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WO2019132117A1 - Composé pour imagerie pet pour le diagnostic précoce de maladies cardiovasculaires et son utilisation - Google Patents

Composé pour imagerie pet pour le diagnostic précoce de maladies cardiovasculaires et son utilisation Download PDF

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Publication number
WO2019132117A1
WO2019132117A1 PCT/KR2018/002661 KR2018002661W WO2019132117A1 WO 2019132117 A1 WO2019132117 A1 WO 2019132117A1 KR 2018002661 W KR2018002661 W KR 2018002661W WO 2019132117 A1 WO2019132117 A1 WO 2019132117A1
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WO
WIPO (PCT)
Prior art keywords
phosphonium
ethyl
pyrimidin
pyridin
butyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/KR2018/002661
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English (en)
Korean (ko)
Inventor
민정준
김동연
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Industry Foundation of Chonnam National University
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Industry Foundation of Chonnam National University
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Filing date
Publication date
Application filed by Industry Foundation of Chonnam National University filed Critical Industry Foundation of Chonnam National University
Publication of WO2019132117A1 publication Critical patent/WO2019132117A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

Definitions

  • the present invention relates to novel compounds and uses thereof, and more particularly to novel compounds for PET imaging and uses thereof.
  • Coronary artery disease accounts for 3-4 of the causes of death in Korea. In particular, the prevalence has increased nearly five times over the past two decades, and this will accelerate further in the global trend. Symptoms of coronary artery disease appear mainly after 45-50 years of age, but the prevalence of coronary artery disease has increased in recent years, and the number of cases with symptoms in younger patients has been increasing, and the importance of early diagnosis and prevention is gradually increasing.
  • Coronary artery disease is diagnosed early by methods of exercise testing, echocardiography, coronary angiography, and nuclear medicine.
  • exercise testing may not reveal any abnormality when examined in a stable state with no symptoms in angina pectoris.
  • Echocardiography can not reliably calculate the size or function of heart if it does not completely contain the heart. There is a drawback that it takes much time to see.
  • coronary angiography can cause complications such as death or acute myocardial infarction at less than 0.1%, so it can not be applied to all patients suspected of angina.
  • the nuclear medicine method used is single photon emission computed tomography (SPECT).
  • SPECT single photon emission computed tomography
  • the radiopharmaceutical used to identify the heart image is 201 Tl complex, 99m Tc-sestamibi, 99m Tc -tetrofosmin is used.
  • PET Positron Emission Tomography
  • PET radiopharmaceuticals labeled with positron emission nuclei are needed.
  • the present inventors have developed a contrast agent for PET containing 18 F based on tetraphenylphosphonium (TPP) salt (Patent No. 1172157).
  • the TPP salt-based contrast agent for PET has a problem in that it has a low cardiac selectivity and a high uptake rate in bones, as well as a problem in heart image analysis due to a high uptake rate in the liver adjacent to the heart.
  • X 1 is O, S, N, or C
  • X 2 to X 10 are each independently C or N
  • X 2 to X 10 are independently C or N
  • L 1 and L 2 Each independently represent an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or a polymer of the repeating units 2 to 4 having 1 to 6 carbon atoms, Ester group, succinimidyl group, carbonyl group and And
  • R 2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a tosyloxy group, -NH 2 , -NH-L 3 -R 5 , -SH, -SL 4 -R 6 , a maleimidyl group or
  • L 2 to R 4 are each independently hydrogen, an alkyl group having 1 to 3 carbon atoms or a haloalkyl group
  • A is carbon
  • a compound of formula I wherein R 1 of said compound or an acceptable salt thereof or at least one hydrogen in said R 1 is selected from the group consisting of 118 F, 76 Br, 123 I, 124 I, and 131 I
  • a radial metal complex comprising a compound having a structure of formula II and a radioisotope element:
  • X 1 is O, S, N, or C
  • each of X 2 to X 10 is independently C or N
  • X 2 to X 10 are independently C or N
  • L 1 and L 2 Each independently represent an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or a polymer of the repeating units 2 to 4 having 1 to 6 carbon atoms, Ester group, succinimidyl group, carbonyl group and , A is carbon or nitrogen
  • R 1 ' is -NH-L 5 -R 6 or -SL 5 -R 7
  • L 1 is a linker selected from the group consisting of L 5 and L 6 are each independently selected from the group consisting of an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or
  • the group consisting of at least one hydrogen atom in the formula (I) compound or a acceptable salt thereof R 1 or the R 1 to 118 F, 76 Br, 123 I , 124 I and 131 I
  • a contrast agent for positron emission tomography comprising the radioactive compound or an acceptable salt thereof or the radioactive metal complex as an active ingredient.
  • novel compounds and their acceptable salts according to one embodiment of the present invention can be used as precursors for the production of radiological compounds for PET imaging and the radioactive compounds prepared using the precursors have improved cardiac targeting capacity and reduced bone resorption capacity This allows us to obtain clear cardiac images during positron tomography.
  • the scope of the present invention is not limited by the above effects.
  • FIG. 1 is a positron emission tomographic image of an experimental animal obtained using the triphosphonium salt ([ 18 F] FPTP) described in Korean Patent No. 1172157.
  • FIG. 2 is a positron emission tomographic image of an experimental animal obtained using [ 18 F] FEPP according to an embodiment of the present invention.
  • FIG 3 is a positron emission tomographic image of an experimental animal obtained using [ 18 F] FDPP according to an embodiment of the present invention.
  • X 1 is O, S, N, or C
  • X 2 to X 10 are each independently C or N
  • X 2 to X 10 are independently C or N
  • L 1 and L 2 Each independently represent an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or a polymer of the repeating units 2 to 4 having 1 to 6 carbon atoms, Ester group, succinimidyl group, carbonyl group and And
  • R 2 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, a tosyloxy group, -NH 2 , -NH-L 3 -R 5 , -SH, -SL 4 -R 6 , a maleimidyl group or
  • L 2 to R 4 are each independently hydrogen, an alkyl group having 1 to 3 carbon atoms or a haloalkyl group
  • A is carbon
  • the compound can be prepared by the following reaction scheme:
  • the compound or an acceptable salt thereof may be prepared by reacting (4 - ((tert-butoxycarbonyl) amino) butyl) diphenyl (pyridin-3-yl) phosphonium, (4- (tert-butoxycarbonyl) amino) -3-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) tri (pyridin-3- ) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) tri (pyrimidin-4-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl) (pyridin-2-yl) (4 - ((tert-butoxycarbonyl) amino) butyl) diphenyl (1,2,3-triazin-4-yl) phosphonium, (1,2,3-triazin-4-yl) phosphonium, (4 - ((tert-butoxycarbonyl) amino) butyl)
  • the "acceptable salt” is preferably a salt with an inorganic or organic acid, more preferably a salt with an aliphatic such as methoxy, acetoxy, trifluoroacetoxy anion, etc., a chloride, a bromide, an iodide, Aliphatic carboxylic acid salts, aliphatic carboxylic acid salts, nitrate salts, sulfate salts, phosphate salts, sulfonate salts, mesylate salts, besylate salts and tosylate salts.
  • acceptable salts of the present invention, -OTos, F - also includes salts with -, Cl -, Br -, or I. However, these do not limit the acceptable salts of the present invention
  • a compound of formula I wherein R 1 of said compound or an acceptable salt thereof or at least one hydrogen in said R 1 is selected from the group consisting of 118 F, 76 Br, 123 I, 124 I, and 131 I
  • the radioactive compound or an acceptable salt thereof is (2- (2- [ 18 F] fluoroethoxy) ethyl) tris (4- (trifluoromethyl) phenyl) phosphonium,
  • the compound or a acceptable salt thereof R 1 118 F, 76 Br, 123 I, substituted with one or more radioisotopes selected from the group consisting of 124 I and 131 I, radioactive A compound or an acceptable salt thereof is provided.
  • the group at least one hydrogen in the compound or a acceptable salt of the general formula I R 1 or the R 1 consists of 118 F, 76 Br, 123 I, 124 I, and 131 I Or a covalent bond with a haloalkyl, halopolyethylene oxide, haloalkylthiol or halopolyethylene oxide thiol having 2 to 6 carbon atoms containing the radioactive isotope, wherein the radioisotope is selected from the group consisting of A method of making a radioactive compound or an acceptable salt thereof is provided.
  • substitution method is not limited, and it is obvious that a person skilled in the art can appropriately select according to the situation.
  • one skilled in the art can substitute the substituent of R 1 with a radioisotope by adding 118 F, 76 Br, 123 I, 124 I, and 131 I to the compound of Formula 1 or an acceptable salt thereof.
  • the above production method can be carried out by the following reaction formula instead of the above substitution method.
  • a radial metal complex comprising a compound having a structure of formula II and a radioisotope element:
  • X 1 is O, S, N, or C
  • each of X 2 to X 10 is independently C or N
  • X 2 to X 10 are independently C or N
  • L 1 and L 2 Each independently represent an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or a polymer of the repeating units 2 to 4 having 1 to 6 carbon atoms, Ester group, succinimidyl group, carbonyl group and , A is carbon or nitrogen
  • R 1 ' is -NH-L 5 -R 6 or -SL 5 -R 7
  • L 1 is a linker selected from the group consisting of L 5 and L 6 are each independently selected from the group consisting of an alkylene group, an alkenylene group, an alkynylene group, an arylene group having 6 or 10 carbon atoms, an alkylene oxide group having 2 to 6 carbon atoms or
  • the chelator is selected from the group consisting of NOTA (1,4,7-triazacyclononane-N, N ', N "-triacetic acid), DOTA (1,4,7,10- tetraazacyclododecane- Tetraacetic acid), TETA (1,4,8,11-tetraazacyclotetradecane-N ', N'',N''- tetraacetic acid), DTPA (diethylenetriaminepentaacetic acid), EDTA (ethylenediamine tetraacetate), nitrilotriacetic acid ) Or a derivative of the chelator.
  • NOTA 1,4,7-triazacyclononane-N, N ', N "-triacetic acid
  • DOTA 1,4,7,10- tetraazacyclododecane- Tetraacetic acid
  • TETA 1,4,8,11-tetraazacyclotetradecane-N ', N'',N''- t
  • radioactive metallic element is 44 Sc, 64 Cu, 66 Cu , 67 Ga, 68 Ga, 71 Ga, 115 Ga, 89 Y, 86 Y, 90 Y, 89 Zr, 99m Tc, 111 In , Or 177 Lu.
  • a contrast agent for positron emission tomography comprising the radioactive compound or an acceptable salt thereof or the radioactive metal complex as an active ingredient.
  • the contrast agent for PET may be combined with a pharmaceutically acceptable carrier according to conventional pharmaceutical preparation techniques.
  • a pharmaceutically acceptable carrier may have a wide variety of forms depending on the preparation desired, for example, for oral or parenteral administration (including intravenous administration).
  • the contrast agent according to one embodiment of the present invention may be administered at a dose of 0.1 mg / kg to 1 g / kg, more preferably 0.1 mg / kg to 500 mg / kg.
  • the dose can be appropriately adjusted according to the age, sex, and condition of the patient within the range of the amount of radiation exposure permitted for the day or the year.
  • the contrast agent according to one embodiment of the present invention further comprises an inert component, including a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier is a term referring to a composition, specifically a component other than the active ingredient of the pharmaceutical composition.
  • pharmaceutically acceptable carriers include binders, disintegrants, diluents, fillers, lubricants, solubilizers or emulsifiers and salts.
  • the new contrast agent may be administered to the subject by parenteral administration, and the parenteral administration may be by intravenous injection, intraperitoneal injection, intramuscular injection, or subcutaneous injection. injection, but intravenous administration is most preferred.
  • [ 18 F] FDPP and [ 18 F] FEPP prepared in Examples 2-1 and 2-2 described above were intravenously injected into the BALB / c wild-type mouse through the tail vein at a dose of 200 ⁇ Ci, respectively After 30 and 60 minutes, whole body images were taken with a positron tomography system for small animals.
  • 5- [ 18 F] fluoropentyl) triphenylphosphonium salt ([ 18 F] FPTP) synthesized in Japanese Patent No. 1172157 was used.
  • FIGS. 1 to 3 the radioactive compound according to one embodiment of the present invention greatly increased the maximum signal value at the heart as compared with [ 18 F] FPTP, which is a conventional radioactive compound.
  • FIG. 1 is a PET image of a whole body including the heart of an experimental animal when administered with [ 18 F] FPTP of the prior art
  • FIGS. 2 and 3 are photographs of [ 18 F] FEPP and a radioactive compound according to an embodiment of the present invention, [ 18 F] PET images taken after administration of FDPP.
  • the above results indicate that the radioactive compound according to one embodiment of the present invention has a better uptake rate at the heart.
  • radioactive compounds of the present invention and compositions comprising them can be used as contrast agents for cardiac imaging.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Physics & Mathematics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pyridine Compounds (AREA)

Abstract

La présente invention concerne un composé précurseur pour préparer un composé radioactif afin d'imager efficacement un coeur, un composé radioactif préparé à l'aide du composé précurseur, et son utilisation en tant qu'agent de contraste pour l'imagerie TEP.
PCT/KR2018/002661 2017-12-27 2018-03-06 Composé pour imagerie pet pour le diagnostic précoce de maladies cardiovasculaires et son utilisation Ceased WO2019132117A1 (fr)

Applications Claiming Priority (2)

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KR10-2017-0181493 2017-12-27
KR1020170181493A KR101920902B1 (ko) 2017-12-27 2017-12-27 심혈관 질환 조기진단 pet 조영용 화합물 및 그의 용도

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WO2019132117A1 true WO2019132117A1 (fr) 2019-07-04

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116693806A (zh) * 2023-07-13 2023-09-05 深圳市嘉卓成科技发展有限公司 一种抗菌水性异氰酸酯固化剂的制备方法
WO2023147161A3 (fr) * 2022-01-31 2023-10-05 New Frontier Bio, Inc. Composés à base de nicotinate riboside et de nicotinamide riboside et leurs dérivés

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20050020755A (ko) * 2002-02-06 2005-03-04 더 존스 홉킨스 유니버시티 방사성 표지된 친유성 염을 사용한 미토콘드리아에 대한비침습적 진단 영상화 기술
WO2015075200A1 (fr) * 2013-11-22 2015-05-28 Medical Research Council Composés de séquestration de groupes dicarbonyles ciblant les mitochondries
US9434753B2 (en) * 2011-09-19 2016-09-06 Gencia Corporation Modified creatine compounds
CN107325173A (zh) * 2016-04-28 2017-11-07 上海惠斯生物科技有限公司 一种25羟基维生素d3人工抗原、制备方法及应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105153227A (zh) 2015-07-04 2015-12-16 河南中医学院 一种[18f]-氟甲基三苯基膦盐及其制备方法与应用

Patent Citations (4)

* Cited by examiner, † Cited by third party
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KR20050020755A (ko) * 2002-02-06 2005-03-04 더 존스 홉킨스 유니버시티 방사성 표지된 친유성 염을 사용한 미토콘드리아에 대한비침습적 진단 영상화 기술
US9434753B2 (en) * 2011-09-19 2016-09-06 Gencia Corporation Modified creatine compounds
WO2015075200A1 (fr) * 2013-11-22 2015-05-28 Medical Research Council Composés de séquestration de groupes dicarbonyles ciblant les mitochondries
CN107325173A (zh) * 2016-04-28 2017-11-07 上海惠斯生物科技有限公司 一种25羟基维生素d3人工抗原、制备方法及应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YUAN, H. ET AL.: "Fluorescent and Radiolabeled Triphenylphosphonium Probes for Imaging Mitochondria", CHEMICAL COMMUNICATIONS, vol. 49, no. 88, 2013, pages 10361 - 10363, XP055622464, ISSN: 1359-7345, DOI: 10.1039/c3cc45802d *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023147161A3 (fr) * 2022-01-31 2023-10-05 New Frontier Bio, Inc. Composés à base de nicotinate riboside et de nicotinamide riboside et leurs dérivés
CN116693806A (zh) * 2023-07-13 2023-09-05 深圳市嘉卓成科技发展有限公司 一种抗菌水性异氰酸酯固化剂的制备方法

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