DK173003B1 - Ether-substituerede isonitriler, radiomærkede komplekser deraf og deres anvendelse - Google Patents
Ether-substituerede isonitriler, radiomærkede komplekser deraf og deres anvendelse Download PDFInfo
- Publication number
- DK173003B1 DK173003B1 DK198606238A DK623886A DK173003B1 DK 173003 B1 DK173003 B1 DK 173003B1 DK 198606238 A DK198606238 A DK 198606238A DK 623886 A DK623886 A DK 623886A DK 173003 B1 DK173003 B1 DK 173003B1
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- DK
- Denmark
- Prior art keywords
- ether
- formula
- substituted
- isonitrile
- complexes
- Prior art date
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- 150000002527 isonitriles Chemical class 0.000 title description 13
- 125000004432 carbon atom Chemical group C* 0.000 description 10
- 150000001412 amines Chemical class 0.000 description 8
- -1 chloro, bromo, iodo Chemical group 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 6
- 238000003384 imaging method Methods 0.000 description 6
- 150000001408 amides Chemical class 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 229910052799 carbon Inorganic materials 0.000 description 4
- 210000004165 myocardium Anatomy 0.000 description 4
- 125000001424 substituent group Chemical group 0.000 description 4
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- 239000003446 ligand Substances 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 125000000962 organic group Chemical group 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 229910052713 technetium Inorganic materials 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 229910001868 water Inorganic materials 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003638 chemical reducing agent Substances 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- QVAWPEGWRUXBQH-UHFFFAOYSA-N formamide;formic acid Chemical compound NC=O.OC=O QVAWPEGWRUXBQH-UHFFFAOYSA-N 0.000 description 2
- XFXPMWWXUTWYJX-UHFFFAOYSA-N isonitrile group Chemical group N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 description 2
- 210000004185 liver Anatomy 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 229910000104 sodium hydride Inorganic materials 0.000 description 2
- GKLVYJBZJHMRIY-UHFFFAOYSA-N technetium atom Chemical compound [Tc] GKLVYJBZJHMRIY-UHFFFAOYSA-N 0.000 description 2
- FGRJGEWVJCCOJJ-UHFFFAOYSA-N 2,2-dimethylaziridine Chemical compound CC1(C)CN1 FGRJGEWVJCCOJJ-UHFFFAOYSA-N 0.000 description 1
- 229940058020 2-amino-2-methyl-1-propanol Drugs 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- SARBHXGUPQRFTC-UHFFFAOYSA-N C(=O)O.N#[C-] Chemical compound C(=O)O.N#[C-] SARBHXGUPQRFTC-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- 238000007167 Hofmann rearrangement reaction Methods 0.000 description 1
- 229910010082 LiAlH Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 125000005262 alkoxyamine group Chemical group 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001414 amino alcohols Chemical class 0.000 description 1
- CBTVGIZVANVGBH-UHFFFAOYSA-N aminomethyl propanol Chemical compound CC(C)(N)CO CBTVGIZVANVGBH-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000000908 ammonium hydroxide Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 125000006267 biphenyl group Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052804 chromium Inorganic materials 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000003948 formamides Chemical class 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012216 imaging agent Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229910052741 iridium Inorganic materials 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 229910052748 manganese Inorganic materials 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 229910052750 molybdenum Inorganic materials 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052758 niobium Inorganic materials 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 230000010412 perfusion Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 229910052702 rhenium Inorganic materials 0.000 description 1
- 229910052703 rhodium Inorganic materials 0.000 description 1
- 229910052707 ruthenium Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 229910052715 tantalum Inorganic materials 0.000 description 1
- FAGLEPBREOXSAC-UHFFFAOYSA-N tert-butyl isocyanide Chemical compound CC(C)(C)[N+]#[C-] FAGLEPBREOXSAC-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 229910052721 tungsten Inorganic materials 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
- C07C291/10—Isocyanides
-
- 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
-
- 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
- A61K51/0476—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 complexes from monodendate ligands, e.g. sestamibi
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
-
- 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)
- Epidemiology (AREA)
- Public Health (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Measurement And Recording Of Electrical Phenomena And Electrical Characteristics Of The Living Body (AREA)
- Position Fixing By Use Of Radio Waves (AREA)
Description
' DK 173003 B1 Ϊ
Opfindelsen angår et radiomærket kompleks af hidtil ukendte ethersubstituerede isonitriler til brug ved afbildning af myocardium, et sæt ti] anvendelse ved dannelse af dette kompleks samt anvendelse af sættet til dannelse af 5 komplekset.
Isonitrilkomplekser af forskellige radionuklider og deres anvendelse som afbildnings- eller billeddannelsesmidler er beskrevet i US patentskrift nr. 4.452.774. De deri beskrevne komplekser har den almene formel 10 [A((CN)xR)yBzBV]n hvori A er et radionuklid valgt blandt radioaktive isotoper af Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, 15 Pd, Nb og Ta, såsom 99mTc, 99TCi 97Ru^ 51cr, 57Co, 188Re og 19 *05, (CN)XR er en monodental eller polydental isonitril-ligand bundet til radionuklidet via carbonatomet i CN-grup-pen, R er en organisk gruppe, B og 8' er hver for sig valgt blandt andre kendte ligander, som resulterer i isonitril-20 kompekser, herunder opløsningsmidler, såsom vand, chlor-og bromatomer, og ligander, der indeholder et eller flere neutrale donoratomer, der er i stand til at danne bindinger med radionuklidet, x og y er hver for sig hele tal fra 1 til 8, z og 2’ er hver for sig 0 eller et helt tal fra 1 25 til 7, med det forbehold, at (xy)+z+z' er højst 8, og n angiver kompleksets ladning og kan være 0 (neutral), eller et positivt eller negativt helt tal, hvis størrelse afhænger af A*s valenstilstand og af ladningerne på R, B og B'. En hvilken som helst ønsket modion kan være til stede svarende 30 til kompleksets ladning med det forbehold, at en sådan modion skal være farmaceutisk acceptabel, hvis komplekset skal anvendes in vivo.
I den ovennævnte formel er R en organisk gruppe, som kan være aliphatisk eller aromatisk og kan være substitueret 35 med forskellige grupper, som eventuelt kan være ladede. Når den organiske gruppe R har en ladet substituentgruppe, er DK 173003 B1 ‘ i 2 s ladningen på det fremkomne kompleks summen af ladningerne på liganderne (R, B og B') og ladningen af radionuklidet.
Blandt de aromatiske F-grupper, scrr kan være til stede, er phenyl, tolyl, xylyl, naphthyl, diphenyl og substituerede 5 aromatiske grupper, der indeholder sådanne substituenter som halogen, såsom chlor, brom, iod eller fluor, og hydroxy, nitro, alkyl og alkoxy? blandt de aliphatiske R-grupper, som kan være til stede, er alkyl, fortrinsvis med 1-20 C-atomer, såsom methyl, ethyl, n-propyl, isopropyl, n-butyl, 10 isobutyl, n-hexyl, 2-ethylhexyl, dodecyl og stearyl. Sub-stituentgrupper kan også være til stede i de aliphatiske grupper, herunder blandt andre de samme substituentgrupper som dem, der er angivet ovenfor for aromatiske grupper.
De komplekser, der er beskrevet i det ovennævnte 15 US patentskrift, angives at være anvendelige til visualisering af hjertevæv, påvisning af tilstedeværelsen af thromber i lungen og tilknyttede områder med mangelfuld blodperfusion, undersøgelse af lungefunktion, undersøgelse af nyreekskretion _ og afbildning af knoglemarv og af lever-galde-systemet.
20 I praksis har man ved det technetium-kompleks af de simple carbonhydrid-isonitriler, såsom t-butylisonitril, der foretrækkes ifølge det ovennævnte US patentskrift, påvist en noget høj koncentration i lungerne og leveren hos mennesker. (Holman et al., J. Nucl. Hed. 1380 (1984)]. Den 25 høje tidlige koncentration af radionuklid i lungerne har krævet, at afbildningen af hjertet må forsinkes for at tillade lungeaktiviteten at vende tilbage til det normale, inden der kan opnås tilfredsstillende afbildning af myocardium. Yderligere har den høje koncentration af radionuklid 30 i leveren gjort påvisningen af per fus ionsdefekter i det apikale område af myocardium vanskeligere. Der eksisterer tydeligvis et behov for et mere selektivt middel til afbildning af myocardium.
Der er nu blevet tilvejebragt hidtil ukendte ether-35 substituerede isonitriler og radiomærkede komplekser af disse. Skønt den almene formel, der er angivet i US patent- • ’i \ DK 173003 B1 3 r skrift nr. 4.452.774, omfatter de radiomærkede, ethersubsti-tuerede isonitrilkomplekser ifølge den foreliggende opfindelse, er disse Komplekser ikke specifikt beskrevne, oc de meget overlegne afbildningsegenskaber, som disse ethersub-5 stituerede isonitriler er i besiddelse af, er ikke antydet i det nævnte US patentskrift.
Det radiomærkede kompleks ifølge opfindelsen til brug ved afbildning af myocardium er ejendommeligt ved, at det har den almene formel 10 [Tc99m(CN-A-0-R)6] i hvilken A er en ligekædet eller forgrenet alkylgruppe, og R er en ligekædet eller forgrenet alkylgruppe, forudsat, at 15 det samlede antal carbonatomer i A plus R er 4-6, endvidere forudsat, at når det totale antal carbonatomer i A plus R er 6, er carbonatomet i α-stilling i forhold til isonitril-gruppen et kvaternært carbonatom, og endvidere forudsat, at A ikke er (CH2)3- 20 Sættet ifølge opfindelsen til anvendelse ved dannelse af et radiomærket kompleks til brug ved afbildning af myocardium, omfattende i steril, ikke-pyrogen form (a) et præparat omfattende en forudbestemt mængde af en isonitrilforbindelse og (b) en forudbestemt mængde af et reduktionsmid-25 del, som er i stand til at reducere technetium, er ejendommeligt ved, at isonitrilforbindelsen er et ethersubstitueret isonitril med den almene formel CN-A-O-R (I) 30 i hvilken A er en ligekædet eller forgrenet alkylgruppe, og R er en ligekædet eller forgrenet alkylgruppe, forudsat, at det samlede antal carbonatomer i A plus R er 4-6, endvidere forudsat, at når det totale antal carbonatomer i A plus R 35 er 6, er carbonatomet i e-stilling i forhold til isonitril-gruppen et kvaternært carbonatom, og endvidere forudsat, at 4 ' DK 173003 B1 * "k A ikke er (CH2)3·
Opfindelsen angår som nævnt også anvendelsen af et sæt som ever.fer angivet ti] dannelse af et radiomærket kompleks med den almene formel 5 [Tc99m(CN—A-O-R)6] i hvilken CN-A-O-R er som angivet ovenfor.
De hidtil ukendte isonitriler kan let fremstilles 10 ved formylering af en alkoxyamin med den almene formel II til dannelse af det tilsvarende formamid med den almene formel III/ efterfulgt af dehydratisering til isonitrilet med den almene formel I:
15 ° H
h2n-a-or hc-n-a-o-r c n-a-o-r II III I
En række forskellige fremgangsmåder til udførelse af formyle-20 rings- og dehydratiseringsreaktionerne er beskrevet i litteraturen og er velkendte for fagfolk inden for den organiske syntese.
Aminerne med formlen II kan fremstilles ved forskellige fremgangsmåder, som er kendte for fagfolk. Især kan 25 aminerne fremstilles ved åbning af en aziridin med formlen IV med en alkohol i nærværelse af en sur katalysator til dannelse af en blanding af de to aminer med formlerne V og VI, som kan adskilles ved destillation: 30 R3 R1 f <κ/.· «o·» -tf· · “tir-.
; V £yre
H
iv v vi 35
Alternativt kan man fremstille aminerne ud fra alkoxyestere i , li \ DK 173003 B1 * 5 med formlen VII, hvor R' er en carbonhydridgruppe med 2 eller 3 carbonatomer. Dannelse af amidet med formlen VIII ved omsætning med ammoniak eller amrnoniumhycrcxid, efterfulgt, af reduktion med lithiumaluminiumhydrid eller et andet reduk-5 tionsmiddel, som vides at reducere amider, giver aminen med formlen IX.
, NH OH LiAlH
RO-A · -C02R3 —* - > . RO-A * -C0NH2 -RO~A *“^2^2
10 V-ΐ1· VIII IX
Aminerne med formlen II kan også fremstilles ud fra alkoxyesterne med formlen X. Dannelsen af amidet med formlen 15 XI forløber som ovenfor beskrevet. Amidet med formlen XI underkastes en Hofmann-omlejring, hvorved man får aminen med formlen II.
c Br 20 RO-A-CO^ -* RO-ACONH2 ~^ > RO-A-NH2
X XI ' ' II
25
Alternativt kan man fremstille etherisonitrilerne ud fra aminoalkoholer med formlen XII ved først at omsætte disse med et formyleringsmiddel, såsom ethylformiat eller myresyreacetanhydrid, til dannelse af formamid-formiatet med 30 formlen XIII. Omdannelse af formamid-formiatet til isonitril-formiatet med formlen XIV gennemføres derpå som allerede beskrevet for de andre formamider. Ved mild vandig hydrolyse af formiatet fås isonitril-alkoholen med formlen XV, som derpå kan alkyleres under standard-alkyleringsbetingelser, 35 såsom anvendelse af natriumhydrid og et methylhalogenid, såsom iodidet: DK 173003 B1 « o.
? J POCl- eller °
HO-A-NH2 -> HCO-A-NHCH ---> HCO-A-N=C
diphcsgen
.. Mi XIII XIV
5
Na-CO NaH
XIV ----—> HO-A-NEC -> BO-A-NEC
H-0 RX
XV X
De ethersubstituerede isonitriler, der er anvendelige io i forbindelse ned den foreliggende opfindelse, omfatter: cnch2ch2ch2och3: cnch2ch2ch2och2ch3 cnc(ch3)2och2ch3: cnc(ch3)2och3: CNCH2C{CH3)2OCH3: *' CNC{CH3)2CHzOCH3; 15 cnch{ch3)ch2och3: cnchcch3)ch2och2ch3: cnch2ch{ch3)och3: cnch2ch(ch3)Och2ch3: CNCH c CH3)CH c CH3)OCH3I CNC^CH(CH3)CH2OCH3: cnch2ch2ch(ch3)och3: cnch2ch2och c ch3)2: CNCH2CH2OCH2CH3; CNCH(CH3)OCH(CH3)2; 20 CNCH2CH(CH2CH3)OCH3; CNCH(CH2CH3)CH2OCH3: CNCH(CH3)CH2CH2OCH3; CNC C ch3)2ch2ch2och3.
Specifikke eksempler på fremstillingen af disse ether-substituerede isonitriler er angivet i det felgende.
25
Fremstilling 1
Syntese af l-methoxy-2-methylpropyl-2-amin og 2-methoxy-2- -methylpropyl-l-amin___ - 30 A· Syntese af 2,2-dimethylaziridin 10O g (1,12 mol) 2-amino-2-methyl-1-propanol opløses i 200 ml vand og anbringes i en 1000 ml rundbundet kolbe. Man opløser 100 g (1,12 mol) koncentreret svovlsyre i 200 ml vand og sætter opløsningen til amin-op løs ningen. Den frem-35
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81247085A | 1985-12-23 | 1985-12-23 | |
| US81247085 | 1985-12-23 | ||
| US92509186A | 1986-11-06 | 1986-11-06 | |
| US92509186 | 1986-11-06 |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK623886D0 DK623886D0 (da) | 1986-12-22 |
| DK623886A DK623886A (da) | 1987-06-24 |
| DK173003B1 true DK173003B1 (da) | 1999-11-01 |
Family
ID=27123612
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK198606238A DK173003B1 (da) | 1985-12-23 | 1986-12-22 | Ether-substituerede isonitriler, radiomærkede komplekser deraf og deres anvendelse |
Country Status (20)
| Country | Link |
|---|---|
| US (1) | US4988827A (da) |
| EP (1) | EP0233368B1 (da) |
| JP (2) | JPH0755914B2 (da) |
| KR (1) | KR940011456B1 (da) |
| CN (1) | CN1057470C (da) |
| AU (1) | AU594407B2 (da) |
| CA (1) | CA1305160C (da) |
| DE (1) | DE3673000D1 (da) |
| DK (1) | DK173003B1 (da) |
| ES (1) | ES2036171T3 (da) |
| FI (1) | FI91747C (da) |
| GR (1) | GR3000681T3 (da) |
| HU (1) | HU201301B (da) |
| ID (1) | ID1037B (da) |
| IE (1) | IE59758B1 (da) |
| IL (1) | IL81055A (da) |
| MX (1) | MX168821B (da) |
| NO (1) | NO166640C (da) |
| PT (1) | PT83996B (da) |
| SU (1) | SU1635903A3 (da) |
Families Citing this family (34)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5028699A (en) * | 1987-09-11 | 1991-07-02 | E. I. Du Pont De Nemours And Company | Process for preparing Tc-99m tris(isonitrile) copper complexes |
| US4885100A (en) * | 1987-09-11 | 1989-12-05 | E. I. Du Pont De Nemours And Company | Tris(isonitrile)copper(I) adducts for preparing radionuclide complexes |
| US5008418A (en) * | 1987-09-11 | 1991-04-16 | E. I. Du Pont De Nemours And Company | Tris(isonitrile)copper(I) adducts for preparing radionuclide complexes |
| US4864051A (en) * | 1988-09-02 | 1989-09-05 | E. R. Squibb & Sons, Inc. | Process for preparing 2-methoxyisobutylisonitrile |
| CA2085364A1 (en) * | 1990-06-18 | 1991-12-19 | Alfons M. Verbruggen | Metal-radionuclide complex comprising isonitrile ligands |
| US5210270A (en) * | 1991-11-25 | 1993-05-11 | Institute Of Nuclear Energy Research | Method for synthesis and 99m C labelling of 2-alkoxyisobutylisonitrile |
| US5420321A (en) * | 1993-08-03 | 1995-05-30 | The Du Pont Merck Pharmaceutical Company | Tris(isonitrile)copper(i) sulfates for preparing radionuclide complexes |
| DE4445004A1 (de) * | 1994-12-16 | 1996-06-20 | Consortium Elektrochem Ind | Zusammensetzung zur delokalisierten Kennzeichnung von Gegenständen, ihre Herstellung und Verwendung |
| US5961952A (en) * | 1996-01-24 | 1999-10-05 | Dupont Pharmaceuticals Company | 99m Tc-tertiary-butyl isonitrile as breast tumor imaging agents |
| US6416733B1 (en) | 1996-10-07 | 2002-07-09 | Bristol-Myers Squibb Pharma Company | Radiopharmaceuticals for imaging infection and inflammation |
| US20030124053A1 (en) * | 1996-10-07 | 2003-07-03 | Barrett John Andrew | Radiopharmaceuticals for imaging infection and inflammation |
| US6537520B1 (en) | 1998-03-31 | 2003-03-25 | Bristol-Myers Squibb Pharma Company | Pharmaceuticals for the imaging of angiogenic disorders |
| US6524553B2 (en) * | 1998-03-31 | 2003-02-25 | Bristol-Myers Squibb Pharma Company | Quinolone vitronectin receptor antagonist pharmaceuticals |
| US6548663B1 (en) | 1998-03-31 | 2003-04-15 | Bristol-Myers Squibb Pharma Company | Benzodiazepine vitronectin receptor antagonist pharmaceuticals |
| JP2002510705A (ja) | 1998-04-03 | 2002-04-09 | デュポン ファーマシューティカルズ カンパニー | 感染および炎症の撮像、ならびに癌の撮像および治療のための放射性医薬品 |
| TR200101757T2 (tr) | 1998-12-18 | 2001-12-21 | Dupont Pharmaceuticais Company | Vitronektin reseptör antagonisti farmasötikler |
| US6794518B1 (en) * | 1998-12-18 | 2004-09-21 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
| US6511649B1 (en) * | 1998-12-18 | 2003-01-28 | Thomas D. Harris | Vitronectin receptor antagonist pharmaceuticals |
| US6569402B1 (en) | 1998-12-18 | 2003-05-27 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
| US6511648B2 (en) | 1998-12-18 | 2003-01-28 | Bristol-Myers Squibb Pharma Company | Vitronectin receptor antagonist pharmaceuticals |
| US6656448B1 (en) | 2000-02-15 | 2003-12-02 | Bristol-Myers Squibb Pharma Company | Matrix metalloproteinase inhibitors |
| WO2001087354A2 (en) * | 2000-05-17 | 2001-11-22 | Bristol-Myers Squibb Pharma Company | Use of small molecule radioligands for diagnostic imaging |
| MXPA02000862A (es) * | 2000-06-01 | 2003-07-14 | Bristol Myers Squibb Pharma Co | Lactamas substituidas por succinatos ciclicos como inhibidores de la produccion de proteina abeta. |
| EP1347784A2 (en) | 2000-11-03 | 2003-10-01 | Bristol-Myers Squibb Pharma Company | Simultaneous dual isotope imaging of cardiac perfusion and cardiac inflammation |
| CN1136921C (zh) * | 2001-04-27 | 2004-02-04 | 北京师范大学 | 一种心肌显像剂及其制备方法 |
| US20090062256A1 (en) * | 2001-06-01 | 2009-03-05 | Bristol-Myers Squibb Pharma Company | LACTAMS SUBSTITUTED BY CYCLIC SUCCINATES AS INHIBITORS OF Abeta PROTEIN PRODUCTION |
| RU2186834C1 (ru) * | 2001-06-22 | 2002-08-10 | Быстров Владимир Николаевич | Металлоплакирующая присадка к смазочным композициям |
| US6838074B2 (en) | 2001-08-08 | 2005-01-04 | Bristol-Myers Squibb Company | Simultaneous imaging of cardiac perfusion and a vitronectin receptor targeted imaging agent |
| EP1423152A4 (en) * | 2001-08-08 | 2006-12-27 | Bristol Myers Squibb Pharma Co | SIMULTANEOUS PRESENTATION OF THE HEART PERFUSION AND IMAGING MEDICINE WITH VITRONECTIN RECEPTOR AS TARGET |
| US20050106100A1 (en) * | 2003-09-03 | 2005-05-19 | Harris Thomas D. | Compounds containing matrix metalloproteinase substrates and methods of their use |
| KR20080022588A (ko) * | 2005-06-30 | 2008-03-11 | 브리스톨-마이어스 스퀴브 파마 컴퍼니 | 영상화제로서의 히드라지드 컨쥬게이트 |
| WO2007123934A2 (en) * | 2006-04-19 | 2007-11-01 | The General Hospital Corporation | Aryl bidentate isonitriles and their uses |
| US7563920B2 (en) | 2006-10-30 | 2009-07-21 | Draximage Limited | Methods for preparing 2-methoxyisobutylisonitrile and tetrakis(2-methoxyisobutylisonitrile)copper(I) tetrafluoroborate |
| EP2821394A1 (en) * | 2013-07-01 | 2015-01-07 | Fundacion MEDINA. Centro de Excelencia en Investigacion de Medicamentos Innovadores en Andalucia | Compounds with antibacterial activity |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1215142B (de) * | 1964-07-09 | 1966-04-28 | Bayer Ag | Verfahren zur Herstellung von araliphatischen Isonitrilen |
| GB1187755A (en) * | 1968-02-24 | 1970-04-15 | Bayer Ag | A Process for the Production of Isonitriles |
| DE1962898A1 (de) * | 1969-12-16 | 1971-06-24 | Bayer Ag | Verfahren zur Herstellung von Isonitrilen |
| JPS57165370A (en) * | 1981-03-18 | 1982-10-12 | Ici Ltd | Triazole or imidazole compounds, manufacture and fungicidal or plant growth regulant agent |
| US4347251A (en) * | 1981-07-13 | 1982-08-31 | American Cyanamid Company | Novel 3-substituted amino-1-substituted heteroaryl-2-pyrazolines |
| US4452774A (en) * | 1982-04-30 | 1984-06-05 | President And Fellows Of Harvard College | Isonitrile radionuclide complexes for labelling and imaging agents |
| DE3343673A1 (de) * | 1983-12-02 | 1985-09-05 | Basf Ag, 6700 Ludwigshafen | Verfahren zur gleichzeitigen herstellung von nitrilen und acrylamid bzw. methacrylamid |
| US4707544A (en) * | 1984-11-28 | 1987-11-17 | President And Fellows Of Harvard College | Metal-isonitrile adducts for preparing radionuclide complexes for labelling and imaging agents |
| US4735793A (en) * | 1985-08-30 | 1988-04-05 | Massachusetts Institute Of Technology | Carboxy, carboalkoxy and carbamile substituted isonitrile radionuclide complexes |
-
1986
- 1986-12-16 CA CA000525461A patent/CA1305160C/en not_active Expired - Lifetime
- 1986-12-20 DE DE8686117847T patent/DE3673000D1/de not_active Expired - Lifetime
- 1986-12-20 EP EP86117847A patent/EP0233368B1/en not_active Expired - Lifetime
- 1986-12-20 ES ES86117847T patent/ES2036171T3/es not_active Expired - Lifetime
- 1986-12-22 HU HU865398A patent/HU201301B/hu unknown
- 1986-12-22 NO NO865247A patent/NO166640C/no unknown
- 1986-12-22 ID IDP355186A patent/ID1037B/id unknown
- 1986-12-22 PT PT83996A patent/PT83996B/pt active IP Right Revival
- 1986-12-22 DK DK198606238A patent/DK173003B1/da not_active IP Right Cessation
- 1986-12-22 IL IL81055A patent/IL81055A/xx not_active IP Right Cessation
- 1986-12-22 FI FI865260A patent/FI91747C/fi not_active IP Right Cessation
- 1986-12-22 MX MX004749A patent/MX168821B/es unknown
- 1986-12-22 IE IE335386A patent/IE59758B1/en not_active IP Right Cessation
- 1986-12-22 AU AU66842/86A patent/AU594407B2/en not_active Expired
- 1986-12-22 JP JP61304069A patent/JPH0755914B2/ja not_active Expired - Lifetime
- 1986-12-22 CN CN91105401A patent/CN1057470C/zh not_active Expired - Lifetime
- 1986-12-22 KR KR1019860011046A patent/KR940011456B1/ko not_active Expired - Lifetime
-
1987
- 1987-06-01 US US07/056,003 patent/US4988827A/en not_active Expired - Lifetime
-
1989
- 1989-01-09 SU SU894613202A patent/SU1635903A3/ru active
-
1990
- 1990-07-27 GR GR90400540T patent/GR3000681T3/el unknown
-
1994
- 1994-09-22 JP JP6227693A patent/JP2774940B2/ja not_active Expired - Lifetime
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| B1 | Patent granted (law 1993) | ||
| PUP | Patent expired |