33 results about "Olaparib" patented technology

This invention belongs to the field of antitumor drug technology, specifically relating to PARP inhibitor-quinoline carboxylic acid coupled derivative compounds, their preparation methods, and uses. This invention synthesizes a novel polyADP-ribose polymerase (PARP) inhibitor derivative, the structure of which includes: a first structural unit with the clinical PARP inhibitor olaparib as the core backbone, a linker arm L, and a quinoline carboxylic acid fragment R; wherein the structural types and substituents of the linker arm L and the quinoline carboxylic acid fragment R are adjustable. This invention also provides a method for preparing the compound, which is characterized by simple steps, strong versatility, and ease of structural expansion, suitable for constructing compound libraries with different combinations of linker arms and different quinoline carboxylic acid fragments. The compound can be used to prepare drugs or drug compositions for inhibiting tumor cell proliferation and treating tumor-related diseases, showing excellent application prospects.

Provided is a method for producing an olaparib precursor, said method comprising the step of performing the following steps (a) to (c) continuously without isolating a reaction intermediate. (a) Reacting dimethyl(3-oxo-1,3-dihydro-2-benzofuran-1-yl)phosphonate and 2-fluoro-5-formylbenzoic acid in DMF, acetonitrile, or THF and in the presence of diazabicycloundecene. (b) Reacting the reaction mixture obtained in the reaction of (a) with hydrazine. (c) Adjusting the reaction liquid obtained in the reaction of (b) to a pH of not more than 4, to obtain 2-fluoro-5-(4-oxo-3,4-dihydro-phthalazine-1-ylmethyl)-benzoic acid, which is an olaparib precursor.

The present invention relates to a composition for the treatment of castration resistant prostate cancer, the composition comprising (i) a first active ingredient comprising a CDK9 degrading agent; and (ii) a second active ingredient, wherein the second active ingredient comprises olaparib. The effects of inhibiting tumor cell proliferation and promoting cell apoptosis of the composition are obviously higher than those of a single drug under the same dosage.

This invention provides a method for preparing high-purity olaparib, belonging to the field of pharmaceutical synthesis technology. The method uses dimethyl (3-oxo-1,3-dihydroisobenzofuran-1-yl)phosphate as the starting material, reacting it with compound 2 via a Wittig reaction to generate compound 3. Compound 3 reacts with hydrazine hydrate to generate compound 4. Compound 4 is hydrolyzed and acidified to give compound 5. Compound 5 reacts with thionyl chloride to give compound 6. Compound 6 is then condensed with compounds 7 and 9 to obtain olaparib. This invention uses readily available raw materials, is simple to operate and process, has mild reaction conditions, achieves a total yield of up to 90%, a purity >99%, is environmentally friendly, and is suitable for industrial production.

The application discloses a solid dispersion of olaparib and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations. The solid dispersion of olaparib adopts polyvinyl alcohol or polyvinyl alcohol and a plasticizer or polyvinyl alcohol and copolymerized povidone or polyvinyl alcohol, copolymerized povidone and an anti-sticking agent as a matrix polymer carrier, can effectively protect the olaparib raw material, reduce the degradation, and improve the drug loading of the solid dispersion. The solid dispersion of olaparib has small hygroscopicity, reduces the requirement of the environment humidity during the storage of the intermediate product of the olaparib preparation, reduces the energy consumption during the preparation process, and significantly improves the stability and effectiveness of the preparation.

The invention discloses a PARP1 inhibitor with methyl-1 'H-spiro [piperidine-4, 2'-quinazoline]-4 '(3' H)-ketone as a mother nucleus and a preparation method and application of the PARP1 inhibitor, a main compound has good PARP1 inhibitory activity (IC50 is at a submicromole level), and compared with a PARP1 inhibitor olaparib on the market, the compound has better anti-myocardial hypertrophy activity, and can be used for preparing a medicine for treating myocardial hypertrophy. The potential of PARP1 as a target spot for treating cardiac hypertrophy is proved, and a potential therapeutic drug is provided for treating cardiac hypertrophy.

The application discloses an anticancer composition of combined medication, and application of the composition in preparation of an anticancer drug. The combined medication composition provided by the application comprises a PARP inhibitor, Olaparib, and a calcium ion antagonist, Amlodipine maleate, and the two components have a synergistic effect, have higher sensitivity to gastric cancer compared with a single PARP inhibitor, and significantly improve the effective rate, thereby having a wide application prospect. The Amlodipine in the combined medication composition provided by the application enhances the curative effect of the PARP inhibitor, Olaparib, on gastric cancer.

The present invention discloses a novel solid oral pharmaceutical composition of olaparib or pharmaceutically acceptable salts thereof in the solid oral dosage form preferably in the form of a tablet and its process for preparations thereof. The present invention further discloses a solid oral pharmaceutical composition of olaparib or its pharmaceutically acceptable salts thereof along with a hydrophilic matrix polymer.

The invention belongs to the technical field of biological medicine, and particularly relates to application of REXO4 interference polypeptide in tumor treatment. It is found for the first time that the REXO4 interference polypeptide can inhibit breast cancer tumor cell proliferation, promote chemotherapy drug-induced DNA damage and improve the breast cancer chemotherapy effect, in addition, through combination of the REXO4 interference polypeptide and Olaparib, the remarkable synergistic anti-tumor effect can be shown, and the effect is better than that of single medication. The invention also finds that the REXO4 interference polypeptide can reverse the drug resistance of breast cancer to chemotherapeutic drugs, and a brand new solution is provided for overcoming the drug resistance of PARP inhibitors.

The invention discloses a pharmaceutical composition for treating KRAS G12D mutation cancer and application of the pharmaceutical composition, and belongs to the technical field of biological medicine. The pharmaceutical composition comprises a KRAS G12D inhibitor and a PARP (poly-ADP-ribose polymerase) inhibitor. The core of the invention lies in that a KRAS G12D inhibitor (such as MRTX1133) can down-regulate expression of homologous recombination (HR) repair related proteins (such as BRCA1, RAD51 and RPA32) and induce HR defects, so that tumor cells carrying KRAS G12D mutation have high sensitivity to a PARP inhibitor (such as Olaparib), and a synthetic lethal effect is formed. The combined strategy not only shows synergistic anti-tumor activity in a model sensitive to the KRAS G12D inhibitor, but also is effective in a model resistant to the KRAS G12D inhibitor. The invention provides a new effective scheme for treating cancers such as pancreatic ductal adenocarcinoma with KRAS G12D mutation, and is expected to expand the applicable patient population of the PARP inhibitor.

This invention belongs to the field of biomedical technology and discloses the application of olaparib in combination with taquimod in the preparation of anti-tumor metastasis drugs. This invention is the first to discover that olaparib and taquimod, even at low concentrations (i.e., concentrations that do not affect tumor cell proliferation), can effectively inhibit the invasion and metastasis of breast cancer cells, exhibiting high safety. Furthermore, when olaparib and taquimod are used in combination, the inhibitory effect on breast cell invasion and metastasis shows a synergistic enhancement trend, with significantly better efficacy than single-drug therapy, overcoming the limitations of monotherapy. Moreover, the combination of olaparib and taquimod can effectively inhibit lung metastasis of breast cancer, providing a new theoretical basis and medication regimen for anti-metastasis treatment of breast cancer.

The application discloses a method for determining and analyzing the content of 2-fluoro-3-methoxyphenylboronic acid in olaparib sodium, which comprises the following steps: derivatizing the 2-fluoro-3-methoxyphenylboronic acid with N-methyliminodiacetic acid, determining the content of the 2-fluoro-3-methoxyphenylboronic acid derivative, and determining the content of the 2-fluoro-3-methoxyphenylboronic acid in the olaparib sodium. Compared with the prior art, the analysis method has the characteristics of good specificity, good reproducibility, extremely high sensitivity, and suitability for trace analysis.

The invention provides a nano preparation co-loaded with olaparib and a cell nucleus targeting photosensitizer as well as a preparation method and application of the nano preparation. The nano preparation is composed of a lipid bilayer membrane, wherein the lipid bilayer membrane is composed of DPPC (Diphenyl Phosphate Polycarbonate), DSPE-PEG2000, DSPE-PEG2000-RGD (Reduced Glutamic Acid), cholesterol, olaparib and a nuclear targeting photosensitizer. The nuclear targeting photosensitizer is obtained by covalent coupling of pyropheophorbide a and a cell nucleus targeting group. The preparation method comprises a film hydration-ultrasonic method. The nano preparation initiates a large amount of DNA damage, effectively induces immunogenic cell death and activates an STING pathway through a synergistic effect of a nuclear targeting photodynamic effect and DNA repair inhibition, so that an anti-tumor immune response is excited, and the nano preparation can be used for photodynamic therapy, photoimmunotherapy and sonodynamic therapy of tumors.

The invention relates to a pharmaceutical formulation comprising olaparib as active agent in solid dispersion with a matrix polymer. In particular, the present invention relates to a pharmaceutical formulation comprising olaparib in a solid dispersion with a matrix polymer that comprises polyvinylpyrrolidone, a daily pharmaceutical dose of olaparib provided by such a formulation and the use of polyvinylpyrrolidone in a solid dispersion composition with Olaparib for increasing the bioavailability and / or stability of Olaparib, and for treating cancer in a patient.

Provided herein are drug implants comprising Pamiparib, Olaparib, or Niraparib for the treatment of disease in a subject. In some cases, the drug implant may comprise a polymer matrix and Pamiparib, Olaparib, or Niraparib disposed therein. Additionally provided are methods for manufacturing the drug implants and methods of treating diseases with the implants. In some cases, the drug implant may be used for the treatment of a proliferative disease.

The application discloses a selective inhibitor for BRCA mutation and application thereof. Specifically, the application relates to a quinazolinone compound shown in a general formula (I) or a pharmaceutically acceptable salt or a solvate thereof, wherein the compound has better selectivity for BRCA mutation, has a good inhibition rate on the proliferation of BRCA mutant cells at a low concentration, and is superior to existing olaparib and AZD5305 and the like. Through a nude mouse tumorigenesis experiment, it is proved that the drug obviously shows an inhibitory effect on tumor growth at a low drug concentration, and has no obvious toxic side effects.

The invention discloses a metformin enhanced PARP inhibitor as well as a preparation method and application thereof, belongs to the technical field of biological medicines, and particularly relates to the metformin enhanced PARP inhibitor. The PARP inhibitor is prepared from metformin and olaparib; the molar ratio of the olaparib to the metformin is 1: (200-600). The energy metabolism states of different BRCA1 mutation subtype triple negative breast cancer cells are remodeled through metformin, the inhibition effect of olaparib on the cancer cells in a drug-resistant environment is remarkably enhanced, cell apoptosis is effectively promoted, cell migration is inhibited, and therefore the synergistic improvement of the curative effect of a PARP inhibitor is achieved.

The application discloses a method for determining the concentration of sofosbuvir in blood plasma and screening a non-isotope labeled internal standard, wherein anlotinib, imatinib, olaparib, osimertinib and pralsetinib are used as internal standards, quantitative analysis is performed by combining LC-MS / MS with protein precipitation pretreatment. The internal standard screening method is screened from candidate compounds by systematically evaluating four dimensions of protein precipitation compatibility, matrix effect, detection stability and extraction recovery, and an internal standard consistent with the behavior of the measured substance is screened. The application solves the problem of the lack of commercial isotope internal standards for sofosbuvir, and provides a reliable and efficient detection and internal standard screening scheme.

This invention relates to the treatment of breast cancer in a subject, and the subject can be either a male or female subject. Including methods of: treating metastatic breast cancer; refractory breast cancer; AR-positive breast cancer; AR-positive refractory breast cancer; AR-positive metastatic breast cancer; AR-positive and ER-positive breast cancer; triple negative breast cancer; advanced breast cancer; breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4 / 6 (CDK 4 / 6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), lerociclib, abemaciclib (Vorzenio), trilaciclib, lerociclib), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), alpelisib (Piqray) (an inhibitor of phosphatidylinositol-3-kinase subunit alpha (PI3Kα)), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose polymerase (PARP)), bevacizumab (Avastin), and / or fulvestrant treatments; metastasis in a subject suffering from breast cancer; HER2-positive; treating a subject suffering from ER mutant expressing breast cancer and / or treating breast cancer in a subject, by first determining the 18F-16β-fluoro-5α-dihydrotestosterone (18F-DHT) tumor uptake and identifying said subject as having AR-positive breast cancer based on 18F-DHT tumor uptake, comprising administering to the subject a therapeutically effective amount of a selective androgen receptor modulator (SARM) compound and a cyclin-dependent kinase 4 / 6 (CDK 4 / 6) inhibitor.

This invention discloses a method for preparing olaparib-copper nanocomplexes. Hydrated copper chloride and olaparib are dissolved separately in DMF, then mixed, and the pH is adjusted to 8-9 with sodium ethoxide. Finally, trimethylamine is added to react and generate the olaparib-copper nanocomplexes. The application of the prepared olaparib-copper nanocomplexes in the preparation of drugs for treating breast cancer is also disclosed. The olaparib-copper nanocomplexes synthesized in this invention exhibit targeting and chemokinetic effects, controllable size, low effective dose, and effectively induce the killing of breast cancer cells, making them suitable for tumor treatment. This material demonstrates strong advantages in tumor-targeted drug delivery and therapy, providing an effective development pathway for the development and design of multifunctional biomaterials.

The application discloses a method for preparing olaparib from sulfur hexafluoride, which takes 1-cyclopropylformylpiperazine and 2-fluoro-5-((4-oxo-3,4-dihydrophthalazine-1-yl)methyl)benzoic acid as raw materials, and performs a photo-illumination reaction in an organic solvent under the conditions of a photocatalyst, an alkali, sulfur hexafluoride and light illumination to obtain the olaparib. The method has the characteristics of mild reaction conditions, cheap and easily available reaction raw materials, cost saving, environmental friendliness and industrial promotion. The method effectively activates and utilizes the greenhouse gas SF6, fully utilizes the decomposition products of SF6 to realize the amidation reaction of the carboxylic acid to prepare the olaparib, changes the SF6 from waste to treasure, the required raw materials are simple and easily available, the reaction conditions are simple, green and energy-saving, and the method has high application value.

The invention discloses application of a USP14 inhibitor in treatment of drug-resistant ovarian cancer, and belongs to the technical field of biological medicine. The invention finds that the high-expression USP14 can improve the drug resistance of ovarian cancer to olaparib, the USP14 inhibitor can reduce the drug resistance of ovarian cancer to olaparib and enhance the treatment effect of olaparib, and the USP14 inhibitor and olaparib have a remarkable synergistic effect in combined treatment of ovarian cancer, so that the research on the drug resistance mechanism and drug combination of ovarian cancer is promoted, and the application prospect is broad. And a new strategy is provided for treatment of the drug-resistant ovarian cancer.

This invention discloses a metformin-enhanced PARP inhibitor, its preparation method, and its application, belonging to the field of biomedical technology. Specifically, it relates to a metformin-enhanced PARP inhibitor comprising metformin and olaparib, with a molar ratio of olaparib to metformin of 1:200-600. This invention reshapes the energy metabolism state of different BRCA1-mutant subtypes of triple-negative breast cancer cells through metformin, significantly enhancing the inhibitory effect of olaparib on these cancer cells under drug-resistant conditions, and effectively promoting apoptosis and inhibiting cell migration, thereby achieving a synergistic enhancement of the efficacy of PARP inhibitors.

The application belongs to the technical field of antitumor drugs, and particularly relates to a PARP inhibitor-quinoline carboxylic acid coupled derivative compound and a preparation method and application thereof. A novel poly-ADP-ribose polymerase (PARP) inhibitor derivative is synthesized, the structure of the derivative comprises a first structural unit of a clinical PARP inhibitor olaparib as a core skeleton, a connecting arm L and a quinoline carboxylic acid segment R; wherein the structural type and the substituent group of the connecting arm L and the quinoline carboxylic acid segment R can be adjusted. The application also provides a preparation method of the compound, the method has the characteristics of simple steps, strong universality and convenience for structure expansion, and is suitable for constructing a compound library combined with different connecting arms and different quinoline carboxylic acid segments. The compound can be used for preparing a drug or a pharmaceutical composition, for inhibiting tumor cell proliferation and treating tumor-related diseases, and has a good application prospect.

The invention belongs to the technical field of biomedicine and tumor treatment, and particularly relates to application of a lutetium-containing self-assembled nanoparticle combined with olaparib in breast cancer treatment. The preparation method of the lutetium-containing self-assembled nanoparticles comprises the following steps: carrying out a coordination reaction on lutetium ions Lu < 3 + > and carboxyl and phenolic hydroxyl groups of sodium salicylate NaSal to form a Lu-Sal complex, carrying out ultrasonic-assisted assembly on the Lu-Sal complex through polyvinylpyrrolidone (PVP) to form nanoparticles LSP, and modifying the nanoparticles LSPA through albumin SA to obtain the nanoparticles LSPA. The LSPA depends on the high Z characteristic of the Lu element, the radiosensitization function is maintained, and meanwhile high-contrast CT imaging is achieved. The CT value is linearly related to the concentration of Lu < 3 + >, so that the tumor tissue position and the drug distribution condition can be clearly displayed, and imaging support is provided for radiotherapy dose planning, effect evaluation and personalized treatment.

The invention belongs to the technical field of biomedical detection, and provides a prostatic cancer olaparione response marker determination system and a determination method and application thereof. A multifunctional polymer brush is grafted on the surface of a core-shell magnetic polymer microsphere, an HRR gene oligonucleotide probe is coupled through carbodiimide-mediated amidation reaction, and efficient enrichment and accurate quantitative detection of ultralow-abundance mutant alleles are achieved by combining a digital PCR technology. The use amount of the magnetic oligonucleotide probe in a single 20L reaction system is 0.5-200g, and the positive detection rate of HRR gene mutation sites with allele frequency of 0.10%-0.50% is not less than 95%. The problems that in the prior art, low-abundance target capturing efficiency is low, non-specific adsorption is high, and digital PCR quantitative accuracy is poor are solved, a high-sensitivity and high-specificity molecular diagnosis tool is provided for olapara utilization drug decision-making of castration-resistant metastatic prostate cancer patients, and wide clinical application value is achieved.

A process for the preparation of Olaparib of formula (9):includes the step of hydrolysis of intermediate of formula (11):with a strong acid to give compound of formula (5):which is then converted to Olaparib of formula (9).

Provided are a fused tricyclic compound as shown in formula (I), a pharmaceutical composition and use thereof. The compound has high selectivity to PARP1, has fewer side effects than oaparib, has high clinical application value, and can be used for preparing medicines for preventing and / or treating diseases, especially diseases improved by inhibiting PARP1.

The object of the present invention is to provide an improved process for the preparation of olaparib of formula (9) comprising the steps of hydrolyzing an intermediate of formula (11) with a strong acid to obtain a compound of formula (5) and then converting it into olaparib of formula (9).