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WO1998005625A1 - Agent de contraste pour l'imagerie diagnostique a relaxivite amelioree dans le serum - Google Patents

Agent de contraste pour l'imagerie diagnostique a relaxivite amelioree dans le serum Download PDF

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Publication number
WO1998005625A1
WO1998005625A1 PCT/EP1997/004096 EP9704096W WO9805625A1 WO 1998005625 A1 WO1998005625 A1 WO 1998005625A1 EP 9704096 W EP9704096 W EP 9704096W WO 9805625 A1 WO9805625 A1 WO 9805625A1
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WIPO (PCT)
Prior art keywords
carboxymethyl
carboxy
bis
groups
solution
Prior art date
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PCT/EP1997/004096
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English (en)
Inventor
Luisella Calabi
Alessandro Maiocchi
Marco Lolli
Fabrizio Rebasti
Original Assignee
Bracco S.P.A.
Dibra S.P.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bracco S.P.A., Dibra S.P.A. filed Critical Bracco S.P.A.
Priority to EP97940037A priority Critical patent/EP0915829A1/fr
Priority to AU42029/97A priority patent/AU4202997A/en
Priority to JP50542598A priority patent/JP4225573B2/ja
Publication of WO1998005625A1 publication Critical patent/WO1998005625A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/34—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C229/36—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton containing six-membered aromatic rings with at least one amino group and one carboxyl group bound to the same carbon atom of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/76—Metal complexes of amino carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D209/20—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals substituted additionally by nitrogen atoms, e.g. tryptophane

Definitions

  • This invention relates to the Magnetic Resonance Imaging (M.R.I. ), a technique used in the medical diagnosis field for a number of years, to rapidly detect a series of anomalies and/or pathological conditions of living human or animal body organs or tissues, (i. e.: Stark D.D., Bradley W.G. Jr., Eds.: "Magnetic Resonance Imaging", the C.V. Mosby Company, St. Louis, Missouri (USA), 1988).
  • the invention relates to new chelating agents, especially aminopolycarboxylic acid derivative compounds and to metal chelates thereof with bivalent or trivalent paramagnetic ions and/or salts thereof as well as their use as M.R.I, contrast agents. Background of the invention
  • Diagnostic imaging techniques such as Magnetic Resonance Imaging -have been used in medical diagnosis for a long time.
  • the use of contrast media to improve tissue differentiation, to delineate structures or monitor physiological functions constitutes in some cases a fundamental contribution in the best formulation of some medical diagnosis and a valid support for radiologist work.
  • contrast agents The medical use of aminopolycarboxylic acid or carboxylic acid derivatives and metal chelates thereof as M.R.I, contrast agents is well known. Said contrast agents, to simplify, can be seen as pertaining to two main groups: the linear and the cyclic ones.
  • the present invention relates to linear polyaminopolycarboxylic acid derivatives, as well as their complexes with paramagnetic metal ions, in particular the Gd 3+ ion.
  • Patent literature is rich in patent and patent applications relating to the use of linear polyaminopolycarboxylic acid derivatives in the preparation of MRI contrast agents.
  • patent literature proposes the preparation of esters or amide derivatives of said acids or the introduction of substituents on the diethylene unit of the diethylenetriamme DTPA skeleton
  • Guerbet EP 661279 Concat Ltd., WO 95/05118; Dibra WO 95/15319; Mallinckrodt WO 94/08630; Green Gross Corp.
  • JP 06016606 and JP 05229998 Mallinckrodt US 5,141,740 and US 5,077,037; Cockbam-Nycomed WO 91/15467 and WO 92/11232; Salutar US 4,889,931 and 4,858,451; Abbot Laboratoires EP 279307; Nyco ed EP 299795; Metasyn Inc. WO 95/28179; Schering EP 680 464; and document cited in these patent publications.
  • the compounds of the present invention are diethylenetriaminepentaacetic acid derivatives characterised in having substituents at the ⁇ position to the carboxy group of two or three of the five acetic groups of DTPA. More precisely, the compounds can have two substituents (the same or different from each other) m ⁇ to the carboxyls of the two acetic groups respectively bound to the two side nitrogen atoms of DTPA; or they can have three substituents (the same or different from each, other) in ⁇ to the carboxyl groups of three acetic groups respectively bound to the three nitrogen atoms of DTPA.
  • the compounds of the present invention are characterized in having some ste ⁇ cal hindrance, due to the presence of two or three substituents at the above mentioned positions.
  • the minimum size of the substituents is that of a chain having at least three carbon atoms.
  • Said hindering groups are probably responsible for the interactions of the paramagnetic chelates with biological components of the fluids in which the agent diffuses, wherein said interactions produce the surprisingly high relaxivity values that we have measured in Human Reconstructed Serum.
  • Relaxivity values of the contrast agent of the present invention have been tested either in saline or in human serum obtained by SeronormTM Human, freeze- dried human serum produced by Nycomed Pharma AS, Oslo,
  • Serum obtained from said SeronormTM is substantially equivalent to the fresh one, so its use in the relaxivity determination grants a good picture of the "in vivo" behaviour and, further, an excellent reproducibility of this test.
  • the compounds object of the present invention are characterised by very high r ⁇ and ⁇ relaxivity values.
  • r * relaxivity equal to or, preferably, higher than 15 s -1 mM _1 .
  • the present invention relates to novel chelating agents, more particularly linear aminopolycarboxylic acid derivatives chelants, and metal chelates thereof and the use of such chelating agents and chelates in the preparation of diagnostic imaging contrast agents and in particular of contrast agents exhibiting improved serum relaxivity.
  • Said compounds are polyaminopolycarboxylic acid derivatives of formula (I), either in their racemic or enantiomeric forms: wherein:
  • R is H or a linear or branched, saturated or unsaturated C,-C '20 alkyl chain, which is interrupted or not by one or more O, N, S atoms or by one or more -CO-, -CH(OH)-, -CH(NH 2 )-, -CONH-, -NHC0-, -SO-, - S0 2- ' ⁇ S0 2 NH-, which is substituted or not with one or more halogen atoms or -COOH groups or their ester or amide derivatives and which is interrupted or not or substituted or not by one or more cyclic R 3 residues which can be the same or different and isolated or fused, with the proviso that, if some of said residues are fused, the maximum number of rings forming the corresponding polycyclic unit is three, in which: is a 5- or 6-membered carbocyclic or heterocyclic , saturated, unsaturated or aromatic cyclic unit, substituted or not with one or more groups X,
  • the invention further relates to complexes of the ligand of formula (I) with metal ions of atomic number from 20 to 31, 39, from 42 to 44, 49 and from 57 to 83; particularly preferred metals being: Fe(2+) ⁇ Fe( 3+ ),
  • the metal chelate carries an overall charge, a salts thereof with a physiologically acceptable counterion, preferably selected from organic bases such as a primary, secondary or tertiary amines, a basic amino acid, or an inorganic base derived from an alkali metal or alkaline-earth metal cation such as: Na + , K + , Mg2 + , Ca 2+ or a mixture thereof.
  • organic bases such as a primary, secondary or tertiary amines, a basic amino acid, or an inorganic base derived from an alkali metal or alkaline-earth metal cation such as: Na + , K + , Mg2 + , Ca 2+ or a mixture thereof.
  • the present invention further relates to the use of the compounds of formula (I) and of the salts of the complexes thereof as well as to the pharmaceutical formulations containing them for a diagnostic or therapeutic scope.
  • R, R ⁇ and R 2 are selected from the following groups:
  • R 4 H, or a linear or branched C 1 ⁇ C 10 alkyl, optionally interrupted by one or more -CONH- , - NHC0-, -CO- groups and/or N.
  • S atoms optionally interrupted or substituted with 1 to 3 saturated rings, that are optionally interrupted by one or more N, 0, S and that are optionally substituted with -OH, -SH, halogen, -COOH, -NH 2 , -N(R") 2 , - CON(R") 2 , -SO3H, C1-C4 alkoxy groups;
  • R 5 independently a linear or branched c ⁇ c ⁇ o alkyl, optionally interrupted by one or more -C0NH-, -NHC0- , -CO- groups and/or N, O, S atoms and interrupted or substituted with 1 to 3 saturated rings, that are optionally interrupted by one or more N, 0, S and that are optionally substituted with -OH, -SH, halogen, -COOH, -NH 2 , -N(R") 2 , -CON(R") 2 , -SO3H, 1 -C 4 alkoxy groups;
  • R" independently H or C j _-C 5 linear or branched alkyl, optionally substituted with from 1 to 5 -OH groups .
  • H or a linear or branched c -C ⁇ o alkyl, optionally interrupted by one or more -CONH-, -NHCO-, -CO- groups and/or N, S atoms and optionally substituted with one or more -OH, -NH 2 ,
  • R 7 independently a linear or branched Q alkyl, optionally interrupted by one or more -CONH-, -NHCO-, -CO- groups and/or N, S atoms and optionally substituted with one or more -OH, -NH 2 ,
  • R '8S H or linear or branched c 1 c 10 alkyl, optionally interrupted by one or more -CONH- , -
  • R 9 independently a linear or branched C ⁇ -Cg alkyl, optionally interrupted by one or more
  • R" independently H or c ⁇ _c 5 linear or branched alkyl, optionally substituted with 1 to 5 -OH groups. Equally preferred are the compounds of formula (V):
  • R 12 a linear or branched C 2 -C 1Q alkyl, optionally interrupted by one or more -CONH-, -NHCO- , -CO- groups and/or N, S atoms, optionally substituted with one or more -COOH, -NH 2 groups, optionally interrupted or substituted with 1 to 3 saturated, unsaturated or- aromatic, isolated or fused rings, that are optionally interrupted by one or more N, O, S and that are optionally substituted with one or more -OH, -COOH, -NH 2 , -N(R") 2 , C 1 -Cg alkyl, C-,-Cg alkoxy groups, and the compounds of formula(VII)
  • R 13 H ' l inear or branched C ⁇ -Cg alkyl, substituted or interrupted with 1 aromatic ring, that is optionally interrupted by one or more N, O, S;
  • R 14 independently linear or branched C 1 -Cg alkyl, substituted or interrupted with one aromatic ring, that is optionally interrupted by one or more N, 0, S. Also preferred among the compounds of the formula
  • R 16 H, OH, N(R") 2 , COOR", -C0N(R") 2 , -S0 3 H, -S0 2 NHR" ,
  • Step (a) involves the protection of the alcohol group of 2-bromoethanol with dihydropyran to give intermediate (1).
  • the reaction is carried out in an organic solvent such as CH 2 C1 2 , CHC1 3 , CH 2 C1CH 2 CL, in the presence of 4-toluenesulfonic acid pyridinium salt or of other acid catalysts.
  • the Br atom can be replaced with any other nucleofugal group (such as Cl, I, -OMs , -OTf , -OTs ) and the alcohol- protecting group can be replaced, for example, by benzyl and t ⁇ tyl.
  • step (b) the ester (for example the t-butyl ester) of a natural or synthetic ⁇ -amino acid (2), in the racemic or optically active form, is reacted with intermediate (1) in the presence of diisopropylethylamine in a solvent such as CH3CN, DMF or a chlorinated solvent, to give intermediate (3).
  • a solvent such as CH3CN, DMF or a chlorinated solvent
  • step (c) The latter is reacted, in step (c), with a bromoacetic acid ester (such as t-butylbromoacetate ) in the presence of diisopropylethylamine, to give intermediate (4), which is reacted, in the subsequent step (d), with 4-toluenesulfon ⁇ c acid pyridinium salt, or other acid catalysts, in a water/ethanol mixture, at a temperature of 20-60 ⁇ C, to give intermediate (5).
  • a bromoacetic acid ester such as t-butylbromoacetate
  • step (e) intermediate (5) is brominated with N- bromosuccmimide in the presence of triphenylphosphme, to give compound (6).
  • the Br atom in intermediates (6) and (7) can be replaced with any other nucleofugal group (such as Cl, I, -OMs, -OTf, -OTs).
  • Step (f) involves the alkylation of the ester of a natural or synthetic ⁇ -amino acid (8) with bro oethyl- derivative (6) using double phase conditions in acetonitrile/aqueous phosphate buffer at pH 8 in a 1:1 molar ratio between the two reagents to give compound
  • Step (9) is further alkylated with the bromoethyl derivative (7), in step (g), in the same conditions, to give the intermediate pentaester (10), which is deprotected, in step (h), in conventional conditions, to give the corresponding pentaacid.
  • the dialkylation product (10) can be obtained directly operating in acetonitrile/aqueous phosphate buffer at pH 8 and in a aminoester (8) to bromoderivative (6) molar ratio ranging from 1:2 to 1:3.
  • Pg protective group (such as t-butyl);
  • Step (a 1 ) involves the condensation of the ester of a natural or synthetic ⁇ -amino acid (2) with an ⁇ - haloacetic acid ester (2) (such as 2-bromoacetic acid t- butyl ester) in double phase conditions in acetonitrile/aqueous phosphate buffer at pH 8, to give the i inodiacetic acid derivative (2'), which is alkylated, in step (b 1 ) in 1 , 2-dibromoethane as the solvent, under reflux, in the presence of N,N- diisopropylethylamine and at a temperature of about 80 * C, to give intermediate (6).
  • an ⁇ - haloacetic acid ester (2) such as 2-bromoacetic acid t- butyl ester
  • Table 1 above discloses the high relaxivity shown in serum by the compounds of the present invention; r ⁇ and ⁇ 2 relaxivity values of some of the preferred compounds are reported, in comparison with the corresponding r * and r 2 values measured for some of the mayor prior-art compounds: Gd-DTPA Dimeglumine salt
  • L-isoleucine 1 1-d ⁇ methylethylester (23.00 g; 122.8 mmol ) , (2-Bromoethoxy )-( 1,1-d ⁇ methylethyl )dimethylsllane (30.26 g, 126.5 mmol) and a 2 C0 3 (26.18 g; 247.0 mmol) were stirred in DMPU (Aldrich art 25,156-9) (300 L ) at 90°C for 20 h.
  • DMPU Aldrich art 25,156-9
  • the intermediate product was not isolated, but after cooling the mixture to roughly 40°C, tert-butyl bromoacetate (commercial product) (19.0 L; 130 mmol) and further Na 2 C0 3 (27.00 g; 254.7 mmol) were added, then heating at 90°C was restored. More tert- butyl bromoacetate (2.0 mL; 14 mmol) was added after 4 h and heating prolonged for another 2 h. The mixture was cooled to O'C, then water (600 mL ) was cautiously added
  • the desired compound was obtained (42.25 g; 91.90 mmol). Yield 75%.
  • Acidic titer (0.1 N HCl) : 99.7 %; equivalent point pH 4.77
  • UV Detection 210 nm , 280 nm;
  • Acidic titer (0.1 N HC10 4 ) : 98.6 %
  • N-Bromosuccinimide (46.3 g; 0.26 mol) was added in portions to a solution of the product obtained in the previous step (75.9 g; 0.20 mol) and triphenylphosphine
  • N-[2-( 1 , 1-d ⁇ methylethoxy )-2-oxoethyl ]-L- tryptophan 1 , l-dimethylethyl ester 5 g; 13.35 mmol was dissolved in CH 3 CN (25 L ) .
  • ethylene oxide 13 mL; 0.26 mol was collected from the cylinder and then quickly dropped into the solution.
  • Acidic titer (0.1 N HC10 4 ) : 98.0 %
  • N-Bromosuccmimide (commercial product) (13.9 g; 0.078 mol) was added in portions to a solution of N-(2- hydroxyethyl )-N-[2-( 1 , 1-d ⁇ methylethoxy ) -2-oxoethyl ] -O- (phenylmethyl )-L-serme 1 , l-dimethylethyl ester and triphenylphosphine (commercial product) (20.5 g; 0.078 mol) in CH 2 C1 2 (250 L ) cooled at 0 - 5°C and stirred.
  • the desired product was obtained (24 g; 0.051 mol).
  • Oven temperature timetable initial temperature: 150°C initial time: 2 mm rate: 20°C mm -1 final temperature: 210°C final time: 25 mm; Injector temperature: 250°C; Detector temperature: 250°C; Injection: 3 ⁇ L; Sample concentration: 25 mg mL- ;
  • the product is prepared according to Example 2.
  • the product is prepared according to Example 1.
  • Mobile phase isocratic elution with premixed mobile phase: 1 g of n-octylamme is added to 240 mL of acetonitrile mixed with 760 L of water The solution is buffered to pH 6 with H 3 P0 4 ;
  • UV Detection 200 nm; Injection: - 10 ⁇ L;
  • HPLC 100% (area) - Chromatographic method: Stationary phase: Lichrospher 100 RP-8 5 ⁇ m;
  • Mobile phase isocratic elution with premixed mobile phase: 1 g of n-octylamme is added to 262 mL of acetonitrile mixed with 738 mL of water. The solution is buffered to pH 6.0 with H 3 P0 4 ; Flow rate: 1.3 mL mm -1 ;
  • Sample concentration 1 or 5 g mL -1 ;
  • UV Detection 200 nm
  • the solution containing the purified product (pH 8.7) was concentrated to 50 mL and, while maintained under stirring, some Dowex CCR-3 LB resin was added until the pH of the solution , was adjusted to 4 The resin was filtered through a G3 septum and washed with warm (40°C) H 2 0 (100 L). The pH of the clear solution was corrected to 7 by addition of IN NaOH. After elimination of the solvent the title compound (2.18 g; 2.41 mmol) was obtained. Yield 40% starting from the pentaester mp- > 250°C
  • HPLC 100% (area %) - Chromatographic method: Stationary phase- Lichrospher 100 RP-8 5 ( 9 )m, 250 x 4 mm column packed by Merck KGaA; Temperature: 45°C;
  • Mobile phase isocratic elution with premixed mobile phase: 1 g of n-nonylamine is added to 330 mL of acetonitrile mixed with 670 mL of water. The solution is buffered to pH 6 with H 3 P0 4 ;
  • the product is prepared according to Example 2.
  • HPLC 98.2% (area) - Chromatographic method: Stationary phase: Lichrospher 100 RP-8 5 ⁇ m;
  • UV Detection UV: 210 nm
  • HPLC 100% (area) - Chromatographic method: Stationary phase: Lichrospher 100 RP-8 5 (?)m;
  • the desired product was obtained (19.9 g, 19 mmol). Yield 90%.
  • Mobile phase- isocratic elution with premixed mobile phase 1 g of n-octylamme s added to 350 mL of acetonitrile mixed with 650 mL of water The solution is buffered to pH 6 with H 3 P0 4 ;
  • the product has been prepared according to Example 2, Step A.
  • the product has been prepared according to Example 5.
  • CF 3 COOH 35 9 mL; 53.4 g, 0 47 mol
  • a solution of the pentaester from the previous preparation 124 g; 0.128 mmol
  • CH 2 C1 2 540 L
  • the resulting solution was evaporated (2 kPa ) and the residue was dissolved in CF 3 COOH (1070 mL; 1600 g; 14.04 mol).
  • the solution was stirred at room temperature for 69 h and then evaporated to dryness (2 kPa).
  • the crude (215.8 g) was dissolved in a 1-1 MeOH/H 2 0 mixture (670 ) and loaded onto a column of Amberlite XAD 1600 polystyrene resin (1.9 L). After elution with 7/3 MeOH/H 2 0 the crude ligand was obtained (71 4 g) The product was dissolved in H 2 0 (300 mL ) and the pH adjusted to.
  • Membrane DESAL DK 4040 Pressure. 1 MPa Retentate max conductivity: 12 mS/cm final conductivity: 3.5 mS/cm volume : 0.3 L Permeate max conductivity: 3.3 mS/cm final conductivity: 0.04 mS/cm volume : 5.23 L .
  • A aqueous solution containing 1 g L -1 n- hexylamine buffered at pH 6 with H 3 P0 4 and 33% v/v CH 3 CN
  • HPLC 100% (area %) - Chromatographic method: Stationary phase: Lichrospher 100 RP-8 5 ⁇ m; 250 x 4 mm column packed by Merck KGaA;
  • Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-octylamine is added to 300 mL of acetonitrile mixed with 700 L of water.
  • the solution is buffered to pH 6 with H 3 P0 4 ;
  • Capillary fused silica 0.56 m x 75 ⁇ m with bubble cell ;
  • Buffer 0.05 M borate pH 9.3, EDTA 0.3 mM; Temperature: 40°C;
  • Acidic titer (0.1 N HCl): 99,8 %
  • Acidic titer (0.1 N HC10 4 in CH 3 COOH): 99,1 %
  • Carrier (He) flow rates column flow rate: 0.9 mL min -1 ; split flow rate: 100 mL min -1 ; make up flow rate: 30 mL min -1 ; septum purge flow rate: 3 mL min -1 ;
  • Oven temperature timetable initial temperature: 120°C; initial time: 2 min; rate: 10°C min -1 ; final temperature: 270°C final time: 5 min,
  • Injector temperature 150°C
  • Retentate max conductivity 11.5 mS/cm final conductivity: 5.1 mS/cm volume: 0.3 L
  • HPLC 97 % (area %) - Chromatographic method: Stationary phase: Spheri -10 RP-2 10 ⁇ m;
  • the product is prepared according to Example 3.
  • Trifluoroacetic acid (96.3 g; 0.845 mol) was dripped, over 30 mm, into a solution of the product obtained at the previous step (33.3 g; 0.039 mol) in CH 2 C1 2 (20 mL) stirred at -15 ⁇ -10°C. The cooling bath was removed and the reaction stirred at room temperature for 64 h. The solvent was removed by evaporation under reduced pressure (2 kPa ) and the residue taken up with fresh trif luoroacetic acid (96.3 g; 0.845 mol).
  • Acidic titer (0.1 N NaOH) : 96.2 %; equivalent point pH
  • Mobile phase isocratic elution with premixed mobile phase: 1 g of n-octylamine is added to 240 mL of acetonitrile mixed with 760 mL of water. The solution is buffered to pH 6 with H 3 P0 4 ;
  • UV Detection UV: 210 nm
  • Trimethylsilyl iodide (commercial product) (80 g; 0.40 mol) was dripped, in 40 mm, into a solution of the compound obtained from the previous preparation (37.8 g; 0.040 mol) in CHC1 3 (200 mL ) maintained under stirring at 5 10°C. After 19 h the mixture was dropped in H 2 0/ ⁇ ce (600 g). The amorphous precipitate was dissolved in MeOH (200 L ) and 2N NaOH (100 mL ) was added to the solution up to pH 7. The solution was concentrated to remove methanol and dropped into 1 N HCl (250 mL ) containing NaHS0 3 (1 g).
  • the precipitate (containing iodide ions) was dissolved in CH 3 CN (80 L ) and the solution was diluted with H 2 0 (300 L ) and few drops of 37% HCl to maintain the solution clear.
  • the solution was loaded on to a column of Amberlite XAD-1600 (1 L), eluted with 4 : 1 CH 3 CN/0.1 N HCl ust before and after the loading to prevent the precipitation of the product on to the res .
  • the column was washed with 4 : 1 CH 3 CN/H 2 0 (2 L), then the product was eluted with 1 • 1 CH 3 CN/H 2 0 (3 L).
  • Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-nonylamme is added to 400 mL of ⁇ acetonitrile mixed with 600 L of water. The solution is buffered to pH 6 with H 3 P0 4 ; Flow rate: 1 mL mm -1 ;
  • UV Detection ( UV ) 210 nm; Injection: 10 ⁇ L; Sample concentration: 1 mg mL -1 ;
  • the solution was filtered through Millipore HA 0.45 m and loaded on to Amberlite ⁇ ' XAD 1600 (1000 mL ) , the resin was washed with H 2 0, 1:9 MeOH/H 2 0, 1:4 MeOH/H 2 0, 2:3 MeOH/H 2 0, 4:1 MeOH/H 2 0 and the product was eluted with MeOH. After evaporation of methanol, the pH of the solution was corrected to 6.8 with 1 N meglumine (0.4 m ) and the solution was concentrated to dryness at 40°C and 1.3 kPa .
  • Acidic titer (0.1 N HCl) : 98.3 %; equivalent point pH
  • Trif luoroacetic acid (commercial product) (81.4 g; 0.714 mol) was dripped, over 30 mm, into a solution of the pentaester obtained in the previous step (29 g; 0.0335 mol) m CH 2 C1 2 (20 L ) stirred at -15 ⁇ -10 * C
  • the cooling bath was removed and the reaction stirred at room temperature for 90 h
  • the solvent was removed by evaporation under reduced pressure (2 kPa) and the residue taken up with fresh tri f luoroacetic acid (81 4 g; 0.714 mol).
  • Acidic titer (0.1 N NaOH) : 96.3 % ; equivalent point pH
  • Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-octylamme is added to 350 mL of acetonitrile mixed with 650 mL of water. The solution is buffered to pH 6 with cone. H 3 P0 4 ;

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  • Investigating Or Analysing Biological Materials (AREA)

Abstract

L'invention concerne les composés de formule (I), sous leurs formes racémique ou énantiomère. Dans cette formule, R est H ou bien une chaîne alkyle C1-C20, laquelle peut être interrompue par O, N, S, -CO-, -CH(OH)-, -CH(NH2)-, -CONH-, -NHCO-, -SO-, -SO2-, -SO2NH-, peut être substituée par des atomes d'halogène ou des groupes -COOH ou bien leurs dérivés ester ou amide, et laquelle est interrompue ou non ou bien substituée ou non par un ou plusieurs résidus cycliques R3, R3 est un motif carbocyclique ou hétérocyclique, saturé, insaturé ou cyclique aromatique pentagonal ou hexagonal, éventuellement substitué, R1 et R2 ont les mêmes notations que R, indépendamment l'un de l'autre, à l'exception de H, à condition que, lorsque R1 et R2 sont tous deux C6H5-CH2-O-CH2, R soit différent de H ou de C6H5-CH2-O-CH2-. L'invention concerne également les complexes des composés de formule (I) avec des ions métal et leurs sels avec des bases organiques physiologiquement acceptables. Ces composés s'utilisent dans la préparation d'agents de contraste pour l'imagerie diagnostique et notamment d'agents de contraste présentant une relaxivité améliorée dans le sérum.
PCT/EP1997/004096 1996-08-02 1997-07-28 Agent de contraste pour l'imagerie diagnostique a relaxivite amelioree dans le serum WO1998005625A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP97940037A EP0915829A1 (fr) 1996-08-02 1997-07-28 Agent de contraste pour l'imagerie diagnostique a relaxivite amelioree dans le serum
AU42029/97A AU4202997A (en) 1996-08-02 1997-07-28 Diagnostic imaging contrast agent with improved in-serum-relaxivity
JP50542598A JP4225573B2 (ja) 1996-08-02 1997-07-28 改善された血清緩和を有する診断用画像造影剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT96MI001684A IT1283650B1 (it) 1996-08-02 1996-08-02 Chelati paramagnetici ad alta relassivita' in siero
ITMI96A001684 1996-08-02

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WO1998005625A1 true WO1998005625A1 (fr) 1998-02-12

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EP (1) EP0915829A1 (fr)
JP (1) JP4225573B2 (fr)
AU (1) AU4202997A (fr)
IT (1) IT1283650B1 (fr)
WO (1) WO1998005625A1 (fr)
ZA (1) ZA976891B (fr)

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WO1999045967A1 (fr) * 1998-03-10 1999-09-16 Bracco S.P.A. Chelates de manganese a relachement eleve dans le serum
WO1999045968A1 (fr) * 1998-03-10 1999-09-16 Bracco S.P.A. Chelates de manganese presentant un pouvoir de relaxation eleve dans du serum
WO2002038546A1 (fr) 2000-11-08 2002-05-16 K.U. Leuven Research & Development Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives
JP2003500369A (ja) * 1999-05-19 2003-01-07 アマシャム・ヘルス・エーエス 方 法
WO2003008390A1 (fr) * 2001-07-17 2003-01-30 Bracco Imaging S.P.A. Ligands aza multicoordinants pouvant complexer des ions metalliques et utilisation dans le diagnostic et la therapie
US6549798B2 (en) 2001-02-07 2003-04-15 Epix Medical, Inc. Magnetic resonance angiography data
US6676929B2 (en) 1995-02-01 2004-01-13 Epix Medical, Inc. Diagnostic imaging contrast agents with extended blood retention
US6861045B1 (en) 1997-10-02 2005-03-01 Randall B. Lauffer Contrast-enhanced diagnostic imaging method for monitoring interventional therapies
US7412279B2 (en) 2001-07-30 2008-08-12 Epix Pharmaceuticals, Inc. Systems and methods for targeted magnetic resonance imaging of the vascular system
US7893223B2 (en) 2001-07-17 2011-02-22 Bracco Imaging S.P.A. Multidentate AZA ligands able to complex metal ions and the use thereof in diagnostics and therapy
CN115611757A (zh) * 2021-07-16 2023-01-17 江苏慧聚药业股份有限公司 mRNA传递剂的合成

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EP0230893A2 (fr) * 1986-01-30 1987-08-05 BRACCO INDUSTRIA CHIMICA Società per Azioni Chelates paramagnétiques
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* Cited by examiner, † Cited by third party
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US6676929B2 (en) 1995-02-01 2004-01-13 Epix Medical, Inc. Diagnostic imaging contrast agents with extended blood retention
US7060250B2 (en) 1995-02-01 2006-06-13 Epix Pharmaceuticals, Inc. Diagnostic imaging contrast agents with extended blood retention
US7229606B2 (en) 1995-02-01 2007-06-12 Epix Pharmaceuticals, Inc. Diagnostic imaging contrast agents with extended blood retention
US7011815B2 (en) 1995-02-01 2006-03-14 Epix Pharmaceuticals, Inc. Diagnostic imaging contrast agents with extended blood retention
US7175829B2 (en) 1997-10-02 2007-02-13 Epix Pharmaceuticals, Inc. Contrast-enhanced diagnostic imaging method for monitoring interventional therapies
US6861045B1 (en) 1997-10-02 2005-03-01 Randall B. Lauffer Contrast-enhanced diagnostic imaging method for monitoring interventional therapies
JP2002506049A (ja) * 1998-03-10 2002-02-26 ブラッコ エッセ ピ ア 血清中で高い緩和性を有するマンガンキレート
WO1999045967A1 (fr) * 1998-03-10 1999-09-16 Bracco S.P.A. Chelates de manganese a relachement eleve dans le serum
JP4643824B2 (ja) * 1998-03-10 2011-03-02 ブラッコ エッセ ピ ア 血清中で高い緩和性を有するマンガンキレート
US6337064B1 (en) 1998-03-10 2002-01-08 Dibra S.P.A. Manganese chelates with high relaxivity in serum
WO1999045968A1 (fr) * 1998-03-10 1999-09-16 Bracco S.P.A. Chelates de manganese presentant un pouvoir de relaxation eleve dans du serum
JP2003500369A (ja) * 1999-05-19 2003-01-07 アマシャム・ヘルス・エーエス 方 法
CN100352805C (zh) * 2000-11-08 2007-12-05 鲁汶天主教大学研究开发部 用作造影剂的取代的联吲哚衍生物、包含它们的药物组合物以及制造它们的中间体
WO2002038546A1 (fr) 2000-11-08 2002-05-16 K.U. Leuven Research & Development Derives de bis-indole substitue utilises comme agents de contraste, compositions pharmaceutiques contenant lesdits derives et intermediaires permettant de preparer ces derives
US7081472B2 (en) 2000-11-08 2006-07-25 K. U. Leuven Research & Development Substituted bis-indole derivatives useful as contrast agents, pharmaceutical compositions containing them and intermediates for producing them
US6549798B2 (en) 2001-02-07 2003-04-15 Epix Medical, Inc. Magnetic resonance angiography data
US6925321B2 (en) 2001-02-07 2005-08-02 Epix Pharmaceuticals, Inc. Magnetic resonance angiography data
KR100890471B1 (ko) * 2001-07-17 2009-03-26 브라코 이미징 에스.피.에이. 금속 이온을 배위할 수 있는 여러자리 아자 리간드 및진단 및 치료에 있어서의 그의 용도
EP1803711A1 (fr) * 2001-07-17 2007-07-04 BRACCO IMAGING S.p.A. Ligands aza multicoordinants pouvant complexer des ions métalliques et utilisation dans le diagnostic et la thérapie
AU2002331348B2 (en) * 2001-07-17 2008-04-10 Bracco Imaging S.P.A. Multidentate aza ligands able to complex metal ions and the use thereof in diagnostics and therapy
CN100443476C (zh) * 2001-07-17 2008-12-17 布雷克成像有限公司 能够络合金属离子的多配基氮杂配体及其在诊断学和治疗学中的用途
US7186400B2 (en) 2001-07-17 2007-03-06 Bracco Imaging S.P.A. Multidentate aza ligands able to complex metal ions and the use thereof in diagnostics and therapy
US7893223B2 (en) 2001-07-17 2011-02-22 Bracco Imaging S.P.A. Multidentate AZA ligands able to complex metal ions and the use thereof in diagnostics and therapy
WO2003008390A1 (fr) * 2001-07-17 2003-01-30 Bracco Imaging S.P.A. Ligands aza multicoordinants pouvant complexer des ions metalliques et utilisation dans le diagnostic et la therapie
US8105567B2 (en) 2001-07-17 2012-01-31 Bracco Imaging Spa Multidentate AZA ligands able to complex metal ions and the use thereof in diagnostics and therapy
US7412279B2 (en) 2001-07-30 2008-08-12 Epix Pharmaceuticals, Inc. Systems and methods for targeted magnetic resonance imaging of the vascular system
CN115611757A (zh) * 2021-07-16 2023-01-17 江苏慧聚药业股份有限公司 mRNA传递剂的合成
WO2023284217A1 (fr) * 2021-07-16 2023-01-19 江苏慧聚药业有限公司 Synthèse d'un agent d'administration d'arnm
US20230357132A1 (en) * 2021-07-16 2023-11-09 Wisdom Pharmaceutical Co., Ltd. SYNTHESIS OF mRNA DELIVERY AGENT

Also Published As

Publication number Publication date
IT1283650B1 (it) 1998-04-23
ZA976891B (en) 1998-05-11
JP2000516915A (ja) 2000-12-19
ITMI961684A1 (it) 1998-02-02
ITMI961684A0 (fr) 1996-08-02
AU4202997A (en) 1998-02-25
JP4225573B2 (ja) 2009-02-18
EP0915829A1 (fr) 1999-05-19

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