TW206231B - - Google Patents
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- TW206231B TW206231B TW078102489A TW78102489A TW206231B TW 206231 B TW206231 B TW 206231B TW 078102489 A TW078102489 A TW 078102489A TW 78102489 A TW78102489 A TW 78102489A TW 206231 B TW206231 B TW 206231B
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- 125000002091 cationic group Chemical group 0.000 claims abstract description 5
- 150000001875 compounds Chemical class 0.000 claims description 21
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 abstract description 10
- 238000003384 imaging method Methods 0.000 abstract description 7
- 229910052698 phosphorus Inorganic materials 0.000 abstract description 7
- 239000011574 phosphorus Substances 0.000 abstract description 7
- 239000003446 ligand Substances 0.000 abstract description 5
- RQNWIZPPADIBDY-UHFFFAOYSA-N arsenic atom Chemical group [As] RQNWIZPPADIBDY-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052785 arsenic Chemical group 0.000 abstract description 3
- GKLVYJBZJHMRIY-OUBTZVSYSA-N Technetium-99 Chemical compound [99Tc] GKLVYJBZJHMRIY-OUBTZVSYSA-N 0.000 abstract description 2
- 230000002107 myocardial effect Effects 0.000 abstract 1
- 229930195734 saturated hydrocarbon Natural products 0.000 abstract 1
- 229940056501 technetium 99m Drugs 0.000 abstract 1
- 239000008280 blood Substances 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 210000004185 liver Anatomy 0.000 description 12
- 238000000034 method Methods 0.000 description 10
- 238000002347 injection Methods 0.000 description 8
- 239000007924 injection Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 241000282414 Homo sapiens Species 0.000 description 6
- 210000003205 muscle Anatomy 0.000 description 6
- -1 phosphorus hexadecane Chemical compound 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 101150080074 TP53 gene Proteins 0.000 description 5
- 238000010521 absorption reaction Methods 0.000 description 5
- 210000004072 lung Anatomy 0.000 description 5
- 210000000056 organ Anatomy 0.000 description 5
- 241000196324 Embryophyta Species 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 238000009826 distribution Methods 0.000 description 4
- 239000007788 liquid Substances 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 241000700199 Cavia porcellus Species 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- IYNWNKYVHCVUCJ-UHFFFAOYSA-N bismuth Chemical compound [Bi].[Bi] IYNWNKYVHCVUCJ-UHFFFAOYSA-N 0.000 description 3
- 150000001768 cations Chemical class 0.000 description 3
- 210000003734 kidney Anatomy 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000011084 recovery Methods 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 210000002700 urine Anatomy 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 229910052797 bismuth Inorganic materials 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- DEFVIWRASFVYLL-UHFFFAOYSA-N ethylene glycol bis(2-aminoethyl)tetraacetic acid Chemical compound OC(=O)CN(CC(O)=O)CCOCCOCCN(CC(O)=O)CC(O)=O DEFVIWRASFVYLL-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 229930195733 hydrocarbon Natural products 0.000 description 2
- 150000002430 hydrocarbons Chemical class 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000002285 radioactive effect Effects 0.000 description 2
- SYLMLKKURPTCSO-UHFFFAOYSA-N 1-phosphanylethylphosphane Chemical compound CC(P)P SYLMLKKURPTCSO-UHFFFAOYSA-N 0.000 description 1
- 238000004679 31P NMR spectroscopy Methods 0.000 description 1
- BDDLHHRCDSJVKV-UHFFFAOYSA-N 7028-40-2 Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O BDDLHHRCDSJVKV-UHFFFAOYSA-N 0.000 description 1
- 241001519451 Abramis brama Species 0.000 description 1
- 208000034656 Contusions Diseases 0.000 description 1
- 241000790917 Dioxys <bee> Species 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000001613 Gambling Diseases 0.000 description 1
- 241000282537 Mandrillus sphinx Species 0.000 description 1
- 241000233805 Phoenix Species 0.000 description 1
- 241001481789 Rupicapra Species 0.000 description 1
- 241000270295 Serpentes Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical class [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 101100462524 Sus scrofa TP53 gene Proteins 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- QYKIQEUNHZKYBP-UHFFFAOYSA-N Vinyl ether Chemical compound C=COC=C QYKIQEUNHZKYBP-UHFFFAOYSA-N 0.000 description 1
- 238000002679 ablation Methods 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 229940125904 compound 1 Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 150000003983 crown ethers Chemical class 0.000 description 1
- 150000004292 cyclic ethers Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N dimethylmethane Natural products CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000002224 dissection Methods 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000001962 electrophoresis Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 238000007429 general method Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 150000002440 hydroxy compounds Chemical class 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 230000001771 impaired effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000010354 integration Effects 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 239000004922 lacquer Substances 0.000 description 1
- 150000002634 lipophilic molecules Chemical class 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- 239000013521 mastic Substances 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- 229910000073 phosphorus hydride Inorganic materials 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004069 plant analysis Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 238000002601 radiography Methods 0.000 description 1
- 235000019699 ravioli Nutrition 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- 239000000779 smoke Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011800 void material Substances 0.000 description 1
Classifications
-
- 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
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
- C07F9/20—Esters of thiophosphoric acids containing P-halide groups
-
- 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
-
- 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
- C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
- C07F13/005—Compounds without a metal-carbon linkage
-
- 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
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/50—Organo-phosphines
- C07F9/5027—Polyphosphines
-
- 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
- C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Physics & Mathematics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Description
2〇6S3l. 乓發明之鮮細銳:明：
本發明係關於可作爲竣i趟成像削一 99 m ( Tc _ 99 m )之陽離子型錯合物，和鼬於用備此植緒舍物之二 官能性间心配舍雔。 W 奴射性粲物可被用作診_莸坫療袈削，此忭用係藉稱成 此樂物之放射性核植的物Μ性貲。因此，此物之软用並 不在於任何樂埋行爲。大邰份臨床上所使用的此類粲物削 係結合一植g amma —射線放射核稂的轸斯裂削，由於此‘ 核植2：配位汪向心龃合it的物垤袈代謝住負，在靜脤注射 後，其會停留狂一_特足的器官中。該栽終的相可反畎出 器官_迤或機能。這些相可藉由可針測具放射活性分子所 放射的_子化射線的分佈之gamma —射線照相檨得到。 在臨床鹼断核«學中所使用的基本同位素係可代謝的Μ— 99m( t%6 小時）0 通式RfQ(CH2 )nQR2 (此處Q可示磷或砷，且η示2 或3 )之中性二配位基向心配合體與 99Tc和 9 9m '
Tc〔1〕肜成後定的陽離子型錯合物的特性係已知的 。歎種專利，包括 US 445 1450，US 4387087, US 4489054，US4 3 7 4 8 2 1 . US4451450 和 US 4 5 2 6 7 7 6 ,已述及各S具有®著的烷基和芳基取 代基的间合餸，其中該酷配位原子係磷或砷。 DE 1917884 述及將（CH OCH CH ) P - 3 2 2 2
Π (21〇Χ297^Λ) 206231 CH2CH2-P(CH2〇CH3 )2 的化合一瀰媒。 厶減’ 於1987年10月6日申齡之央申餹罙8723458 保_於一楦以磷袈為中心目含；rf%槠之中性二配位給予 性冋心配合餸和包含道些间心配合體之T c — 99陽離子型 錯含胺I。與不含_械之賭合物比較下此植始台物妈示了令 人驁Ιί的性Μ »此性貲使得具肽撝礙異的人膛成像製削， 尤其跫心_成像製剤。本發明保關於一Μ在此一般餛域中 的特定類向心配合餸，及此配合艎與Tc — 99111所_成之 錯合物。 本Μ明之第一倘狀況保撻供一種具有式Y2 Q：Z QY2之间 心配合鱧， 此m每一個Q均示磷就钾， ' Z示一CC—或一 CCC-或一 COC —鏈或可經一 C 烷氧基或烷氧基烷基的伸茏基或媒環醚， 4 基團Y可相同或不闻含有2 ~ 8 碳原子和1至 3餡醚氧原子的娌和煙烴，其先決條件係該4個Y-
:’杯I 起含有至少13個碳原^¾¾每一個基團Y係以具有式 —〔（CH2 ) m—(CRl R2 )厂〇〕nR 3 者較佳 此跑/示0或1， πι示1至6 » 其允決條件保（)示1至6， η示1至3， Τ4 (Μ0Χ 297Λ-Λ) 4 206231 此處Θ示O，R3示一C.Ht;或i一C。H7或 2 5 3 7
-CH 一CH F 2 x 3 — x 此M x示0至2，或 此處/示1 ，R 3和/或R2 示CH 或Η且 0 R3 示一CH。或一C #「 3 2 5 以i示0，m示1至3，η示1且r3示一 較佳。 一個較佳的例子係下文中稱之爲P 53的向心配位體， 其中 Q示磷， Z 示一C。Ηλ —，且 ' 2 4 每一個 Υ 示一0C Η κ， L 4 L 〇 因此具有式
H 40C 2H H4°SH5 5 這些向心配合體时一較佳族群係： 任意具有.一個C 群__之 一 每一基團Y包無^和0原子的5 —或6 —員環 — 每一基團Y S有式： Ψ4 (Ϊ10Χ 297^Λ) 5 20 206^31
CmH2m-l ^CH2)i〇r4) 此處m示1至6 β示D或1，故（i+m)示1至6
R’示C 1至C 烷基銳被烷基 Q示磷，且各連接每一個Q的二個基ίιϋΥ係不同且係遒 目具有下式者 10
-(CH2)m〇R
此趟m示1至3 且 示C^;解至C4烷基或氟烷基 這些向心|齡合體係以z爲中心呈對稱者爲宜。 在所有的狀沉中，賅附著於磷，或鉀原子的四個基團均含 醚氧原子。 道些向心配位魈可藉上文之英國枣利申猜茱8723438 中所述的方法製得。Y2QZQY2型之向心配合M，（此處 所有的Y均相同）可藉由使一莫耳巳知化©合物雙（._基 )一醚與四英耳之含有·一烯鍵式不和基2：適當铋反應製 得。針稱的冋心配合® (此處基幽Υ不同）可藉由使 — ---------------------------------------------------------------—---—-------------------------------- (210 x 297厶薦） fi Y(H)QZQ(H)Y型之已知化合物與烷基鋰反應並接著使 其産物與YX型之化合物（此處X示頊如豳朵痛鉍 塩之離去基）〇:' >
Tc 一 99m之皭隖雖子型錯合物可藉已知的方法來製得 。例如： 一 〔TcO^^ + A—型之遛合物巧藉US Patent 4374821所述的方法製得。 -〔TcL3〕+ A一型之錯合物可藉US Patent 4481181所述的方法製得。 一 CTcCi L 〕+型之錯舍物可藉US Patent 2 2 438 7 087和4489054所迦的方法袈得° 尤其是，道些向心祀合蜷極易於標示以提供Tc _99m 錯合物之1一步驟室湿合成。當這些錯舍物形成時，其是 以適於杖服的形式穢定的存在於液態介質中。道些已製成 且已鎮示出特別遯於用傲心肌病用成像製削的性質之錯合 物包括道些具有下式者（"mTc縮爲成Tc〕： a) 〔TcL2〇2〕+ ，此處L示向心配合HP 53;及 b) — 〔TcC^2L2〕+，此處L示向心配合體P53。 本發明係包括了道些可被下實例所述者所製既，無論其是 否具有這些式》 雖此發明係關於裢果而非機祕，申請人仍企_提供這些 機裤的可能:解禪。明白的說：，對相似結傷的化合物而言其 f 4 («0 x 297公廉〉 268231 親脂性和蛋白質的鍵結力間具有某種關係。κ親脂性的化 合物對蛋白質的結合力此低親脂性化合物强。 99ra tc m 離子所親示出之裔度蛋白質鍵結敫果係枉於其停留在循遒 系犹中一段長時間以致於汪注射經一段合宜的脱像時闻後 心肌的像會被傷血活性（blood pool activity 所遄蔹 '對較1¾朽.親脂性陽離子2：—般:所得到之進一步 的&丨句係在於這些陽離子通過肝與Λ的系統之緩掻的肅淸 力，此#%到心鏽成像會硖肝活性所滅福。 貫質上，"mTc裙合物之親水性的提鬲夹有降低蛋白質 鍵結力的所需敖果，但同時亦會绛低心Μ吸收力（ heart uptake )。然而》其已顯示出在心腿吸收力被 維捋之踺會有一溫和親脂性區域且此亦會造成蛋白質鍵結 力的缺之（或足夠低）以允許血液所産生之迅速肅淸力。 此一現縝可藉由參照上述之錯合物而證K : a與TcL^HL·^^®•言f c 0"^核心之高楹性氧（每一分子2 )與向心配合饈的八個乙氧舅官能基的結合， h=,\ 丌.除巾，m錾麟—腽雕子有.6,低U. /Ψψ 加-十ΐϊτ r / 肘门-r .挺:苘絍某u (毎=.隄靡 亦賓結仓。 .尋’ 可達_需之良好心臟吸收力與低蛋白質鍵葙力的結合 。相汶的，其中該向心配合艇係P 53 (其中毎一基MY示 一 C fi 0 C (化合物2 )之異_物的a )型之錯合物 2 ) ).Ifej 2紐合物具有低的心臟吸收力和寅
LM Τ4 (210Χ 297Α-Λ) 206231 質上高的親水性c係由其画的尿楡出得知） 其亦頭示楹性的分佈可能會有TcO大於MeO大於EtO 的次序。由上述可知，經由氫取代基之加成性親水性炊果 興分子內之烴郤份的親脂性效應之均衡亦可能達到所需之 親脂性/親水性平衡狀態。 下列貫例係用以例證本發明。 實例1 向心配合饉2合成 C P 53，化 (EtOC2H4 )2P-C2 H4-P(C2H4〇Et
合物D 所有的反應和操作均在眞空或無氧之M氣壓下進行。在 使用前乾燥溶削。且通入氮瓶以除去其上文敢髗。各由 BDH和Aldrich製得β —偶氮一異丁膪（ΑΓΒΝ )和 乙基乙燁基醚。根據文猷⑴製備雙（二膦基）一乙烷。 由 Jeol 2 7 0 MHz 儎器得到1H nmr 和 31P〔 1H〕 nmr光譜。將樣品溶解於CDC^3中。h nmr係以 TMS爲內標毕且31P〔 nmr係以H gPO#爲外標準。 反腱槪要
AXBN T4 (UCX297XSJ) 206231 Η P-C Η -PH +CH CHOE t----> 2 2 4 2 2 (E tOC H ) P-C Η -P(C H 0£ t) 2 4^ 2 4 24 2 將乙基乙烯基醚C 5咖3 ，52.3 mmol )，叟C二 _基）乙烷（1颂3 ，10mraol )和α —偶氮一異丁膪（ 0 . 1 g » 0.61 mmo 1〕充械至裝置一鈸氟龍抶拌棒的 Fisher型壓力瓶。接著攙拌該反腱混合物並將之加热至 75°經16小時》冷却至茧溫後，將黏性液體轉送至50««3 底焼瓶。在眞空下加热以移除瘅發性铛物質。所得之非 餾性物質以nmr分析是純的。產量：3.〇g ,80%。 lH nmr (CDC%) (ppm)
積分 確認 12 H 三傰二重峰， J=1.16Hz, 7.ISHz, OCH9CH. 寬的多董峰》PC / 8 H 寬的三重峰，J = 7 . 4Hz PCH CH OEt -2 2 T4 (210X29T公虞） —10 — 206231 (ppm) 積分 確認
8H
3·49 8H 四個二重峄， J =1 . 1 6 H z , 7.15Hz, OCH CH„ —L i 寬的多重峰， PCH CH OEt 2-2 10 15 31 1 , P C XH J nmr d = — 3 3.17 p pm 以類似的方法製備化合物2至38且藉iH和31P NMR 性（結果如表1所示）。所需的不泡和醚先質係商用級或 文獻化合物。乙燔基醚類備巳經評論（參考桨2 )。 最廣泛Μ用之合成法由相麵一鹵醚除去KOH C參考 案3 )並與乙烯基交換考案4 )。使用相轉移方法（ /U,i/ 參考案5，6 )迅速製丙塍醚類 參考案 1=sInorganJLc Synthesis, Vol 10· 2· Ρ* Fiseller in wThe Chemistry οΓ Ethers, Crown Ethers, Hydroxy Compounds and their Sulphur Analogues1·» Part 2 (1980)· S· Patai (Ed·), p76l. 3* R· E· Ireland and D. Kabicht Chem· Ber” 114, 1418 f4 (210X2W^A) —li 20 206231 (1981). k, ¥. H. Vatanabe and L. £. Conlon, J· Am, Chem. Soc” 79, 2828 (1957). 5. A· Merz， Ang, Chem. Int. Ed. Engl., 12,8^6 (1973)· 6. B. Boutevin et al., J» Fluorine Chem., 35, 399 ( 1987). 實例 10 〔T c Ο n L。〕Hl.i 二氧基錯合物 CH.CH„OEt M P 53 M = EtOCH XH,
P^P
EtOCH XH CH„CH0OEt la 材料 食塩水 =3.5ml “ P 53 ” = 10 "mT c 0(j Na+發生器，洗出液15 ml，於1.19 4
GBq/mlT 方法 Τ4"(ϊΐ6χ297Λ-Λ) ~ __12 Γ 10 J5 206231 在勉氣下將道些成份魔於經隔板封閉之玻璃管形瓶中並 靜置在MM下經30分鐘（ρκ=6·8 ) °使錢終溶液接受 各毺分析技術，秸果如下： 色層分析數· 上述;2最終溶液不含膘質或無"mTcOp ，且指 錯合趲以92%左右的產置存在於溶液中 食塩水 甲乙_ 乙水 50 : 50 r f = 〇 . 0 0 r f = 0.70 r f = 1 . 0 0
If HPLC數據 在7.2分左右，該錯合物以一尖峰形籐洗出。 凝滕電泳歡據 該鑌合物以一單一帶狀形想向陰棰移酌Γ (一係表示向陰極移酌） 生物分佈結果 0.44 參凫表2和3。 Ψ4 (21〇X297^it) 13- 20 206231 K例3 質ii鍵結力硏究 . 將1 之幾內亞豬或人類的血漿或食塩水（控制組樣 品加至2 ml Eppendorf管中。將數個用於研究之 ^Tc製削整份加至其中。轉動道些試管數次以進 行混合。接著取出50 ui樣品用以評估並定量地將剩餘的 樣品（1050 ui )轉送至PD 10管柱的頂部。使樣品進 入管柱本镫並接着以1.5 ml食塩水淸洗。首先收集 2.5 ml整份以供評估，一直到16 ml的組體稹已用於洗 提管柱後接著收集15 ml整餘胺槙）。一般:而言， 對於不非特異性，卽*不可_至管柱的成份之錯合物而 言，此Μ理係足以足置的洗載於管柱上之所有活性。 在一 r孔狀計歡器內計歡所集的部份並由初姶預承載的 樣品和累稹組計算由囘收百分此黏出的座標圖。 當使用以P 53间心配合餹爲中心之錯合物時所得到之 Tc99m活性的囘收百分比囘收毕如下所示： —食塩水（控制組）一 90.82 % _人類血槳 -66.23 % —幾內亞豬血淸 一 9 0.3 4 %* 雎然低於其餘二者，由人頬血淸所得之囘收麵形可視爲 令人滿意的，且如所指者，並無任何邊合物a )明顯的鍵 一 14 T 4 («〇Χ 297公Λ ) 2〇623ΐ· 結至人類血漿的任何成份。 賞例 除了使用化合物2至38以替代化合物1 ( Ρ53 )外，以 的T c 一 99 m錯
萸例2的一般方法製備式〔TcO〇L 合物。觳終混合物之凰生物分佈性質係記錄於表4中。 警5 1 ., II !] :_·ϋί 二谈二氯一錯合物〔TcCi 〇〕 1 1 L = P 53 : CH 3CH2 OCH 2CH 2 CH 2~CH2 CHgCH ^DCH^C^ \丨 \ / P \p ch3ch2〇ch2ch2 CHXH^OCH <Ci[. 合成法 材料 5 mg ίο μ £ 15 mg F e C/j . 6 H 2〇
P 53 EGTA 甲4 (M0X297公厲） 15
NaCi 100 mg ϋ t OH 2 99mTc〇_( aq) 0.4mZ〜4BGq鉍生器½出液 食塩水 2 . 6 EGTA =伸乙基甘醇一 ϋ,Ο，一雙C2 —胺乙基） 一Ν,Ν,Ν， ·Ν，一四乙酸 製備FeC^和1> 53之紫色乙醇溶液，並將之加全含 ίο @有額外之反應物的水溶液。在1 2 O’C加热最終浞合物 60分鐘，顔色變至淡黃色。令産物接受各植分析技術，褚 果如下： 色餍分析歎據 上述之最終溶液不含膨質或無"mTc〇·"， 4
合物以85 — 95%左右的產量於溶液中 食塩水 rf = 〇.l〇 甲乙 _ r f = 〇 . 7 5 乙脯 / 水（50 : 50) r f = 〇 . 9 (寬） HPLC數據 r 4 "<?ibx Srjsjt) ***-，ϋό 一_ 2〇623i 在9.8分鎗下，該錯会物以尖峰形態洗出（在8.9分 鍾下有<10 維質尖峰） 凝肱電泳數據 該錯合物以一簞一帯狀形態冋陰極移射rf = — 0.42 c —保表示向陰極移io ) 生物分佈楮果 表.5 m縉内 —在老鼠和幾內亞豬饈內，Tc111 — 表6 幾內亜豬餹內 P 53顯示良好的心臟吸收力》戾 一好的血液和肝臟牖淸力，但由各 別的心膽疣出。 血漿鍵結力葙果 此錯合物顯示與人類血渡有痤微的作用力（囘收93% ) f 4 «10x297^4) _ 17
-表 1 YQZQY r〇r Q - P, Z CH2CH2 丨 NO./ 化合 丨物 Y I'31P 1 NHR j |i/ppra|CHP,CH2 ί 1 P| OCH2 I OCH 1 1 ΧΗ NHR； OMe j 1 '5 (ppm) och2ch3ich2ch2 ~ 1 ~ 1其他 1 1 1 1 -CH2CH2〇Ec 1 |1.7 (m) 1-33.1|1.5 (ra) l 1 |3.5 (m)| |3.4 (q)| 1 1 l-l (t)l 1 I 1 [2 1 -CH2CH2〇Me 1 11.77⑻ |-33.〇tl.58(ra) 1 1 1 1 |3.55(m)1 1 1 3.34(s) 1 1 1 1 1 3 1 -CH2CH2CH2〇Me 1 il.75(m) 1 -28.5|1.55(ra) 1 1 1 1 |3.3 (c)| 1 1 3.2 (s) |1.48(m) 1 1 1 1 A 卜 CH2CH2CH2〇Et: 1 |1.8 (m) 1-26.0|1.6 (ni) 1 1 1 1 |3.4 (m)| 1 1 1.2 (C)|1.4 (m) ( 1 1 1 5 1 -CH2〇Ec 1 1 1-30.611.78(ra) 1 1 |3.6 (q)| |3.9 (d)[ 1 1 1-3 (c)| 1 1 1 1 6 1 -CH-CHOEc ' 1 |6.“7 |-55.1|2.75(ni) 1 1 |3.9 (q)| A.61 1 1 1-3 (C)| 1 i 1 1 7 1-CH2CH2〇CH2CH2〇Me 丨 11.73(c) |-33.0|1.5 (m) 1 1 1 1 |3.5 (m)1 1 1 3.3 (s) 1 1 I ! 8 j -ch2ch2och2ch2oei： 1 |l-7 (c) |-34.0|1.5 (ra) 1 I 1 1 |3.5 (n>)| 1.15(c) 1 1 1 1 9 卜ch2ch2ocf2cf2h 1 11.85(c) [-32.1(1.55(c) 1 1 1 1 |4.1 ⑻ 1 1 1 |CF2H |5.62(t〇 1 1 10 卜ch2ch2ch2och2cf3 1 |1.6 (m) |-26.9|1.5 (m) 1 1 |3.75(q)| |3.6⑴丨 1 1 1 1 1 ! 1 1 11 [-CH2CHMeOMe I |1.7 (m) 1-34.611.5 (m) 1 丨3.4 (m) 1 i 3.3(s) 1 1 1 1 IMa 1.08(d) 1 1 | .,12 1 -CH2CHEcOHe 1 1 |-25.3|1.57(ni) 1 1 |3.2(m) 1 f 1 3.A(s) 1 0.98(c)1 1 1 1 I _ 1 -33.6|1.70(m) 1 l 1 1 13 j-CH2CHMeOEt |-34.^|l.A8(m) i 1 |3.30(m)|4.50(m) 1 1 1.12(c)! |Me 1.18(d) 1 U 卜 CH2CHMeCH2G)Me 1 |X.7(m) 1 -37.1|X.5(m) 1 1 1 1 |3.2(m) J 1 1 3.3(s) 1 1 1 1 |Ke 0.98(d) 1 ；1 2〇623i
—19 — 7 2〇623i
For Q - P, Z - CH2CH2CH2
I 36j-CH2CH2〇Ec I -40.9(1.8 (m)|3.5 (ra)| |3.37(ra)11.1 (c)|
I_1__I I_I_!_I_[_L fi Q - P. Z - 0 伸苯某. 1 1 1 |3-65(ra)j i 1 1 37|-CH2CH2〇Ec 1 |-A5.1|2.3(m) 1 1 |3.25(q)| 1 1 |1.1 (t)| 1 1 |Arom 7.2(m) 1 1 1 1 13.5 (m)t 1 33i-CH2CH2CH2〇Ec 1 |-38.0|X.9(ra) 1 1 13.4 (q)| 1 1 μ.15 ⑴ μ I I .8 (in) 1 Arom 7.3 (m) 1 附記：化合物27 — 32具有不同的丫取代基，即具有下通式丫'丫？(^2〇112¥丫 所示的結構 —20— 2 讲 表 鼠趙內之勐生物分佈數據〔Tc〇2(P53)2〕 f P 53 f l"X 2h5〇C2H4 C2 H 4〇C2H5
\rV
P P C2H5〇C2H4 C2H4〇C2H5 10 生韪儺內之皮 2分鐘 %注射削量 60分鏜 下注射時間 /器官 平均値 標準誤差 平均値 標毕誤羞 心 1.66 0.11 1.68 0.13 血液 2 .25 0.43 0.28 0.00 肌肉 3 1.6 9 . 3 31.6 2. 4 肺 1.44 0.05 0.65 0.20 Sf 14.1 1 . 3 1.62 0.34 肝+ Gi 37.8 2.9 42.5 3.5 腎+尿 13.2 1.8 9.29 2 . 53 腦 0.03 0.05 0.02 0.01 T4 (210 x 297公Λ) 21 206231 表 2 ( _ ) 次數/克比 心 / 血液 10.5 1.8 8 6 . 4 9.8 心 / 肌肉 5. 9 4 2 . 5 7 5 . 7 4 0 . 9 3 心 / 肝 1.52 0.08 1 4 . 4 1.8 心 / 肺 2 . 0 0 . 3 4 . 3 1.9 10 表3 Μ內亞豬髏內之肋物生物分佈數撅〔TcO (P53)〕+ L· L· 15 P53 C2H5OC2H4
C2H4〇C2H5
\H4〇C2H5 20 甲4 <210χ»7公Λ) 2〇623ΐ· 表：3 C纘） 在生媵内經皮 2分鐘 60分鐘 下注射時阍 ％注射剤蜇/器官 平均値 襪毕眹差 平均値 搮毕誤差 心 1.3 3 0.14 0.99 0.12 血液 3.11 0 . 8 ΰ 0.41 0.07 肌肉 3 0. 0 4.4 4 3.4 2 8.4 肺. 1.14 0.19 0.47 0.03 肝 11.6 2 . 5 2.13 0.56 肝+ Gi 3 8.7 4 . 1 4 4.6 2.8 腎+尿 1 6. 7 1.2 16.1 1 . 4 腦 次數/見比 心/血液 10.9 2 . 7 6 1.9 12.0 心/肌肉 6.12 0.44 4.10 2.09 心/肝 1 · 9·0 0.87 7.51 2.40 心/肺 1.2 0.2 2.0 0.2 (M0X257公廉> —-2^-— 表_
TcO(膦）?+之鼠生物分佈 心 s:注射劑量/器官 血液 肝 :/g比 2分鐘6祝鐘 60分鐘 心/血液 60^
14.1 5.90 3.62 18 . S 33.1 44.3 19.0 35.2 20.3 1.62 2.37 1.35 6.96 8.85 30.6 12.0 48.8 12.0 25 • 2 9. 72 22 • 0 10 .6 5 . SO 1. 8. 22 2.24 19 .2 7 . 71 17 .1 7. 88 35 .1 36 • 0 3. 27 0. 67 2厶 .50 14.90 9. 83 1· 95 15.7 16.A 5.74 11.0 18.6 7.69 25.0 10.8 39.4 29.7 28.2 18 . 8 29.7 3.41 8.56 1.60 2.94 11.5 1.89 12.4 1.78 11 乂 10.9 10.7 6.6“ 12.0 1 1 1.66 1.6S ι 2 .25 0.28 2 1 0.66 0.17 ι 19 .85 0.54 3 1 0.A4 0:09 I IS .8 0.77 4 1 1.00 0.96 1 7 .46 0.7 3 5 1 0.54 0.27 1 12 Λ 1.63 6 j 0.58 0.46 1 15 .6 3.26 δ ι 0.54 0.42 1 11 .0 1.69 10 ι 0.厶3 0. ΙΑ 1 40 .5 7.59 11 ι 0.81 0.62 9. Α5 1.93 12 1 0.70 0.68 1 11 .7 1.63 13 1 1.21 0.96 1 7· 17 1.77 14 ί 0.41 0.05 1 15 .A 1.02 15 1 0.62. 0.51 1 12 .2 0.67 16 1 0.79 0.54 1 11 • 4 1.58 17 1 1.14 0.86 1 5. 86 1.03 18 1 0.58 0.Α1 1 24 .2 5.78 19 1 0.46 0.03 1 18 .8 0.88 20 1 1.01 0.81 1 7. 14 1.52 21 1 0.37 0.04 1 18 .6 1.14 22 j 0.99 1.00 1 10 Λ 1.23 24 1 1.82 1.Α2 1 3. 92 0.55 25 1 ΟΛΟ 0.04 1 18 .10 1.51 28 1 0.82 0.69 1 9. 0 0.73 29 1 1.23 1.15 1 8. 75 1.64 30 1 0.73 0.70 1 9 . 52 0.34 31 1 1.21 0.99 1 6 . S3 1.22 32 1 0.85 0.81 1 5. S5 0.38 33 1 0.50 0.29 1 17 .9 3 20 36 1 0.41 0.16 1 19 .S 4.56 35 1 0.59 0.32 1 10 .5 36 1 1.05 0.73 1 10 .8 2 18 37 I 0.82 0.5^ 12 .U 3.25 1.52 1.57 1.71 0.81 0.20 0.13 0ΛΙ 0.16 0.57 0.39 0.70 0.98 1.01 ,58 .92 ,24 ,29 .50 53 79 1.74 0.94 1.28 0.95 1.2S ο.ε^- 1 . 27 10.5 0.44 0.35 1.96 0.68 0.61 0.72 0.17 1.27 1.04 2.54 0.41 0.70 1.01 2.99 37 37 95 33 1.20 6.93 0.34 1.62 2.20 1 . 14 3.05 2.31 0 7*3 0.34 0.88 1 . A5 0.99
86.A 5.4 1.82 20.〇 2.6 2.2 4.0 0.3 5.70 U.1 7.9 0.7 9.4 4.69 13.9 1.0 0.6 7.9 0.5 12.3 39.7 0.41 15.5 11.5 27.4 13.4 33.2 14 . U 1.17 0.8S 2.13 0.37 0.19 0.66 0.0厶 0.75 0.63 1.25 0.39 2.4S 0.96 1 . Γ>9 0.14 0.76 0.69 0.26 3 . 99 2.62 0. 34 3.93 1. Λ0 HU 1.21 7 .么6 1 . 3 ι 0.16 0.29 0.52 ι 0.22 0.21 3.8 I 0.23 0 . Λ 6 5.69 1 0.7 3 1.62 2.62 1 0.35 0.6 3 —24 — 嵗體內2鲂物 錯合物： 表 5 丰郗分佈歡據 [見山二氣一C P 53 ) 〕+ ' .:! L -''1 . : , s l·; k 一:i_ ____ … 陽離子 Ιίϋ* 在生趙內經皮 2分踵 60分鐘 下注射時間 %注射削；iJ /器官 平均値 樑準誤差 平均値 様準誤差 心 1.51 0.20 0 . 16 0.01 血液 5.24 0.11 0.71 0.03 肌肉 34.92 12.89 11.68 1.69 肺 1.45 0.08 0.47 0.18 肝 28. 87 4.71 4.78 0.28 肝+ GI 41.13 5.54 61.34 0.90 腎+尿 4.48 0.56 4.95 1.00 次歎/克比 心/血液 3.90 〇· 45 3.09 0.07 心/肌肉 4.68 1.40 1.41 0.20 心/肝 t 0.64 0.10 0.46 0.03 ¥4 (Ϊ10Χ 297Λ-Λ) _25
Claims (1)
- 、。一 ρ告本 附件一CA): 第7810248Θ號專利申請案 中文申請專利範圍修正本 民國82年4月呈 1. 一種具有下式之化合物， (C2H5〇CsH4)2P-C2H4-P(C2H4OC2H5)2, 其偽作為向心，配合體之用。 2. —種陽離子型錯合物，其係由得-99m與申請專利範 圍第1項之化合物所構成者，具有式〔TcL2〇2] +，其中L為 該化合物，用作向心配合體。 T4 (210X2S7公笈）
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB888808414A GB8808414D0 (en) | 1988-04-11 | 1988-04-11 | Ligands & cationic complexes thereof with technetium-99m |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TW206231B true TW206231B (zh) | 1993-05-21 |
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| Application Number | Title | Priority Date | Filing Date |
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| TW078102489A TW206231B (zh) | 1988-04-11 | 1989-04-01 |
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| Country | Link |
|---|---|
| US (1) | US5045302A (zh) |
| EP (1) | EP0337654B1 (zh) |
| JP (2) | JP2690142B2 (zh) |
| KR (1) | KR0149439B1 (zh) |
| CN (2) | CN1022633C (zh) |
| AT (1) | ATE133956T1 (zh) |
| CA (1) | CA1336437C (zh) |
| DE (1) | DE68925594T2 (zh) |
| DK (1) | DK171416B1 (zh) |
| ES (1) | ES2082771T3 (zh) |
| GB (1) | GB8808414D0 (zh) |
| HK (1) | HK98097A (zh) |
| IL (1) | IL89779A (zh) |
| TW (1) | TW206231B (zh) |
Families Citing this family (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DD291327A5 (de) * | 1989-12-29 | 1991-06-27 | �������@����@�K@��@��k�� | Myokardgaengige technetium-komplexverbindungen und verfahren zu deren herstellung |
| US5338864A (en) * | 1992-07-06 | 1994-08-16 | Mallinckrodt Medical, Inc. | Hexadentate ligands useful in radiographic imaging agents |
| US5744120A (en) * | 1993-03-30 | 1998-04-28 | The Dupont Merick Pharmaceutical Company | Ternary radiopharmaceutical complexes |
| US5750088A (en) * | 1993-03-30 | 1998-05-12 | The Dupont Merck Pharmaceutical Company | Stable hydrazones linked to a peptide moiety as reagents for the preparation of radiopharmaceuticals |
| US7575653B2 (en) * | 1993-04-15 | 2009-08-18 | 3M Innovative Properties Company | Melt-flowable materials and method of sealing surfaces |
| CA2215833A1 (en) * | 1995-03-29 | 1996-10-03 | Alan R. Ketring | Hydroxyalkyl phosphine compounds for use as diagnostic and therapeutic pharmaceuticals and method of making same |
| AU6231699A (en) * | 1998-09-30 | 2000-04-17 | Atofina Vlissingen B.V. | Fluorous phosphines and processes for their preparation |
| GB0427392D0 (en) * | 2004-12-15 | 2005-01-19 | Amersham Plc | Stabilised 99mTc compositions |
| JP4863345B2 (ja) * | 2005-03-18 | 2012-01-25 | 国立大学法人金沢大学 | 心筋用放射性画像診断剤又は放射性治療薬 |
| US10328164B2 (en) * | 2006-06-21 | 2019-06-25 | Ge Healthcare Limited | Radiopharmaceutical products |
| JP5427483B2 (ja) * | 2009-06-19 | 2014-02-26 | 株式会社化研 | 放射性医薬品およびその標識化合物原料としての放射性テクネチウムの濃縮および溶出回収方法、およびシステム |
| US9321095B2 (en) | 2010-06-30 | 2016-04-26 | General Electric Company | Apparatuses and methods for cutting porous substrates |
| EP2899195A1 (en) | 2014-01-28 | 2015-07-29 | ROTOP Pharmaka AG | Stabilized form of Tetrofosmin and its use |
| CN108884073A (zh) | 2017-03-08 | 2018-11-23 | 朱比兰特通用有限公司（原朱比兰特生命科学有限公司之部门） | 一种制备替曲膦或其酸加成盐的改进方法 |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1917884A1 (de) * | 1968-04-08 | 1969-10-16 | Toa Gosei Chem Ind | Verfahren zur Herstellung von 1-Buten-2,3,4-tricarbonsaeureestern |
| US4451450A (en) * | 1981-10-15 | 1984-05-29 | New England Nuclear Corporation | Cationic compounds useful for making radiodiagnostic agents |
| US4481184A (en) * | 1983-02-14 | 1984-11-06 | E. R. Squibb & Sons, Inc. | Cationic technetium (I) complexes |
| US4526776A (en) * | 1983-04-15 | 1985-07-02 | E. I. Du Pont De Nemours & Company | Cationic cyanato and thiocyanato complexes useful as radiodiagnostic agents |
| GB8723438D0 (en) * | 1987-10-06 | 1987-11-11 | Amersham Int Plc | Cationic complexes of technetium-99m |
| JP3176489B2 (ja) * | 1993-07-22 | 2001-06-18 | 中部電力株式会社 | 真空バルブ |
-
1988
- 1988-04-11 GB GB888808414A patent/GB8808414D0/en active Pending
-
1989
- 1989-03-28 US US07/329,639 patent/US5045302A/en not_active Expired - Lifetime
- 1989-03-28 IL IL8977989A patent/IL89779A/en unknown
- 1989-04-01 TW TW078102489A patent/TW206231B/zh active
- 1989-04-05 AT AT89303374T patent/ATE133956T1/de not_active IP Right Cessation
- 1989-04-05 ES ES89303374T patent/ES2082771T3/es not_active Expired - Lifetime
- 1989-04-05 EP EP89303374A patent/EP0337654B1/en not_active Expired - Lifetime
- 1989-04-05 DE DE68925594T patent/DE68925594T2/de not_active Expired - Lifetime
- 1989-04-05 CA CA000595715A patent/CA1336437C/en not_active Expired - Lifetime
- 1989-04-05 JP JP1086711A patent/JP2690142B2/ja not_active Expired - Lifetime
- 1989-04-05 DK DK163289A patent/DK171416B1/da not_active IP Right Cessation
- 1989-04-06 KR KR1019890004588A patent/KR0149439B1/ko not_active IP Right Cessation
- 1989-04-06 CN CN89102600A patent/CN1022633C/zh not_active Expired - Lifetime
-
1993
- 1993-02-23 CN CN93102336A patent/CN1031828C/zh not_active Expired - Lifetime
-
1997
- 1997-02-28 JP JP9046316A patent/JP2764037B2/ja not_active Expired - Lifetime
- 1997-06-26 HK HK98097A patent/HK98097A/xx not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| ES2082771T3 (es) | 1996-04-01 |
| HK98097A (en) | 1997-08-08 |
| EP0337654A2 (en) | 1989-10-18 |
| KR0149439B1 (ko) | 1998-10-15 |
| DK163289D0 (da) | 1989-04-05 |
| DE68925594T2 (de) | 1996-06-20 |
| ATE133956T1 (de) | 1996-02-15 |
| DK163289A (da) | 1989-10-12 |
| DK171416B1 (da) | 1996-10-21 |
| JPH0222286A (ja) | 1990-01-25 |
| DE68925594D1 (de) | 1996-03-21 |
| CA1336437C (en) | 1995-07-25 |
| EP0337654A3 (en) | 1991-04-24 |
| US5045302A (en) | 1991-09-03 |
| CN1040373A (zh) | 1990-03-14 |
| IL89779A0 (en) | 1989-09-28 |
| CN1022633C (zh) | 1993-11-03 |
| JP2764037B2 (ja) | 1998-06-11 |
| JP2690142B2 (ja) | 1997-12-10 |
| EP0337654B1 (en) | 1996-02-07 |
| CN1079746A (zh) | 1993-12-22 |
| JPH09328495A (ja) | 1997-12-22 |
| CN1031828C (zh) | 1996-05-22 |
| IL89779A (en) | 1995-01-24 |
| KR900016237A (ko) | 1990-11-13 |
| GB8808414D0 (en) | 1988-05-11 |
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