34 results about "2-nitroimidazole" patented technology

The invention provides an anoxia-responsive nano drug carrier and a preparation method and application thereof. The nano drug comprises a hydrophobic seed core and an amphiphilic shell, wherein the hydrophobic seed core comprises chlorin e 6 and tirazamine, and the amphiphilic shell is hydrophilic macromolecular hyaluronic acid modified by hydrophobic molecule 2-nitroimidazole, the hydrophobic seed core and the amphiphilic shell form a non-conjugated position relationship by hydrophilic and hydrophobic forces. According to the preparation method, the nano drug is finally successfully preparedby optimizing the preparation process, the particle size of the product is moderate and controllable, the nano drug is irradiated by laser for photodynamic treatment, oxygen is consumed, and hydrophobic molecules 2-nitroimidazole is transformed into hydrophilic molecules 2-aminoimidazole under the anoxic condition, and the nano drug is dissolved, the drug release is achieved, the chemotherapy toxicity of the chemotherapeutic drug tirazamine is activated under the anoxic condition, the combined treatment is synergistic, cancer cells are effectively killed, the application prospect is wide and the market value is huge.

The invention features a class of 2-nitroimidazole compounds with a secondary basic nitrogen atom and a linker bearing one or more therapeutic agents, cytotoxic agents, detectable labels, or chelating groups. In particular, the invention provides 2-nitroimidazole compounds containing a cluster of boron atoms for use in boron neutron capture therapy (BNCT). The 2-nitroimidazole compounds can be used to treat hypoxic conditions, including, e.g., cancer, inflammation, and ischemia. The weakly basic 2-nitroimidazole compounds target to hypoxic tissue and provide increased tissue concentration overall.

The invention features a class of 2-nitroimidazole compounds with a secondary basic nitrogen atom and a linker bearing one or more therapeutic agents, cytotoxic agents, detectable labels, or chelating groups. In particular, the invention provides 2-nitroimidazole compounds containing a cluster of boron atoms for use in boron neutron capture therapy (BNCT). The 2-nitroimidazole compounds can be used to treat hypoxic conditions, including, e.g., cancer, inflammation, and ischemia. The weakly basic 2-nitroimidazole compounds target to hypoxic tissue and provide increased tissue concentration overall.

The present invention relates to novel radioactively labeled bioreducible tracers of Formula I useful for detecting hypoxic tumors or ischemic tissue in vivo. In one embodiment, the tracers consist of a 2-nitroimidazole moiety, a triazole, metabolically stable linker with pharmacokinetics enhancing substituents, and a radioisotope. The preferred in vivo imaging modality is positron emission tomography.

The invention discloses a hypoxia-activated prodrug based on 2-nitroimidazole-1-alkanol. The 2-nitroimidazole-1-alkanol of the prodrug is connected to an antineoplastic drug through a carbonate bond. The prodrug has a structure shown in the formula I and in the formula, n represents 0, 1, 2 or 3, and R1, R2, R3 and R4 include but not limited to hydrogen, hydroxyl, chlorine, bromine, fluorine, C1-C6 alkyl, C1-C6 alkyl containing alkenyl and C1-C6 alkyl containing alkynyl. The prodrug can target the hypoxia region of the tumor and is reduced by the high expressed specific enzyme in the hypoxic tumor tissue so that the original drug is released. The prodrug is stable in vitro and in vivo, and the released drug can be specifically reduced in hypoxic tumor tissue so that the targeting of the anti-tumor drug is improved, toxic or side effects are reduced and the curative effect is improved.

The present invention incorporates weakly basic substituents (pKa about 8 or greater) such as pyrrolidine, piperidine, piperazine and azapane moieties in halogenated 2-nitromidazoles as a major improvement over prior art for the non-invasive detection of cellular hypoxia in normal and malignant tissues. The invention features the use of [18F] positron emission tomography, [19F] magnetic resonance spectroscopy, and [19F] magnetic resonance imaging. Improvements over prior art compounds are six-fold. 1) Salts of weakly basic reagents are highly water-soluble which facilitates administration. 2) Unreacted reagents are rapidly cleared from systemic circulation thereby decreasing background noise. 3) Reagents with weakly basic substituents are concentrated in tissue ˜3 fold above plasma levels thereby increasing binding intensity and enhancing signal detection. 4) Conjugate bases of weakly basic reagents have intermediate octanol-water partition coefficients that facilitate their penetration into all tissues including brain. 5) Cellular adducts of reagents containing weakly basic substituents are more stable than reagents of prior art. 6) Reagents with weakly basic substituents are effective for the detection of transient hypoxia in solid tissue.

The invention provides a radiation sensitizer used for brain tumor, which is a radiation sensitizer in the radiation treatment of brain tumor and used for improving the radiation treatment effect in the radiation treatment of the brain tumor. Particularly, the invention provides a radiation sensitizer which takes 1-[2,3-dihydroxy-1-(hydroxy-methyl) propoxy]methyl-2-nitroimidazole shown in a formula (I) as an active component in the radiation treatment of the brain tumor.

The invention relates to a novel F-triazole ring-PEG-2-nitroimidazole compound and a preparation method thereof, and the structural general formula of the compound is shown on the right. A triazole ring, a PEG group, 2-nitroimidazole and a <18 / 19>F nuclide are connected by using nitroimidazole as a targeting group by a click method, and are designed to synthesize a series of novel F-triazole ring-polyethyleneglycol-2-nitroimidazole derivatives, and the nitroimidazole derivative is used as a novel compound capable of improving the metabolic property of medicaments and is used for PET anaerobic visualization studies.

The invention provides an application of a photoacoustic probe in preparation of an NTR photoacoustic detection reagent. The provided photoacoustic probe adopts 2-(2-nitroimidazole)ethylamine as a specific response group, and is weak in signal; when a nitro group is reduced to an amino group, the photoacoustic signal is greatly enhanced, so that NTR detection can be realized successfully, and thephotoacoustic probe is a first probe compound that can realize NTR photoacoustic detection; meanwhile, the photoacoustic probe is not be disturbed by common reducing substances Vc, GSH and Cys in a biological body; under physiological conditions, pH fluctuation does not affect the photoacoustic detection performance of the IR1048 MZ; furthermore, an excitation wave of the photoacoustic probe is ina near infrared region, so that bio-imaging can be realized more favorably, background influence of a biological body to be detected is smaller, and tissue penetration depth is deeper; since the probe is positively charged, the probe can quickly complete trans-membrane movement under the action of the negative charge of a cell membrane; and meanwhile, the probe is low in toxicity and good in biological compatibility, and can be used for imaging analysis of NTR in vivo.

The invention discloses a technetium carbonyl marked 2-nitroimidazole complex as well as a preparation method and application thereof, wherein the technetium carbonyl marked 2-nitroimidazole complex is a radionuclide-marked compound. The preparation method of the technetium carbonyl marked 2-nitroimidazole complex comprises the following steps of: firstly synthesizing ligands of NNN-PEGn-NIM or NNO-PEGn-NIM or NOO-PEGn-NIM, and then respectively heating each ligand and freshly prepared [<99m>Tc (CO) 3 (H2O) 3]<+> intermediate in boiling water bath and making the ligand and the freshly prepared [<99m>Tc (CO) 3 (H2O) 3]<+> intermediate react to obtain the corresponding technetium carbonyl marked 2-nitroimidazole complex. The technetium carbonyl marked 2-nitroimidazole complex is condensed in hypoxic tumor cells through the target action of nitroimidazole and can be used for SPECT (Single Photon Emission Computed Tomography) development diagnosis of the hypoxic tumor cells.

A photosensitive nano-liposome targeting triple-negative breast cancer stem cells is disclosed. The active component of the liposome is a 2-nitroimidazole type prodrug. The liposome includes the active component, lecithin, cholesterol, a target molecule and a photosensitizer, wherein the lecithin and the cholesterol form a nanosphere, the active component and the photosensitizer are covered withinthe nanosphere, and the target molecule is connected to the outside of the nanosphere. The photosensitive nano-liposome has advantages including a uniform particle size, a high encapsulation efficiency and high stability, has a specific targeting treatment function, improves the capability of a medicine to enter cells, and allows the medicine to specifically gather at a tumor position to kill tumor without toxic or side effects on normal tissue. The photosensitive nano-liposome can utilize complementary treatment combining a photodynamic therapy and a hypoxic activation and chemotherapeutic activation, and provides reliable experiment research data and theoretical basis for clinical application and research.

The invention discloses a 99mTc (HYNICNM) (tricine / TPPTS) complex and a preparation method and application thereof. The 99mTc (HYNICNM) (tricine / TPPTS) complex is obtained through two steps of synthesis of a ligand HYNICNM and preparation of a 99mTc (HYNICNM) (tricine / TPPTS) complex. The complex is simple and convenient to prepare and has oxygen deficiency selectivity. Tumor-bearing mice have highuptake and good retention in tumor parts, the tumor / non-target ratio is high, the uptake of non-target organs such as the liver and intestines is obviously reduced, and the 99mTc (HYNICNM) (tricine / TPPTS) complex is a novel tumor hypoxia imaging agent with excellent performance.

To provide a pharmaceutical composition containing a 2-nitroimidazole derivative, which has high solubility in an aqueous carrier and high stability.The pharmaceutical composition is characterized by containing 1-(1-hydroxymethyl-2,3-dihydroxypropyl)oxymethyl-2-nitroimidazole and creatinine, and containing creatinine of 0.001 to 1 part by mass with respect to 1 part by mass of 1-(1-hydroxymethyl-2,3-dihydroxypropyl)oxymethyl-2-nitroimidazole.

The invention discloses a method for preparing 2-nitroimidazole, which comprises the following steps of: adding 40% of fluoboric acid and water in 2-amino-imidazole sulfate; dropwise adding a sodium nitrite aqueous solution at -30-3 DEG C while stirring to obtain a diazonium salt; pouring the diazonium salt into a copper salt aqueous solution or a mixed catalyst aqueous solution of the copper salt which is -5-10 DEG C while stirring; adding sodium nitrite and stirring for 2-9 hours at room temperature and then adjusting the pH value to be 2; extracting continuously by using an extractor, concentrating an extract and standing to separate out a rough product; and recentralizing the rough product, wherein mother liquid can be added in an extraction kettle for recycling. The invention has the advantages of reducing the volume of reaction liquid, lowering the consumption of the extract during recycling the extract, improving the yield and facilitating the industrialized production.

To provide a pharmaceutical composition which can enhance the storage stability of 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole without impairing the effect of the compound.The pharmaceutical composition includes 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole, which is represented by formula (1):and a compound having chelating ability.

The invention discloses a branched-chain 2-nitroimidazole compound and application thereof in a dosing system. The branched-chain 2-nitroimidazole compound is of the structure of formula I as shown in the specification, in the formula, R1 and R2 are H or CH3; X comprises but is limited to the following structures: -OH, -COOH, -CONH2, -C identically equal to CH, -CH2OH, -CH2COOH, -CH2CONH2, -CH2C identically equal to CH, -CH2OCH2C identically equal to CH, C1-C6 alkyl, C1-C6 alkyl with alkenyl, and C1-C6 alkyl with alkynyl. The medicine can target a tumor hypoxia area and is reduced by highly expressed specific enzymes in hypoxia tumor tissue, and thus active compounds can be released. The compound disclosed by the invention can be connected with a ligand, is applied to research on dosing systems and is capable of improving dissolubility of medicines, improving targeting properties, reducing toxic or side effects and improving anti-tumor treatment effects.

The invention relates to a PET tracer agent precursor-2-nitroimidazole compound and a preparation method thereof.The chemical name of the precursor is 2-[4-(carboxymethyl)-7-[2-(2-(2-nitro-1H-imidazole-1-yl)acetylamino)ethyl]-1,4,7-triazacyclononane-1-yl]acetic acid, and the structural formula of the precursor is shown as a formula (I) (please see the formula in the description).The PET tracer agent precursor solves the technical problems that an existing hypoxic imaging agent is complex in labeling operation and low in labeling rate, overcomes the high lipophilicity application defect and is particularly suitable for diagnosis, treatment, treatment effect monitoring and the like of hypoxic tumors.

The invention discloses a branched 2-nitroimidazole compound and application thereof in hypoxic selective antitumor prodrugs. The branched 2-nitroimidazole compound has a structure represented by formula I, wherein R1 and R2 include but are not limited to the following structures: hydrogen and methyl. The branched 2-nitroimidazole compound can be targeted to a hypoxic region of tumor, and is reduced by specific enzymes that are highly expressed in hypoxic tumor tissues to release active drugs. The branched 2-nitroimidazole compound can be connected with ligands and anti-tumor drugs, is appliedto the hypoxic selective antitumor prodrugs, improves the solubility of the drugs, improves the targeting, reduces toxic and side effects, and enhances anti-tumor efficacy.

It is an object to provide a method for producing a 2-nitroimidazole derivative having an acyclic sugar chain in a side chain, which is suitable for production of a derivative having a radioisotope.A method for producing 1-(1-benzoyloxymethyl-2-hydroxyethyl)oxymethyl-2-nitroimidazole, characterized by reacting glycerin with a benzoylating agent to obtain 1-O-benzoylglycerin, reacting 1-O-benzoylglycerin with dimethoxymethane in the presence of a dehydrating agent to obtain 4-benzoyloxymethyl-1,3-dioxolane, and then reacting this product with 2-nitroimidazole or 2-nitro-1-trialkylsilylimidazole in the presence of a Lewis acid.

Provided in the following specification are precursors or synthons that are useful for the synthesis of various arabinose based chemical and radiochemical derivatives of nitroimidazole-containing azomycin arabinosides, such as radioiodinated 1-#-D-(5-deoxy-5-[I*]-iodoarabinofuranosyl)-2-nitroimidazole (*IAZA), and radiofluorinated 1-#-D-(5-deoxy-5-[18F]-iodoarabinofuranosyl)-2-nitroimidazole (18FAZA). Such compounds are useful in imaging, therapy, or radiotherapy. Further, various syntheses of said precursors / synthons and the incorporation of said precursors / synthons into kits is provided. The precursors / synthons provided herein allow for an improved and facile manufacturing process for nitroimidazole-containing azomycin arabinosides.

The invention provides a radiation sensitizer used for brain tumor, which is a radiation sensitizer in the radiation treatment of brain tumor and used for improving the radiation treatment effect in the radiation treatment of the brain tumor. Particularly, the invention provides a radiation sensitizer which takes 1-[2,3-dihydroxy-1-(hydroxy-methyl) propoxy]methyl-2-nitroimidazole shown in a formula (I) as an active component in the radiation treatment of the brain tumor.

Provided in the following specification are precursors or synthons that are useful for the synthesis of various arabinose based chemical and radiochemical derivatives of nitroimidazole-containing azomycin arabinosides, such as radioiodinated 1-#-D-(5-deoxy-5-[I*]-iodoarabinofuranosyl)-2-nitroimidazole (*IAZA), and radiofluorinated 1-#-D-(5-deoxy-5-[18F]-iodoarabinofuranosyl)-2-nitroimidazole (18FAZA). Such compounds are useful in imaging, therapy, or radiotherapy. Further, various syntheses of said precursors / synthons and the incorporation of said precursors / synthons into kits is provided. The precursors / synthons provided herein allow for an improved and facile manufacturing process for nitroimidazole-containing azomycin arabinosides.

It is an object to provide a method for producing a 2-nitroimidazole derivative having an acyclic sugar chain in a side chain, which is suitable for production of a derivative having a radioisotope.A method for producing 1-(1-benzoyloxymethyl-2-hydroxyethyl)oxymethyl-2-nitroimidazole, characterized by reacting glycerin with a benzoylating agent to obtain 1-O-benzoylglycerin, reacting 1-O-benzoylglycerin with dimethoxymethane in the presence of a dehydrating agent to obtain 4-benzoyloxymethyl-1,3-dioxolane, and then reacting this product with 2-nitroimidazole or 2-nitro-1-trialkylsilylimidazole in the presence of a Lewis acid.

A contrast agent precursor is revealed. The contrast agent precursor includes a 1,4,7-Tris(carbonylmethyl)-1,4,7,10-tetraazacyclododecane that forms complexes with radioisotopes or connects to a peptide. The contrast agent precursor also includes a 2-nitroimidazole that allows the precursor to become retained in hypoxic tissues According to the features mentioned above, the contrast agent prepared by the precursor has a better binding specificity, labeling accuracy and detection sensitivity. Moreover, a method for preparing the contrast agent precursor not only solves the emulsion problem generated during conventional synthesis of intermediate products but also provides a solution to the problem of residual trifluoroacetic acid. Both the yield rate and the purity of the final product are also improved.

The present invention relates to novel radioactively labeled bioreducible tracers of Formula I useful for detecting hypoxic tumors or ischemic tissue in vivo. In one embodiment, the tracers consist of a 2-nitroimidazole moiety, a triazole, metabolically stable linker with pharmacokinetics enhancing substituents, and a radioisotope. The preferred in vivo imaging modality is positron emission tomography.

The present invention relates to a 2-nitroimidazole derivative, a diagnostic pharmaceutical composition which contains such 2-nitroimidazole derivative, the use of the 2-nitroimidazole derivative for the detection of hypoxic biological tissue as well a method for the detection of hypoxic biological tissue by the use of the 2-nitroimidazole derivative.

To provide a pharmaceutical composition which can enhance the storage stability of 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole without impairing the effect of the compound.The pharmaceutical composition includes 1-(1-hydroxymethyl-2,3-dihydroxypropyloxymethyl)-2-nitroimidazole, which is represented by formula (1):and a compound having chelating ability.