NO317788B1 - Paramagnetic 3-, 8-substituted deuteroporphine derivatives, pharmaceutical compositions containing them, processes for their preparation and their use in magnetic resonance imaging of necrosis and infarction - Google Patents
Paramagnetic 3-, 8-substituted deuteroporphine derivatives, pharmaceutical compositions containing them, processes for their preparation and their use in magnetic resonance imaging of necrosis and infarction Download PDFInfo
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- NO317788B1 NO317788B1 NO20010392A NO20010392A NO317788B1 NO 317788 B1 NO317788 B1 NO 317788B1 NO 20010392 A NO20010392 A NO 20010392A NO 20010392 A NO20010392 A NO 20010392A NO 317788 B1 NO317788 B1 NO 317788B1
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- 206010061216 Infarction Diseases 0.000 title claims abstract description 28
- 230000007574 infarction Effects 0.000 title claims abstract description 28
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
-
- 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
Abstract
Description
Oppfinnelsen angår gjenstanden kjennetegnet i patentkravene, dvs. para- The invention relates to the object characterized in the patent claims, i.e. para-
magnetiske 3-, 8-substituerte deuteroporfyirnderivater, farmasøytiske preparater inneholdende disse, fremgangsmåter for fremstilling av slike og anvendelse av disse ved MR-avbildning av nekroser og infarkt. magnetic 3-, 8-substituted deuteroporphyrin derivatives, pharmaceutical preparations containing these, methods for producing such and their use in MR imaging of necrosis and infarction.
Påvisning, lokalisering og kontroll av nekroser eller infarkt er et viktig område Detection, localization and control of necrosis or infarction is an important area
innen medisin. Slik er ikke myokardinfarktet en stasjonær prosess, snarere en dynamisk prosess, som strekker seg over et lengre tidsrom, fra uker til måneder. Infarktet forløper i faser som ikke er sterkt adskilt fra hverandre, men heller overlapper hverandre. Den første fase, utviklingen av myokardinfarktet, omfatter de 24 timene etter infarktet, der forstyrrelsen sprer seg som en bølge fra endokard til myokard. Den andre fasen, det allerede inntrufne infarkt, omfatter stabilisering av området der fiberdannelse (fibrose) in medicine. Thus, the myocardial infarction is not a stationary process, rather a dynamic process, which extends over a longer period of time, from weeks to months. The infarction proceeds in phases that are not strongly separated from each other, but rather overlap. The first phase, the development of the myocardial infarction, comprises the 24 hours after the infarction, during which the disturbance spreads like a wave from the endocardium to the myocardium. The second phase, the infarction that has already occurred, includes stabilization of the area where fiber formation (fibrosis)
oppstår som en del av helingsprosessen. Den tredje fasen, helingen av infarktet, begynner etter at alt ødelagt vev erstattes gjennom fibrøst arrvev. I denne perioden finner det sted en omfangsrik vevsomtrukturering. occurs as part of the healing process. The third phase, the healing of the infarct, begins after all damaged tissue is replaced by fibrous scar tissue. During this period, extensive tissue restructuring takes place.
Hittil er ingen presis og pålitelig fremgangsmåte kjent, som gjør de aktuelle faser So far, no precise and reliable method is known, which makes the phases in question
i et myokardinfarkt påvisbare hos levende pasienter. For vurdering av et myokardinfarkt er det av avgjørende betydning å vite hvor stor andel vev som er gått tapt (mistet) ved infarktet og på hvilket sted tapet inntreffer, da behandlingsformen avhenger av denne kunnskap. Infarkt inntreffer ikke bare i myokard, men også i andre vev, da særlig i hjernen. in a myocardial infarction detectable in living patients. For the assessment of a myocardial infarction, it is of crucial importance to know what proportion of tissue has been lost (lost) during the infarction and where the loss occurs, as the form of treatment depends on this knowledge. Infarction occurs not only in the myocardium, but also in other tissues, especially in the brain.
Mens infarkt til en viss grad kan helbredes, kan bare de skadelige følger for den resterende organisme forhindres eller i det minste formildes ved en nekrose med lokalt begrenset vevsdød. Nekrosen kan oppstå på flere måter: Ved sår, kjemikalier, oksygen-mangel eller stråling. While infarction can be healed to some extent, only the harmful consequences for the remaining organism can be prevented or at least mitigated by a necrosis with locally limited tissue death. Necrosis can occur in several ways: through wounds, chemicals, lack of oxygen or radiation.
Som ved infarkt, er kunnskap om omfang og type nekrose viktig for den videre medisinske behandling. Ganske tidlig ble det utført forsøk på å forbedre deteksjon og lokalisering av infarkt og nekrose ved administrering av kontrastmidler ved ikke-invasive fremgangsmåter som scintigrafi eller MR. I litteraturen innhar forsøkene på å admini- As with infarction, knowledge of the extent and type of necrosis is important for further medical treatment. Quite early on, attempts were made to improve the detection and localization of infarction and necrosis by the administration of contrast agents by non-invasive methods such as scintigraphy or MRI. In the literature, the attempts to administer
strere porfyrin for nekroseavbildning en stor plass. De oppnådde resultater viser imidler- strain porphyrin for necrosis imaging a large space. However, the obtained results show
tid et motstridende bilde. time a contradictory image.
Slik beskriver Winkelmann og Hayes i Nature 200,903 (1967) at Mn-5,10,15,20- This is how Winkelmann and Hayes describe in Nature 200,903 (1967) that Mn-5,10,15,20-
tetrakis (4-sulfonatfenyl)-porfyrin (TPPS) selektivt anrikes i nekrotiske deler av en tumor. Lyon et al., Magn. Res. Med. 4,24 (1987) observerte derimot at Mn-TPPS . tetrakis (4-sulfonatephenyl)-porphyrin (TPPS) is selectively enriched in necrotic parts of a tumor. Lyon et al., Magn. Res. With. 4.24 (1987), on the other hand, observed that Mn-TPPS .
fordelte seg i kroppen, og riktignok i nyre, lever, tumor og bare i en liten del i muskelen. Interessant er det dermed at konsentrasjonen i tumor først på den 4. dagen når sitt distributed in the body, and indeed in the kidney, liver, tumor and only in a small part in the muscle. It is therefore interesting that the concentration in the tumor only reaches its peak on the 4th day
maksimum og bare etter at forskeren har øket dosen til 0,2 mmol/kg. Forfatteren skriver derfor også om et tydelig uspesifikt opptak av TPPS i tumoren. maximum and only after the researcher has increased the dose to 0.2 mmol/kg. The author therefore also writes about a clearly non-specific uptake of TPPS in the tumour.
Bockhorst et al., beskriver videre i Acta Neurochir. 1994 [Suppl.] 60,347, at MnTPPS bindes selektivt til tumorceller. Foster et al., J. Nucl. Med. 26,756 (1985), fant på sin side at In-111 5,10,15,20-tetrakis (4-N-metyl-pyirdin)-porfyrin (TMPyP) ikke ble anriket i nekrotiske områder, men i den levende randsonen. Bockhorst et al., further describe in Acta Neurochir. 1994 [Suppl.] 60,347, that MnTPPS binds selectively to tumor cells. Foster et al., J. Nucl. With. 26,756 (1985), in turn found that In-111 5,10,15,20-tetrakis(4-N-methyl-pyridine)-porphyrin (TMPyP) was not enriched in necrotic areas, but in the living marginal zone.
Derav sluttes, at det eksisterer en porfyrintype vevsavhengig vekselvirkning, men den er ikke avgjørende. It is therefore concluded that a porphyrin-type tissue-dependent interaction exists, but it is not decisive.
I Circulation, Vol. 90, nr. 4,1994, del 2, s.1468, abstr. nr. 2512, beskriver Ni et al., at de med et Mn-tetrafenyl-porfyrin (Mn-TPP) og et Gd-Mesporfyrin (Gd-MP) tydelig kan avbilde infarktområder. In Circulation, Vol. 90, No. 4, 1994, part 2, p. 1468, abstr. no. 2512, Ni et al. describe that with a Mn-tetraphenyl-porphyrin (Mn-TPP) and a Gd-Mesporphyrin (Gd-MP) they can clearly image infarct areas.
Begge substanser er formål ved patent WO 95/31219. Ved scintograiffremgangs-måter ligger den administrerte dose i nanomolområdet. Substansens kompatibilitet spiller bare en underordnet rolle. Ved MR-avbildning ligger dosen imidlertid i millimolområdet. Her spiller kompabilitet en ganske avgjørende rolle. Both substances are the subject of patent WO 95/31219. In the case of scintografic methods, the administered dose is in the nanomolar range. The compatibility of the substance plays only a minor role. In MR imaging, however, the dose is in the millimolar range. Compatibility plays a rather decisive role here.
Den lave akutte forenlighet (LD50) målt for MnTPP eller MnTPPS utelukker deres anvendelse på mennesker. The low acute compatibility (LD50) measured for MnTPP or MnTPPS precludes their application to humans.
Hertil kommer at porfyrin, og også for eksempel mesoporfyrin, har tendens til å bli lagret i huden, hvilket medfører en fotosensibilisering. Denne sensibilisering kan vare i dager, ja opptil uker. Ved scintigrafiske fremgangsmåter ville denne effekt som en følge av den lave dose være uten betydning. Ved en bred anvendelse av scintigrafiske fremgangsmåter er det allikevel av betydning at oppløsningen til et gamma-kamera er mye dårligere enn det som oppnås ved MR-avbildning. In addition, porphyrin, and also for example mesoporphyrin, tend to be stored in the skin, which causes photosensitisation. This sensitization can last for days, even weeks. In the case of scintigraphic procedures, this effect would be insignificant as a result of the low dose. In the case of a wide application of scintigraphic methods, it is nevertheless important that the resolution of a gamma camera is much worse than that achieved by MR imaging.
Ved MR-avbildning av myokardinfarkt ble også GD-komplekser av DTPA (K. Bockhorst et al., Acta Neurochir. (1997) Suppl., 60:347-349); De Roos et al.,Radiology 1989; 172:717-720) og deres bis (metylamider) (M. Saced et al., Radiology, 1992; 182:675-683) anvendt. Det viste seg at begge kontrastmidler bare i et lite tidsvindu kunne differensiere mellom frisk vev og infarktvev. Sammenlignbare resultater ble også opp-nådd med manganforbindelsen DTPA (Immunomedics, WO 94/22490) og DPDP (Radiology 1989; 172:59-64). In MR imaging of myocardial infarction, GD complexes were also of DTPA (K. Bockhorst et al., Acta Neurochir. (1997) Suppl., 60:347-349); De Roos et al., Radiology 1989; 172:717-720) and their bis(methylamides) (M. Saced et al., Radiology, 1992; 182:675-683) used. It turned out that both contrast media could only differentiate between healthy tissue and infarcted tissue in a small time window. Comparable results were also obtained with the manganese compound DTPA (Immunomedics, WO 94/22490) and DPDP (Radiology 1989; 172:59-64).
En betydelig forbedring oppnådde Weissleder et al., Radiology 1992; 182:675-683, som koplet antimyosin til jernoksid (MION). På grunn av dens spesifikke struktur er dette kontrastmiddel ikke egnet for nekroseavbildning. A significant improvement was achieved by Weissleder et al., Radiology 1992; 182:675-683, which coupled antimyosin to iron oxide (MION). Due to its specific structure, this contrast agent is not suitable for necrosis imaging.
Det er derfor et klart behov for å ha forbindelser til MR-infarkt- og -nekroseavbildning som: There is therefore a clear need to have links to MR infarct and necrosis imaging such as:
har god forenlighet, has good compatibility,
ikke er fototoksisk, is not phototoxic,
er kjemisk stabil, is chemically stable,
utskilles fullstendig, excreted completely,
anrikes i nekroser, enriched in necroses,
ikke anrikes i hud, not enriched in skin,
har høy relaksivitet, has high relaxivity,
viser en høy vannløselighet, shows a high water solubility,
gir et bredt tidsvindu for måling, og provides a wide time window for measurement, and
muliggjør en god differensiering mellom friskt vev og nekrotisk vev/infarktvev. enables a good differentiation between healthy tissue and necrotic tissue/infarct tissue.
Det er overraskende funnet at porfyrinkomplekser bestående av én ligand med den generelle formel I It has surprisingly been found that porphyrin complexes consisting of one ligand of the general formula I
så vel som minst et ion av et element med atomnummer 20-32,37-39,42-51 eller 57-83, der as well as at least one ion of an element with atomic number 20-32,37-39,42-51 or 57-83, where
M betegner et paramagnetisk ion, M denotes a paramagnetic ion,
R<1> betegner et hydrogenatom, en rettkjedet Ci-C6-alkylrest, en C7-C12- R<1> denotes a hydrogen atom, a straight-chain Ci-C6 alkyl radical, a C7-C12-
aralkylrest eller en OR' gruppe der aralkyl residue or an OR' group there
R' betegner et hydrogenatom eller en Ci-C3-alkylrest, R' denotes a hydrogen atom or a Ci-C3 alkyl residue,
R<2> betegner R<3>, en -CO-Z-gruppc eller en -(NH)0-(A)q-NH-D -gruppe, der Z er en -OL-gruppe, der L betegner et uorganisk eller organisk kation eller en C|-C4-alkylrest, R<2> denotes R<3>, a -CO-Z groupc or a -(NH)0-(A)q-NH-D -group, where Z is an -OL group, where L denotes an inorganic or organic cation or a C1-C4 alkyl residue,
A betegner en fenylenoksy- eller en Ci-Cu-alkylen- eller CrCi2-aralkylengruppe avbrutt A denotes a phenyleneoxy or a Ci-Cu-alkylene or CrCi2-aralkylene group interrupted
med ett eller flere oksygenatomer, with one or more oxygen atoms,
o og q betegner uavhengige tallet 0 eller 1 og o and q denote independent numbers 0 or 1 and
D betegner et hydrogenatom eller en -CO-A-CCOOLVtH),,, -gruppe der m er Hk 0 eller 1 D denotes a hydrogen atom or a -CO-A-CCOOLVtH),,, -group where m is Hk 0 or 1
under forutsetning av at summen av m og o er 1, under the assumption that the sum of m and o is 1,
R<3> betegner en -(C=Q)(NR<4>)0-(A)q-(NR<5>)-K -gruppe der R<3> denotes a -(C=Q)(NR<4>)0-(A)q-(NR<5>)-K group where
Q betegner ett oksygenatom eller to hydrogenatomer, Q denotes one oxygen atom or two hydrogen atoms,
R<4> betegner en -(A)q-H -gruppe og R<4> denotes a -(A)q-H group and
K er en kompleksdanner av den generelle formel (Ila), (Ilb), (lic), (Ild) eller (Ile) hvor R<5> i det tilfelle at K er en kompleksdanner av formel (Ila) har den samme betydning som R<4> og R<5> i det tilfelle at K er en kompleksdanner av formel (Ilb), (Tic), (Ild) eller (Ile) har samme betydning som D, med den forutsetning at direkte oksygen-nitrogenbinding ikke tillates, og K betegner en kompleksdanner av den generelle formel (Ila), (Ilb), (lic), (Ild), (Ile) eller (Hf) K is a complex former of the general formula (Ila), (Ilb), (lic), (Ild) or (Ile) where R<5> in the case that K is a complex former of formula (Ila) has the same meaning as R<4> and R<5> in the event that K is a complexing agent of formula (Ilb), (Tic), (Ild) or (Ile) have the same meaning as D, with the proviso that direct oxygen-nitrogen bonding is not allowed , and K denotes a complexing agent of the general formula (Ila), (Ilb), (lic), (Ild), (Ile) or (Hf)
der there
q har den ovennevnte betydning, q has the above meaning,
A<1> har den angitte betydning for A, A<1> has the specified meaning for A,
R<6> betegner et hydrogenatom, en rettkjedet eller forgrenet Ci-C7-alkylgruppe, R<6> denotes a hydrogen atom, a straight-chain or branched Ci-C7 alkyl group,
en fenyl- eller benzylgruppe, a phenyl or benzyl group,
A2 betegner fenylen-, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-P-, -CeH^CHCHjWP, A2 denotes phenylene-, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-P-, -CeH^CHCHjWP,
-C6H4-(OGH2CH2)o.,-N(CH2COOH)-CH2-p, -C6H4-(OGH2CH2)o.,-N(CH2COOH)-CH2-p,
eller en Ci-Ci2-alkylen- eller C7-C12-alkylengruppe som eventuelt er avbrutt med en eller flere oksygenatomer, 1 til 3 NHCO-, 1 til 3 CONH-grupper og/eller substituert med 1 til 3-(CH2VsCOOH-grupper, der p betegner or a Ci-Ci2-alkylene or C7-C12-alkylene group which is optionally interrupted by one or more oxygen atoms, 1 to 3 NHCO, 1 to 3 CONH groups and/or substituted by 1 to 3-(CH2VsCOOH groups, where p denotes
bindingsstedet til X, the binding site of X,
X betegner en -CO- eller NHCS-gruppe og X denotes a -CO or NHCS group and
L1, L2, L3 og L<4> betegner uavhengig av hverandre et hydrogenatom eller en metallion-ekvivalent av et element med de ovennevnte atomnummer, under den forutsetning at minst to av disse substituenter betegner metallionekvivalenter, og at for å utlikne eventuelt forekommende ladninger i metallporfyrin foreligger ytterligere anioner, og der frie karbonsyregrupper som ikke er nødvendige for kompleksering også kan foreligge som salter med fysiologisk akseptable uorganiske og/eller organiske kationer eller som estere eller amider, L1, L2, L3 and L<4> independently denote a hydrogen atom or a metal ion equivalent of an element with the above atomic numbers, under the condition that at least two of these substituents denote metal ion equivalents, and that in order to equalize any charges in metal porphyrin additional anions are present, and where free carboxylic acid groups that are not necessary for complexation can also be present as salts with physiologically acceptable inorganic and/or organic cations or as esters or amides,
er overraskende egnet for MR-avbildning av nekrose og infarkt. De oppfyller kravene som stilles til slike forbindelser (de kan også anvendes ved behandlingskontroll ved fotodynamisk terapi (PDT). is surprisingly suitable for MR imaging of necrosis and infarction. They meet the requirements set for such compounds (they can also be used for treatment control in photodynamic therapy (PDT).
Porfyrinkompleksene ifølge oppfinnelsen inneholder som paramagnetiskt ion i porfyrinskjelettet jern (III)-, mangan (III)-, kobber (II)-, kobolt (TII)-, krom (III)-, nikkel (II)- eller vanadyl (Il)-ion, der de tre førstnevnte er foretrukket. The porphyrin complexes according to the invention contain iron (III), manganese (III), copper (II), cobalt (TII), chromium (III), nickel (II) or vanadyl (II) as a paramagnetic ion in the porphyrin skeleton. ion, where the first three are preferred.
Overraskende viste kompleksene ifølge oppfinnelsen en betydelig høyere relaksivitet i forhold til de lenge kjente, strukturelt like forbindelser. Da relaksivitet kan anses som et mål for kontrastmiddeleffektiviteten til en forbindelse, lyktes det kompleksforbindelsene ifølge oppfinnelsen å oppnå, i NMR-diagnostikkområdet, en sammen-liknbar, positiv signalpåvirkning allerede ved en lav dose. Derigjennom øker sikkerhets-avstanden betydelig til det som kan ansees retningsgivende verdi for produktet når det gjelder relaksivitet og forenlighet. Surprisingly, the complexes according to the invention showed a significantly higher relaxivity compared to the long-known, structurally similar compounds. Since relaxivity can be considered a measure of the contrast agent effectiveness of a compound, the complex compounds according to the invention succeeded in achieving, in the NMR diagnostic area, a comparable, positive signal influence already at a low dose. As a result, the safety distance increases significantly to what can be considered an indicative value for the product in terms of relaxivity and compatibility.
Hvis et av ionene bundet i porfyrin har et oksidasjonstall høyere enn +2, blir overskuddsladningen utliknet gjennom anioner fra organiske eller uorganiske syrer, fortrinnsvis gjennom acetat-, klorid-, sulfat-, nitrat-, tartrat-, suksinat- og maleationer eller gjennom de negative ladninger som forefinnes i R<2> og/eller R<3>. If one of the ions bound in the porphyrin has an oxidation number higher than +2, the excess charge is balanced through anions from organic or inorganic acids, preferably through acetate, chloride, sulfate, nitrate, tartrate, succinate and maleate ions or through the negative charges present in R<2> and/or R<3>.
Fortrinnsvis kan karboksylgruppen som ikke er nødvendig for kompleksering av metallionet foreligge som ester, som amid eller som salter av uorganiske eller organiske baser. Egnede esterrester er slike med 1 til 6 C-atomer, fortrinnsvis etylester; egnede uorganiske kationer er for eksempel litium- og kaliumioner og i særdeleshet natriumionet. Egnede kationiske organiske baser er slike fra primære, sekundære eller tertiære aminer, som for eksempel etanolamin, dietanolamin, morfolin, glukamin, Preferably, the carboxyl group which is not necessary for complexation of the metal ion can be present as an ester, as an amide or as salts of inorganic or organic bases. Suitable ester residues are those with 1 to 6 C atoms, preferably ethyl esters; suitable inorganic cations are, for example, lithium and potassium ions and in particular the sodium ion. Suitable cationic organic bases are those from primary, secondary or tertiary amines, such as for example ethanolamine, diethanolamine, morpholine, glucamine,
N, N-dimetylglukamin, i særdeleshet meglumin. N,N-dimethylglucamine, in particular meglumine.
Fortrinnsvis betegner R<2> og R<3> gruppene -CONHNHK, -CONH(CH2)2NHK, Preferably, R<2> and R<3> denote the groups -CONHNHK, -CONH(CH2)2NHK,
-CONH(CH2)3NHK, -CONH(CH2)4NHK og -CONH(CH2)20(CH2)2NHKJ der den første gruppen foretrekkes, R<2>, R<3> betegner fortrinnsvis den samme resten. A2 betegner fortrinnsvis en alkylen-, -CH2-, -(CH^-, -CH2OC6H4-P, -CH2OCH2-, - C6IU-, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-13-, -C6H4-OCHr<p-> eller -C<^-OHC2CH2-N(CH2COOH)CT2-P-gnippe, der p betegner bindingsstedet til X. X betegner fortrinnsvis CO-gruppen. -CONH(CH2)3NHK, -CONH(CH2)4NHK and -CONH(CH2)20(CH2)2NHKJ where the first group is preferred, R<2>, R<3> preferably denote the same residue. A2 preferably denotes an alkylene-, -CH2-, -(CH^-, -CH2OC6H4-P, -CH2OCH2-, -C6IU-, -CH2-NHCO-CH2-CH(CH2COOH)-C6H4-13-, -C6H4- OCHr<p-> or -C<^-OHC2CH2-N(CH2COOH)CT2-P group, where p denotes the binding site of X. X preferably denotes the CO group.
R<6> betegner fortrinnsvis et hydrogenatom eller en metylgruppe. R<6> preferably denotes a hydrogen atom or a methyl group.
Fortrinnsvis betegner A Preferably denotes A
q betegner fortrinnsvis tallet 0. q preferably denotes the number 0.
Særlig foretrukne forbindelser er Particularly preferred compounds are
{mu-[{16,16'-[klormangan(III)-7,12-dietyl-3, 8,13,17-ettrametylporfyrin-2,18-diyl]- {mu-[{16,16'-[chloromanganese(III)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-
bis[3, 6,9-tris(karboksymetyl)-ll, 14-diokso-3,6,9,12,13-pentaazaheksadecan-oato]} (8-)]} -digadolinato(2-),-dinatrium, {mu[{16,16'-[klorjern(in)-7,12-dietyl-3, 8,13,17-tetrametylporfyrin-2,18-diyl]-bis[3, 6,9-tris(karboksymetyl)-ll, 14-diokso-3, 6,9,12,13-pentaazaheksadecanoato]}(8-)]}-digadolinato(2-),-dinatrium, bis[3,6,9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]} (8-)]}-digadolinato(2-),-disodium, {mu[{16,16'-[chloroiron(yne)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis[3,6,9-tris(carboxymethyl) -ll, 14-dioxo-3, 6,9,12,13-pentaazhexadecanoato]}(8-)]}-digadolinato(2-),-disodium,
{mu-[{16,16'-[kobber(H)-7,12-dietyl-3,8,13,17-teti^etylporfyrin-2,18-diyl]-bis[3, 6,9-tris(karboksymetyl)-ll, 14-diokso-3,6,9,12,13-pentaazaheksadecanoato]}(8-)]}-digadolinato(2-),-dinatrium. {mu-[{16,16'-[copper(H)-7,12-diethyl-3,8,13,17-tethi^ethylporphyrin-2,18-diyl]-bis[3,6,9-tris (carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]}(8-)]}-digadolinato(2-),-disodium.
Som kompleksdannerrest K nevnes fortrinnsvis derivater av dietyltriaminpentaeddiksyre og l,4,7,10-tetraazaayklododekan-l,4,7-trieddiksyre, som bindes gjennom en linker til porfyrinet. As complex-forming residue K, mention is preferably made of derivatives of diethyltriaminepentaacetic acid and 1,4,7,10-tetraazaacyclododecane-1,4,7-triacetic acid, which are bound through a linker to the porphyrin.
Fremstillingen av kompleksforbindelsene med den generelle formel I utføres The preparation of the complex compounds of the general formula I is carried out
etter fremgangsmåter kjent fra litteraturen (se for eksempel DE 4232925 for II a og II b; according to methods known from the literature (see for example DE 4232925 for II a and II b;
f. eks. DE 19507822, DE 19580858 og DE 19507819 for III c; B. US-5 053 503, WO 96/02669, WO 96/01655, EP 0430863, EP 255471, US-5 277 895, EP 0232751, US-4 885 363 for Ild, Ue og Hf). e.g. DE 19507822, DE 19580858 and DE 19507819 for III c; B. US-5 053 503, WO 96/02669, WO 96/01655, EP 0430863, EP 255471, US-5 277 895, EP 0232751, US-4 885 363 for Ild, Ue and Hf).
Forbindelsene der R<2> og R<3> betegner CONHNHK-gruppen er foretrukket. Syntesen som for det benytter aduktet 3, 3'-(7,12-dietyl-3, 8,13,17-tetrametylporfyrin-2,18-diyl)di(propanhydrazid) blir beskrevet i Z. Physiol. Chem. 24_1,209 (1936). The compounds in which R<2> and R<3> denote the CONHNHK group are preferred. The synthesis using the adduct 3,3'-(7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl)di(propanehydrazide) is described in Z. Physiol. Chem. 24_1,209 (1936).
Innføringen av det ønskede metall (for eksempel Mn) i porfyrinet skjer ifølge fremgangsmåter kjent fra litteraturen (se The Porphyrins, red. D. Dolphin, Academic Press, New York 1980, vol. V, s. 459; DE 4232925), der det i hovedsak nevnes: a) substitusjon av pyrol-NH (ved oppvarming av den metallfrie ligand med det tilsvarende metallsalt, fortrinnsvis acetat, eventuelt under tilsetning av syrebuffrende The introduction of the desired metal (for example Mn) into the porphyrin takes place according to methods known from the literature (see The Porphyrins, ed. D. Dolphin, Academic Press, New York 1980, vol. V, p. 459; DE 4232925), where mainly mentioned: a) substitution of pyrrole-NH (by heating the metal-free ligand with the corresponding metal salt, preferably acetate, optionally with the addition of acid-buffering
midler, som for eksempel natriumacetat, i et polart løsningsmiddel) eller agents, such as sodium acetate, in a polar solvent) or
b) omkompleksering, ved at et allerede ligandkompleksert metall fortrenges av det ønskede metall. b) re-complexation, whereby an already ligand-complexed metal is displaced by the desired metal.
Alle polare løsningsmidler som for eksempel metanol, iseddik, dimetylformamid, kloroform og vann er egnet som løsningsmiddel. All polar solvents such as methanol, glacial acetic acid, dimethylformamide, chloroform and water are suitable as solvents.
Innføring av det paramagnetiske metall M i porfyrinsystemet kan skje før eller etter binding av kompleksdannerresten K. Derigjennom muliggjøres en særdeles fleksibel fremgangsmåte for syntesen av forbindelsene ifølge oppfinnelsen. Introduction of the paramagnetic metal M into the porphyrin system can take place before or after binding of the complex-forming residue K. This enables a particularly flexible method for the synthesis of the compounds according to the invention.
Gelateringen av resten K utføres ifølge fremgangsmåte kjent fra litteraturen (se for eksempel DE 34 01 052) idet metalloksidet eller -saltet (for eksempel nitratet, acetatet, karbonatet, kloridet eller sulfatet) til det ønskede metall suspenderes eller løses i polare løsningsmidler som vann eller vandig alkohol og reageres med den tilsvarende mengde av kompleksdannende ligand. Etter ønske kan tilgjengelige, sure hydrogenatomer eller syregrupper substitueres ved kationer fra uorganiske og /eller organiske baser eller aminosyrer. The gelation of the residue K is carried out according to a method known from the literature (see for example DE 34 01 052), whereby the metal oxide or salt (for example the nitrate, acetate, carbonate, chloride or sulphate) of the desired metal is suspended or dissolved in polar solvents such as water or aqueous alcohol and is reacted with the corresponding amount of complexing ligand. If desired, available acidic hydrogen atoms or acid groups can be substituted by cations from inorganic and/or organic bases or amino acids.
Nøytraliseringen utføres deretter ved hjelp av uorganiske baser som for eksempel alkali- eller jordalkalihydroksider, -karbonater eller bikarbonater og/eller organsike baser som blant annet primære, sekundære og tertiære aminer, som for eksempel etanolamin, morfolin, glukamin, N-metyl- og N, N-dimetylglukamin, så vel som basiske aminosyrer, som for eksempel lysin, arginin og ornitin eller fra opprinnelige nøytrale amider eller sure aminosyrer. The neutralization is then carried out using inorganic bases such as alkali or alkaline earth hydroxides, carbonates or bicarbonates and/or organic bases such as primary, secondary and tertiary amines, such as ethanolamine, morpholine, glucamine, N-methyl- and N , N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine or from original neutral amides or acidic amino acids.
For fremstilling av nøytrale kompleksforbindelser kan man for eksempel tilsette det sure komplekssaltet i vandig løsning eller suspensjon så vel som den ønskede base, slik at nøytraliseirngspunktet oppnås. Den resulterende løsning kan deretter tørkes i vakuum. Vanligvis er det en fordel å utfelle de dannede nøytrale salter gjennom tilsetting av løsningsmidler som er blandbare med vann, som for eksempel lavere alkoholer (for eksempel metanol, etanol, isopropanol), lavere ketoner (for eksempel aceton), polare etere (for eksempel tetrahydrofuran, dioksan, 1,2-dimetoksyetan) og dermed oppnå lett isolerbare og godt rensede krystaller. Det har vist seg å være en særlig fordel å tilsette den ønskede base allerede under kompleksdannelsen i reaksjonsblandingen og derigjennom innspare et fremgangsmåtetrinn. For the production of neutral complex compounds, one can, for example, add the acidic complex salt in aqueous solution or suspension as well as the desired base, so that the neutralization point is achieved. The resulting solution can then be dried under vacuum. Generally, it is advantageous to precipitate the formed neutral salts through the addition of solvents that are miscible with water, such as for example lower alcohols (for example methanol, ethanol, isopropanol), lower ketones (for example acetone), polar ethers (for example tetrahydrofuran , dioxane, 1,2-dimethoxyethane) and thus obtain easily isolated and well-purified crystals. It has proven to be a particular advantage to add the desired base already during complex formation in the reaction mixture and thereby save a process step.
Inneholder de sure kompleksforbindelsene flere frie syregrupper, er det ofte hensiktsmessig å fremstille nøytrale blandingssalter som inneholder så vel uorganiske som også organiske kationer som motioner. If the acidic complex compounds contain several free acid groups, it is often appropriate to prepare neutral mixed salts that contain inorganic as well as organic cations such as counterions.
Det kan for eksempel skje idet man reagerer den kompleksdannende ligand i vandig suspensjon eller løsning med oksidet eller saltet til elementet som frigir sentral-ionet og ved hjelp av den nødvendige mengde av en organisk base for nøytralisering, der det dannede komplekssalt isoleres, og om nødvendig renses og deretter fortsette til fullstendig nøytralisering med den nødvendige mengde uorganisk base. Rekkefølgen på tilsetting av base kan også være omvendt. This can happen, for example, by reacting the complex-forming ligand in aqueous suspension or solution with the oxide or salt of the element that releases the central ion and with the help of the necessary amount of an organic base for neutralization, where the formed complex salt is isolated, and if necessary cleaned and then proceed to complete neutralization with the required amount of inorganic base. The order of addition of base can also be reversed.
En annen mulighet for å komme til nøytrale kompleksforbindelser består i å overføre de gjenværende syregruppene i komplekset fullstendig eller delvis til ester. Dette kan skje ved etterfølgende reaksjoner på det ferdige kompleks (for eksempel ved reaksjon med dimetylsulfat som forbruker de frie karboksygruppene). Another possibility for arriving at neutral complex compounds consists in transferring the remaining acid groups in the complex completely or partially to esters. This can happen by subsequent reactions on the finished complex (for example by reaction with dimethylsulphate which consumes the free carboxyl groups).
Fremstilling av de farmasøytiske preparater utføres eventuelt på en kjent måte, idet kompleksforbindelsene ifølge oppfinnelsen, eventuelt under tilsetning av galenisk vanlige additiver, suspenderes eller løses i vandig medium, eventuelt etterfulgt av sterili-sering av suspensjonen eller løsningen. Egnede additiver er for eksempel fysiologisk akseptable buffere (f. eks. trometamin), små tilsetninger av kompleksdannere (f. eks. dietyltriaminpentaeddiksyre) eller om nødvendig elektrolytter som for eksempel natriumklorid eller antioksydanter som for eksempel askorbinsyre. Production of the pharmaceutical preparations is optionally carried out in a known manner, with the complex compounds according to the invention, optionally with the addition of galenically common additives, suspended or dissolved in an aqueous medium, optionally followed by sterilization of the suspension or solution. Suitable additives are, for example, physiologically acceptable buffers (e.g. tromethamine), small additions of complex formers (e.g. diethyltriaminepentaacetic acid) or, if necessary, electrolytes such as sodium chloride or antioxidants such as ascorbic acid.
Ønskes det for enteral administrering eller av andre årsaker, suspensjoner eller løsninger av preparatene ifølge oppfinnelsen i vann eller i fysiologisk saltløsning, blandes de med en eller flere galenisk vanlige hjelpestoffer (f. eks. metylcellulose, laktose, mannit), og /eller tensider (f. eks. lecitin, 'Tween", "Myrj") og/eller aromatiske stoffer for smaksregulering (f. eks. eteriske oljer). If it is desired for enteral administration or for other reasons, suspensions or solutions of the preparations according to the invention in water or in physiological salt solution, they are mixed with one or more galenically common excipients (e.g. methylcellulose, lactose, mannitol), and/or surfactants ( e.g. lecithin, 'Tween", "Myrj") and/or aromatic substances for flavor regulation (e.g. essential oils).
Prinsipielt er det også mulig å fremstille de farmasøytiske preparater ifølge oppfinnelsen uten isolering av komplekssaltet. I det tilfellet må spesiell forsiktighet utøves for å foreta chelatdannelsen slik at saltet og saltløsningen ifølge oppfinnelsen praktisk talt er fri for ikke-kompleksérte, toksisk virkende metallioner. In principle, it is also possible to prepare the pharmaceutical preparations according to the invention without isolating the complex salt. In that case, special care must be exercised to carry out the chelation so that the salt and the salt solution according to the invention are practically free of non-complexed, toxic-acting metal ions.
Dette kan for eksempel garanteres ved hjelp av fargeindikatorer som xylen-oransje ved kontrolltitrering under fremstillingsprosessen. Oppfinnelsen angår også fremgangsmåter for fremstilling av kompleksforbindelsene og deres salter. Som en siste sikkerhet foretas en rensing av de isolerte komplekssalt. This can, for example, be guaranteed by means of color indicators such as xylene orange in control titrations during the manufacturing process. The invention also relates to methods for producing the complex compounds and their salts. As a last precaution, a purification of the isolated complex salt is carried out.
De farmasøytiske preparater ifølge oppfinnelsen inneholder fortrinnsvis 20 umol/1 til 200 mmol/1 av komplekssaltet og blir som regel dosert i en mengde fra 1 umol til 2 mmol/kg kroppsvekt, så vel ved anvendelse ved MR-avbildning av nekroser og infarkt som ved behandlingskontroll ved hjelp av MRI-diagnostikk. De kan anvendes ved enterale og parenterale applikasjoner eller appliseres ved intervensjonene radiologifrem-gangsmåter. The pharmaceutical preparations according to the invention preferably contain 20 umol/1 to 200 mmol/1 of the complex salt and are usually dosed in an amount from 1 umol to 2 mmol/kg body weight, as well as when used in MR imaging of necrosis and infarction as well as in treatment control using MRI diagnostics. They can be used for enteral and parenteral applications or applied for interventional radiology procedures.
Preparatene ifølge oppfinnelsen oppfyller de mangfoldige forutsetninger som " gjør preparatet egnet som MRI-kontrastmiddel. Slik er de særdeles egnet til å forbedre påliteligheten av uttalelser etter applikasjon ved forhøyelse av signalintensiteten ved hjelp av bilder fremkommet fra kjemespinntomografen. Videre viser de høy effektivitet, som er nødvendig for at kroppen skal bli belastet med minst mulig mengde fremmed-stoff, og god forenlighet som er nødvendig for å opprettholde den ikke-invasive karakter ved undersøkelsen. The preparations according to the invention fulfill the diverse requirements which "make the preparation suitable as an MRI contrast agent. Thus, they are particularly suitable for improving the reliability of statements after application by increasing the signal intensity with the help of images obtained from the chemical spin tomograph. Furthermore, they show high efficiency, which is necessary for the body to be burdened with the least possible amount of foreign matter, and good compatibility which is necessary to maintain the non-invasive nature of the examination.
Forbindelsene med den generelle formel I er også egnet for avbilding av intravasalrommet (blood-pool). The compounds of the general formula I are also suitable for imaging the intravascular space (blood pool).
Den gode vannløselighet av preparatene ifølge oppfinnelsen tillater at det fremstilles høykonsentrerte løsninger, dermed holdes volumbelastningen på kretsløpet innen forsvarlige grenser og fortynning gjennom kroppsvæsker utjevnes. Videre viser preparatene ifølge oppfinnelsen ikke bare en høy stabilitet in vitro, men også en overraskende høy stabilitet in vivo, slik at en frigivelse av eller en utveksling av toksiske ioner som ikke er kovalent bundet i komplekset innenfor det tidsrom at kontrastmiddelet fullstendig er utskilt, er neglisjerbart. The good water solubility of the preparations according to the invention allows highly concentrated solutions to be prepared, thereby keeping the volume load on the circuit within reasonable limits and dilution through body fluids is equalised. Furthermore, the preparations according to the invention not only show a high stability in vitro, but also a surprisingly high stability in vivo, so that a release of or an exchange of toxic ions that are not covalently bound in the complex within the time period that the contrast agent is completely secreted, is negligible.
Oppfinnelsen forklares ved de følgende eksempler. The invention is explained by the following examples.
Eksempel 1 Example 1
a) Acetat [7, 12-dietyl-3,8,13,17-tetrametylporfyirn-2,18-dipropionylhydrazinat(2-)-KN21, K N22, KN23, K N24]-jern a) Acetate [7, 12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-dipropionylhydrazinate(2-)-KN21, KN22, KN23, KN24]-iron
1190 mg (2 mmol) 3,3'-(7,12-metyl-3,8,13,17-tetrametylporfyirn-2,18-diyl)-di(propanhydrazid), fremstilles analogt med H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241_,209 (1936), og 706,36 mg (2 mmol) jern(III)-acetyl-acetonat ble oppvarmet i 150 ml eddiksyre/100 ml kloroform i 5 timer ved 70 °C. 1190 mg (2 mmol) 3,3'-(7,12-methyl-3,8,13,17-tetramethylporphyrin-2,18-diyl)-di(propanehydrazide), prepared analogously to H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241_,209 (1936), and 706.36 mg (2 mmol) of ferric acetylacetonate was heated in 150 ml acetic acid/100 ml chloroform for 5 hours at 70 °C.
Deretter ble det inndampet i vakuum, resten oppslemmet i vann, filtrert og vasket med vann. Det tørkede, urensede produkt ble omkrystallisert fra pyridin/dietyleter. Utbytte: 1,25 g (89 % av teoretisk) rødbrunt pulver. It was then evaporated in vacuo, the residue slurried in water, filtered and washed with water. The dried, crude product was recrystallized from pyridine/diethyl ether. Yield: 1.25 g (89% of theory) red-brown powder.
Elementanalyse: Elemental Analysis:
beregnet: C 61,10 H6,12 N 15,84 Fe 7,89 calculated: C 61.10 H6.12 N 15.84 Fe 7.89
funnet: C 60,95 H6,31 N 15,70 Fe 7,68 found: C 60.95 H6.31 N 15.70 Fe 7.68
b) Acetat [7,12-dietyl-3,8,13,17-teytrametyl-2,18-bis{3,6,16-triokso-8,l 1,14-tris(karboksymetyl) 17-oksa-4,5,8,l l,14-pentaazanonadec-l-yl}porfyinato (3-)]-jern b) Acetate [7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,16-trioxo-8,1 1,14-tris(carboxymethyl) 17-oxa-4 ,5,8,l l,14-pentaazanodec-l-yl}porphyinato (3-)]-iron
806,8 mg (2 mmol) 3-etoksy-lrarbonylmetyl-6-[2-(2,6-dioksomorfolin)etyl]-3,6-diazaoktandisyre (DTPA-monoetylester-monoanhydrid) ble suspendert i 250 ml absolutt dimetylformamid. Det ble overlagt med nitrogen, tilsatt 1,0 g (10 mmol) trietylamin og 707 mg (1 mmol) av tittelforbindelsen fra eksempel la og den resulterende reaksjonsblanding ble omrørt i 3 dager ved romtemperatur. Etter endt reaksjon ble det filtrert, løsningsmiddelet fjernet i vakuum og den dannede olje finfordelt med 500 ml dietyleter. Det utfelte faste stoff ble filtrert og vasket med dietyleter og n-heksan. For å rense ble en kiselgel RP-18 kromatografert (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,62 g (93 % av teoretisk) rødbrunt pulver. Vanninnhold: 5,2 % 806.8 mg (2 mmol) of 3-ethoxy-1-carbonylmethyl-6-[2-(2,6-dioxomorpholine)ethyl]-3,6-diazaoctanoic acid (DTPA monoethyl ester monoanhydride) was suspended in 250 ml of absolute dimethylformamide. It was blanketed with nitrogen, 1.0 g (10 mmol) of triethylamine and 707 mg (1 mmol) of the title compound from Example 1a were added and the resulting reaction mixture was stirred for 3 days at room temperature. After completion of the reaction, it was filtered, the solvent removed in vacuo and the resulting oil finely divided with 500 ml of diethyl ether. The precipitated solid was filtered and washed with diethyl ether and n-hexane. To purify, a silica gel RP-18 was chromatographed (eluent: H 2 O/tetrahydrofuran: 0-30%). Yield: 1.62 g (93% of theory) red-brown powder. Water content: 5.2%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 53,93 H6,19 N12,95 Fe 3,69 funnet: C 53,75 H6,37 N 12,81 Fe 3,49 c) Klor[7,12-dietyl-3,8,13,17-tetrametyl-2,18-bis{3,6,18-triokso-8,l 1,14-tris(karbolcsymetyl)-4,5,8,ll,14-pentaazaheksadekanoato}porfi 1,59 g (0,660 mmol) av liganden fremstilt under for eksempel lb ble løst i 400 ml vann. Ved tilsetting av 10 molar vandig natronlut ble pH justert til 13 og blandingen omrørt i 5 timer ved romtemperatur. Etter gjennomføring av forsåpning av estergruppen ble pH justert til 3 med konsentrert saltsyre. Deretter inndampet til tørrhet i vakuum. Resten ble kromatografert på kieselgel RP-18 (elueringsmiddel: HzO/terrahydrofuran/gradient). Utbytte: 0,89 g (95 % av teoretisk) rødbrunt pulver. calculated: C 53.93 H6.19 N12.95 Fe 3.69 found: C 53.75 H6.37 N 12.81 Fe 3.49 c) Chloro[7,12-diethyl-3,8,13,17 -tetramethyl-2,18-bis{3,6,18-trioxo-8,11,14-tris(carbolcoxymethyl)-4,5,8,11,14-pentaazhexadecanoato}porphy 1.59 g (0.660 mmol) of the ligand prepared under, for example, lb was dissolved in 400 ml of water. By adding 10 molar aqueous caustic soda, the pH was adjusted to 13 and the mixture stirred for 5 hours at room temperature. After carrying out saponification of the ester group, the pH was adjusted to 3 with concentrated hydrochloric acid. Then evaporated to dryness in vacuo. The residue was chromatographed on silica gel RP-18 (eluent: HzO/terrahydrofuran/gradient). Yield: 0.89 g (95% of theory) red-brown powder.
Vanninnhold: 6,1 % Water content: 6.1%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 51,90 H5,76 N 13,67 Fe 3,89 Cl 2,47 calculated: C 51.90 H5.76 N 13.67 Fe 3.89 Cl 2.47
funnet: C 51,75 H 5,88 N 13,54 Fe 3,75 Cl 2,38 found: C 51.75 H 5.88 N 13.54 Fe 3.75 Cl 2.38
d) {mu-[ {16,16' -[klorjem(III)-7,12-dietyl-3,8,l 3,17-tetrametylporfyrin-2,l 8-diyl]-bis[3,6,9-tris(karboksymetyl)-11,14-diokso-3,6,9,12,13-pentaazaheksadekanoato]} (8-)]} - d) {mu-[ {16,16'-[chloroene(III)-7,12-diethyl-3,8,1 3,17-tetramethylporphyrin-2,1 8-diyl]-bis[3,6,9 -tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]} (8-)]} -
digadolinato(2-), dinatrium digadolinato(2-), disodium
0,86 g (0,599 mmol) av liganden fremstilt ved eksempel lc ble løst i 400 ml vann og vekselvis porsjonsvis tilsatt 316,3 mg (1,2 mmol) gadoliniumklorid og 2N vandig natronlut, slik at pH-verdien i reaksjonsblandingen varierte mellom 6,8 og 7,2. Når alt gadoliniumklorid er tilsatt omrøres det hele over natten ved romtemperatur. Ved 0.86 g (0.599 mmol) of the ligand prepared in example 1c was dissolved in 400 ml of water and 316.3 mg (1.2 mmol) of gadolinium chloride and 2N aqueous sodium hydroxide solution were added alternately in portions, so that the pH value in the reaction mixture varied between .8 and 7.2. When all the gadolinium chloride has been added, the whole thing is stirred overnight at room temperature. By
bearbeiding ble løsningsmiddelet fjernet ved vakuum og resten kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte. 1,04 g (98 % av teoretisk) rødbrunt pulver. Vanninnhold: 6,9 % work-up, the solvent was removed under vacuum and the residue chromatographed on silica gel RP-18 (eluent: H20/tetrahydrofuran: 0-30%). Dividend. 1.04 g (98% of theory) reddish-brown powder. Water content: 6.9%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 41,67 H4,17 N 10,97 Gd 17,60 Fe 3,13 Cl 1,98 Na 2,61 funnet: C 41,48 H4,32 N 10,80 Gd 17,43 Fe 3,07 Cl 1,78 Na 2,38 calculated: C 41.67 H4.17 N 10.97 Gd 17.60 Fe 3.13 Cl 1.98 Na 2.61 found: C 41.48 H4.32 N 10.80 Gd 17.43 Fe 3.07 Cl 1.78 Na 2.38
Eksempel 2 Example 2
a) Acetat [7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-dopropionyl-hydrazinato(2-)-K N21, K N22, KN23, K N24]-mangan a) Acetate [7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-dopropionyl-hydrazinato(2-)-K N21, K N22, KN23, K N24]-manganese
1190 mg (2 mmol) 3,3'-(7,12-dietyl-3,8,13,17-tetrametylporfyirn-2,18-diyl)-di(propanhydrazid), fremstilt analogt med H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), og 704,5 mg (2 mmol) mangan(III)-acetylacetonat-dihydrat ble oppvarmet i 150 ml eddiksyre/100 ml kloroform i 5 timer ved 80 °C. Deretter inndampet i vakuum, resten oppslemmet i vann, filtrert og vasket med vann. Det tørkede, urensede produkt ble omkrystallisert på pyridin/dietyleter. Utbytte: 1,29 g (91 % av teoretisk) rødbrunt pulver 1190 mg (2 mmol) 3,3'-(7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl)-di(propanehydrazide), prepared analogously to H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), and 704.5 mg (2 mmol) of manganese(III) acetylacetonate dihydrate was heated in 150 ml acetic acid/100 ml chloroform for 5 h at 80 °C. Then evaporated in vacuo, the residue slurried in water, filtered and washed with water. The dried, crude product was recrystallized from pyridine/diethyl ether. Yield: 1.29 g (91% of theory) red-brown powder
Elementanalyse: Elemental analysis:
beregnet: C 61,18 H6,13 N15,86 Mn 7,77 calculated: C 61.18 H6.13 N15.86 Mn 7.77
funnet: C 61,03 H6,29 N 15,75 Mn 7,58 found: C 61.03 H6.29 N 15.75 Mn 7.58
b) Acetat [7,12-dietyl-3,8,13,17-tetrametyl-2,18-bis {3,6,18-triokso-8,ll,14-trisfkarboksymetyl) 17-oksa-4,5,8,11,14-pentaazanonadec-1 -yl}porfyrinato(3-)]-mangan b) Acetate [7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,18-trioxo-8,11,14-triscarboxymethyl) 17-oxa-4,5, 8,11,14-pentaazanonadec-1-yl}porphyrinato(3-)]-manganese
806,8 mg (2 mmol) 3-etoksy-karbonmetyl-6-[2-(2,6-Æoksomorfolino)etyl]-3,6-diazaoktandi-syre (DTPA-monoetylester-monoanhydrid) ble suspendert i 250 ml absolutt dimetylformamid. Overlagt med nitrogen, tilsatt 1,0 g (10 mmol) trietylamin og 706 mg (lmmol) av tittelforbindelsen fra eksempel 2a og reaksjonsblandingen ble omrørt i 3 dager ved romtemperatur. Etter endt reaksjon ble løsningen filtrert, løsningsmiddelet fjernet i vakuum og den dannede olje finfordelt i 500 ml dietyleter. Det utfelte, faste stoff ble filtrert og vasket med dietyleter og N-heksan. For å rense ble det kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,35 g (89 % av teoretisk) rødbrunt pulver. Vanninnhold: 5,9 % 806.8 mg (2 mmol) of 3-ethoxy-carbonmethyl-6-[2-(2,6-Ooxomorpholino)ethyl]-3,6-diazaoctanedioic acid (DTPA monoethyl ester monoanhydride) was suspended in 250 ml of absolute dimethylformamide . Overhead with nitrogen, added 1.0 g (10 mmol) of triethylamine and 706 mg (lmmol) of the title compound from Example 2a and the reaction mixture was stirred for 3 days at room temperature. After completion of the reaction, the solution was filtered, the solvent removed in vacuo and the resulting oil finely divided in 500 ml of diethyl ether. The precipitated solid was filtered and washed with diethyl ether and N-hexane. To purify, it was chromatographed on silica gel RP-18 (eluent: H2O/tetrahydrofuran: 0-30%). Yield: 1.35 g (89% of theory) red-brown powder. Water content: 5.9%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 53,96 H6,19 N 12,96 Mn 3,63 calculated: C 53.96 H6.19 N 12.96 Mn 3.63
funnet: C 53,83 H6,34 N 12,81 Mn 3,49 found: C 53.83 H6.34 N 12.81 Mn 3.49
c) Klor {[7,12-dietyl-3,8,13,17-tetrametyl-2,18-bis{3,6,18-triokso-8,l 1,14-tris(karboksymetyl)-4,5,8,l 1,14-pentaazaheksadekanoato}porfinato(3-)]-mangan c) Chloro {[7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,18-trioxo-8,1 1,14-tris(carboxymethyl)-4,5 ,8,l 1,14-pentaazhexadecanoato}porphinato(3-)]-manganese
1,31 g (0,865 mmol) av liganden fremstilt i eksempel 2b ble løst i 400 ml vann. Ved tilsetting av 10-molar vandig natronlut ble pH justert til 13 og omrørt i 5 timer ved romtemperatur. Etter utført forsåpning av estergruppen ble pH justert til 3 med konsentrert saltsyre. Deretter inndampet til tørrhet i vakuum. Resten ble kromatografert på kieselgel RP-18 (elueringsmiddel: H20/te1rahydrofuran/gradient). Utbytte: 1.31 g (0.865 mmol) of the ligand prepared in example 2b was dissolved in 400 ml of water. By adding 10-molar aqueous caustic soda, the pH was adjusted to 13 and stirred for 5 hours at room temperature. After saponification of the ester group, the pH was adjusted to 3 with concentrated hydrochloric acid. Then evaporated to dryness in vacuo. The residue was chromatographed on silica gel RP-18 (eluent: H 2 O/tetrahydrofuran/gradient). Dividend:
1,15 g (93 % av teoretisk) rødbrunt pulver. Vanninnhold: 7,2 % 1.15 g (93% of theory) red-brown powder. Water content: 7.2%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C51,93 H5,76 NI3,68 Mn3,83 Cl2,47 calculated: C51.93 H5.76 NI3.68 Mn3.83 Cl2.47
funnet: C 51,81 H 5,93 N 13,49 Mn 3,70 Cl 2,32 found: C 51.81 H 5.93 N 13.49 Mn 3.70 Cl 2.32
d) {mu-[{16,16'-[klormangan(IIi)-7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl]-bis [3,6,9-tris(karboksymetyl)-11,14-diokso-3,6,9,12,13 -pentaazaheksadekanoato]} (8-)]} -digadolinato(2-), -dinatrium d) {mu-[{16,16'-[chloromanganese(IIi)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis [3,6,9-tris (carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]} (8-)]}-digadolinato(2-), -disodium
1,12 g (0,781 mmol) av liganden fremstilt under eksempel 2c ble løst i 400 ml vann og vekselvis tilsatt posrsjonsvis 411,8 mg (1,56 mmol) gadoliniumklorid og 2N vandig natronlut, slik at pH-verdien i reaksjonsblandingen varierte mellom 6,8 og 7,2. Når alt gadoliniumklorid var tilsatt ble blandingen omrørt over natten ved romtemperatur. For opparbeiding ble løsningsmiddelet fjernet i vakuum og resten kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,35 g (97 % av teoretisk) rødbrunt pulver. Vanninnhold: 6,5 % 1.12 g (0.781 mmol) of the ligand prepared under example 2c was dissolved in 400 ml of water and 411.8 mg (1.56 mmol) of gadolinium chloride and 2N aqueous caustic soda were alternately added, so that the pH value in the reaction mixture varied between 6 .8 and 7.2. When all the gadolinium chloride had been added, the mixture was stirred overnight at room temperature. For work-up, the solvent was removed in vacuo and the residue chromatographed on silica gel RP-18 (eluent: H20/tetrahydrofuran: 0-30%). Yield: 1.35 g (97% of theory) red-brown powder. Water content: 6.5%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 41,69 H 4,18 N 10,98 Gd 17,61 Mn 3,08 Cl 1,98 Na 2,57 funnet: C 41,48 H4,33 N 10,81 Gd 17,50 Mn 2,89 Cl 1,85 Na 2,34 calculated: C 41.69 H 4.18 N 10.98 Gd 17.61 Mn 3.08 Cl 1.98 Na 2.57 found: C 41.48 H4.33 N 10.81 Gd 17.50 Mn 2, 89 Cl 1.85 Na 2.34
Eksempel 3 Example 3
a) Acetat[7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-dipropionylhydrazinato(2-)-K N21, KN22, KN23, KN24]-kobolt 1190 mg (2 mmol) 3,3'-(7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl)-di(propanhydrazid), fremstilt analogt med H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), og 712,52 mg (2 mmol) kobolt(ffl)-acetylacetonat ble oppvarmet i 150 ml eddiksyre/100 ml kloroform i 5 timer ved 80 °C. Deretter inndampet i vakuum, resten oppslemmet i vann, filtrert og vasket med vann. Det tørkede, urensede produkt ble omkrystallisert på pyridin/dietyleter. Utbytte: 1,31 g (92 % av teoretisk) rødbrunt pulver. a) Acetate [7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-dipropionylhydrazinato(2-)-K N21, KN22, KN23, KN24]-cobalt 1190 mg (2 mmol) 3.3 '-(7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl)-di(propanehydrazide), prepared analogously to H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), and 712.52 mg (2 mmol) cobalt(ffl)-acetylacetonate was heated in 150 ml acetic acid/100 ml chloroform for 5 h at 80 °C. Then evaporated in vacuo, the residue slurried in water, filtered and washed with water. The dried, crude product was recrystallized from pyridine/diethyl ether. Yield: 1.31 g (92% of theory) red-brown powder.
Elementanalyse: Elemental analysis:
beregnet: C 60,84 H6,10 N 15,77 Co 8,29 calculated: C 60.84 H6.10 N 15.77 Co 8.29
funnet: C 60,71 H 6,29 N 15,58 Co 8,14 found: C 60.71 H 6.29 N 15.58 Co 8.14
b) Acetat[7,12-dietyl-3,8,13,17-tetrametyl-2,l8-bis{3,6,18-triokso-8,l 1,14-tris(karboksymetyl)-l 7-oksa-4,5,8,11,14-pentaazanonadec-l-yl}porfinato(3-)]-kobolt b) Acetate[7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,18-trioxo-8,11,14-tris(carboxymethyl)-17-oxa -4,5,8,11,14-pentaazanodec-1-yl}porphinato(3-)]-cobalt
806,8 mg (2 mmol) 3-etoksy-karbonylmetyl-6-[2-(2,6-dioksomorfolin)etyl]-3,6-diaza octandi-syre (DTPA-monoetylester-monoanhydrid) ble suspendert i 250 ml absolutt dimetylformamid. Overlagt med nitrogen, tilsatt 1,0 g (10 mmol) trietylamin og 710 mg (1 mmol) av tittelforbindelsen fra eksempel 3a og blandingen ble omrørt i 3 dager ved romtemperatur. Etter endt reaksjon ble det hele filtrert, løsningsmiddelet 806.8 mg (2 mmol) of 3-ethoxy-carbonylmethyl-6-[2-(2,6-dioxomorpholine)ethyl]-3,6-diaza octandioic acid (DTPA monoethyl ester monoanhydride) was suspended in 250 ml of absolute dimethylformamide. Overhead with nitrogen, added 1.0 g (10 mmol) of triethylamine and 710 mg (1 mmol) of the title compound from Example 3a and the mixture was stirred for 3 days at room temperature. After the end of the reaction, the whole thing was filtered, the solvent
fjernet i vakuum og den dannede olje ble polert med 500 ml dietyleter. Det utfelte, faste stoff ble filtrert og vasket med dietyleter og n-heksan. For å rense ble det removed in vacuo and the oil formed was polished with 500 ml of diethyl ether. The precipitated solid was filtered and washed with diethyl ether and n-hexane. To clean it was
kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,32 g (87 % av teoretisk) rødbrunt pulver. Vanninnhold 6,7 % chromatographed on silica gel RP-18 (eluent: H2O/tetrahydrofuran: 0-30%). Yield: 1.32 g (87% of theory) red-brown powder. Water content 6.7%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 53,82 H6,18 N 12,92 Co 3,88 funnet: C 53,72 H6,35 N 12,81 Co 3,69 c) Klor [7,12-dietyl-3,8,13,17-tetrametyl-2,l8-bis{3,6,18-triokso-8,l 1,14-tris(karboksymetyl)-4,5,8s 11,14-pentaazaheksadecanoato}porfinato(3-)]-kobolt 1,28 g (0,844 mmol) av liganden fremstilt under eksempel 3b ble løst i 400 ml vann. Ved tilsetting av 10-molar vandig natronlut ble pH justert til 13 og det hele omrørt i 5 timer ved romtemperatur. Etter fullstendig forsåpning av estergmppen ble pH justert til 3 med konsentrert saltsyre. Inndampet til tørrhet ved vakuum. Resten ble kromatografert på en kieselgel RP-18 (elueringsmiddel: HiO/tetrahydrofuran/gradient). Utbytte: 1,15 g (95 % av teoretisk) rødbrunt pulver. calculated: C 53.82 H6.18 N 12.92 Co 3.88 found: C 53.72 H6.35 N 12.81 Co 3.69 c) Chlorine [7,12-diethyl-3,8,13, 17-tetramethyl-2,18-bis{3,6,18-trioxo-8,11,14-tris(carboxymethyl)-4,5,8s 11,14-pentaazazhexadecanoato}porphinato(3-)]-cobalt 1 .28 g (0.844 mmol) of the ligand prepared under example 3b was dissolved in 400 ml of water. By adding 10-molar aqueous caustic soda, the pH was adjusted to 13 and the whole was stirred for 5 hours at room temperature. After complete saponification of the ester group, the pH was adjusted to 3 with concentrated hydrochloric acid. Evaporated to dryness under vacuum. The residue was chromatographed on a silica gel RP-18 (eluent: H1O/tetrahydrofuran/gradient). Yield: 1.15 g (95% of theory) red-brown powder.
Vanninnhold: 4,9 % Water content: 4.9%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 51,79 H5,75 N 13,64 Co 4,10 Cl 2,47 calculated: C 51.79 H5.75 N 13.64 Co 4.10 Cl 2.47
funnet: C 51,60 H 5,89 N 13,51 Co 3,97 Cl 2,35 found: C 51.60 H 5.89 N 13.51 Co 3.97 Cl 2.35
d) {mu-[ {16,16'-[klorkobolt(ni)-7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl]-bis[3,6,9-tris(l^olcsymetyl)-ll,14-diokso-3,6,9,12,13-pentaazaheksadekanoato]} (8-)]} -digadolinato(2-), -dinatrium d) {mu-[ {16,16'-[chlorocobalt(ni)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis[3,6,9-tris (1^olccymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]} (8-)]}-digadolinato(2-), -disodium
1,12g (0,779 mmol) av liganden fremstilt under eksempel 3c ble løst i 400 ml vann og tilsatt vekslende porsjonsvis 410,6 mg (1,59 mmol) gadoliniumklorid og 2N vandig natrolut, slik at pH-verdien i reaksjonsblandingen varierte mellom 6,8 og 7,2. Når alt gadoliniumklorid var tilsatt ble det hele omrørt over natten ved romtemperatur. For opparbeiding ble løsningsmiddelet fjernet ved vakuum og resten kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,34 g (96 % av teoretisk) rødbrunt pulver. Vanninnhold 7,8 % 1.12g (0.779 mmol) of the ligand prepared under example 3c was dissolved in 400 ml of water and 410.6 mg (1.59 mmol) of gadolinium chloride and 2N aqueous sodium hydroxide were added in alternating portions, so that the pH value in the reaction mixture varied between 6, 8 and 7.2. When all the gadolinium chloride had been added, it was all stirred overnight at room temperature. For work-up, the solvent was removed under vacuum and the residue chromatographed on silica gel RP-18 (eluent: H2O/tetrahydrofuran: 0-30%). Yield: 1.34 g (96% of theory) red-brown powder. Water content 7.8%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 41,59 H4,17 N 10,95 Gd 17,57 Co 3,29 Cl 1,98 Na 2,57 funnet: C 41,48 H4,32 N 10,84 Gd 17,43 Co 3,14 Cl 1,81 Na 2,31 calculated: C 41.59 H4.17 N 10.95 Gd 17.57 Co 3.29 Cl 1.98 Na 2.57 found: C 41.48 H4.32 N 10.84 Gd 17.43 Co 3.14 Cl 1.81 Na 2.31
Eksempel 4 Example 4
a) [7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-dipropionylhydrazinato(2->K N21, K N22, K N23, K N24]-kobber a) [7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-dipropionylhydrazinato(2->K N21, K N22, K N23, K N24)-copper
1190 mg (2 mmol) 3,3^(7,12-dietyl-3,8,13,17-tetrametylporfyirn-2,18-diyl)-di(propanhydrazid), fremstilt analogt med H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), og 523,5 mg (2mmol) kobber(II)-acetylacetonat ble oppvarmet i 150 ml eddiksyre/100 ml kloroform i 5 timer ved 80 °C. Deretter inndampet i vakuum, resten oppslemmet i vann, filtrert og vasket med vann. Det tørkede urensede produkt ble omkrystallisert på pyridin/dietyleter. 1190 mg (2 mmol) 3,3^(7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl)-di(propanehydrazide), prepared analogously to H. Fischer, E. Haarer und F. Stadier, Z. Physiol. Chem. 241: 209; (1936), and 523.5 mg (2 mmol) of copper(II) acetylacetonate was heated in 150 ml acetic acid/100 ml chloroform for 5 h at 80 °C. Then evaporated in vacuo, the residue slurried in water, filtered and washed with water. The dried crude product was recrystallized from pyridine/diethyl ether.
Utbytte: 1,19 g (91 % av teoretisk) rødbrunt pulver. Yield: 1.19 g (91% of theory) red-brown powder.
Elementanalyse: Elemental Analysis:
beregnet: C 62,22 H6,14 N 17,07 Cu 9,68 calculated: C 62.22 H6.14 N 17.07 Cu 9.68
funnet: C 62,10 H6,33 N 16,92 Cu 9,51 found: C 62.10 H6.33 N 16.92 Cu 9.51
b) [7,12-dietyl-3,8,13,17-tetrametyl-2,18-bis {3,6,18-triokso-8,11,14-tris(karboksymetyl)-17-oksa-4,5,8,11,14-pentaazanonadec- l-yl}porfinato(2-)]-kobber b) [7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis {3,6,18-trioxo-8,11,14-tris(carboxymethyl)-17-oxa-4, 5,8,11,14-pentaazanodec-1-yl}porphinato(2-)]-copper
806,8 mg (2 mmol) 3-etoksy-karbonylmetyl-6-[2-(2,6-dioksomorfolin)etyl]-3,6-diaza octandi-syre (DTPA-monoetylester-monoanhydrid) ble suspendert i 250 ml 806.8 mg (2 mmol) of 3-ethoxycarbonylmethyl-6-[2-(2,6-dioxomorpholine)ethyl]-3,6-diaza octandioic acid (DTPA monoethyl ester monoanhydride) was suspended in 250 ml
absolutt dimetylformamid. Overlagt med nitrogen, tilsatt 1,01 g (10 mmol) trietylamin og 656 mg (1 mmol) av tittelforbindelsen fra eksempel 4a og den resulterende reaksjonsblanding ble omrørt ved romtemperatur i 3 dager. Etter endt reaksjon, filtrert, løsningsmiddelet fjernet i vakuum og den dannede olje polert med 500 ml dietyleter. Det utfelte, faste stoff ble filtrert og vasket med dietyleter og n-heksan. For å rense ble det hele kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,27 g (87 % av teoretisk) rødbrunt pulver. absolute dimethylformamide. Overlaid with nitrogen, 1.01 g (10 mmol) of triethylamine and 656 mg (1 mmol) of the title compound from Example 4a were added and the resulting reaction mixture was stirred at room temperature for 3 days. After completion of the reaction, filtered, the solvent removed in vacuo and the resulting oil polished with 500 ml of diethyl ether. The precipitated solid was filtered and washed with diethyl ether and n-hexane. For purification, the whole was chromatographed on silica gel RP-18 (eluent: H20/tetrahydrofuran: 0-30%). Yield: 1.27 g (87% of theory) red-brown powder.
Vanninnhold: 6,2 % Water content: 6.2%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 54,18 H6,20 N 13,40 Cu 4,34 calculated: C 54.18 H6.20 N 13.40 Cu 4.34
funnet: C 54,02 H6,31 N 13,29 Cu 4,18 found: C 54.02 H6.31 N 13.29 Cu 4.18
c) [7,12-dietyl-3,8,13,17-tetrametyl-2,18-bis{3,6,18-triokso-8,l 1,14-tris(karbolcsymetyl)-4,5,8,ll,14-pentaa2^ c) [7,12-diethyl-3,8,13,17-tetramethyl-2,18-bis{3,6,18-trioxo-8,1 1,14-tris(carboxymethyl)-4,5,8 ,11,14-pentaa2^
1,24 g (0,848 mmol) av liganden fremstilt under eksempel 4b ble løst i 400 ml vann. Ved tilsetting av 10-molar vandig natronlut ble pH justert til 13 og det hele omrørt i 5 timer ved romtemperatur. Etter fullstendig forsåpning av eiergruppen ble pH justert 1.24 g (0.848 mmol) of the ligand prepared under Example 4b was dissolved in 400 ml of water. By adding 10-molar aqueous caustic soda, the pH was adjusted to 13 and the whole was stirred for 5 hours at room temperature. After complete saponification of the ownership group, the pH was adjusted
til 3 med konsentrert saltsyre. Inndampet til tørrhet ved vakuum. Resten ble kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran/gradient). to 3 with concentrated hydrochloric acid. Evaporated to dryness under vacuum. The residue was chromatographed on silica gel RP-18 (eluent: H 2 O/tetrahydrofuran/gradient).
Utbytte: 1,15 g (96 % av teoretisk) rødbrunt pulver. Vanninnhold: 4,4 % Yield: 1.15 g (96% of theory) red-brown powder. Water content: 4.4%
Elementanalyse ( beregnet på vannfri substans): Elemental analysis (calculated for anhydrous substance):
beregnet: C 52,93 H 5,87 N 13,94 Cu 4,52 calculated: C 52.93 H 5.87 N 13.94 Cu 4.52
funnet: C 52,83 H6,04 N 13,85 Cu 4,38 found: C 52.83 H6.04 N 13.85 Cu 4.38
d) {mu-[ {16,16'-[kobber(n)-7,12-dietyl-3,8,l 3,17-tetrametylporfyrin-2,l 8-diyl]-bis[3,6,9-tris(karboksymetyl)-11,14-diokso-3,6,9,12,13-pentaazaheksade-canoato]} (8-)]} -digadolinato(2-), -dinatrium d) {mu-[ {16,16'-[copper(n)-7,12-diethyl-3,8,1 3,17-tetramethylporphyrin-2,1 8-diyl]-bis[3,6,9 -tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]} (8-)]} -digadolinato(2-), -disodium
1,12 g (0,796 mmol) av liganden fremstilt under eksempel 4c ble løst i 400 ml vann og tilsatt vekslende porsjonsvis 420 mg (1,59 mmol) gadoliniumklorid og 2N vandig natronlut, slik at pH-verdien av reaksjonsblandingen ble justert mellom 6,8 og 7,2. Når alt gadoliniumklorid var tilsatt ble det hele omrørt over natten ved romtemperatur. For opparbeiding ble løsningsmiddelet fjernet i vakuum og resten kromatografert på kieselgel RP-18 (elueringsmiddel: H20/tetrahydrofuran: 0-30 %). Utbytte: 1,37 g (98 % av teoretisk) rødbrunt pulver. Vanninnhold 7,6 % 1.12 g (0.796 mmol) of the ligand prepared under example 4c was dissolved in 400 ml of water and 420 mg (1.59 mmol) of gadolinium chloride and 2N aqueous caustic soda were added in alternating portions, so that the pH value of the reaction mixture was adjusted between 6, 8 and 7.2. When all the gadolinium chloride had been added, it was all stirred overnight at room temperature. For work-up, the solvent was removed in vacuo and the residue chromatographed on silica gel RP-18 (eluent: H20/tetrahydrofuran: 0-30%). Yield: 1.37 g (98% of theory) red-brown powder. Water content 7.6%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C42,32 H4,24 NI 1,15 Gd 17,88 Cu3,61 Na2,61 calculated: C42.32 H4.24 Ni 1.15 Gd 17.88 Cu3.61 Na2.61
funnet: C 42,18 H4,38 N 11,09 Gd 17,70 Cu 3,48 Na 2,47 found: C 42.18 H4.38 N 11.09 Gd 17.70 Cu 3.48 Na 2.47
Eksempel 5 Example 5
a) Acetat{7,12-dietyl-3,8,13,17-tetnura {N,N-bis[(t butoksykarbonyl)metyl]amino}-etyl)-l l-[(t butoksy-karbonyl)- a) Acetate {7,12-diethyl-3,8,13,17-tetnura {N,N-bis[(t-butoxycarbonyl)methyl]amino}-ethyl)-1 l-[(t-butoxy-carbonyl)-
metyl] 14-oksa-4,5,8,11 -tetraazaheksadec- 1-yl]} -porfyrinato(3-)mangan methyl] 14-oxa-4,5,8,11-tetraazahexadec-1-yl]}-porphyrinato(3-)manganese
8,31 g (13,45 mmol) 3,9-bis(tbutoksykarbonyl)metyl]-6-karboksymetyl-3,6,9-triazaundecandisyre-di-t.butylester, og 2,09 g (15 mmol) 4-nitrofenol ble løst i 60 ml dimetylformamid og tilsatt 5,16 g (25 mmol) NjN^disykloheksylkarbodiimid ved 0 °C. Det hele ble omrørt i 3 timer ved 0 °C, og deretter over natten ved romtemperatur. Til den slik fremstilte aktive esterløsning setter man til 2,37 g (3,36 mmol) av tittelforbindelsen fra eksempel 2a, (løst i 50 ml pyridin) og rører over natten. Det tillsettes 100 ml av en 5 %ig, vandig ammoniumkloridløsning, inndamper til tørrhet ved vakuum og kromatograferer resten på kieselgel (løpemiddel: diklormetan/2-propanol = 20:1). Utbytte: 5,25 g (86 % av teoretisk) av et mørkebrunt, fast stoff. 8.31 g (13.45 mmol) 3,9-bis(tbutoxycarbonyl)methyl]-6-carboxymethyl-3,6,9-triazaundecanedioic acid di-t.butyl ester, and 2.09 g (15 mmol) 4- nitrophenol was dissolved in 60 ml of dimethylformamide and 5.16 g (25 mmol) of NjN^dicyclohexylcarbodiimide was added at 0 °C. The whole was stirred for 3 hours at 0 °C, and then overnight at room temperature. To the active ester solution prepared in this way, 2.37 g (3.36 mmol) of the title compound from example 2a (dissolved in 50 ml pyridine) are added and stirred overnight. 100 ml of a 5% aqueous ammonium chloride solution is added, evaporated to dryness under vacuum and the residue is chromatographed on silica gel (eluent: dichloromethane/2-propanol = 20:1). Yield: 5.25 g (86% of theory) of a dark brown solid.
Elementanalyse: Elemental analysis:
beregnet: C 59,97 H7,82 N 10,42 Mn 2,92 Cl 1,88 calculated: C 59.97 H7.82 N 10.42 Mn 2.92 Cl 1.88
funnet: C 59,83 H8,03 N 10,28 Mn 2,83 Cl 1,67 found: C 59.83 H8.03 N 10.28 Mn 2.83 Cl 1.67
b) {mu-[-acetatmangan(in)- {13,13 '-[7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl]-bis {3-karboksymetyl-6-(2- {N,N-bis[(karboksy)metyl]amino} etyl)-8,11 -diokso-3,6,9,10-tetraazatridecanoato]} (8-)]} digadolinato(2-), -dinatrium 5,25 g (2,79 mmol) av tittelforbindelsen under eksempel 5a ble løst i 100 ml trifluoreddiksyre og omrørt i 8 timer ved romtemperatur. Deretter inndampet til tørrhet ved vakuum. Den slik fremstilte ligand ble løst i 100 ml vann og tilsatt 1,01 g (2,79 mmol) gadoliniumoksid. Det omrøres ved 60 °C og holder ved tilsetting av IN vandig natronlut pH-verdien ved 5. Løsningen filtreres og filtratet justeres til pH 7,2 med IN vandig natronlut. Deretter ble det hele kromatografert på kieselgel RP-18 b) {mu-[-acetate manganese(yn)- {13,13 '-[7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis {3-carboxymethyl-6- (2- {N,N-bis[(carboxy)methyl]amino} ethyl)-8,11-dioxo-3,6,9,10-tetraazatridecanoato]} (8-)]} digadolinato(2-), - disodium 5.25 g (2.79 mmol) of the title compound under example 5a was dissolved in 100 ml of trifluoroacetic acid and stirred for 8 hours at room temperature. Then evaporated to dryness under vacuum. The ligand thus prepared was dissolved in 100 ml of water and 1.01 g (2.79 mmol) of gadolinium oxide was added. It is stirred at 60 °C and, by adding 1N aqueous caustic soda, keeps the pH value at 5. The solution is filtered and the filtrate is adjusted to pH 7.2 with 1N aqueous caustic soda. The whole thing was then chromatographed on silica gel RP-18
(løpemiddel: Gradient av vann/acetonitril). Utbytte: 4,63 g (93 % av teoretisk) av et brunt, amorft fast stoff. Vanninnhold: 9,2 % (eluent: Gradient of water/acetonitrile). Yield: 4.63 g (93% of theory) of a brown, amorphous solid. Water content: 9.2%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 41,69 H4,18 N 10,98 Mn 3,08 Cl 1,98 Gd 17,61 Na 2,57 funnet: C 41,54 H4,35 N 10,82 Mn 2,91 Cl 1,85 Gd 17,45 Na 2,34 calculated: C 41.69 H4.18 N 10.98 Mn 3.08 Cl 1.98 Gd 17.61 Na 2.57 found: C 41.54 H4.35 N 10.82 Mn 2.91 Cl 1.85 Gd 17,45 Nah 2,34
Eksempel 6 Example 6
a) {10,1 <O>Hm<y-a>cetatman<g>an(ffl)- {10,10'-(7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl)bis[(lRS)-l-metyl-2,5,8-triotø^ a) {10,1 <O>Hm<y-a>cetatman<g>an(ffl)- {10,10'-(7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl )bis[(1RS)-1-methyl-2,5,8-triotyl
tetraazasyklododekan-1,4,7-triacetat(3 -)]} digadolinium tetraazacyclododecane-1,4,7-triacetate(3 -)]} digadolinium
8,47 g (13,45 mmol) av Gd-komplekset av 10-(4-karboksy-2-okso-3-aza-1 -metyl-butyl)-l,4,7,10-tetraazasyldododekan-l,4,7-trisssyre, 0,64 g lithiumklorid (15 mmol) og 2,09 g (15 mmol) 4-nitrofenol ble løst i 100 ml dimetylsulfoksid ved 50 °C. Etter avkjøling til romtemperatur ble 5,16 g (25 mmol) N,N'disykloheksylkarbodiimid tilsatt og foraktivert i 12 timer. Til den slik fremstilte løsning tilsettes 2,37 g (3,36 mmol) av tittelforbindelsen ifølge eksempel 2a, 0,71 g (7 mmol) trimetylamin som omrøres over natten ved romtemperatur. Den oppnådde suspensjon ble deretter overført til fullstendig felling med tilstrekkelig aceton, bunnfallet suges opp, tørkes, tatt opp i vann, filtrert fra uløselig disykloheksylurea og filtratet kromatografert på kieselgel RP-18 (løpemiddel: Gradient av telrahydrofuran/vann). Utbytte: 5,06 g (79 % av teoretisk) av et mørkebrunt, amorft pulver. Vanninnhold: 8,3 % 8.47 g (13.45 mmol) of the Gd complex of 10-(4-carboxy-2-oxo-3-aza-1-methyl-butyl)-1,4,7,10-tetraazasyldododecane-1,4 ,7-trisic acid, 0.64 g of lithium chloride (15 mmol) and 2.09 g (15 mmol) of 4-nitrophenol were dissolved in 100 ml of dimethyl sulfoxide at 50 °C. After cooling to room temperature, 5.16 g (25 mmol) of N,N'dicyclohexylcarbodiimide was added and preactivated for 12 hours. To the solution prepared in this way, 2.37 g (3.36 mmol) of the title compound according to example 2a, 0.71 g (7 mmol) of trimethylamine are added, which is stirred overnight at room temperature. The obtained suspension was then transferred to complete precipitation with sufficient acetone, the precipitate was sucked up, dried, taken up in water, filtered from insoluble dicyclohexylurea and the filtrate chromatographed on silica gel RP-18 (eluent: gradient of telirahydrofuran/water). Yield: 5.06 g (79% of theory) of a dark brown, amorphous powder. Water content: 8.3%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 45,36 H5,08 N 13,22 Gd 16,50 Mn 2,88 Cl 1,86 calculated: C 45.36 H5.08 N 13.22 Gd 16.50 Mn 2.88 Cl 1.86
funnet: C 45,24 H5,21 N 13,13 Gd 16,38 Mn 2,71 Cl 1,72 found: C 45.24 H5.21 N 13.13 Gd 16.38 Mn 2.71 Cl 1.72
Eksempel 7 Example 7
a) Konjugat av acetat [7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-dipropionyl-hydrazinato(2-)-K N21, K N22, K N23, K N24]-jern og 10-[7-(4-isotiocyanatfenyl))-2-hydroksy-5-okso-7-(karboksymetyl)-4-a2a-heptyl)]-1,4,7-tris(karboksylatometyl)-1,4,7-tris(karboksylatometyl)-1,4,7,10-tetraazasyklododekan, gadoliniumkompleks, natriumsalt {10,10'-{my-Woijem(ni){10,10'-[(7,12-dietyl-3,8,13,17-tetarmetylpor-fyrin-2,18-diyl)bis {(1 -oksopropan-3,1 -diyl)hydrazin-tiokarbonylamino-4,1 - a) Conjugate of acetate [7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-dipropionyl-hydrazinato(2-)-K N21, K N22, K N23, K N24] iron and 10 -[7-(4-isothiocyanatephenyl))-2-hydroxy-5-oxo-7-(carboxymethyl)-4-a2a-heptyl)]-1,4,7-tris(carboxylatomethyl)-1,4,7- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane, gadolinium complex, sodium salt {10,10'-{my-Woijem(ni){10,10'-[(7,12-diethyl-3,8,13 ,17-tetramethylporphyrin-2,18-diyl)bis {(1-oxopropane-3,1-diyl)hydrazine-thiocarbonylamino-4,1 -
fenylen[(3RS)-3-karboksymetyl-l-olcsopro 3,1 -diyl)} ]} bis[ 1,4,7,10-tetraazasyklododekan-1,4,7-triacetat (4-)]} digadolinium, dinatrium) phenylene[(3RS)-3-carboxymethyl-1-olcsopro 3,1-diyl)} ]} bis[ 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate (4-)]} digadolinium, disodium )
Til 708 mg (1 mmol) av tittelforbindelsen fra eksempel la og 1806 mg (2,2 mmol) i 50 ml vann tilsettes 1,0 g (10 mmol) trietylamin og det hele omrøres i 12 timer ved To 708 mg (1 mmol) of the title compound from example 1a and 1806 mg (2.2 mmol) in 50 ml of water, 1.0 g (10 mmol) of triethylamine is added and the whole is stirred for 12 hours at
romtemperatur. Det inndampes til tørrhet i vakuum og kromatograferes på kieselgel (løpemiddel: metanol/vann/iseddik = 10/5/1). Fraksjonene som inneholder produktet inndampes til tørrhet, resten løses i 100 ml vann og pH justeres til 7,2 med 2N room temperature. It is evaporated to dryness in vacuo and chromatographed on silica gel (eluent: methanol/water/glacial vinegar = 10/5/1). The fractions containing the product are evaporated to dryness, the residue is dissolved in 100 ml of water and the pH is adjusted to 7.2 with 2N
natronlut. Deretter frysetørkes det. baking soda. It is then freeze-dried.
Utbytte: 2,11 g (92 % av teoretisk) av et mørkebrunt, amorft pulver. Yield: 2.11 g (92% of theory) of a dark brown, amorphous powder.
Vanninnhold: 8,5 % Water content: 8.5%
Elementanalyse ( beregnet på vannfri substans) : Elemental analysis (calculated for anhydrous substance):
beregnet: C 44,95 H5,09 N 12,19 Cl 1,54 Fe 2,43 S2,79 Gd 13,69 Na 2,00 funnet: C 44,83 H 5,19 N 12,03 Cl 1,38 Fe 2,38 S2,58 Gd 13,48 Na 1,78 calculated: C 44.95 H5.09 N 12.19 Cl 1.54 Fe 2.43 S2.79 Gd 13.69 Na 2.00 found: C 44.83 H 5.19 N 12.03 Cl 1.38 Fe 2.38 S2.58 Gd 13.48 Na 1.78
Eksempel 8 Example 8
Fremstilling av en formulering av {mu-[{16,16'-[klorjem(III)-7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl]-bis[3,6,9-tirs(karboksymetyl)-11,14-diokso-3,6,9,12,13-pentaazaheksadekanoato]}(8-)]}-digadolinato(2-), -dinatrium (tilsatt fra mannitol) 50 mmol av tittelforbindelsen under eksempel lb, 10 mmol tris-buffer (tris(hydrok-symetyl)aminometansaltsyre pH 7,4) og 120 mmol mannitol ble løst i 500 ml dobbeltdestillert vann og fylt opp til 1 liter med vann i en målekolbe. Den oppnådde løsning ble filtrert med en 0,2 um membran og fylt på ampuller. Den fremstilte løsning kan anvendes direkte for NMR-diagnostikk. Preparation of a formulation of {mu-[{16,16'-[chloroene(III)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis[3,6, 9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]}(8-)]}-digadolinato(2-), -disodium (added from mannitol) 50 mmol of the title compound under example 1b, 10 mmol of tris buffer (tris(hydroxymethyl)aminomethane hydrochloric acid pH 7.4) and 120 mmol of mannitol were dissolved in 500 ml of double-distilled water and filled up to 1 liter with water in a measuring flask. The solution obtained was filtered with a 0.2 µm membrane and filled into ampoules. The prepared solution can be used directly for NMR diagnostics.
Eksempel 9 Example 9
Fremstilling av en formulering av {mu-[{16,16'-[klonnangan(in)-7,12-dietyl-3,8,13,17-tetrametylporfyrin-2,18-diyl]-bis[3,6,9-tirs(karboksymetyl)-11,14-diokso-3,6,9,12,13-pentaazaheksadekanoato]}(8-)]}-digadolinato(2-), -dinatrium (tilsatt fra koksalt) 10 mmol av tittleforbindelsen fra eksempel 2d, 10 mmol tris-buffer (tris(hydrok-symetyl)aminometan saltsyre pH 7,4) og 60 mmol natriumklorid ble løst i 500 ml dobbeltdestillert vann og fylt opp til 1 liter med vann i en målekolbe. Den oppnådde løsning ble filtrert gjennom en 0,2 um membran og fylt på ampuller. Den fremstilte løsning kan anvendes direkte for NMR-diagnostikk. Preparation of a formulation of {mu-[{16,16'-[clonanganan(yne)-7,12-diethyl-3,8,13,17-tetramethylporphyrin-2,18-diyl]-bis[3,6, 9-tris(carboxymethyl)-11,14-dioxo-3,6,9,12,13-pentaazhexadecanoato]}(8-)]}-digadolinato(2-), -disodium (added from common salt) 10 mmol of the title compound from example 2d, 10 mmol of tris buffer (tris(hydroxymethyl)aminomethane hydrochloric acid pH 7.4) and 60 mmol of sodium chloride were dissolved in 500 ml of double-distilled water and filled up to 1 liter with water in a volumetric flask. The solution obtained was filtered through a 0.2 µm membrane and filled into ampoules. The prepared solution can be used directly for NMR diagnostics.
Eksempel 10 Example 10
MRI-eksperiment på dyr med indusert myokardinfarkt MRI experiment on animals with induced myocardial infarction
Den nekroseselektive forsterkning ble undersøkt etter en intravenøs administrering av substansen fra eksempel ld hos et dyr med eksperimentelt fremstilt myokardinfarkt i et MRI-eksperiment. Induksjonen av hjerteinfarktet ble utført på anestiserte The necrosis-selective enhancement was examined after an intravenous administration of the substance from example 1d in an animal with experimentally produced myocardial infarction in an MRI experiment. The induction of the heart attack was performed on anesthetized subjects
("Domitor'V"Dormicum", i. m.) rotter (Han. Wistar, Schering SPF, ca. 300 g kroppsvekt) ved okklusjon av den venstre coronararterie. Kontrastmiddeladministreringen (dose: 100 umol Gd/kg kroppsvekt) ble utført 24 timer etter infarktinduksjonen. Dyret ble undersøkt før og inntil 24 timer etter KM-acurunistreringen i en MR-tomograf (SISCO SIS 85,2 Tesla; SE-sekvens, EKG-trigget, TR: ca. 400ms, TE: 10 ms, nt = 4, ni = 256, FOV: 7<*>7 cm, SD « 3 mm, pr 1 aksiallag). Ca. 24 timer etter injeksjon ble dyret - i MRT - avlivet ("Domitor'V"Dormicum", i. m.) rats (Han. Wistar, Schering SPF, approx. 300 g body weight) by occlusion of the left coronary artery. The contrast agent administration (dose: 100 umol Gd/kg body weight) was performed 24 hours after the infarct induction . The animal was examined before and up to 24 hours after the KM accurunistration in an MR tomograph (SISCO SIS 85.2 Tesla; SE sequence, ECG triggered, TR: approx. 400ms, TE: 10 ms, nt = 4, ni = 256, FOV: 7<*>7 cm, SD « 3 mm, per 1 axial layer).Approximately 24 hours after injection, the animal - in MRT - was euthanized
ved en anestesioverdose og i tillegg gjennomført et MRI-eksperiment på "friskt dødt" dyr (ingen bevegelsesartefakt). For å verifisere infarktet (størrelse og posisjon) ble hjertet preparert, snittet i skiver og deretter ble det gjennomført en NBT-("Vital-") farging. Før KM-administrering kan infarktområdet ikke skilles fra normalt myocard, da begge områdene avbildes med samme intensitet (se bilde: la). Rett etter administrering av substans avbildes den ikke-perfunderte del av myocard som hypointens (se avbilding: lb). Ved ca. 30 minutter etter injeksjon steg signalintensiteten i det ikke-perfunderte område henholdsvis avtar (langsom diffusjon i nekrosen) størrelsen av det avgrensede (signalfattige) areal. I midtfasen og senere faser (fra 2,5 til ca. 24 timer etter injeksjon) konstateres betydelig forsterkning i nekrotiserte områder av myocard (se avbilding: lc, d, e). Avgrensningen av det nekrotiserte område i MRI-eksperimentet korrelerte svært godt med resultatene fra den histologiske "vital"-farging. in the event of an anesthetic overdose and in addition carried out an MRI experiment on a "freshly dead" animal (no movement artefact). To verify the infarct (size and position), the heart was prepared, cut into slices and then an NBT ("Vital") staining was carried out. Before KM administration, the infarct area cannot be distinguished from normal myocardium, as both areas are imaged with the same intensity (see image: la). Immediately after administration of the substance, the non-perfused part of the myocardium is imaged as hypointense (see image: lb). At approx. 30 minutes after injection, the signal intensity in the non-perfused area increases, respectively the size of the delimited (signal-poor) area decreases (slow diffusion in the necrosis). In the middle phase and later phases (from 2.5 to approx. 24 hours after injection), significant strengthening is observed in necrotic areas of the myocardium (see image: lc, d, e). The delineation of the necrotic area in the MRI experiment correlated very well with the results of the histological "vital" staining.
Eksempel 11 Example 11
MRI-eksperiment på dyr med indusert myokardinfarkt MRI experiment on animals with induced myocardial infarction
Den nekroseselektive forsteikmng ble undersøkt etter en intravenøs administrering av substansen fra eksempel 2d hos et dyr med eksperimentelt fremstilt myokardinfarkt i et MRI-eksperiment. Induksjonen av hjerteinfarktet ble utført på anestiserte The necrosis-selective staining was investigated after an intravenous administration of the substance from example 2d in an animal with experimentally produced myocardial infarction in an MRI experiment. The induction of the heart attack was performed on anesthetized subjects
0'DomitorTTJonnicum", i. m.) rotter (Han. Wistar, Schering SPF, ca. 300 g kroppsvekt) ved okklusjon av den venstre koronararterie. Konti^tmiddeladniinistreringen (dose: 100 umol Gd/kg kroppsvekt) ble utført 24 timer etter infarktinduksjonen. Dyret ble undersøkt før og inntil 3 timer (kontinuerlig) så vel som 24 timer etter KM-administreringen i en 0'DomitorTTJonicum", i. m.) rats (Han. Wistar, Schering SPF, approx. 300 g body weight) by occlusion of the left coronary artery. The intravenous administration (dose: 100 umol Gd/kg body weight) was performed 24 hours after the infarct induction. The animal were examined before and up to 3 hours (continuously) as well as 24 hours after KM administration in a
MR-tomograf (SISCO SIS 85,2 Tesla; SE-sekvens, EKG-trigget, TR: ca. 400ms, TE: 10 ms, nt = 4, ni - 256, FOV: 7<*>7 cm, SD w 3 mm, pr 1 aksiallag). Ca. 24 timer etter injeksjon ble dyret - i MRT - avlivet ved en anestesioverdose og i tillegg gjennomført et MRI-eksperiment på "friskt dødt" dyr (ingen bevegelsesartefakt). For å verifisere infarktet (størrelse og posisjon) ble hjertet preparert, snittet i skiver og deretter ble det gjennomført en NBT (nitro-blå-tetrazolinklorid) farging. Før KM-administrering kan infarktområdet ikke skilles fra normalt myocard, da begge områdene avbildes med samme intensitet (se bilde: 2a). Rett etter administrering av substans avbildes den ikke-perfunderte del av myocard som hypointens (se avbilding: 2b). Ved ca. 30 minutter etter injeksjon steg signalintensiteten i det ikke-perfunderte område henholdsvis avtar (langsom diffusjon i nekrosen) størrelsen av det avgrensede (signalfattige) areal. I midtfasen og senere faser (fra 2,5 til ca. 24 timer etter injeksjon) konstateres betydelig forsterkning i nekrotiserte områder av myocard (se avbilding: 2c, 2d). Avgrensningen av det nekrotiserte område i MRI-eksperimentet korrelerte svært godt med resultatene fra den histologiske "vitaT-farging. MR tomograph (SISCO SIS 85.2 Tesla; SE sequence, ECG triggered, TR: approx. 400ms, TE: 10 ms, nt = 4, ni - 256, FOV: 7<*>7 cm, SD w 3 mm, per 1 axial layer). About. 24 hours after injection, the animal - in MRT - was euthanized by an anesthetic overdose and in addition an MRI experiment was carried out on a "freshly dead" animal (no movement artefact). To verify the infarct (size and position), the heart was prepared, cut into slices and then an NBT (nitro-blue-tetrazoline chloride) staining was carried out. Before KM administration, the infarct area cannot be distinguished from normal myocardium, as both areas are imaged with the same intensity (see image: 2a). Immediately after administration of the substance, the non-perfused part of the myocardium is imaged as hypointense (see image: 2b). At approx. 30 minutes after injection, the signal intensity in the non-perfused area increases, respectively the size of the delimited (signal-poor) area decreases (slow diffusion in the necrosis). In the middle phase and later phases (from 2.5 to approx. 24 hours after injection), significant strengthening is observed in necrotic areas of the myocardium (see image: 2c, 2d). The delineation of the necrotic area in the MRI experiment correlated very well with the results of the histological "vitaT staining.
Eksempel 12 Example 12
MRI-eksperiment på dyr med indusert myokardinfarkt MRI experiment on animals with induced myocardial infarction
Den nekroseselektive forsterkning ble undersøkt etter en intravenøs administrering av substansen fra eksempel 4d hos et dyr med eksperimentelt fremstilt myokardinfarkt i et MRI-eksperiment. Induksjonen av hjerteinfarktet ble utført på anesnserte The necrosis-selective enhancement was investigated after an intravenous administration of the substance from Example 4d in an animal with experimentally produced myocardial infarction in an MRI experiment. The induction of the myocardial infarction was performed in anesthetized patients
("Domitor"/"Dormicum", i. m.) rotter (Han. Wistar, Schering SPF, ca. 300 g kroppsvekt) ved okklusjon av den venstre coronararterie. Kontrastmiddeladministreringen (dose: 100 umol Gd/kg kroppsvekt) ble utført 24 timer etter infarktinduksjonen. Dyret ble undersøkt før og inntil 3 timer (kontinuerlig) så vel som 24 timer etter KM-administreringen i en MR-tomograf (SISCO SIS 85,2 Tesla; SE-sekvens, EKG-trigget, TR: ca. 400ms, TE: 10 ms, nt = 4, ni = 256, FOV: 7<*>7 cm, SD » 3 mm, pr 1 aksiallag). Ca. 24 timer etter injeksjon ble dyret - i MRT - avlivet ved en anestesioverdose og i tillegg gjennomført et MRI-eksperiment på "friskt dødt" dyr (ingen bevegelsesartefakt). For å verifisere infarktet (størrelse og posisjon) ble hjertet preparert, snittet i skiver og deretter ble det gjennomført en NBT (nitro-blå-tetrazolinklorid) farging. Før KM-administrering kan infarktområdet ikke skilles fra normalt myocard, da begge områdene avbildes med samme intensitet (se bilde: 3a). Rett etter administrering av substans avbildes den ikke-perfunderte del av myocard som hypointens (se avbilding: 3b). Ved ca. 30 minutter etter injeksjon steg signalintensiteten i det ikke-perfunderte område henholdsvis avtar (langsom diffusjon i nekrosen) størrelsen av det avgrensede (signalfattige) areal. I midtfasen og senere faser (fra 2,5 til ca. 24 timer etter injeksjon) konstateres betydelig forsterkning i nekrotiserte områder av myocard (se avbilding: 3c, 3d). Avgrensningen av det nekrotiserte område i MRI-eksperimentet korrelerte svært godt med resultatene fra den histologiske "vital"-farging. ("Domitor"/"Dormicum", i. m.) rats (Han. Wistar, Schering SPF, approx. 300 g body weight) by occlusion of the left coronary artery. The contrast agent administration (dose: 100 umol Gd/kg body weight) was performed 24 hours after the infarct induction. The animal was examined before and up to 3 hours (continuously) as well as 24 hours after the KM administration in an MR tomograph (SISCO SIS 85.2 Tesla; SE sequence, ECG triggered, TR: approx. 400ms, TE: 10 ms, nt = 4, ni = 256, FOV: 7<*>7 cm, SD » 3 mm, per 1 axial layer). About. 24 hours after injection, the animal - in MRT - was euthanized by an anesthetic overdose and in addition an MRI experiment was carried out on a "freshly dead" animal (no movement artefact). To verify the infarct (size and position), the heart was prepared, cut into slices and then an NBT (nitro-blue-tetrazoline chloride) staining was carried out. Before KM administration, the infarct area cannot be distinguished from normal myocardium, as both areas are imaged with the same intensity (see image: 3a). Immediately after administration of the substance, the non-perfused part of the myocardium is imaged as hypointense (see image: 3b). At approx. 30 minutes after injection, the signal intensity in the non-perfused area increases, respectively the size of the delimited (signal-poor) area decreases (slow diffusion in the necrosis). In the middle phase and later phases (from 2.5 to approx. 24 hours after injection), significant strengthening is observed in necrotic areas of the myocardium (see image: 3c, 3d). The delineation of the necrotic area in the MRI experiment correlated very well with the results of the histological "vital" staining.
Eksempel 13 Example 13
Påvirkning av lys (ED50) på en tumorcellekultur ved tilstedeværelse av porfyrin Effect of light (ED50) on a tumor cell culture in the presence of porphyrin
I kulturflaske på 25 ml ble en cellekultur av humane kolonkarsinom (HT-29 P9) dyrket i 3 dager ved 37 °C. Kulturen ble oppdelt i to grupper og tilsatt løsning av testsubstans (50 mmol porfyrinenhet (PE)/1, fortynnet med føtalt kalveserum) i økende mengde (0; 1,5; 5; 8,5; 12; 15,5; 19 jimol PE/1). Prøven ble belyst i 3 dager med en xenonlampe (8,5 k lux, UV-filter). Den første gruppen fikk daglig 2 bestrålinger av 13 minutters varighet med 4 timers mellomrom. Resten av tiden oppbevart i mørke i inkubator. Den andre gruppen ble ikke belyst og ble hele tiden oppbevart i mørke i inkubator. Den fjerde dagen ble celleveksten bestemt ved viabilitetsfarging og telling i tellekammer. I tabellen er en konsentrasjon angitt der omtrent halvparten av cellene ikke lenger var levende. In a 25 ml culture flask, a cell culture of human colon carcinoma (HT-29 P9) was grown for 3 days at 37 °C. The culture was divided into two groups and a solution of test substance (50 mmol porphyrin unit (PE)/1, diluted with fetal calf serum) was added in increasing amounts (0; 1.5; 5; 8.5; 12; 15.5; 19 μmol PE/1). The sample was illuminated for 3 days with a xenon lamp (8.5 k lux, UV filter). The first group received 2 daily irradiations of 13 minutes duration at 4 hour intervals. The rest of the time kept in the dark in an incubator. The other group was not illuminated and was constantly kept in the dark in an incubator. On the fourth day, cell growth was determined by viability staining and counting in a counting chamber. The table shows a concentration at which approximately half of the cells were no longer alive.
Eksempel 14 Example 14
Bestemmelse av kontatibilitet til tittelforbindelsen ifølge eksempel 2d Determination of compatibility with the title compound according to example 2d
Den akutte toksisitet av tittelforbindelsen ifølge eksempel 2d undersøkes hos mus etter en intravenøs dose. The acute toxicity of the title compound according to example 2d is examined in mice after an intravenous dose.
Forsøk: Attempt:
Testmetode: Metode KM DI, 5. versjon Test method: Method KM DI, 5th version
Forsøksdyr: SPF-mus (NMRI, Schering), 18-22 g, f:m = 50:50 Injeksjonshastighet: 2 ml/min. Experimental animal: SPF mice (NMRI, Schering), 18-22 g, f:m = 50:50 Injection rate: 2 ml/min.
Effektivitetskriterie: exitus letalis Efficacy criterion: exitus lethalis
Observasjonstidsrom: 7 dager Observation period: 7 days
Lever og nyre fra alle overlevende dyr var uten spesielle anmerkninger. En LD50 (mmol Gd/kg) forventes fra > 5. Liver and kidney from all surviving animals were without special remarks. An LD50 (mmol Gd/kg) is expected from > 5.
Eksempel 15 Example 15
Bestemmelse av relaksivitet RI [L-mmorV1] Determination of relaxivity RI [L-mmorV1]
Apparatur: Minispec PC 20" Equipment: Minispec PC 20"
Måling ved 40 °C; 0,47 tesla Measurement at 40 °C; 0.47 tesla
Tl-sekvens: 180 ° - Tl-90 °, inversjonsrestitusjon Tl sequence: 180° - Tl-90°, inversion recovery
Eksempel 16 Example 16
In- vivo sammenlikning av tittelforbindelsen fra eksempel ld med Dy-DTPA med hensyn på blodkinetikk In-vivo comparison of the title compound from example 1d with Dy-DTPA with regard to blood kinetics
Som forsøksdyr ble det benyttet tre hannrotter (Schering-SPF) 250 gram. Hvert dyr fikk administrert intravenøst 0,5 ml av en kontrastmiddelblanding av forbindelsen ifølge eksempel ld (45 mmol Gd/l), heretter betegnet forbindelse 1, og dysprosium-komplekset (Dy-DTPA, 57 mmol Dy/l), heretter betegnet forbindelse 2. Den administrerte dose utgjorde derigjennom 82 umol Gd/kg (forbindelse 1), henholdsvis 103 umol Dy/kg (forbindelse 2). Fra et kateter i arteria carotis communis ble blodprøve tatt på følgende tidspunkter: 1, 3, 5,10,15,20,30,45,60, 90 og 120 min p.i. Konsentrasjonen av gadolinium (Gd) og dysprosium (Dy) i blodprøvene ble målt ved hjelp av atomemisjonspektrometri (ICP-AES). Andelen av den injiserte kontrast-middelforbindelse 1 (Gd) og -forbindelse 2 (Dy, sammenlikningssubstans) som forblir i blodvolumet, kan ved de forskjellige markeringer i samme dyr sammenliknes. Fra blod- eller plasmakonsentrasjonen kan det ved hjelp av spesielle dataprogrammer (Topfit-program) som beregner a-t- lA og p-tVi eliminasjonshalveringstiden i fordelingsvolumet så vel som total Clearance for blod og plasma. Dermed gir disse data informasjon om forløpet til forbindelsene i intravasalrommet, fordelingsfor-holdene i organismen og eliminasjon. Three male rats (Schering-SPF) 250 grams were used as experimental animals. Each animal was administered intravenously 0.5 ml of a contrast agent mixture of the compound of Example 1d (45 mmol Gd/l), hereafter referred to as compound 1, and the dysprosium complex (Dy-DTPA, 57 mmol Dy/l), hereafter referred to as compound 2 The administered dose thereby amounted to 82 umol Gd/kg (compound 1), respectively 103 umol Dy/kg (compound 2). From a catheter in the common carotid artery, a blood sample was taken at the following times: 1, 3, 5, 10, 15, 20, 30, 45, 60, 90 and 120 min p.i. The concentration of gadolinium (Gd) and dysprosium (Dy) in the blood samples was measured using atomic emission spectrometry (ICP-AES). The proportion of the injected contrast agent compound 1 (Gd) and compound 2 (Dy, comparison substance) that remains in the blood volume can be compared at the different markings in the same animal. From the blood or plasma concentration, it is possible with the help of special computer programs (Topfit program) which calculate a-t-lA and p-tVi the elimination half-life in the volume of distribution as well as total clearance for blood and plasma. Thus, these data provide information about the course of the compounds in the intravascular space, the distribution conditions in the organism and elimination.
Resultat: Blodeliminasjonskinetikken av forbindelse 1 skiller seg betydelig fra det ekstracellulære kontrastmiddel (forbindelse 2)(se avbilding 4, tabell 1). Blodkon-sentrasjonen ligger etter 3 minutter fortsatt ved 56 - 63 % av dosen og etter 120 minutter ved 22 - 25 % av dosen. Utskillelsen/diffusjon i vev er betydelig forlenget (halveringstid 173 minutter). Fordelingsvolumet og den totale clearance er ikke så betydelig mindre sammenliknet med Dy-DTPA, dvs. forbindelse 1 fordeler seg ikke som forbindelse 2 i intravasalrommet (karene) og i ekstracellulærrommet, snarere for det meste bare i intravasalrommet (blood-pool-egenskapene til porfyriner). Result: The blood elimination kinetics of compound 1 differs significantly from the extracellular contrast agent (compound 2) (see Figure 4, Table 1). The blood concentration remains after 3 minutes at 56 - 63% of the dose and after 120 minutes at 22 - 25% of the dose. The excretion/diffusion in tissues is significantly prolonged (half-life 173 minutes). The volume of distribution and the total clearance are not so significantly less compared to Dy-DTPA, i.e. compound 1 does not distribute like compound 2 in the intravasal space (the vessels) and in the extracellular space, rather mostly only in the intravasal space (the blood-pool properties of porphyrins ).
Den lange oppholdstiden i blod av forbindelse 1 tyder på en svært høy plasmaproteinbinding. Resultatene fra forbindelsene beskrevet i eksemplene antyder derfor et "blood-pool"-middel. The long residence time in blood of compound 1 indicates a very high plasma protein binding. The results from the compounds described in the examples therefore suggest a "blood-pool" agent.
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PCT/EP1999/005522 WO2000005235A1 (en) | 1998-07-24 | 1999-07-15 | Paramagnetic 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical preparations containing same, method for producing same and their use in magnetic resonance imaging of necrosis and infarction |
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