derivatives are also mentioned.

Chemiluminescent 3-(substituted adamant-2'-ylidene) 1,2-dioxetanes

Enzymatically cleavable chemiluminescent 1,2-dioxetane compounds capable of producing light energy when decomposed, substantially stable at room temperature before a bond by which an enzymatically cleavable labile substituent thereof is intentionally cleaved, are disclosed. These compounds can be represented by the formula: ##STR1## wherein: X and X 1 each represent, individually, hydrogen, a hydroxyl group, a halo substituent, an unsubstituted lower alkyl group, a hydroxy (lower) alkyl group, a halo (lower) alkyl group, a phenyl group, a halophenyl group, an alkoxyphenyl group, a hydroxyalkoxy group, a cyano group or an amide group, with at least one of X and X 1 being other than hydrogen; and R 1 and R 2 , individually or together, represent an organic substituent that does not interfere with the production of light when the dioxetane compound is enzymatically cleaved and that satisfies the valence of the dioxetane compound's 4-carbon atom, with the provisos that if R 1 and R 2 represent individual substituents the R 2 substituent is aromatic, heteroaromatic, or an unsaturated substituent in conjugation with an aromatic ring, and that at least one of R 1 and R 2 is, or R 1 and R 2 taken together are, an enzymatically cleavable labile group-substituted fluorescent chromophore group that produces a luminescent substance when the enzymatically cleavable labile substituent thereof is removed by an enzyme. The corresponding dioxetanes which, instead of being substituted at the 5' or 7', or at the 5' and 7' positions, instead contain a 4' methylene group, are also disclosed, as are intermediates for all these 3-substituted adamant-2'-ylidenedioxetanes, and their use as reporter molecules in assays.

Deoxy taxols

本发明提供了新的式I脱氧红豆杉醇，用于制备 式I化合物的中间体及其药物配方，还提供了用式I 化合物治疗哺乳动物肿瘤的方法。

Chemiluminescence assays using stabilized dioxetane derivatives

A multi-pH chemiluminescence-based assay method comprising first-stage light production by the activation by cleavage of a phosphatase cleavable dioxetane derivative within a pH range optimal for enzyme catalysis, followed by the second-stage generation of increased light energy from the products of enzyme-catalyzed cleavage of the dioxetane derivative by the adjustment of the pH to a strongly alkaline pH optimal for the generation of light energy. The assay method is suitable for both solution phase and solid state assay formats. Light generation enhancers can be used further to increase the light yield.

Chemiluminescent double-triggered 1, 2-dioxetanes

A stable 1,2-dioxetane of the formula: ##STR1## wherein X' is a phenyl group with 0 to 2 Cl or I atoms. This 1,2-dioxetane is a double-trigger substrate. The 2-methyl-4-hydroxy-naphthyl group is first removed by horseradish peroxidase. The exposed phosphate group is then removed with alkaline phosphatase. The exposed phenoxy 1,2-dioxetane decomposes to generate chemiluminescence output in immunoassays or nucleic acid hybridization assays.

Chemiluminescent probes for diagnostic and in-vivo imaging

본 발명은 디옥세테인-기재의 화학발광 프로브, 더욱 특히 플루오로포어-테더링된 디옥세테인-기재의 화학발광 프로브 및 π* 수용기-함유 디옥세테인 기재의 화학발광 프로브, 및 그 조성물을 제공한다. 본원에 개시된 화학발광 프로브는 진단 및 인비보 영상 모두에 유용하다.

PHOSPHOLIPID-ETHER ANALOGES AS CANCER-DISABLING MEDICINES

CHEMOLUMINESCENT ELECTRONIC ARYL-SUBSTITUTED 1,2-DIOXETANES

Chemiluminescent dialkyl-substituted 1,2-dioxetanes, methods of synthesis and use

A chemiluminescent assay method and compositions are described which use a dialkyl-substituted dioxetane which is deprotected to trigger a chemiluminescent reaction. Chemiluminescent 1,2-dioxetane compounds substituted on the dioxetane ring with two nonspirofused alkyl groups which can be triggered by a reagent to generate light are disclosed. Dialkyl-substituted dioxetanes are useful for the detection of triggering agents including enzymes. The enzyme may be present alone or linked to a member of a specific binding pair in an immunoassay, DNA probe assay or other assay where the enzyme is bound to a reporter molecule.

(phosphate- and mercaptan-substituted)methoxy-substituted taxane derivatives and medicaments

The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.

Chemiluminescent 1,2-dioxetane compounds

Novel light producing 1,2-dioxetanes are described of the formula (see formula I) wherein ArOX is an aryl ring substituted with an X oxy group and A are passive organic groups which allow the 1,2-dioxetane to produce light when triggered by removing X. X is a chemically labile group which is removed by an activating agent. The 1,2-dioxetane compounds can be triggered to produce light at room temperatures.

Chemiluminescent 1,2-dioxetanes

Chemiluminescent 1,2-dioxetanes derived from substituted aromatic esters or ketones and spiro-fused ketones with either π-electron system in the ring or with carbon-carbon double bond or triple bond(s) in the spiro-fused ring are provided herein. These 1,2-dioxetanes have electron donating or withdrawing groups at the four-membered peroxide ring, thus, the 1,2-dioxetanes ring hereof is affected by the added electronic charge.

METHOD FOR THE PRODUCTION OF VINYL ETHERS.

A COMPOSITION THAT GENERATES LIGHT WHEN ACTIVATED AND ITS METHOD OF PREPARATION.

SE DESCRIBE UN METODO Y COMPOSICIONES INCLUYENDO UN 1,2-DIOXANO Y UN COMPUESTO FLUORESCENTE. EN PARTICULAR SE DESCRIBE, INICIADOR ENCIMATICO DE UN 1,2-DIOXANO MEZCLABE INICIALIZABLE CON UN AGENTE ACTIVO DE SUPERFICIE Y EL COMPUESTO FLUORESCENTE UNIDO A UN HIDROCARBURO PARA PROVEER UN AGENTE ACTIVO DE SUPERFICIE COOPERANTE, EN MICELIO U OTRA ESTRUCTURA, PROVEIENDO ASOCIACION CERRADA DE ESTAS MOLECULAS. EL METODO Y COMPOSICIONES SON USADOS EN INMUNOENSAYOS Y EN PRUEBAS DE DNA USADAS PARA VARIOS PROPOSITOS. FIG 2A.

PHOSPHONOOXIMETIL-ETERES OF TAXANE DERIVATIVES.

LA PRESENTE INVENCION SE REFIERE A NUEVOS ETERES DE FOSFONOOXIMETILO SOLUBLES EN AGUA, DE DERIVADOS DE TAXANO, SU USO COMO AGENTES ANTITUMORES, Y COMPOSICIONES FARMACEUTICAS QUE CONTIENEN LOS COMPUESTOS NUEVOS.

Improving one's methods of preparation vinyl ether

一种改进的制备乙烯基醚的方法，它通过将式 (1)的酯和式(2)的含羰基化合物偶联而完成，其中 A和R为钝态有机基团，OY为羟基或OP(P为保 护基团)。酯和含羰基化合物在有机溶剂中在钛盐、 金属还原剂和胺碱的存在下反应，得到乙烯基醚。该 反应安全且产率高。乙烯基醚用于生产二氧杂环丁 烷，后者一旦发生连锁反应可发光。

Enzymatically-cleavable chemiluminescent fused polycyclic ring-containing 1,2-dioxetanes

Chemiluminescent 1,2-dioxetane compounds are disclosed in which the molecule is stabilized at the 3-position on the dioxetane ring against decomposition prior to the molecule's coming in contact with a labile group-removing substance (e.g., an enzyme that will cleave the labile group to cause the molecule to decompose to form at least one light-emitting fluorophore) and substituted at the 4-position on the dioxetane ring with a fused polycyclic ring-containing fluorophore moiety bearing a labile ring substituent whose point of attachment to the fused polycyclic ring, in relation to this ring's point(s) of attachment to the dioxetane ring, is such that the total number of ring atoms separating these points of attachment, including the ring atoms at the points of attachment, is an odd whole number. These odd pattern substituted compounds decompose to emit light of greater intensity and of a different wavelength than that emitted by the corresponding even pattern substituted isomers. They are useful in detecting the presence or determining the concentration of chemical or biological substances in immunoassays, chemical assays and nucleic acid probe assays, and in chemical/physical probe procedures for studying the microstructures of macromolecules. Two or more of them can also be used in combination, or one or more of them can be used together with other chemiluminescent compounds, in multi-channel assays to detect two or more different analytes simultaneously. Novel intermediates used in the preparation of these odd pattern substituted compounds are also disclosed.

Improved enhancement of chemiluminescent assays

Chemiluminescent bioassays for the presence or concentration of an analyte in a sample use 1,2-dioxetanes as substrates for the enzyme of an enzyme complex that bind to the analyte. The chemiluminescence obtained from the decomposition of the dioxetane trigerred by the enzyme through the formation of the corresponding 1,2-dioxetane oxyanion of the enzyme complex is enhanced by the addition of TBQ as an enhancement agent. Other polymeric quatenary onium salts can be used as enhancements agents in conjunction with enhancement additives which improve the ability of the enhancement agent to form hydrophobic regions in the aqueous sample, in which regions the 1-2-dioxetane oxyanion and its chemiluminescent decomposition products can be sequestered. A kit for performing such assays is also provided.

Chemiluminescent 1,2-dioxetanes

Novel 1,2-dioxetanes with improved chemiluminescent properties, such as signal intensity, S/N ratio, T1/2, etc. are provided by spiroadamantyl 1,2-dioxetanes, wherein the remaining carbon atom of the ring bears an alkoxy, aryloxy, or arylalkoxy substituent, and either a phenyl or naphthyl ring, this aromatic ring bearing, at the meta position on the phenyl group, or a non-conjugated position on the naphthyl ring, a OX moiety wherein X is an enzyme-cleavable group, which when removed from the dioxetane, leaves the oxyanion which decomposies with chemiluminescence, the aryl ring further bearing an electron active substituent Z. The nature and placement of the Z substituent, at a position not adjacent the point of attachment to the dioxetane ring, strongly influences the properties of the dioxetane. Assays, as well as kits for the performance of those assays, include the dioxetane, an enzyme capable of cleaving the X group, and in certain cases, membranes and chemiluminscent enhancement agents.

PREPARATION PROCEDURE OF 1,2-DIOXETHANES THAT PRODUCE QUIMIOLUMINESCENCE BY DOUBLE ACTIVATION

Water soluble tri-substituted 1,2-dioxetane compounds having increased storage stability, synthetic processes and intermediates

Stable, enzymatically triggered chemiluminescent 1,2-dioxetanes with improved water solubility and storage stability are provided as well as synthetic processes and intermediates used in their preparation. Dioxetanes further substituted with two or more water-solubilizing groups disposed on the dioxetane structure and an additional fluorine atom or lower alkyl group provide superior performance by eliminating the problem of reagent carryover when used in assays performed on capsule chemistry analytical systems. These dioxetanes display substantially improved stability on storage. Compositions comprising these dioxetanes, a non-polymeric cationic surfactant enhancer and optionally a fluorescer, for providing enhanced chemiluminescence are also provided.

Improved chemiluminescent 1,2-dioxetanes

Flash glow type 1,2-dioxetane

Phospholipid ether analogs as cancer-targeting drug vehicles

본 발명은 암세포 및 암 줄기세포를 표적화할 수 있는 치료 화합물에 관한 것이다. 나아가, 본 발명은 이들 치료 화합물을 포함하는 조성물, 및 이들 치료 화합물을 투여하는 단계를 포함하는 암 치료 방법에 관한 것이다. The present invention relates to therapeutic compounds capable of targeting cancer cells and cancer stem cells. Further, the present invention relates to compositions comprising these therapeutic compounds, and methods of treating cancer comprising administering these therapeutic compounds.

Cell-penetrating, guanidinium-rich oligophosphotriesters for drug and probe delivery

Guanidinium-rich oligophosphotriesters transporter compounds and methods of making and using the same are provided. Also provided are pharmaceutical compositions that include the subject transporter compounds, where the transporter can be joined to a cargo of interest, and is formulated with a pharmaceutically acceptable excipient. Formulations may be provided in a unit dose, where the dose provides an amount of the compound effective to afford a desired therapeutic effect. Methods of using the subject transporter compounds to deliver a cargo moiety to a cell are provided, where the method can include contacting a target cell with the transporter compound. The subject methods can be performed in vitro or in vivo.

Alkene compounds

An alkene compound of the formula <CHEM> wherein R1 is selected from an alkyl, alkoxy, aryloxy, and aryl group or R1 and R2 together form a condensed polycyclic aryl group bonded to the carbon atom through a spiro linkage, R2 is an aryl group and is substituted with an X-oxy group wherein X is a group removable by an activating agent selected from bases, enzymes and electron donors, and R3 and R4 are combined together to form a polycyclic carbon containing organic group which is spirofused to the carbon atom.

Synthesis of 1,2-dioxetanes and intermediates therefor

Compounds having the formula: ##STR1## wherein T is a polycycloalkylidene group (e.g., adamant-2-ylidene); R is a C 1-20 alkyl, aralkyl or cycloalkyl group; and Y is a fluorescent chromophore (e.g., m-phenylene), produced by reacting a compound having the formula: ##STR2## with an R-ylating agent (e.g., R 2 SO 4 ) in the presence of an alkali metal alkoxide in a polar aprotic solvent. Also, compounds having the formula: ##STR3## are produced by reacting a compound having the formula: ##STR4## wherein X is an electronegative leaving group (e.g., a halogen anion such as chloride ion) in the presence of a Lewis base (e.g., a trialkyl-amine) dissolved in an aprotic organic solvent (e.g., benzene or toluene). Also, compounds having the formula ##STR5## are produced by reacting a compound of the formula ##STR6## with a tetra-O-acylated-O-hexopyranoside halide, then hydrolyzing off the protective acyl groups. The aforementioned compounds and procedures are useful in the synthesis of enzyme-cleavable 1,2-dioxetane ring systems that can serve as members of a binding pair employed, for example, in chemiluminescent immunoassays, DNA probe assays, and direct assays for an enzyme.

Chemiluminescent dialkyl-substituted 1,2-dioxetane compounds, methods of synthesis and use

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetanes

Chemiluminescent electron-rich aryl-substituted 1,2-dioxetane compounds are disclosed in which the aryl group is poly-substituted with suitable electron-donating groups such that the light-emitting pattern of the molecule results in a very high luminescent count, thus providing for a sensitive and precise assay for haptens, analytes, polynucleotides and the like. These substituted aryl-containing 1,2-dioxetane compounds can be used as direct labels in an immunoassay or when derivatized with an appropriate leaving group, can be used as a substrate for an enzyme immunoassay. The unusual chemiluminescence of the compounds allows the timing of the luminescent reaction to be exactly controlled.

Substance detection method using enzymatically induced degradation of dioxetanes

PHOSPHONOOXIMETHYL ETHER OF TAXANE DERIVATIVES, SOLUBLE IN WATER AND PHARMACEUTICAL COMPOSITIONS INCLUDING THEM.

La presente invención se refiere a éteres fosfonooximetílicos de derivados de taxano, solubles en agua, novedosos, a su uso como agentes antitumorales y a las composiciones farmacéuticas que contienen los compuestos novedosos.

Prodrugs of paclitaxel derivatives.

Alkene compounds

An alkene compound of the formula <CHEM> wherein R1 is selected from an alkyl, alkoxy, aryloxy, and aryl group or R1 and R2 together form a condensed polycyclic aryl group bonded to the carbon atom through a spiro linkage, R2 is an aryl group and is substituted with an X-oxy group wherein X is a group removable by an activating agent selected from bases, enzymes and electron donors, and R3 and R4 are combined together to form a polycyclic carbon containing organic group which is spirofused to the carbon atom.

Synthesis of 1,2-dioxetanes and intermediates therefor

Fluoro taxols

Prodrugs of paclytaxel-derivatives

Prodrugs of paclitaxel derivatives

本发明涉及新的派克利太素(paclitaxel)衍生物，其作为抗肿瘤剂的应用，和药物制剂。

Pharmaceutical derivatives

Taxane derivatives their preparation and pharmaceutical compositions containing them

Phosphate derivatives of pharmaceutical products

According to the invention, there is provided a complex of a pharmaceutical compound selected from the group consisting of opioids, hormones, anaethetics and chemotherapeutic agents comprising the reaction product of: (a) one or more phosphate derivatives of one or more opioids, steroid hormones, thyroid hormones, anaesthetics or chemotherapeutic agents having a phenolic, primary alcohol, secondary alcohol or tertiary hydroxyl group; and (b) a complexing agent selected from the group comprising amphoteric surfactants, cationic surfactants, amino acids having nitrogen functional groups and proteins rich in these amino acids.

Phosphonoxymethyl ethers of taxane derivatives

1,2-dioxetane derivatives and compositions for producing light comprising the same

Phosphonooxy and carbonate derivatives of taxol

Phosphonooxymethyl ethers of taxan derivatives

The present invention concerns antitumor compounds. More particularly, the invention provides novel taxane derivatives, pharmaceutical compositions thereof, and their use as antitumor agents.

Process and intermediates for the synthesis of 1,2-dioxetanes

Contain stable state 1, the composition and the application thereof of 2-dioxane and the fluorescent chemicals that interrelates with narrow spacing with it

本文介绍了涉及1，2-二氧环乙烷和荧光化合物 的组合物及应用该组合物检测DNA的方法。实际 上，将可触发的1，2-二氧环乙烷与表面活性剂及连 接在烷烃上的荧光化合物预混合。经酶促触发，得到 一胶束态共表面活性剂或经证实与这些分子密切相 关的其他分子。该组合物可用于为各种目的而采用 的免疫测定和DNA探针。

Improved methods of using chemiluminescent 1,2-dioxetanes.

On a mis au point des procédés dans lesquels de la lumière de différentes longueurs d'ondes est simultanément libérée à partir de deux composés de 1,2-dioxétanes chimioluminescents décomposables de manière enzymatique ou plus, lesdits composés étant configurés, grâce à l'inclusion dans chacun d'eux d'un fluorophore différent émetteur de lumière, de manière à ce qu'ils émettent chacun de la lumière de longueurs d'ondes différentes, chacun desdits composés étant décomposé par une enzyme différente. On peut utiliser de tels procédés dans des analyses à canaux multiples, des techniques immunologiques, des dosages chimiques et des analyses mettant en oeuvre des sondes d'acide nucléique, pour détecter la présence ou déterminer la concentration de substances chimiques ou biologiques, et dans des procédés mettant en oeuvre des sondes chimiques/physiques à canaux multiples permettant d'étudier les microstructures de macromolécules. Methods have been developed in which light of different wavelengths is released simultaneously from two or more enzymatically decomposable 1,2-dioxetane chemiluminescent compounds, said compounds being configured by inclusion in each of them a different light-emitting fluorophore, so that they each emit light of different wavelengths, each of said compounds being broken down by a different enzyme. Such methods can be used in multi-channel assays, immunoassays, chemical assays and assays employing nucleic acid probes, to detect the presence or determination of the concentration of chemical or biological substances, and in methods using multichannel chemical / physical probes for studying macromolecule microstructures.

Flash of light and aura 1,2-dioxetanes alkanes

本发明公开了具有化学发光的闪光和辉光性能的化合物。也公开了使用所述化合物产生光、检测和／或定量酶、抗原和／或核酸的方法。也公开了与这些化合物有关的试剂盒。

Chemiluminescent 1,2-dioxetanes

Chemiluminescent 1,2-dioxetanes derived from substituted aromatic esters or ketones and spiro-fused ketones with either π-electron system in the ring or with carbon-carbon double bond or triple bond(s) in the spiro-fused ring are provided herein. These 1,2-dioxetanes have electron donating or withdrawing groups at the four-membered peroxide ring, thus, the 1,2-dioxetanes ring hereof is affected by the added electronic charge.

Dioxetanes for use in assays

A dioxetane that includes a fluorescent chromophore spiro-bound at the 4-carbon of the dioxetane. The dioxetane has formula (I), where X is CR7R8, O, S, or N-R (where each R7, R8, and R, independently, is H, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, cycloheteroalkyl, aralkyl, alkaryl, or an enzyme cleavable group), and each R1, R2, R3, R4, R5, and R6, independently, is H, an electron-withdrawing group, an electron-donating group, heteroaryl, or an enzyme cleavable group, or groups R1-R6 together form a ring, and T is a substituted or unsubstituted aryl, polyaryl, cycloalkylidene or polycycloalkylidene group spiro-bound at the 3-carbon of the dioxetane. The dioxetane can be decomposed by direct cleavage of the dioxetane O-O bond or by cleavage of an enzyme cleavable group bonded to the dioxetane to form a luminescent substance that includes the coumarin portion of the dioxetane. The dioxetanes are used in an assay to detect a member of a specific binding pair or an enzyme.

Phosphonooxymethyl or methylthiomethyl ether of taxane derivatives as an anti-tumor agent

DIOXETANES FOR USE IN IMMUNITY TESTS.