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US 2003/0232012 A1Published application
Metal complexes that contain perfluoroalkyl, process for their production and their use in NMR diagnosis
AssigneeSchering Corporation
InventorsJohannes Platzek, Ulrich Niedballa, Bernd Raduchel, Wolfgang Schlecker, Hanns-Joachim Weinmann, Thomas Frenzel, Bernd Misselwitz, Wolfgang Ebert
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Abstract
The invention relates to new, monomeric, perfluoroalkyl-substituted metal complexes, processes for their production, and their use in diagnosis and therapy. The compounds according to the invention are suitable especially as in vivo contrast media in nuclear spin tomography (MRT). They can preferably be used as blood-pool agents and as lymphographic agents.
Claims17
Perfluoroalkyl-containing compounds of general formula I
- RF-L-A I
- in which
- RF is a perfluorinated, straight-chain or branched carbon chain with formula —CnF2nX, in which
- X represents a terminal fluorine, chlorine, bromine, iodine or hydrogen atom, and n stands for numbers 4-30,
- L means a direct bond, a methylene group, an —NHCO group, a group
- 67
- whereby p means numbers 0 to 10, q and u, independently of one another, mean numbers 0 or 1 and
- R1 is a hydrogen atom, a methyl group, a —CH2—OH group, a —CH2—CO2H group or a C2-C15 chain, which optionally is interrupted by 1 to 3 oxygen atoms, 1 to 2>CO groups or an optionally substituted aryl group and/or is substituted with 1 to 4 hydroxyl groups, 1 to 2 C1-C4 alkoxy groups, 1 to 2 carboxy groups, a group —SO3H,
- or L is a straight-chain, branched, saturated or unsaturated C2-C30 carbon chain, which optionally contains 1 to 10 oxygen atoms, 1 to 3 —NR1 groups, 1 to 2 sulfur atoms, a piperazine, a —CONR1 group, a —NR1CO-group, an —SO2 group, an —NR1—CO2 group, 1 to 2 —CO groups, a group
- —CO—N-T-N(R1)—SO2—RF or 1 to 2 optionally substituted aryls and/or is interrupted by these groups and/or is optionally substituted with 1 to 3 —OR1 groups, 1 to 2 oxo groups, 1 to 2 —NH—COR1 groups, 1 to 2 —CONHR1 groups, 1 to 2 —(CH2)p—CO2H groups, 1 to 2 groups of —(CH2)p—(O)q—CH2CH2—RF,
- whereby
- R1, RF and p and q have the above-indicated meanings, and
- T means a C2-C10 chain, which optionally is interrupted by 1 to 2 oxygen atoms or 1 to 2 —NHCO groups,
- A stands for a complexing agent or metal complex or their salts of organic and/or inorganic bases or amino acids or amino acid amides, specifically for a complexing agent or complex of general formula II
- 68
- in which R3, Z1 and Y are independent of one another, and
- R3 has the meaning of R1 or means —(CH2),-L-RF, whereby m is 0, 1 or 2 and L and RF have the above-mentioned meaning,
- Z1 independently of one another, mean a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 39, 42, 44 or 57-83,
- Y means —OZ1 or
- 69
- whereby Z1, L, RF and R3 have the above-mentioned meanings,
- or
- A stands for a complexing agent or complex of general formula III
- 70
- in which R3 and Z1 have the above-mentioned meanings and R2 has the meaning of R1,
- or
- A stands for a complexing agent of complex of general formula IV
- 71
- in which Z1 has the above-mentioned meaning,
- or
- A stands for a complexing agent or complex of general formula V
- 72
- in which Z1 has the above-mentioned meaning, and o and q stand for numbers 0 or 1 and the sum o+q=1 results,
- or
- A stands for a complexing agent or complex of general formula VI
- 73
- in which Z1 has the above-mentioned meaning
- or
- A stands for a complexing agent or complex of general formula VII
- 74
- in which Z1 and Y have the above-mentioned meanings
- or
- A stands for a complexing agent or complex of general
- 75
- in which R3 and Z1 have the above-mentioned meanings, and R2 has the above-mentioned meaning of R1,
- or
- A stands for a complexing agent or complex of general formula IX
- 76
- in which R3 and Z1 have the above-mentioned meanings,
- or
- A stands for a complexing agent or complex of general formula X
- 77
- in which R3 and Z1 have the above-mentioned meanings,
- or
- A stands for a complexing agent or complex of general formula XI
- 78
- in which Z1, p and q have the above-mentioned meanings and R2 has the meaning of R1,
- or
- A stands for a complexing agent or complex of general formula XII
- 79
- in which L, RF and Z1 have the above-mentioned meanings,
- or
- A stands for a complexing agent or complex of general formula XIII
- 80
- in which Z1 has the above-mentioned meaning.
62 more elements
Process for the production of perfluoroalkyl-containing compounds of general formula I, wherein
- a) Compounds of general formula I with A in the meaning of general formula IX are produced by compounds of general formula 20
- 83
- in which
- R4 means hydrogen, methyl, ethyl, isopropyl, t-butyl or benzyl, being reacted with epoxides of general formula 21
- 84
- in which
- R3 has the meaning of R1, optionally in protected form, or means —(CH2)m-L-RF, whereby m can be 0, 1 or 2, L′ has the meaning of L, optionally in protected form, and RF is a perfluorinated carbon chain,
- in alcohol, ethers, water or in mixtures of water and an organic solvent at temperatures between −10° C. and 180° C. with the addition of inorganic and/or organic bases, then optionally present protective groups being cleaved, the thus obtained complexing agents being reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 at room temperature or elevated temperature, and then—if desired—acid hydrogen atoms that are present being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides,
- b) compounds of general formula I with A in the meaning of general formula VIII are produced by compounds of general formula 20 being alkylated in a way known in the art with compounds of general formula 28
- 85
- in which R2 has the meaning of R1, Hal means chlorine, bromine and iodine, and RF, L′ and R3 have the above-mentioned meanings, then optionally present protective groups being cleaved and the procedure further being performed as under a) with the thus obtained complexing agents,
- c) compounds of general formula I with A in the meaning of general formula VII are produced by compounds of general formula 20 being reacted in a way known in the art with compounds of general formula 34
- 86
- in which Hal′ has the meaning of Hal, F, —OTs, OMs, Y′ stands for radicals —OH and —N—CH2—CH2—RF
- R3 and L′ and RF have the above-mentioned meaning, then optionally present protective groups being cleaved and the procedure further being performed as under a) with the thus obtained complexing agents,
- d) compounds of general formula I with A in the meaning of general formula XI with q meaning the number 0 are produced by compounds of general formula 20 being reacted with compounds of general formula 68
- 87
- in which RF, L′, R2 and Hal have the above-mentioned meanings,
- in an organic solvent at elevated temperatures for several hours, then optionally present protective groups being cleaved and the procedure further being performed as under a) with the thus obtained completing agents,
- e) compounds of general formula I with A in the meaning of general formula XI with q meaning the number 1 are produced by compounds of general formula 20 being reacted with compounds of general formula 68a
- 88
- in which RF, L′, R2, p and Hal have the above-mentioned meanings,
- in an organic solvent at elevated temperatures for several hours, then optionally present protective groups being cleaved and the procedure further being performed as under a) with the thus obtained complexing agents.
20 more elements
Process for the production of perfluoroalkyl-containing compounds of general formula I, wherein
- a) compounds of general formula I with A in the meaning of general formula II are produced by, if Y in general formula II stands-for an OH group, compounds of general formula 48
- 89
- in which R4 has the above-mentioned meaning, being reacted with an amine of general formula 29
- 90
- in which R3, L′ and RF have the above-mentioned meanings,
- in an organic solvent, optionally with the addition of inorganic and/or organic bases, at elevated temperatures, then optionally present protective groups being cleaved, the thus obtained complexing agents being reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 at room temperature or elevated temperature, and then—if desired—acid hydrogen atoms that are present being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides, or, if Y in general formula II stands for group —N—CH2—CH2-L′-RF R3,
- the bisanhydride of the diethylenetriamine-pentaacetic acid (Merck) of general formula 49
- 91
- being reacted under analogous conditions with an amine of formula 29 and the procedure further being performed as in the first case,
- b) compounds of general formula I with A in the meaning of general formula XII are produced by bisanhydride 49 being reacted with piperazine derivatives of general formula 67
- 92
- in which RF and L′ have the above-mentioned meaning,
- under the same conditions as under a), then optionally present protective groups being cleaved and the procedure further being performed as under a).
10 more elements
Process for the production of perfluoroalkyl-containing compounds of general formula I, wherein
- a) Compounds of general formula I with A in the meaning of general formula III are produced by halocarboxylic acid derivatives of general formula 52
- 93
- in which Hal and R4 have the above-mentioned meaning,
- being reacted in a way known in the art with compounds of general formula 51
- 94
- in which RF, L′, R2 and R3 have the above-mentioned meaning,
- then optionally present protective groups being cleaved, the thus obtained complexing agents being reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 at room temperature or elevated temperature and then—if desired—acid hydrogen atoms that are present being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides,
- b) compounds of general formula I with A in the meaning of general formula XIII are produced by halocarboxylic acid derivatives of general formula 52 being reacted analogously to a) with piperazine derivatives of general formula 66
- 95
- in which RF, L′ and R2 have the above-mentioned meaning,
- then optionally present protective groups being cleaved and the procedure further being performed as under a).
8 more elements
Process for the production of perfluoroalkyl-containing compounds of general formula I, wherein compounds with A in the meaning of general formula IV are produced by hydroxy acids or hydroxy esters of general formula 56
- 96
- in which R4 has the above-mentioned meaning, being reacted with halogen compounds of general formula
- Hal-L′-RF (55)
- in which RF, L′ and Hal have the above-mentioned meanings,
- in a mixture consisting of an organic solvent and a buffer at slightly alkaline pH at room temperature for several hours, then optionally present protective groups being cleaved, the thus obtained complexing agents being reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 at room temperature or elevated temperature and then—if desired—acid hydrogen atoms that are present being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides.
2 more elements
Process for the production of perfluoroalkyl-containing compounds of general formula I, wherein
- a) Compounds of general formula I with A in the meaning of general formula V are produced by a-halocarboxylic acid ester or α-halocarboxylic acids of general formula 18
- Hal-CH2—CO2R4 (18)
- in which Hal and R4 have the above-mentioned meaning,
- being reacted in a way known in the art with amines of general formula 39
- 97
- in which L′, RF, o and q have the mentioned meanings,
- then optionally present protective groups being cleaved, the thus obtained complexing agents being reacted with at least one metal oxide or metal salt of an element of atomic numbers 21-29, 39, 42, 44 or 57-83 at room temperature or elevated temperature and then—if desired—acid hydrogen atoms that are present being substituted by cations of inorganic and/or organic bases, amino acids or amino acid amides,
- b) compounds of general formula I with A in the meaning of general formula VI are produced by α-halocarboxylic acid esters or α-halocarboxylic acids of general formula 18 being reacted in a way known in the art with compounds of general formula 36
- 98
- in which L′ and RF have the above-mentioned meanings,
- and the procedure further is performed as under a),
- c) compounds of general formula I with A in the meaning of general formula X are produced by α-halocarboxylic acid esters or α-halocarboxylic acids of general formula 18 being reacted in a way known in the art with compounds of general formula 70
- 99
- in which RF, L′, R3 have the above-mentioned meaning, and Sg is in the meaning of a protective group,
- and the procedure further is performed as under a).
12 more elements
Dependencies are inferred from the claim text.