EP1848429A1 - Pharmazeutische mittel enthaltend fluoralkylhaltige metallkomplexe und epothilone - Google Patents
Pharmazeutische mittel enthaltend fluoralkylhaltige metallkomplexe und epothiloneInfo
- Publication number
- EP1848429A1 EP1848429A1 EP06706829A EP06706829A EP1848429A1 EP 1848429 A1 EP1848429 A1 EP 1848429A1 EP 06706829 A EP06706829 A EP 06706829A EP 06706829 A EP06706829 A EP 06706829A EP 1848429 A1 EP1848429 A1 EP 1848429A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- dihydroxy
- dione
- tetramethyl
- oxacyclohexadec
- ene
- Prior art date
- Legal status (The legal status 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 status listed.)
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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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/244—Lanthanides; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
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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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
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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
- A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
- A61K49/10—Organic compounds
- A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
- A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
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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
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/243—Platinum; Compounds thereof
Definitions
- compositions comprising at least one fluoroalkyl-containing metal complex having a critical micelle concentration of ⁇ 10 "3 mol / l and a hydrodynamic diameter (2Rh) of> 1 nm, and at least one natural or synthetic one Epothilone or epothilone derivative, and their use for the diagnosis, therapy and treatment course monitoring of tumors, in particular by intravenous administration.
- Tumor therapy faces a number of problems, most of which stem from the fact that the chosen therapeutic modality is not solely focused on the tumor and its metastases, but usually also affects the surrounding normal tissue.
- the unavoidable damage to the normal tissue surrounding the tumor, or of the whole organism, in many cases does not permit the administration of the substance or radiation doses sufficient for tumor healing.
- Radiation therapy can be focused on the tumor by physical means, but the surrounding tissue can not be completely excluded from the radiation field. Similar arguments apply to the local application of cytotoxic drugs such as epothilones and epothilone derivatives.
- compositions may contain adjuncts for interventional radiology or for tumor therapy, eg chemotherapeutic agents (especially cytostatics, eg 5-fluorouracil, cisplatin, doxorubicin, mitomycin C).
- chemotherapeutic agents especially cytostatics, eg 5-fluorouracil, cisplatin, doxorubicin, mitomycin C.
- the combination ensures that the therapeutic agent is slowly released from the embolus over a longer period of time (chemoembolization).
- this method has the disadvantage that the tumor can only be addressed locally, since the compositions immediately cause a closure of the vessel (embolus) at the site of the application.
- the cytostatic agent contained in the composition then also diffuses only locally at the site of the occlusion into the adjacent tissue.
- the targeted, local application requires the introduction of a catheter selectively into the tumor-supplying blood vessel. Due to the high viscosity of the compositions, they must be applied under high pressure. This is therefore a highly invasive treatment that is very distressing for the patient and associated with the increased risk of side effects.
- the method has the disadvantage that the therapeutic effect can occur only locally - in the vicinity of the embolus, and thus, on the one hand, tumor metastases are not detected and, on the other hand, there is the danger that the embolus will not be formed exactly on the tumor and therefore the therapy the tumor is insufficiently achieved.
- the method requires the presence of a sufficiently large, tumor-supplying vessel to allow catheterization in the first place. This severely restricts the choice of tumor types which can be treated by this method, essentially this method is therefore used only for the treatment of liver tumors.
- the invention is thus based on the object of providing pharmaceutical agents which, on the one hand, have high activity and specificity with respect to tumors, address all regions of the body and therefore also treat distant metastases, and at the same time for the patient are as gentle as possible, in particular with regard to the application of pharmaceutical agents .. This object is achieved by the invention.
- compositions comprising at least one fluoroalkyl-containing metal complex having a critical micelle concentration of ⁇ 10 -3 mol / l and a hydrodynamic diameter (2Rh) of> 1 nm and at least one natural or synthetic epothilone or epothilone derivative
- the agents are solutions of comparatively low viscosity (Example 1) which can be distributed throughout the body as a result of systemic (intravenous) administration (Example 2) and can thus also be used to address distant metastases.
- This intravenous administration has, in comparison to Catheter application (as required for the agents disclosed in WO 97/30969) provides significant patient benefits in terms of exercise.
- fluoroalkyl compounds described for example in patent applications WO 02/14309 and WO 97/30969 have the ability to mediate the dissolution of hydrophobic substances, eg epothilones, in aqueous systems and according to their pharmacokinetic and pharmacodynamic properties , ie, without their distribution behavior changes significantly to transport.
- the resulting structures have a smaller hydrodynamic diameter than, for example, liposomes and are intercepted only to a small extent by the MPS in the liver and spleen.
- the therapeutic agent eg natural or synthetic epothilones or epothilone derivatives
- the target site tumor
- the aid of the fluoroalkyl-containing compound has a longer residence time there.
- the micellar encapsulation leads to an increased stability of the epothilones in the aqueous Milieu.
- the local therapeutic effect (tumor control, partial or complete tumor remission) can be monitored without re-application of a diagnostic agent with the appropriate radiological procedure, since its long residence time extends over a chemotherapy cycle.
- the fluoroalkyl-containing metal complex fulfills several functions: contrast agent in the imaging for the representation of the tumor, carrier for the epothilone to the site of action (tumor) and contrast agent for therapy control.
- the pharmaceutical compositions according to the invention are therefore also very well suited for diagnostic imaging of tumors (Example 2, Fig. 1).
- the therapeutic effectiveness of the agents according to the invention can be enhanced by X-rays or other rays which cause an accumulation or release of the active substance in the tumor, or increase their effect.
- the pharmaceutical compositions of the invention comprising at least one fluoroalkyl-containing compound and at least one natural or synthetic epothilone or epothilone derivative usually have a hydrodynamic diameter of ⁇ 1 nm.
- Particularly suitable according to the invention are those fluoroalkyl-containing metal complexes whose 2Rh 2 nm, preferably ⁇ 3 nm.
- the hydrodynamic diameter is determined by dynamic photocorrelation spectroscopy.
- the critical micelle concentration (CMC) is the inventive substances typically ⁇ 10 "3 mol / l, in appropriate cases, particularly ⁇ 10" 4 mol / l, and in most cases suitable ⁇ 10 "5 mol / l.
- the determination the CMC is described in H. -D. Dörfler "Grenz lake und Kolloidchemie”; Weinheim, New York, Basel, Cambridge, Tokyo; VSH 1994 described.
- epothilones or epothilone derivatives it is possible to use, for example, those described in DE 19907588, WO 98/25929, WO 99/58534, WO 99/2514, WO 99/67252, WO 99/67253, WO 99/7692, EP 99/4915, WO 00 / 485, WO 00/1333, WO 00/66589, WO 00/49019, WO 00/49020, WO 00/49021, WO 00/71521, WO 00/37473, WO 00/57874, WO 01/92255, WO 01 / 81342, WO 01/73103, WO 01/64650, WO 01/70716, US 6204388, US 6387927, US 6380394, US 02/52028, US 02/58286, US 02/62030, WO 02/32844, WO 02/30356 , WO 02/32844, WO 02/14323,
- Preferred epothilones or epothilone derivatives are described in claim 8. Particularly useful epothilones and epothilone derivatives are described in Table 2.
- combination therapy means the temporally separate administration of two therapeutically active principles; ie two monotherapies are performed side by side: in this case the treatment with a cytostatic (epothilone or epothilone derivative) on the one hand, and on the other hand with the cytotoxic substance cisplatin, which binds to DNA and thus kills especially fast-growing cells.
- cytostatic epothilone or epothilone derivative
- fluoroalkyl-containing metal complexes of the present invention with epothilones in a single preparation as a formulation for epothilones.
- the fluoroalkyl-containing metal complexes are characterized by particularly good compatibility and have no antitumor effect themselves.
- preferred compounds are the compounds of general formula I.
- Rp is a fluorinated, straight-chain or branched carbon chain of the formula -C n F 2 n E in which
- E is a terminal fluorine, chlorine, bromine, iodine or
- n represents the numbers 4 to 30,
- L is a direct bond, a methylene group, an -NHCO group, a group
- R a is a hydrogen atom, a methyl group, a -CH 2 -OH group, a -CH 2 -CO 2 H- group or a C 2 -C 15 chain, which is optionally interrupted by 1 to 3
- Oxygen atoms 1 to 2 C (O) groups or an optionally substituted aryl group and / or is substituted by 1 to 4 Hydroxyl groups, 1 to 2 C 1 -C 4 -alkoxy groups, 1 to 2 carboxy groups, a group -SO 3 H-,
- Piperazine a -CONR a group, an -NR a CO group, an -SO 2 group, an -NR a -CO 2 group, 1 to 2 CO groups, a group
- R a , R ⁇ and p and q have the meanings given above and
- T is a C2-Cirj chain which is optionally interrupted by 1 to 2 oxygen atoms or 1 to 2 -NHCO groups,
- R c has the meaning of R a or - (CH 2 ) m -LR F , where m is 0, 1 or 2 and L and R F have the abovementioned meaning, R 1 independently of one another denote a hydrogen atom or a metal ion equivalent of atomic numbers 20 - 29, 39, 42, 44, 58-70 or 83, wherein at least two R 1 a
- R 1 , L, R F and R c have the meanings mentioned above,
- R c and R ⁇ have the abovementioned meanings and R b has the meaning of R a
- R 1 has the abovementioned meaning.
- n in the formula -C n F 2n E represents the numbers 4-15 and / or E in this formula denotes a fluorine atom.
- A is a moiety containing 2-6 metal complexes attached directly or via a linker to a nitrogen atom of an annular skeleton chain
- RF is a perfluorinated, straight-chain or branched carbon chain of the formula -C n F2nE, in which
- E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is the numbers 4 to 30,
- K is a complexing agent or metal complex or salts thereof of organic and / or inorganic bases or amino acids or amino acid amides,
- X is a direct bond to the perfluoroalkyl group, a phenylene group or a C 1 -C 6 -alkylene chain which optionally has 1 to 15 oxygen, 1 to 5 sulfur atoms, 1 to 10 carbonyl, 1 to 10 (NR d ), 1 to 2 NR d SO 2 -, 1 - 10 CONR d -, 1 piperidine, 1 - 3 SO 2 -, 1 - contains 2 phenylene groups or optionally substituted by 1 - 3 radicals R F , wherein R d is a hydrogen atom, a phenyl, benzyl or a C 1 C 15 alkyl group which optionally contains 1 - 2 NHCO, 1 - 2 CO groups, 1-5 oxygen atoms and optionally by 1-5 hydroxy, 1-5
- V is a direct bond or a chain of general formula IIa or IIIa:
- R e is a hydrogen atom, a phenyl group, a benzyl group or a
- ⁇ W is a direct bond, a polyglycol ether group with up to 5 glycol units or a Molecule part of the general formula IVa
- R h is a C 1 -C 7 carboxylic acid, a phenyl group, a benzyl group or a - (CH 2 ) 1 -5 -NH-K group,
- compounds of general formula Ia are used in which the moiety X is an alkylene chain containing 1-10 CH 2 CH 2 O- or 1-5 COCH 2 NH groups, a direct bond or one of following structures
- R4 independently of one another is a hydrogen atom or a metal ion equivalent of the elements of atomic numbers 23-29, 42-46 or 58-70,
- R5 is a hydrogen atom or a straight-chain, branched, saturated or unsaturated C 1 -C 3 -j-alkyl chain which is optionally substituted by 1 -5 hydroxy, 1 to 3 carboxy or 1 phenyl group (s) and / or optionally by 1 to 10 Oxygen atoms, 1 phenylene or 1 phenylenoxy group is interrupted
- R 6 is a hydrogen atom, a straight-chain or branched C 1 -C 7 -alkyl radical, a phenyl or benzyl radical,
- R 7 is a hydrogen atom, a methyl or ethyl group which is optionally substituted by a hydroxy or carboxy group
- U 3 is an optionally 1-5 imino, 1 -3 phenylene, 1 -3 phenyleneoxy, 1 to 3 phenyleneimino, 1 to 5 amide, 1 to 2 hydrazide, 1 to 5 carbonyl, 1 to 5 ethyleneoxy,
- T 1 is a -CO-ß, -NHCO-ß or -NHCS-ß group, where ß represents the binding site to V.
- Ci-C20-alkylene chain which is present for U 3 preferably contains the groups
- the perfluoroalkyl chain is
- K is a complexing agent or a metal complex of the general formula IIb
- R 1 is a hydrogen atom or a metal ion equivalent of atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83
- R 2 and R 3 is a hydrogen atom, a Ci-C 7 alkyl group, a benzyl group, a phenyl group, -CH 2 OH or -CH 2 -OCH 3
- U 2 is the radical L 1 , wherein L 1 and U 2 may be the same or different independently
- a 1 is a hydrogen atom, one straight-chain or branched C 1 -C 30 -alkyl group which is optionally interrupted by 1-15 oxygen atoms and / or is optionally substituted by 1-10 hydroxyl groups, 1-2 COOH groups, a phenyl group, a benzyl group and / or 1 -5 -
- OR 9 groups with R 9 meaning a hydrogen atom or a C 1 -C 7 -alkyl radical, or -L 1 -R F ,
- L 1 is a straight-chain or branched C 1 -C 30 -alkylene group which is optionally interrupted by 1-10 oxygen atoms, 1-5 -NH-CO- groups, 1-5 -CO-NH- groups, by an optionally one
- R F represents a straight-chain or branched perfluorinated alkyl radical of the formula C n F 2n E, where n is the number 4-30 and E is a terminal fluorine atom, chlorine atom, bromine atom, iodine atom or a hydrogen atom, and optionally present acid groups Salts of organic and / or inorganic bases or amino acids or amino acid amides can be used, as they are and their preparation in WO 00/56723 disclosed and defined are used.
- compounds of general formula Ib are used in which R 2 , R 3 and R 9 independently of one another are hydrogen or a C 1 -C 4 -alkyl group.
- a 1 is hydrogen, a C 1 -C 15 -alkyl radical, the radicals C 2 H 4 -O-CH 3 , C 3 H 6 -O-CH 3 ,
- E is a hydrogen, fluorine, chlorine, bromine or iodine atom and, if possible, their branched isomers.
- E is a fluorine atom and, if possible, its branched isomers.
- L 1 is ⁇ - (CH 2 ) s - ⁇ ⁇ -CH 2 -CH 2 - (O-CH 2 -CH 2 -) y - ⁇ ⁇ -CH 2 - (O-) CH 2 -CH 2) -Y- ⁇ , ⁇ -CH 2 -NH-CO- ⁇ ⁇ -CH 2 -CH 2 -NH-SO 2 - ⁇ ⁇ -CH 2 -NH-CO-CH 2 -N (CH 2 COOH) -SO 2 - ⁇ ⁇ -CH 2 -NH-CO-CH 2 -N (C 2 H 5) -SO 2 - ⁇ ⁇ -CH 2 -NH-CO-CH 2 -N (C o oH21) -SO 2 - ⁇ ⁇ -CH 2 -NH-CO-CH 2 -N (C 6 H-) 3) -SO 2 - ⁇ ⁇ -CH 2 -NH-CO- (CH 2 ) io-
- R F denotes a straight-chain or branched perfluorinated alkyl radical of the formula C n F 2n E, where n is the number 4 to 15 and E is a terminal fluorine atom.
- the perfluoroalkyl-containing complexes with sugar residues of the general formula Ic (see also WO 02/13874)
- R represents a mono- or oligosaccharide radical attached via the 1-OH or 1-SH position
- R F is a perfluorinated, straight-chain or branched carbon chain with the formula -C n F 2n E, in which E is a terminal fluorine, chlorine Represents -, bromine, iodine or hydrogen atom and n stands for the numbers 4-30,
- R 1 represents a hydrogen atom or a metal ion equivalent of
- Atomic numbers 21-29, 31-33, 37-39, 42-44, 49 or 57-83 means with the proviso that at least two R 1 are metal ion equivalents
- R 2 and R 3 independently of one another represent hydrogen, C 1 -C 7 -alkyl, benzyl, phenyl, -CH 2 OH or -CH 2 OCH 3 and U -C 6 H 4 -O-CH 2 -CO-, - (CH 2 ) I-5- CO, a phenylene group, -CH 2 -NHCO-CH 2 -
- R 4 is hydrogen or a metal ion equivalent mentioned under R 1 and U 1 -C 6 H 4 -OC H 2 - ⁇ -, where ⁇ is the binding site to -CO-
- R 1 and R 2 have the abovementioned meaning
- U 1 is -CeH 4 -O-CH 2 -CD-, where ⁇ is the binding site to -CO-
- optionally present free acid groups may optionally be present as salts of organic and / or inorganic bases or amino acids or amino acid amides,
- ⁇ is the binding site of G to the complex K
- ⁇ is the binding site of G to the radical Y
- ⁇ represents the binding site of G to the radical Z.
- Y is -CH 2 -, ⁇ - (CH 2 ) i- 5 CO- ⁇ , ⁇ - (CH 2 ) i -5 CO- ⁇ , ⁇ -CH 2 -CHOH-CO- ⁇ or ⁇ -CH (CHOH-CH 2 OH) ⁇ CHOH-CHOH-CO-ß, where ⁇ represents the binding site to the sugar residue R and ß is the binding site to the radical G.
- I 1 , m 1 independently of one another denote the integers 1 or 2 and p 1 denotes the integers 1 to 4,
- R is a monosaccharide radical having 5 to 6 C atoms or its deoxy compound, preferably glucose, mannose or galactose.
- compounds of the general formula Ic are used in which R 2 and R 3 independently of one another are hydrogen or C 1 -C 4 -alkyl and / or E in the formula -C n F 2n E is a fluorine atom.
- compounds of the general formula Ic are used, in which G represents the lysine residue (a) or (b).
- YN ⁇ ⁇ M-SQ 2 -E means, wherein ⁇ is the binding site of Z to the radical G and ⁇ is the binding site of Z to the perfluorinated radical R F and / or Y ⁇ - ChfeCO-ß, where ⁇ is the binding site to the sugar moiety R and ß the binding site to the rest G represents.
- compounds of the general formula Ic are used in which U in the metal complex K is -CH 2 - or -C 6 H 4 -O-CHa-O, where ⁇ is the binding site on -CO-.
- the most preferred compound of the general formula Ic is the gadolinium complex of 6-N- [1,4,7-tris (carboxylatomethyl) -1,4,7,10-tetraazacyclododecane-10-N- (pentanoyl) 3-aza-4-oxo-5-methyl-5-yl)] - 2-N- [1-O- ⁇ -D-carbonylmethyl-mannopyranose] -L-lysine [1- (4-perfluorooctylsulfonyl) -piperazine ] - amide used.
- R F is a perfluorinated, straight-chain or branched carbon chain of the formula -C n F 2n E, in which E is a terminal fluorine, chlorine, bromine, iodine or hydrogen atom and n is the numbers 4-30,
- (Ud) in the R 1 represents a hydrogen atom or a metal ion equivalent of
- Atomic numbers 23-29, 42-46 or 58-70 means
- R 1 are metal ion equivalents
- R 2 and R 3 are independently hydrogen, C 1 -C 7 -alkyl, benzyl, phenyl,
- R 1 has the abovementioned meaning
- R 4 is hydrogen or a metal ion equivalent mentioned under R 1 and U 1 -C 6 H 4 -O-CH 2 -o -, where ⁇ is the binding site on -CO- means or the general formula IVd
- R 1 has the abovementioned meaning and U 1 -C 6 H 4 -O-CH 2 -O-, where ⁇ is the binding site to -CO-
- ⁇ is the binding site of G to the complex K
- ⁇ is the binding site of G to the radical R
- ⁇ represents the binding site of G to the radical Z.
- R represents a polar radical selected from the complexes K of the general formulas Hd to VIId, where R 1 is here
- radicals R 2 , R 3 , R 4 , U and U 1 have the meaning given above or the folic acid radical or an over -CO-, SO 2 - or means a direct bond to the radical G bonded carbon chain having 2-30 C atoms, linear or branched, saturated or unsaturated, optionally interrupted by 1-10 oxygen atoms, 1-5 -
- SOsH groups may be substituted or optionally substituted with 1-8 OH groups, 1-5 COOH groups, 1-2 SO 3 H groups, 1-5 NH 2 groups, 1-5 C 1 -C 4 -
- Alkoxy groups, and I 1 , m 1 , p 2 are independently the integers 1 or 2.
- compounds of the general formula Id are used in which K is a metal complex of the general formula Hd, IHd, VdB or VI Id.
- compounds of the general formula Id are used in which the polar radical R has the meaning of the complex K, preferably the complexes K of the general formulas Hd, IHd, VdA or VIId.
- compounds of the general formula Id are used in which the polar radical R has the following meanings:
- compounds of the general formula Id are used in which the polar radical R is the folic acid radical.
- compounds of the general formula Id are used, in which G represents the lysine residue (a) or (b).
- compounds of the general formula Id are used, in which U in the metal complex K represents the group -CH 2 - or -C 6 HIO-CH 2 - (U, where ⁇ is the binding site on -CO-.
- Particularly preferred compounds of the general formula Id are those having the macrocycle K of the general formula Hd, IUd, VdB or VIId.
- galenic formulations containing paramagnetic and diamagnetic fluoroalkyl-containing substances are preferably used.
- the paramagnetic and diamagnetic substances are dissolved in an aqueous solvent.
- diamagnetic perfluoroalkyl-containing substances are those of the general formula XX (see WO 02/13874):
- the linker L 2 is preferably a direct bond, an -SO 2 - group or a straight-chain or branched carbon chain having up to 20 carbon atoms, which may be substituted by one or more -OH, -COO " , -SO ß groups and / / or optionally one or more -O-, -S-, -CO-, -CONH-, -NHCO-, -CONR 9 -, -NR 9 CO-, -SO 2 -, -PO 4 " -, -NH- contains -NR 9 groups, an aryl ring or a piperazine, where R 9 stands for a C20 alkyl group C1 to C, which in turn one or more O atoms may contain
- the hydrophilic group B 2 is a mono- or disaccharide containing one or more adjacent -COO- or -SO 3 - groups, a dicarboxylic acid, an isophthalic acid, a picolinic acid, a benzenesulfonic acid, a tetrahydropyranedicarboxylic acid, a 2,6 -Pyridindicarbonklare, a quaternary ammonium ion, a Ami 'nopoly carboxylic acid, a
- Aminopolyethylene glycol sulfonic acid an aminopolyethylene glycol group, an SO 2 - (CH 2 ) 2 -OH group, a polyhydroxyalkyl chain having at least two hydroxyl groups, or one or more polyethylene glycol chains having at least two glycol units, wherein the polyethylene glycol chains terminate with an -OH or -OCH 3 group are.
- Suitable diamagnetic perfluoroalkyl-containing compounds are conjugates of cyclodextrin and perfluoroalkyl-containing compounds. These conjugates consist of ⁇ -, ⁇ - or ⁇ -cyclodextrin and compounds of general formula XXII (see WO 02/13874)
- a 1 is an adamantane, biphenyl or anthracene molecule
- L 3 is a linker and R F is a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms.
- the linker L 3 is a straight-chain one A hydrocarbon chain having 1 to 20 carbon atoms, which may be interrupted by one or more oxygen atoms, one or more CO, SO2, CONH, NHCO, CONR, NRCO, NH, NR groups or a piperazine, wherein R a C 1 -C 5 alkyl radical.
- diamagnetic perfluoroalkyl-containing substances of the general formula XXI can be used:
- R F is a straight-chain or branched perfluoroalkyl radical having 4 to 30 carbon atoms and X 1 is a radical selected from the group of the following radicals (n is a number between 1 and 10):
- the gadolinium complexes 1-19 listed in Table 1 fulfill the criteria according to the invention.
- paramagnetic compounds of the general formulas I, Ia, Ib, Ic, and Id according to the invention and the formulations of paramagnetic and diamagnetic fluoroalkyl-containing substances according to the invention are outstandingly suitable together with epothilones or epothilone derivatives for the diagnosis, therapy and therapeutic monitoring of tumors ,
- metal ion equivalent a conventional and known in the art concept in the field of coordination chemistry.
- a metal ion equivalent is capable of binding one equivalent of metal ions that instead of hydrogen, a eg carboxylate group.
- a Gd 3+ to 3 carboxylate groups ie 1/3 Gd 3+ corresponds to the metal ion equivalent R 1 in formula (III) when the metal is gadolinium.
- Preferred ratios of fluoro complex: epothilone molecule are 100: 1 to 1: 1, more preferably the ratios are 20: 1 to 5: 1.
- the pharmaceutical compositions of the invention are administered intravenously.
- the invention therefore relates to pharmaceutical agents according to the invention for intravenous administration.
- these are used in the therapy of tumors.
- these are used in the imaging of tumors, in particular in the course of therapy monitoring in the treatment of tumors.
- the invention further relates to the use of pharmaceutical agents according to the invention for the preparation of a medicament or diagnostic agent for intravenous administration.
- these are used in the therapy of tumors.
- these are used in the imaging of tumors, in particular in the course of therapy monitoring in the treatment of tumors.
- the agents according to the invention can furthermore be used in combination with an additional radiotherapy for the therapy of tumors.
- the invention further relates to a method for the treatment of tumors, characterized in that the agents according to the invention are administered intravenously to the patient in a pharmaceutically effective amount.
- the invention further relates to a method for the imaging of tumors, characterized in that the agents according to the invention are administered to the patient intravenously and the metal complex contained in the agent is detected in the body by means of a suitable system, wherein a local increase of the signal indicates the presence of the tumor , Depending on the metal ion contained in the metal complex, the detection can take place, for example, by MRI or CT.
- the imaging of tumors can be used to monitor the course of therapy of tumors. In this case, the beginning of the tumor treatment and / or during the tumor treatment and / or after completion of the tumor treatment at least twice applied the method for imaging tumors and compared the result of the subsequent detection with the previous detection (s). Thus, the course of the therapy can be monitored.
- Figure 1 shows an MR section (axial) 24 h (a), 192 h (b), and 336 h (c) after iv application of 200 .mu.mol Gd / kg body weight of
- Tumor inoculation On nu / n nude mice, by inoculation of A549 cells (4x10 6 cells / 30 ⁇ l of complete medium), a human non-small cell lung tumor was induced subcutaneously in the area of the right femoral muscle. The slowly growing tumor reached rice grain size about 4 weeks after tumor induction. Imaging started at that time. Mf? Imaging: (Siemens 1.5 T. SE sequence, TR / TE 400/15 ms, ⁇ 90 °, axial, 7 layers). Images of the tumor before (baseline) and 5, 10, 20 min, 24, 96, 192 and 336 h after intravenous (iv) application of 200 .mu.mol Gd / kg body weight of the formulation of Example 1, F1-E.
- FIG. 1 Exemplary sectional images are shown in FIG.
- the cross-sectional images of Figure 1 show the strong accumulation (homogeneous enhancement) of the formulation in the tumor at the time of 24 h pi, as well as their fangsame decrease in the further course of time with a simultaneous increase in signal intensity in tumor necrosis.
- Example 3
- x mmol epothilone (Table 2) are dissolved in 50 ⁇ l of ethanol (40 ° C.) and transferred into 1 ml of a gadolinium complex solution of z mmol of Gd / I of the compound from Table 1 (complex no.). After shaking briefly, a clear homogeneous solution is obtained.
- Table 4 Very particularly preferably used according to the invention formulations of epothilones with fluorine chain-containing Gd complexes (increased EPO content)
- A549 lung tumors were induced on nude mice (4x10 6 cells / 30 ⁇ l of complete medium). Animal weights and tumor area / volume were determined, thereby the tumor area or the tumor volume were calculated (on the basis of an ellipsoid of revolution). The length and width of the tumor were measured with a vernier caliper. After reaching pea size, treatment was started.
- Table 4 below gives the dosages of tumor therapy experiments 1-16 used: Table 4:
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- Tab. 2 Relative animal weights. The animal weights at the beginning of treatment (day O, about 30-35 g) were normalized to 1.
- the substances according to the invention are outstandingly suitable for intravenous administration.
- Intravenous administration of the low-osmolar solutions only minimally stresses the patient's body.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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DE102005008309A DE102005008309A1 (de) | 2005-02-17 | 2005-02-17 | Pharmazeutische Mittel enthaltend fluoralkylhaltige Metallkomplexe und Epothilone |
PCT/EP2006/001200 WO2006087145A1 (de) | 2005-02-17 | 2006-02-06 | Pharmazeutische mittel enthaltend fluoralkylhaltige metallkomplexe und epothilone |
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EP1848429A1 true EP1848429A1 (de) | 2007-10-31 |
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EP06706829A Withdrawn EP1848429A1 (de) | 2005-02-17 | 2006-02-06 | Pharmazeutische mittel enthaltend fluoralkylhaltige metallkomplexe und epothilone |
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US (1) | US20060257322A1 (un) |
EP (1) | EP1848429A1 (un) |
JP (1) | JP2008530157A (un) |
AR (1) | AR052912A1 (un) |
DE (1) | DE102005008309A1 (un) |
DO (1) | DOP2006000038A (un) |
GT (1) | GT200600073A (un) |
PA (1) | PA8663801A1 (un) |
PE (1) | PE20061064A1 (un) |
TW (1) | TW200640456A (un) |
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WO (1) | WO2006087145A1 (un) |
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DE19603033A1 (de) * | 1996-01-19 | 1997-07-24 | Schering Ag | Perfluoralkylhaltige Metallkomplexe, Verfahren zu deren Herstellung und ihre Verwendung in der NMR-Diagnostik |
DE19608278A1 (de) * | 1996-02-23 | 1997-08-28 | Schering Ag | Pharmazeutische Mittel enthaltend perfluoralkylhaltige Metallkomplexe, und ihre Verwendung in der Tumortherapie und interventioniellen Radiologie |
FR2775187B1 (fr) * | 1998-02-25 | 2003-02-21 | Novartis Ag | Utilisation de l'epothilone b pour la fabrication d'une preparation pharmaceutique antiproliferative et d'une composition comprenant l'epothilone b comme agent antiproliferatif in vivo |
DE10066210B4 (de) * | 2000-08-11 | 2008-02-28 | Bayer Schering Pharma Ag | Verwendung von perfluoralkylhaltigen Metallkomplexen als Kontrastmittel im MR-Imaging zur Darstellung von Plaques |
EP1475105A1 (en) * | 2003-05-09 | 2004-11-10 | Schering AG | Bone localising radiopharmaceutical and tubulin-interacting compound combinatorial radiotherapy |
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2005
- 2005-02-17 DE DE102005008309A patent/DE102005008309A1/de not_active Withdrawn
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- 2006-02-06 JP JP2007555508A patent/JP2008530157A/ja not_active Withdrawn
- 2006-02-06 WO PCT/EP2006/001200 patent/WO2006087145A1/de active Application Filing
- 2006-02-06 EP EP06706829A patent/EP1848429A1/de not_active Withdrawn
- 2006-02-14 DO DO2006000038A patent/DOP2006000038A/es unknown
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- 2006-02-16 UY UY29382A patent/UY29382A1/es not_active Application Discontinuation
- 2006-02-16 US US11/355,251 patent/US20060257322A1/en not_active Abandoned
- 2006-02-17 TW TW095105537A patent/TW200640456A/zh unknown
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AR052912A1 (es) | 2007-04-11 |
US20060257322A1 (en) | 2006-11-16 |
UY29382A1 (es) | 2006-10-02 |
GT200600073A (es) | 2007-01-03 |
PE20061064A1 (es) | 2006-11-08 |
PA8663801A1 (es) | 2006-12-07 |
DOP2006000038A (es) | 2006-08-15 |
TW200640456A (en) | 2006-12-01 |
DE102005008309A1 (de) | 2006-08-24 |
WO2006087145A1 (de) | 2006-08-24 |
JP2008530157A (ja) | 2008-08-07 |
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