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WO2020093272A1 - Composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis du récepteur parp, préparation et utilisation associées - Google Patents

Composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis du récepteur parp, préparation et utilisation associées Download PDF

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Publication number
WO2020093272A1
WO2020093272A1 PCT/CN2018/114371 CN2018114371W WO2020093272A1 WO 2020093272 A1 WO2020093272 A1 WO 2020093272A1 CN 2018114371 W CN2018114371 W CN 2018114371W WO 2020093272 A1 WO2020093272 A1 WO 2020093272A1
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membered
group
substituted
unsubstituted
parp
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PCT/CN2018/114371
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English (en)
Chinese (zh)
Inventor
杨光
许红涛
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ShanghaiTech University
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ShanghaiTech University
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Priority to PCT/CN2018/114371 priority Critical patent/WO2020093272A1/fr
Priority to CN201880099237.6A priority patent/CN112969689A/zh
Publication of WO2020093272A1 publication Critical patent/WO2020093272A1/fr
Anticipated expiration legal-status Critical
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/32—Phthalazines with oxygen atoms directly attached to carbon atoms of the nitrogen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the present invention relates to the field of organic chemistry, in particular to a sulfonyl fluoride-containing compound with high affinity for PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • Positron Emission Computed Tomography is a medically advanced clinical examination imaging technology.
  • the general method is to inject a radionuclide (such as 18 F, 11 C, etc.) on a certain substance and inject it. After the human body, by detecting the accumulation of the substance in the target tissue to reflect the status of life metabolic activities, so as to achieve the purpose of diagnosis.
  • a radionuclide such as 18 F, 11 C, etc.
  • PET may be the only new imaging technology that can display biomolecule metabolism, receptors and neural mediator activity on the living body, so how to further promote the application of PET is a hot topic in this field.
  • the object of the present invention is to provide a sulfonyl fluoride-containing compound with high affinity for PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof , Used to solve the problems in the prior art.
  • one aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug, or solvate thereof.
  • the structural formula of the compound is shown in Formula I:
  • R1 is selected from groups having affinity for PARP receptors
  • R2 is selected from substituted or unsubstituted, branched or unbranched C2-C10 terminal alkenyl, substituted or unsubstituted C6-C20 phenolic hydroxyaryl, substituted or unsubstituted C2-C20 phenolic hydroxyheteroaryl, Substituted or unsubstituted, branched or unbranched C6 ⁇ C20 (phenol hydroxyaryl) alkyl, substituted or unsubstituted, branched or unbranched C2 ⁇ C20 (phenol hydroxyheteroaryl) alkyl ;
  • the -SO 2 F group is -SO 2 18 F and / or -SO 2 19 F.
  • Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a PARP receptor inhibitor.
  • the PARP receptor is preferably selected from PARP-1 Receptor, PARP-2 receptor.
  • Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of an imaging agent, preferably the imaging agent uses PARP as a biomarker
  • the developer is preferably a positron tomographic developer.
  • Another aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a medicament for diagnosis, prevention or treatment of diseases associated with PARP enzymes, preferably
  • the PARP enzyme-related diseases include cancer, ischemic diseases and neurodegenerative diseases.
  • compositions comprising the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • FIG 1 shows the thermal standard spectrum of compound P4
  • FIG. 1 shows the UV spectrum of compound P4
  • FIG. 3 shows the trace of [ 18 F] P4 on MCF-7 transplanted tumor in nude mice
  • Figure 4a shows the uptake curve of [ 18 F] P4 in tumor tissue and muscle tissue in MCF-7 transplanted nude mice
  • Figure 4b shows the uptake curve of tumor tissues and muscle tissues in the pre-injection of Oliparib in MCF-7 transplanted nude mice to saturate the PARP-1 receptor on the tumor surface, and then [ 18 F] P4 injection after 30 minutes;
  • Figure 4c shows PARP-1 immunohistochemical staining of tumor tissue
  • Figure 4d shows PARP-1 immunohistochemical staining of the muscle tissue opposite to the tumor.
  • the inventors of the present invention have provided a compound against PARP receptor or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, the compound having a high affinity for PARP receptor, while It is also possible to exchange 19 F in the compound into the radioisotope 18 F by the method of 19 F- 18 F isotope exchange.
  • the obtained 18 F-labeled compound can be used as a positron emission computed tomography (PET) developer, or As a small molecule of PARP inhibitor, it is a new type of PARP inhibitor that integrates treatment and diagnosis. Based on this, the present invention has been completed
  • the first aspect of the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the structural formula of the compound is shown in Formula I:
  • R1 is selected from groups having affinity for PARP receptors
  • R2 is selected from substituted or unsubstituted, branched or unbranched C2-C10, C2-C6, C2-C3 terminal alkenyl, substituted or unsubstituted C6-C20, C6-C12, C6-C8 phenolic hydroxy aromatic Group, substituted or unsubstituted C2-C20, C2-C12, C2-C8, C2-C6 phenolic hydroxyheteroaryl, substituted or unsubstituted, branched or unbranched C6-C20, C6-C12, C6 ⁇ C8 (phenol hydroxyaryl) alkyl, substituted or unsubstituted, branched or unbranched C2-C20, C2-C12, C2-C8, C2-C6 (phenol-hydroxyheteroaryl) alkyl;
  • the -SO 2 F group is -SO 2 18 F and / or -SO 2 19 F.
  • R1 generally has good affinity for PARP receptors, for example, it may include various groups formed by PARP inhibitors, tracers, etc. that have good affinity for PARP receptors, and these groups usually have an affinity for Said has a key role.
  • R1 may be selected from the groups shown in Formula II:
  • X, Y, Z form a benzo five-membered aromatic heterocycle, and the hetero atom is selected from N, O or S;
  • X may be selected from O, S, N, NR ', C
  • Y may be selected from C, N
  • Z may be selected from O, S, N, NR ", C;
  • R, R ', R " may be independently selected from H, substituted or unsubstituted, branched or unbranched C1-C20, C1-C12, C1-C6, C1-C3 alkyl, wherein The substituent of the group may be selected from hydroxyl, cyano, carbonyl, carboxyl, amide, sulfonyl, halogen atom (fluorine, chlorine, bromine or iodine), etc .;
  • R' When X is NR ', R' may be bridged with R to form a benzoheterocycloalkyl, the heterocycloalkyl may be six-membered, seven-membered, eight-membered, nine-membered, ten-membered, the hetero
  • the hetero atom of the cycloalkyl group is selected from N, O, S, P and the like.
  • the benzo five-membered aromatic heterocyclic ring formed by X, Y, and Z may be specifically selected from benzimidazole, benzopyrazole, benzothiazole, benzoxazole, benzopyrrole (indole), benzene And furan.
  • the R1 may be selected from the following groups:
  • R1 may also be a group shown below:
  • the terminal alkenyl group when R2 is selected from a terminal alkenyl group, the terminal of the terminal alkenyl group is connected to -SO 2 F through a covalent bond, the terminal alkenyl group may be mono- or poly-substituted, and the substitution of the terminal alkenyl group
  • the groups may be independently selected from alkyl groups, alkynyl groups, aryl groups, carbonyl groups, amide groups, sulfonyl groups, halogen atoms (for example, fluorine, chlorine, bromine or iodine), etc .;
  • R2 is selected from a phenolic hydroxyaryl group
  • the phenolic hydroxyl group on the phenolic hydroxyaryl group forms a covalent bond with -SO 2 F
  • the phenolic hydroxyaryl group may be five-membered, six-membered, seven-membered, five-membered and six-membered , Six-membered and six-membered
  • the phenolic hydroxyaryl group may be mono-substituted or multi-substituted
  • the substituents of the phenolic hydroxyaryl group may be independently selected from halogen atoms, the substituents are selected from halogen atom substitutions or
  • the unsubstituted C1-C3 alkyl group and the substituent are selected from halogen atom-substituted or unsubstituted C1-C3 alkoxy groups, which may specifically be, for example, methyl, difluoromethyl, trifluoromethyl, methoxy, tri
  • R2 is selected from a phenolic hydroxyheteroaryl group
  • the phenolic hydroxyl group on the phenolic hydroxyheteroaryl group forms a covalent bond with -SO 2 F
  • the phenolic hydroxyheteroaryl group may be five-membered, six-membered, seven-membered, five-membered and Six-membered, six-membered and six-membered
  • the phenolic hydroxyheteroaryl group may be mono- or polysubstituted
  • the substituents of the phenolic hydroxyheteroaryl group may be independently selected from halogen atoms, and the substituent is selected from halogen Atom-substituted or unsubstituted C1-C3 alkyl groups
  • the substituents are selected from halogen atom-substituted or unsubstituted C1-C3 alkoxy groups, and may specifically be, for example, methyl, difluoromethyl, tri
  • R2 is selected from (phenol hydroxyaryl) alkyl group
  • the phenolic hydroxyl group on the phenolic hydroxy group forms a covalent bond with -SO 2 F
  • the (phenol hydroxyaryl) alkyl group may be five-membered, six-membered, Seven-membered, five-membered and six-membered, six-membered and six-membered
  • the (phenolic hydroxyaryl) alkyl group may be mono-substituted or multi-substituted
  • the substituents may be independently selected from halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkyl groups of halogen atoms, the substituents are selected from substituted or unsubstituted C1-C3 alkoxy groups of halogen atoms, alkyl groups
  • the substituents on can be independently selected
  • R2 is selected from (phenol hydroxyheteroaryl) alkyl
  • the phenolic hydroxyl group on the phenol hydroxyheteroaryl group forms a covalent bond with -SO 2 F
  • the (phenol hydroxyheteroaryl) alkyl group may be a five-membered, Six-membered, seven-membered, five-membered and six-membered, six-membered and six-membered
  • the (phenolic hydroxyheteroaryl) alkyl group may be mono- or polysubstituted
  • the (phenolic hydroxyheteroaryl) alkyl group may be independently selected from halogen atoms
  • the substituents are selected from halogen atoms substituted or unsubstituted C1-C3 alkyl groups
  • the substituents are selected from halogen atoms substituted or unsubstituted C1-C3 alkyl groups
  • the substituents on the oxy may be independently selected from
  • the terminal alkenyl group may be a terminal vinyl group, a terminal propenyl group, a terminal butenyl group, a terminal pentenyl group, and the like.
  • the phenolic hydroxy group generally refers to a ring system having at least one aromatic ring and containing a phenolic hydroxyl group, but without a heteroatom, the aryl group may be phenyl, naphthyl, or the like.
  • the phenolic hydroxyheteroaryl group generally refers to having at least one aromatic ring, and may optionally contain one or more selected from N, O, and S as heteroatoms, and the heteroaryl group may be pyridyl or pyrimidinyl , Pyrrolyl, furanyl, pyrazolyl, imidazolyl, thienyl, thiazolyl and so on.
  • the alkyl group generally refers to a saturated aliphatic group, and the alkyl group may be methyl, ethyl, propyl, butyl, pentyl, hexyl, and the like.
  • the R2 is selected from the following groups:
  • the compound represented by the above formula I may include an enantiomer depending on the presence of a chiral center or an isomer depending on the presence of a double bond (for example, Z, E), specifically, for example, a single isomer
  • enantiomers or diastereomers and mixtures thereof may fall within the scope of the present invention.
  • a solvate generally refers to a compound connected to another molecule (most likely a polar solvent) via a non-covalent bond, especially including hydrates and alcoholates, such as methanolates.
  • prodrugs generally refer to those derivatives that can be converted into the compounds of the present invention in vivo.
  • the second aspect of the present invention provides the use of the compound or its pharmaceutically acceptable salts, isomers, prodrugs or solvates in the preparation of PARP receptor inhibitors.
  • the PARP receptor may be a PARP-1 receptor or a PARP-2 receptor.
  • the third aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of an imaging agent.
  • the imaging agent may use PARP as a biomarker.
  • the developer is a positron tomography developer.
  • the PARP receptor may be a PARP-1 receptor or a PARP-2 receptor.
  • the fourth aspect of the present invention provides the use of the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the preparation of a medicament for diagnosis, prevention or treatment of diseases associated with PARP enzymes.
  • PARP enzyme-related diseases include cancer (for example, breast cancer, ovarian cancer, prostate cancer, colon cancer, pancreatic cancer, liver cancer, melanoma, gastric cancer and solid tumors, etc.), various ischemic diseases and neurodegenerative diseases (for example, Parkinson's disease, Alzheimer's disease, etc.).
  • a fifth aspect of the present invention provides a composition comprising the compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof.
  • the composition may be a pharmaceutical composition, a developer Compositions, etc., the content of the compound or the pharmaceutically acceptable salt, isomer, prodrug or solvate thereof in the composition may generally be a therapeutically effective amount and / or a developing effective amount.
  • the present invention provides a compound or a pharmaceutically acceptable salt, isomer, prodrug or solvate thereof, the method may isotope exchange by the 19 F- 18 F fluoride-based compounds exchanged into 19 F
  • the radioactive isotope 18 F, the resulting 18 F-labeled compound can be used as a positron tracer, so that PARP probe molecules containing 18 F nuclides can be synthesized, and the PARP-1 protein in patients can be dynamically evaluated by PET-CT technology Expression level, which can provide accurate tumor treatment plan based on PARP inhibitors.
  • the compound provided by the invention is a safer and more efficient new PARP inhibitor drug and a positron tomography imaging agent using PARP as a biomarker, and has great social value and economic value.
  • one or more of the method steps mentioned in the present invention does not exclude that there may be other method steps before or after the combination step or that other method steps may be inserted between these explicitly mentioned steps unless otherwise Explained; It should also be understood that the combined connection relationship between one or more devices / devices mentioned in the present invention does not exclude that there may be other devices / devices or those mentioned explicitly Other devices / apparatuses can also be inserted between the two devices / apparatuses unless otherwise stated.
  • each method step is only a convenient tool to identify each method step, not to limit the order of each method step or to limit the scope of the present invention can be implemented, the relative relationship changes or adjustments, in If there is no substantial change in the technical content, it should also be regarded as the scope of the invention.
  • the overall preparation route of the compounds P1-P6 refers to the above figure.
  • the overall preparation method is as follows:
  • Trevigen colorimetric PARP assay (commercially available) was used to determine the activity of PARP-1 in the presence of various concentrations of compounds P1-P6. The experiment was performed in a histone-coated 96-well plate. The specific results are shown in Table 1:
  • [18F] F- generated from the cyclotron was captured on a QMA Sep-Pak column (Waters, USA) and eluted with a solution containing 2.52 mg KHCO 3 , 9 mg Kryptofix 2.2.2, 0.72 mL acetonitrile, and 0.18 mL water, followed by Add 1mL of acetonitrile and evaporate at 120 ° C for 3 minutes. Under a nitrogen atmosphere, dry at 120 ° C for 3 minutes and then cool to room temperature. Then add 1mL of acetonitrile and evaporate at 120 ° C for 3 minutes.
  • Inhale isoflurane in medical air; induce 5% v / v; maintain 2.0-2.5% v / v
  • mice received a bolus injection of 0.8 MBq 18 F P4 via the tail vein and immediately started a 60-minute or 120-minute dynamic PET scan (continuous list mode).
  • the reconstructed PET data is automatically registered with the MRI data and then analyzed. (Shown in Figures 3 and 4)
  • the compounds provided by the present invention have high affinity for PARP receptors, and can be used as PARP inhibitor drugs and positron tomography imaging agents with PARP as biomarkers.
  • the present invention effectively overcomes various shortcomings in the prior art and has high industrial utilization value.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention se rapporte au domaine technique de la chimie organique, et concerne en particulier un composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis d'un récepteur PARP, ou un sel, un isomère, un promédicament ou un solvate pharmaceutiquement acceptable de celui-ci. La présente invention concerne un composé ou un sel, un isomère, un promédicament ou un solvate pharmaceutiquement acceptable de celui-ci, le composé ayant la formule structurale représentée par la formule I. Le composé fourni par la présente invention est un nouveau médicament inhibiteur de PARP sans danger et hautement efficace, et un agent d'imagerie par tomographie par positrons ayant PARP comme biomarqueur, qui présente une valeur socioéconomique significative.
PCT/CN2018/114371 2018-11-07 2018-11-07 Composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis du récepteur parp, préparation et utilisation associées Ceased WO2020093272A1 (fr)

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PCT/CN2018/114371 WO2020093272A1 (fr) 2018-11-07 2018-11-07 Composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis du récepteur parp, préparation et utilisation associées
CN201880099237.6A CN112969689A (zh) 2018-11-07 2018-11-07 一种含磺酰氟的对parp受体具有高亲和力的化合物及其制备和用途

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PCT/CN2018/114371 WO2020093272A1 (fr) 2018-11-07 2018-11-07 Composé contenant du fluorure de sulfonyle ayant une affinité élevée vis-à-vis du récepteur parp, préparation et utilisation associées

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Cited By (2)

* Cited by examiner, † Cited by third party
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CN112375070A (zh) * 2020-06-29 2021-02-19 中国药科大学 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途
WO2022000946A1 (fr) * 2020-06-29 2022-01-06 中国药科大学 Inhibiteur de parp contenant une structure de phtalazin-1(2h)-one, son procédé de préparation et son utilisation pharmaceutique

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WO2016033293A1 (fr) * 2014-08-27 2016-03-03 Memorial Sloan Kettering Cancer Center Agents thérapeutiques et de diagnostic ciblés marqués avec un radiohalogénure

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US20220017471A1 (en) * 2018-07-18 2022-01-20 Shanghai Tech University Functionality independent labeling of organic compounds
CN112480082B (zh) * 2020-12-17 2022-05-17 天津市肿瘤医院 一种化合物、制备方法及其在制备治疗小细胞肺癌药物中的应用

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WO2016033293A1 (fr) * 2014-08-27 2016-03-03 Memorial Sloan Kettering Cancer Center Agents thérapeutiques et de diagnostic ciblés marqués avec un radiohalogénure

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FILIP ZMUDA ET AL.: "An 18F-Labeled Poly(ADP-ribose) Polymerase Positron Emission Tomography Imaging Agent", J. MED. CHEM., 9 April 2018 (2018-04-09), XP055705752, DOI: 10.1021/acs.jmedchem.8b00138 *
WENHUA CHEN ET AL.: "Discovery, mechanism and metabolism studies of 2, 3- difluorophenyl-linker-containing PARP1 inhibitors with enhanced in vivo efficacy for cancer therapy", J. MED. CHEM., 27 June 2017 (2017-06-27), XP085163761 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112375070A (zh) * 2020-06-29 2021-02-19 中国药科大学 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途
WO2022000946A1 (fr) * 2020-06-29 2022-01-06 中国药科大学 Inhibiteur de parp contenant une structure de phtalazin-1(2h)-one, son procédé de préparation et son utilisation pharmaceutique
CN112375070B (zh) * 2020-06-29 2023-03-28 中国药科大学 含有酞嗪-1(2h)-酮结构的parp抑制剂、其制法及医药用途

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