JP6140187B2 - 心筋灌流イマジニング用造影剤 - Google Patents
心筋灌流イマジニング用造影剤 Download PDFInfo
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- JP6140187B2 JP6140187B2 JP2014548735A JP2014548735A JP6140187B2 JP 6140187 B2 JP6140187 B2 JP 6140187B2 JP 2014548735 A JP2014548735 A JP 2014548735A JP 2014548735 A JP2014548735 A JP 2014548735A JP 6140187 B2 JP6140187 B2 JP 6140187B2
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- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000006242 amine protecting group Chemical group 0.000 description 1
- 210000003484 anatomy Anatomy 0.000 description 1
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- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960000686 benzalkonium chloride Drugs 0.000 description 1
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical compound [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 description 1
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 description 1
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- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
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- 239000011575 calcium Substances 0.000 description 1
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- 125000006244 carboxylic acid protecting group Chemical group 0.000 description 1
- 150000001735 carboxylic acids Chemical group 0.000 description 1
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- 150000001768 cations Chemical class 0.000 description 1
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- 239000007979 citrate buffer Substances 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
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- 239000003623 enhancer Substances 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
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- 239000012458 free base Substances 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229940093915 gynecological organic acid Drugs 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 210000002064 heart cell Anatomy 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
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- 238000002347 injection Methods 0.000 description 1
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- CDAISMWEOUEBRE-GPIVLXJGSA-N inositol Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](O)[C@@H]1O CDAISMWEOUEBRE-GPIVLXJGSA-N 0.000 description 1
- 229960000367 inositol Drugs 0.000 description 1
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- 150000002500 ions Chemical class 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 238000002372 labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000000787 lecithin Substances 0.000 description 1
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- 229940067606 lecithin Drugs 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
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- 239000000463 material Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 239000004005 microsphere Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 230000010016 myocardial function Effects 0.000 description 1
- QGVQPJYIRWNBOR-UHFFFAOYSA-N n-[[3-fluoro-4-(2-fluoroethoxymethyl)phenyl]methyl]-2-methyl-1,8-naphthyridine-3-carboxamide Chemical compound CC1=NC2=NC=CC=C2C=C1C(=O)NCC1=CC=C(COCCF)C(F)=C1 QGVQPJYIRWNBOR-UHFFFAOYSA-N 0.000 description 1
- 238000011328 necessary treatment Methods 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 150000002924 oxiranes Chemical class 0.000 description 1
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical compound P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 238000004393 prognosis Methods 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000000700 radioactive tracer Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 238000004366 reverse phase liquid chromatography Methods 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- MOODSJOROWROTO-UHFFFAOYSA-N salicylsulfuric acid Chemical compound OC(=O)C1=CC=CC=C1OS(O)(=O)=O MOODSJOROWROTO-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- CDAISMWEOUEBRE-UHFFFAOYSA-N scyllo-inosotol Natural products OC1C(O)C(O)C(O)C(O)C1O CDAISMWEOUEBRE-UHFFFAOYSA-N 0.000 description 1
- 150000003335 secondary amines Chemical class 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 229940001584 sodium metabisulfite Drugs 0.000 description 1
- 235000010262 sodium metabisulphite Nutrition 0.000 description 1
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
- 230000007928 solubilization Effects 0.000 description 1
- 238000005063 solubilization Methods 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 125000006850 spacer group Chemical group 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 150000003459 sulfonic acid esters Chemical class 0.000 description 1
- 229940071103 sulfosalicylate Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
Images
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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- A—HUMAN NECESSITIES
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- A61K49/00—Preparations for testing in vivo
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- 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
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- 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
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0455—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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- 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
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
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- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
本願及び本発明の内容において、次の定義を適用する。
[式中、R1はH、F、CF3、Clであり、Rはリンカーであり、Xは前記イメージング剤のイメージング成分又は類似体若しくは薬学的に許容される塩である]に関する。
一般に、本明細書に記載するイメージング剤は、少なくとも第1の成分と第2の成分とを、結合がその間に形成されるように反応させることによって合成することができる。例えば、18F標識化合物は、少なくとも1つの成分に結合している適切な脱離基の置換を経由して2つの成分を反応させることによって合成することができる。かかる脱離基の例には、スルホン酸エステル、例えばトルエンスルホン酸エステル(トシラート、TsO−−)、メタンスルホン酸エステル(メシラート、MsO−−)若しくはトリフルオロメタンスルホン酸エステル(トリフラート、TfO−−)、ノナフラート又はハロゲンが含まれる。脱離基は、ハロゲン化物、ホスフィンオキシド(光延反応による)、又は分子内脱離基(エポキシド又は環状硫酸エステルなど)とすることもできる。精製は一般に逆相クロマトグラフィーによる除塩によって実施される。
イメージング化合物の合成
実施例1
N−[[3−フルオロ−4−(2−フルオロエトキシメチル)フェニル]メチル]−2−メチル−1,8−ナフチリジン−3−カルボキサミド
19mgの2−[[2−フルオロ−4−[[(2−メチル−1,8−ナフチリジン−3−カルボニル)アミノ]メチル]フェニル]メトキシ]エチル4−メチルベンゼンスルホナート(0.036mmol)と、26mgのクリプトフィックス222(4,7,13,16,21,24−ヘキサオキサ−1、10−ジアザビシクロ[8.8.8]−ヘキサコサン)(0.069mmol)と、1.0mlの乾燥MeCN中4mgのKF(0.069mmol)との溶液を入れたフラスコを、余熱した油浴に加え、90Cで30分間加熱した。反応混合物を室温まで冷却し、水で希釈した。混合物をEtOAcで2回抽出した。複合有機相を塩水で洗浄し、乾燥させ(MgSO4)、濃縮した。フラッシュクロマトグラフィーにより9.6mg(72%)を得た。
1H NMR(CDCl3)δ8.97(dd,1H),8.03(s,1H),8.01(m,1H),7.42(m,2H),7.19(dd,1H),7.13(m,1H),7.08(t,1H),4.67(m,2H),4.65(s,3H),4.53(m,1H),3.80(m,1H),3.73(m,1H)。
25mgのトシルクロリド(0.13mmol)を、40mgのN−[[3−フルオロ−4−(2−ヒドロキシエトキシメチル)フェニル]メチル]−2−メチル−1,8−ナフチリジン−3−カルボキサミド(0.11mmol)と、23μlのジイソプロピルエチルアミン(6.13mmol)と、1.0mlのCH2Cl2中13mgのDMAP(0.11mmol)との溶液に、室温で添加した。この溶液を2時間攪拌した。反応混合物をSiO2カラムに直接入れ、フラッシュクロマトグラフィー(CH2Cl2/MeOH50:1)によって精製した。52mg(90%)を得た。
1H NMR(CDCl3)δ8.89(m,1H),7.99(s,1H),7.82(m,1H),7.73(m,3H),7.31(m,4H),7.13(m,2H),4.65(d,2H),4.51(s,2H),4.15(d,2H),3.68(m,2H),2.77(s,3H),2.41(s,3H)
45μlの塩化オキサリル(0.53mmol)を、3mlのCH2Cl2に一滴のDMFを加えた中に50mgの2−メチル−1,8−ナフチリジン−3−カルボン酸(0.27mmol)を溶解した混合物に添加した。反応混合物を1.5時間攪拌し、次いで、減圧下で蒸発させて乾燥した。残留物を3mlのCH2Cl2に溶解した。4mgのDMAP(0.03mmol)及び188μlのトリエチルアミン(1.35mmol)を、溶液に添加し、次いで54mgの2−[[4−(アミノメチル)−2−フルオロ−フェニル]メトキシ]エタノール(0.27mmol)を添加した。反応混合物を4時間攪拌し、次いで、水で希釈した。相を分離し、水相をCH2Cl2で抽出した。複合有機相を乾燥させ(MgSO4)、濃縮した。フラッシュクロマトグラフィー(SiO2、CH2Cl2/MeOH20:1)により36mg(36%)の標題化合物を得た。
1H NMR(CDCl3)δ8.82(m,1H),7.96(s,1H),7.95(m,1H),7.88(m,1H),7.31(m,2H),7.10(m,2H),4.60(d,2H),4.56(s,2H),3.75(m,2H),3.61(m,2H),2.68(s,3H)
Claims (8)
- 請求項1に記載の医薬組成物において、前記リンカーが、直鎖、分岐若しくは環状のアルキル、アリール、エーテル、ポリヒドロキシ、ポリエーテル、ポリアミン、複素環式、芳香族、ヒドラジド、ペプチド、ペプトイド又はこれらの組合せからなる群から選択されることを特徴とする医薬組成物。
- 請求項1乃至3の何れか1項に記載の医薬組成物において、Xが、18F、19F、120I、121I、122I、123I、124I、125I、127I、131I、35Cl、37Cl、75Br、76Br、77Br、79Br、80Br、80mBr又は81Brであることを特徴とする医薬組成物。
- 請求項4に記載の医薬組成物において、Xが18F又は19Fであることを特徴とする医薬組成物。
- キットであって、請求項1乃至5の何れか1項に記載の医薬組成物及び前記キットの使用の仕方の説明書を含むことを特徴とするキット。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
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US201161579113P | 2011-12-22 | 2011-12-22 | |
SE1151249-8 | 2011-12-22 | ||
US61/579,113 | 2011-12-22 | ||
SE1151249 | 2011-12-22 | ||
PCT/SE2012/051421 WO2013095273A1 (en) | 2011-12-22 | 2012-12-18 | Contrast agent for imagining myocardial perfusion |
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JP6140187B2 true JP6140187B2 (ja) | 2017-05-31 |
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JP2014548735A Expired - Fee Related JP6140187B2 (ja) | 2011-12-22 | 2012-12-18 | 心筋灌流イマジニング用造影剤 |
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JP (1) | JP6140187B2 (ja) |
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CN (1) | CN104114191A (ja) |
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US9955876B2 (en) * | 2016-09-08 | 2018-05-01 | Raul Chirife | Device and method for assessment of left ventricular ejection fraction and other parameters of cardiac performance |
CN107233585B (zh) * | 2017-06-09 | 2021-01-22 | 四川大学华西医院 | 黄连素或其衍生物在制备心肌灌注显像剂中的用途 |
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US7344702B2 (en) | 2004-02-13 | 2008-03-18 | Bristol-Myers Squibb Pharma Company | Contrast agents for myocardial perfusion imaging |
US7932272B2 (en) * | 2003-09-30 | 2011-04-26 | Eisai R&D Management Co., Ltd. | Antifungal agent containing heterocyclic compound |
US7824659B2 (en) * | 2005-08-10 | 2010-11-02 | Lantheus Medical Imaging, Inc. | Methods of making radiolabeled tracers and precursors thereof |
ES2432070T3 (es) | 2009-02-24 | 2013-11-29 | Respiratorius Ab | Diazaheteroarilos broncodilatadores novedosos |
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IL233219A0 (en) | 2014-08-31 |
CA2859773A1 (en) | 2013-06-27 |
EP2793952A1 (en) | 2014-10-29 |
CA2859773C (en) | 2020-09-01 |
SG11201403429YA (en) | 2014-07-30 |
EP2793952A4 (en) | 2015-09-09 |
KR20140107411A (ko) | 2014-09-04 |
KR101931792B1 (ko) | 2019-03-13 |
HK1201459A1 (en) | 2015-09-04 |
CN104114191A (zh) | 2014-10-22 |
EP2793952B1 (en) | 2018-06-13 |
ES2687234T3 (es) | 2018-10-24 |
BR112014015124A2 (pt) | 2017-06-13 |
RU2629840C2 (ru) | 2017-09-04 |
US20140341808A1 (en) | 2014-11-20 |
MX356258B (es) | 2018-05-16 |
ZA201405199B (en) | 2015-12-23 |
IL233219A (en) | 2016-08-31 |
RU2014125849A (ru) | 2016-02-10 |
MX2014007491A (es) | 2015-02-17 |
WO2013095273A1 (en) | 2013-06-27 |
US9295738B2 (en) | 2016-03-29 |
US20160101195A1 (en) | 2016-04-14 |
AU2012354223B2 (en) | 2017-03-16 |
AU2012354223A1 (en) | 2014-07-03 |
JP2015500873A (ja) | 2015-01-08 |
US9687565B2 (en) | 2017-06-27 |
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