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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
• • 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
• • 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
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/48—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C233/00—Carboxylic acid amides
  • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
  • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
  • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
  • C07C233/51—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
  • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
  • C07C237/06—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
  • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
  • C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D263/18—Oxygen atoms
  • C07D263/20—Oxygen atoms attached in position 2
  • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
  • C07C2601/14—The ring being saturated

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 G ⁇ + 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.
• the compounds of the present invention are diethylenetriaminepentaacetic acid derivatives characterised by having a hindering group in ⁇ to at least one of the 5 DTPA carboxylic groups wherein said substituent has the dimension of a alkyl, linear or branched, saturated or unsaturated chain, which is substituted or interrupted by at least two cyclic, optionally aromatic, carbocyclic or eterocyclic, saturated or unsaturated, isolated or fused units.
• Said hindering group is probably responsible for the interaction of the paramagnetic chelates with biological components of the fluids in which the agent diffuses, wherein said interaction produces 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 Nyco ed Phar a AS, Oslo, Norway. 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 r 2 relaxivity values.
• compounds of the present invention When measured in SeronormTM Human at 20 MHz, at a temperature of 39 * C, and at a concentration comprised from 0 to 1 M, compounds of the present invention usually have ⁇ 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)
• R is H, or a linear or branched, saturated or unsaturated C 1 -C 2 Q alkyl, optionally interrupted by one or more -CH(OH)-, -CONH- , -NHCO- , -CO-, -CH(NH 2 )-, -SO-, -S0 2 -, S0 2 NH- groups and/or one or more N, 0, S atoms, optionally substituted with one or more -COOH groups and/or amide or ester derivatives thereof, and in which said alkyl chain is interrupted or substituted by at least 2, which are independently the same or different, isolated or fused, cyclic L residues, with the proviso that, when some L residues are fused together, the resulting polycyclic unit comprises no more than 3 cyclic group, and in which
• L is a carbocyclic or heterocyclic , saturated or unsaturated or aromatic cyclic unit, comprising from 5 to 6 atoms, optionally substituted by one or more X groups, which are independently the same or different, in which
• X is OH, halogen, NH 2 , NHZ , N(Z) 2 , -0Z- , -SZ, -COZ, where the Z groups can independently be a C ⁇ -Cc linear or branched alkyl, optionally substituted with one or more -OH, -COOH or alkoxy groups, or said X group is a -COOH group or a derivative thereof, such as an ester or an amido group, or an
• Ri is the same as R with the provisos that:
• R and R cannot be at the same time H; when R is different from H, R ⁇ . is H; when R ⁇ is different from H, R is H.
• the compounds comprised within formula (I) can be either race ic or optically active.
• the invention further comprises 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+) , Cu ( 2+) t Cr ( 3+ ), Gd ⁇ 3+ >, Eu ⁇ +) , Dy (3+ ), La ⁇ 3+ >, Yb ⁇ 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 + , Mg 2+ , Ca 2+ or a mixture thereof.
• 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 + , Mg 2+ , 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 the pharmaceutical formulations containing them for a diagnostic or therapeutic scope.
• R or R- are selected from the following groups:
• RI is H and R is as defined above in formula (I), but is different from H.
• R' independently H, halogen
• R'i H, OH, N(R") 2 , COOR", -CON(R") 2 , -SO3H, -S0 2 NHR", C 1 -C 6 alkyl, C j -Cg alkoxy;
• R' independently H, halogen;
• R" independently H or c ⁇ C 5 linear or branched alkyl, optionally substituted with 1 to 5 -OH groups; with the proviso that at least one of the substituents
• R' is different from hydrogen, as well as compounds of formula (V)
• R" independently H or c ⁇ c 5 linear or branched alkyl, optionally substituted with 1 to 5 -OH groups .
• R 2 C ⁇ -C ⁇ alkyl, optionally interrupted by one or more -CONH-, -NHCO- , -CO- groups and/or N, S atoms, optionally substituted with -OH, -COOH, -NH 2 ,
• alkyl being interrupted or substituted with a polycyclic unit comprising from
• polycyclic unit being interrupted by one or more N, 0, S and optionally substituted with
• R" independently H or c ⁇ c $ linear or branched alkyl, optionally substituted with 1 to 5 -OH groups; and particularly preferred are the compounds of general formula (VII)
• a polycyclic unit comprising from 2 to 3 saturated or unsaturated or aromatic fused rings, said polycyclic unit being interrupted by one or more N, 0, S and optionally substituted with -OH, -COOH, -NH 2 , -N(R") 2 , C ⁇ -Cg alkyl, C 1 -C ⁇ alkoxy, Cg-C 20 arylalkoxy groups;
• R 4 independently saturated, unsaturated or aromatic ring, optionally interrupted by one or more N, 0, S atoms and optionally substituted with one or more -OH, -COOH, -NH 2 , -N(R") 2 , -C0N(R M ) 2 , -SO3H;
• R" independently H or C ⁇ -C j linear or branched alkyl, optionally substituted with 1 to 5 -OH groups; and the compounds of formula (IX)
• the preparation of the compounds of the present application comprises the regiospecific introduction of the hindering substituent in ⁇ to a carboxylic group of the acetic acid bound to the central nitrogen atom of
• Rapoport J. Org. Chem. 1993, 58,
• An alternative way comprises the use of synthons such as glutamic acid or lysine, which allows the introduction of hindering groups quite distant from the carbon atom in ⁇ to a carboxylic group of the central acetic acid residue, exploiting the terminal acid or amino functions, respectively, of a.m. amino acids.
• B z+ Na + , K + , Mg ++ , Ca ++ or mixtures thereof, or it is the salt of a physiologically acceptable organic base;
• z number of the positive charges of B;
• Table 1 above discloses the high relaxivity shown in serum by the compounds of the present application; r, and r 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
• Ethanolamine (15.15 g; 0.25 mol ) was dropped in 10 minutes into a suspension of t-butyl bromoacetate (112.3 g; 0.58 mol) and KHCO3 (62.57 g; 0.62 mol) in DMF (400 mL) , maintained at 0 * C under inert atmosphere. After 22 h at 20°C the suspension was diluted with a saturated solution of NaHCC- 3 (400 m ) and Et 2 0 (400 mL ) . After separation, the aqueous phase was extracted with Et 2 0 (800 mL); the organic phases were collected, dried
• Chromatographic method Stationary phase: DB 5 (OV-73); Film thickness: 0,25 ⁇ ; Column: 30 m x 0,25 mm; He flow rates at 130 ⁇ C: column flow rate 0,9 mL-min -1 ; split flow rate 100 mL-min -1 ; column flow rate + make-up 30 mL-min -1 ; septum purge flow rate 3 mL-min -1 ; Detector feeding (FID):
• the compound was prepared according to: Bentley, P.H.; Stachulski, A. V.. J. Che . Soc . Perkin Trans. I 1983, 1187-1192.
• the desired product (190 g; 0.216 mol) was obtained. Yield 90 %.
• UV Detection UV: 210 n ;
• Acidic titer (0.1 N HC1) : first inflection point 93.7 %; Second inflection point 95.3 %; Equivalent points pH 7.3 and 7.8 TLC : Rf 0.08
• HPLC 98.4 % (area %) - Chromatographic method: Stationary phase: Lichrosorb RP-Select B 5 (?)m;
• UV Detection UV: 210 nm
• Acidic titer (0.1 M HC10 4 ) : 102 % Complexo etric titer (0.001 M GdCl 3 ): 99.7 % HPLC : 99 % (area %) - Chromatographic method: Stationary phase: Lichrospher 100 RP-8 5 ⁇ ;
• UV detector attenuation 256; Injection: 100 mL;
• Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-octylamine is added to 350 mL of acetonitrile mixed with 650 L of water. The solution is buffered to pH 6 with H 3 P0 4
• N N-Bis [ 2- [ bis ( carboxymethyl ) amino ] ethyl ] -0- ( 4-hy- droxyphenyl ) -3 , 5-diiodo-L-tyrosine
• N-bis [2-[bis(carbo- xymethyl)amino]ethyl]-0-( 4-hydroxyphenyl )-3 5-diicdo-L- tyrosine (5,1 g; 6 mmol) 1 M NaOH (15 L; 15 mmol) was added until pH 7 then Pd on carbon (3 g) was added.
• the suspension was stirred over 90 min under a hydrogen atmosphere (consumed H 2 300 mL; 12.2 mmol) at 26°C and atmospheric pressure, maintaining pH 7 by the addition of 1 M NaOH (11.33 mL; 11.33 mmol) through a pH-stat apparatus.
• Mobile phase isocratic elution with premixed mobile phase: 1 g of n-octylamine is added to 230 mL of acetonitrile mixed with 770 mL of water. The solution is buffered to pH 6 with H 3 P0 4 ;
• UV Detection UV: 210 nm
• Mobile phase isocratic elution with premixed mobile phase: 1 g of n-octylamine is added to 270 mL of acetonitrile mixed with 730 mL of water and 2 mL of 0.1
• UV Detection UV: 210 nm
• Acidic titer (0.1 N NaOH): 101.1 % Acidic titer (0.1 N HC10 4 ) : 97.4 % Complexometric titer (0.1 N GdCl 3 ): 96.7 % TLC : Rf 0.36 Stationary phase: Silica gel plates 60 F 254 Merck KGaA art 5715 Mobile phase: 4/4/2 CHCl 3 /CH 3 OH/25% aq NH 4 OH Detection: 1% KMn0 4 in 1 M NaOH
• Mobile phase isocratic elution with premixe ⁇ mobile phase: 1 g of n-octylamine is added to 280 L of acetonitrile mixed with 720 mL of water and 2 mL of 0.1 M EDTA. The solution is buffered to pH 6 with H 3 P0 4 ; Flow rate: 1 mL mm -1 ;
• UV Detection UV: 210 nm
• UV Detection (UV) Injection 10 ⁇ L;
• Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-octylamine is added to 400 mL of acetonitrile mixed with 600 mL of water. The solution is buffered to pH 6 with H 3 P0 4 ; Flow rate: 1 mL min -1 ;
• UV Detection UV: 210 nm
• the desired product was obtained (6.22 g; 34.4 mmol).
• Mobile phase isocratic elution with pre ixed mobile phase: 1 g of n-octylamine is added to 270 mL of acetonitrile mixed with 730 mL of water. The solution is buffered to pH 6 with H 3 P0 4 ; Flow rate: 1 mL min -1 ;
• UV Detection 210 n ; Injection: 5 ⁇ L;

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• 1996
  • 1996-08-02 IT IT96MI001685A patent/IT1283651B1/it active IP Right Grant
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